diff --git a/evaluation/benchmark/JNLPBA_gene_protein_test_entities_mapping.jsonl b/evaluation/benchmark/JNLPBA_gene_protein_test_entities_mapping.jsonl
new file mode 100644
index 0000000..4b35f75
--- /dev/null
+++ b/evaluation/benchmark/JNLPBA_gene_protein_test_entities_mapping.jsonl
@@ -0,0 +1,3856 @@
+{"sentence_id": 0, "sentence_text": "Number of glucocorticoid receptors in lymphocytes and their sensitivity to hormone action .", "sentence_char_start_global": 0, "sentence_char_end_global": 91, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 10, "char_end": 34, "token_start": 2, "token_end": 3}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 10, "char_end": 34, "token_start": 2, "token_end": 3, "note": null}]}
+{"sentence_id": 1, "sentence_text": "The study demonstrated a decreased level of glucocorticoid receptors ( GR ) in peripheral blood lymphocytes from hypercholesterolemic subjects , and an elevated level in patients with acute myocardial infarction .", "sentence_char_start_global": 92, "sentence_char_end_global": 305, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 44, "char_end": 68, "token_start": 7, "token_end": 8}, {"text": "GR", "type": "ENTITY", "char_start": 71, "char_end": 73, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 136, "char_end": 160, "token_start": 7, "token_end": 8, "note": null}, {"text": "GR", "type": "ENTITY", "char_start": 163, "char_end": 165, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 2, "sentence_text": "In the lymphocytes with a high GR number , dexamethasone inhibited [ 3H ] - thymidine and [ 3H ] - acetate incorporation into DNA and cholesterol , respectively , in the same manner as in the control cells .", "sentence_char_start_global": 306, "sentence_char_end_global": 513, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 31, "char_end": 33, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 337, "char_end": 339, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 3, "sentence_text": "On the other hand , a decreased GR number resulted in a less efficient dexamethasone inhibition of the incorporation of labeled compounds .", "sentence_char_start_global": 514, "sentence_char_end_global": 653, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 32, "char_end": 34, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 546, "char_end": 548, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 4, "sentence_text": "These data showed that the sensitivity of lymphocytes to glucocorticoids changed only with a decrease of GR level .", "sentence_char_start_global": 654, "sentence_char_end_global": 769, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 105, "char_end": 107, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 759, "char_end": 761, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 5, "sentence_text": "[ 1 , 25 - Dihydroxyvitamin D3 receptors in lymphocytes and T - and B - lymphocyte count in patients with glomerulonephritis ]", "sentence_char_start_global": 770, "sentence_char_end_global": 896, "entities": [{"text": "1 , 25 - Dihydroxyvitamin D3 receptors", "type": "ENTITY", "char_start": 2, "char_end": 40, "token_start": 1, "token_end": 7}], "entities_global": [{"text": "1 , 25 - Dihydroxyvitamin D3 receptors", "type": "ENTITY", "char_start": 772, "char_end": 810, "token_start": 1, "token_end": 7, "note": null}]}
+{"sentence_id": 6, "sentence_text": "Content of receptors to hormonal form of vitamin D3 , 1 . 25 ( OH ) 2D3 , constituted 27 . 3 fmole / mg of protein in lymphocytes of peripheric blood of children with glomerulonephritis .", "sentence_char_start_global": 897, "sentence_char_end_global": 1084, "entities": [], "entities_global": []}
+{"sentence_id": 7, "sentence_text": "In the patients concentration of total and ionized form of Ca2 + was decreased down to 2 . 04 mmole / L and 1 . 09 mmole / L , respectively , while an increase in parathormone ( PTH ) by 36 % and a distinct decrease in 25 ( OH ) D concentration ( lower than 1 . 25 ng / ml ) was found in blood ; content of cAMP was also decreased in lymphocytes by 33 % .", "sentence_char_start_global": 1085, "sentence_char_end_global": 1440, "entities": [], "entities_global": []}
+{"sentence_id": 8, "sentence_text": "At the same time , total content of T lymphocytes was decreased 1 . 5 - fold in peripheric blood .", "sentence_char_start_global": 1441, "sentence_char_end_global": 1539, "entities": [], "entities_global": []}
+{"sentence_id": 9, "sentence_text": "Treatment with I - hydroxyvitamin D3 ( 1 - 1 . 5 mg daily , within 4 weeks ) led to normalization of total and ionized form of Ca2 + and of 25 ( OH ) D , but did not affect the PTH content in blood .", "sentence_char_start_global": 1540, "sentence_char_end_global": 1739, "entities": [], "entities_global": []}
+{"sentence_id": 10, "sentence_text": "Concentration of the receptors to 1 . 25 ( OH ) 2D3 was elevated up to 39 . 7 fmole / mg after I week of the treatment , whereas it was decreased to the initial level 24 . 8 fmole / mg within 4 weeks ; simultaneous alteration in the cAMP content was observed in lymphocytes .", "sentence_char_start_global": 1740, "sentence_char_end_global": 2015, "entities": [{"text": "receptors", "type": "ENTITY", "char_start": 21, "char_end": 30, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "receptors", "type": "ENTITY", "char_start": 1761, "char_end": 1770, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 11, "sentence_text": "Treatment with 1 - ( OH ) D3 normalized also the T lymphocytes content in peripheric blood .", "sentence_char_start_global": 2016, "sentence_char_end_global": 2108, "entities": [], "entities_global": []}
+{"sentence_id": 12, "sentence_text": "The data obtained suggest that under conditions of glomerulonephritis only high content of receptors to 1 . 25 ( OH ) 2D3 in lymphocytes enabled to perform the cell response to the hormone effect .", "sentence_char_start_global": 2109, "sentence_char_end_global": 2306, "entities": [{"text": "receptors", "type": "ENTITY", "char_start": 91, "char_end": 100, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "receptors", "type": "ENTITY", "char_start": 2200, "char_end": 2209, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 13, "sentence_text": "Tumor and serum beta - 2 - microglobulin expression in women with breast cancer .", "sentence_char_start_global": 2307, "sentence_char_end_global": 2388, "entities": [], "entities_global": []}
+{"sentence_id": 14, "sentence_text": "To investigate whether the tumor expression of beta - 2 - microglobulin ( beta 2 - M ) could serve as a marker of tumor biologic behavior , the authors studied specimens of breast carcinomas from 60 consecutive female patients .", "sentence_char_start_global": 2389, "sentence_char_end_global": 2617, "entities": [{"text": "beta - 2 - microglobulin", "type": "ENTITY", "char_start": 47, "char_end": 71, "token_start": 7, "token_end": 11}, {"text": "beta 2 - M", "type": "ENTITY", "char_start": 74, "char_end": 84, "token_start": 13, "token_end": 16}], "entities_global": [{"text": "beta - 2 - microglobulin", "type": "ENTITY", "char_start": 2436, "char_end": 2460, "token_start": 7, "token_end": 11, "note": null}, {"text": "beta 2 - M", "type": "ENTITY", "char_start": 2463, "char_end": 2473, "token_start": 13, "token_end": 16, "note": null}]}
+{"sentence_id": 15, "sentence_text": "Presence of beta 2 - M was analyzed by immunohistochemistry .", "sentence_char_start_global": 2618, "sentence_char_end_global": 2679, "entities": [{"text": "beta 2 - M", "type": "ENTITY", "char_start": 12, "char_end": 22, "token_start": 2, "token_end": 5}], "entities_global": [{"text": "beta 2 - M", "type": "ENTITY", "char_start": 2630, "char_end": 2640, "token_start": 2, "token_end": 5, "note": null}]}
+{"sentence_id": 16, "sentence_text": "No significant correlations were found between tumor beta 2 - M expression and several histologic attributes such as type , histologic and nuclear grades , mitotic index , necrosis , vascular invasion , and lymphocytic infiltration .", "sentence_char_start_global": 2680, "sentence_char_end_global": 2913, "entities": [{"text": "tumor beta 2 - M", "type": "ENTITY", "char_start": 47, "char_end": 63, "token_start": 6, "token_end": 10}], "entities_global": [{"text": "tumor beta 2 - M", "type": "ENTITY", "char_start": 2727, "char_end": 2743, "token_start": 6, "token_end": 10, "note": null}]}
+{"sentence_id": 17, "sentence_text": "Likewise , beta 2 - M was not associated with markers of disease extension such as TNM , ( UICC , classification of malignant tumors ) staging and axillary lymph node involvement or with estrogen , progesterone , and glucocorticoid receptor levels .", "sentence_char_start_global": 2914, "sentence_char_end_global": 3163, "entities": [{"text": "beta 2 - M", "type": "ENTITY", "char_start": 11, "char_end": 21, "token_start": 2, "token_end": 5}], "entities_global": [{"text": "beta 2 - M", "type": "ENTITY", "char_start": 2925, "char_end": 2935, "token_start": 2, "token_end": 5, "note": null}]}
+{"sentence_id": 18, "sentence_text": "However , there was a significantly positive association between tumor beta 2 - M expression and the degree of lymphocytic infiltration in the tumor tissue .", "sentence_char_start_global": 3164, "sentence_char_end_global": 3321, "entities": [{"text": "tumor beta 2 - M", "type": "ENTITY", "char_start": 65, "char_end": 81, "token_start": 9, "token_end": 13}], "entities_global": [{"text": "tumor beta 2 - M", "type": "ENTITY", "char_start": 3229, "char_end": 3245, "token_start": 9, "token_end": 13, "note": null}]}
+{"sentence_id": 19, "sentence_text": "Beta 2 - M serum levels were determined by an enzyme - linked immunosorbent assay in samples from 22 of the above women .", "sentence_char_start_global": 3322, "sentence_char_end_global": 3443, "entities": [{"text": "Beta 2 - M", "type": "ENTITY", "char_start": 0, "char_end": 10, "token_start": 0, "token_end": 3}], "entities_global": [{"text": "Beta 2 - M", "type": "ENTITY", "char_start": 3322, "char_end": 3332, "token_start": 0, "token_end": 3, "note": null}]}
+{"sentence_id": 20, "sentence_text": "Although some of the highest values had been obtained in women with larger ( T4 ) primary tumors , the authors failed to detect any statistical relationship between beta 2 - M expression in the tumor with serum levels or between serum beta 2 - M and the above histologic , laboratory , and clinical factors .", "sentence_char_start_global": 3444, "sentence_char_end_global": 3752, "entities": [{"text": "beta 2 - M", "type": "ENTITY", "char_start": 165, "char_end": 175, "token_start": 28, "token_end": 31}, {"text": "serum beta 2 - M", "type": "ENTITY", "char_start": 229, "char_end": 245, "token_start": 41, "token_end": 45}], "entities_global": [{"text": "beta 2 - M", "type": "ENTITY", "char_start": 3609, "char_end": 3619, "token_start": 28, "token_end": 31, "note": null}, {"text": "serum beta 2 - M", "type": "ENTITY", "char_start": 3673, "char_end": 3689, "token_start": 41, "token_end": 45, "note": null}]}
+{"sentence_id": 21, "sentence_text": "[ Preliminary observation of level free - form E receptor levels in serum of normal childbearing - aged and pregnant women ]", "sentence_char_start_global": 3753, "sentence_char_end_global": 3877, "entities": [{"text": "free - form E receptor", "type": "ENTITY", "char_start": 35, "char_end": 57, "token_start": 5, "token_end": 9}], "entities_global": [{"text": "free - form E receptor", "type": "ENTITY", "char_start": 3788, "char_end": 3810, "token_start": 5, "token_end": 9, "note": null}]}
+{"sentence_id": 22, "sentence_text": "In 137 cases of childbearing - aged and pregnant women , free form E receptor levels ( sE ) in serum were measured by ELISA .", "sentence_char_start_global": 3878, "sentence_char_end_global": 4003, "entities": [{"text": "free form E receptor", "type": "ENTITY", "char_start": 57, "char_end": 77, "token_start": 11, "token_end": 14}, {"text": "sE", "type": "ENTITY", "char_start": 87, "char_end": 89, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "free form E receptor", "type": "ENTITY", "char_start": 3935, "char_end": 3955, "token_start": 11, "token_end": 14, "note": null}, {"text": "sE", "type": "ENTITY", "char_start": 3965, "char_end": 3967, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 23, "sentence_text": "The level of sE was significantly decreased during the first trimester , slightly higher in the second trimester , and recovered to normal in the third trimester .", "sentence_char_start_global": 4004, "sentence_char_end_global": 4167, "entities": [{"text": "sE", "type": "ENTITY", "char_start": 13, "char_end": 15, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "sE", "type": "ENTITY", "char_start": 4017, "char_end": 4019, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 24, "sentence_text": "The level remained lower in 29 PIH women but appeared higher in overdue pregnancies as compared with the normal 3rd trimester range .", "sentence_char_start_global": 4168, "sentence_char_end_global": 4301, "entities": [], "entities_global": []}
+{"sentence_id": 25, "sentence_text": "The results indicate that there is a relationship between a change in T cell function and pregnancy .", "sentence_char_start_global": 4302, "sentence_char_end_global": 4403, "entities": [], "entities_global": []}
+{"sentence_id": 26, "sentence_text": "Kappa B - specific DNA binding proteins : role in the regulation of human interleukin - 2 gene expression .", "sentence_char_start_global": 4404, "sentence_char_end_global": 4511, "entities": [{"text": "Kappa B - specific DNA binding proteins", "type": "ENTITY", "char_start": 0, "char_end": 39, "token_start": 0, "token_end": 6}, {"text": "human interleukin - 2 gene", "type": "ENTITY", "char_start": 68, "char_end": 94, "token_start": 13, "token_end": 17}], "entities_global": [{"text": "Kappa B - specific DNA binding proteins", "type": "ENTITY", "char_start": 4404, "char_end": 4443, "token_start": 0, "token_end": 6, "note": null}, {"text": "human interleukin - 2 gene", "type": "ENTITY", "char_start": 4472, "char_end": 4498, "token_start": 13, "token_end": 17, "note": null}]}
+{"sentence_id": 27, "sentence_text": "Transcriptional activation of the human interleukin - 2 ( IL - 2 ) gene , like induction of the IL - 2 receptor alpha ( IL - 2R alpha ) gene and the type 1 human immunodeficiency virus ( HIV - 1 ) , is shown to be modulated by a kappa B - like enhancer element .", "sentence_char_start_global": 4512, "sentence_char_end_global": 4774, "entities": [{"text": "human interleukin - 2 ( IL - 2 ) gene", "type": "ENTITY", "char_start": 34, "char_end": 71, "token_start": 4, "token_end": 13}, {"text": "IL - 2 receptor alpha ( IL - 2R alpha ) gene", "type": "ENTITY", "char_start": 96, "char_end": 140, "token_start": 19, "token_end": 30}, {"text": "kappa B - like enhancer element", "type": "ENTITY", "char_start": 229, "char_end": 260, "token_start": 51, "token_end": 56}], "entities_global": [{"text": "human interleukin - 2 ( IL - 2 ) gene", "type": "ENTITY", "char_start": 4546, "char_end": 4583, "token_start": 4, "token_end": 13, "note": null}, {"text": "IL - 2 receptor alpha ( IL - 2R alpha ) gene", "type": "ENTITY", "char_start": 4608, "char_end": 4652, "token_start": 19, "token_end": 30, "note": null}, {"text": "kappa B - like enhancer element", "type": "ENTITY", "char_start": 4741, "char_end": 4772, "token_start": 51, "token_end": 56, "note": null}]}
+{"sentence_id": 28, "sentence_text": "Mutation of a kappa B core sequence identified in the IL - 2 promoter ( - 206 to - 195 ) partially inhibits both mitogen - and HTLV - I Tax - mediated activation of this transcription unit and blocks the specific binding of two inducible cellular factors .", "sentence_char_start_global": 4775, "sentence_char_end_global": 5031, "entities": [{"text": "kappa B core sequence", "type": "ENTITY", "char_start": 14, "char_end": 35, "token_start": 3, "token_end": 6}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 54, "char_end": 69, "token_start": 10, "token_end": 13}, {"text": "transcription unit", "type": "ENTITY", "char_start": 170, "char_end": 188, "token_start": 36, "token_end": 37}, {"text": "inducible cellular factors", "type": "ENTITY", "char_start": 228, "char_end": 254, "token_start": 45, "token_end": 47}], "entities_global": [{"text": "kappa B core sequence", "type": "ENTITY", "char_start": 4789, "char_end": 4810, "token_start": 3, "token_end": 6, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 4829, "char_end": 4844, "token_start": 10, "token_end": 13, "note": null}, {"text": "transcription unit", "type": "ENTITY", "char_start": 4945, "char_end": 4963, "token_start": 36, "token_end": 37, "note": null}, {"text": "inducible cellular factors", "type": "ENTITY", "char_start": 5003, "char_end": 5029, "token_start": 45, "token_end": 47, "note": null}]}
+{"sentence_id": 29, "sentence_text": "These kappa B - specific proteins ( 80 to 90 and 50 to 55 kilodaltons ) similarly interact with the functional kappa B enhancer present in the IL - 2R alpha promoter .", "sentence_char_start_global": 5032, "sentence_char_end_global": 5199, "entities": [{"text": "kappa B - specific proteins", "type": "ENTITY", "char_start": 6, "char_end": 33, "token_start": 1, "token_end": 5}, {"text": "kappa B enhancer", "type": "ENTITY", "char_start": 111, "char_end": 127, "token_start": 21, "token_end": 23}, {"text": "IL - 2R alpha promoter", "type": "ENTITY", "char_start": 143, "char_end": 165, "token_start": 27, "token_end": 31}], "entities_global": [{"text": "kappa B - specific proteins", "type": "ENTITY", "char_start": 5038, "char_end": 5065, "token_start": 1, "token_end": 5, "note": null}, {"text": "kappa B enhancer", "type": "ENTITY", "char_start": 5143, "char_end": 5159, "token_start": 21, "token_end": 23, "note": null}, {"text": "IL - 2R alpha promoter", "type": "ENTITY", "char_start": 5175, "char_end": 5197, "token_start": 27, "token_end": 31, "note": null}]}
+{"sentence_id": 30, "sentence_text": "These data suggest that these kappa B - specific proteins have a role in the coordinate regulation of this growth factor - growth factor receptor gene system that controls T cell proliferation .", "sentence_char_start_global": 5200, "sentence_char_end_global": 5394, "entities": [{"text": "kappa B - specific proteins", "type": "ENTITY", "char_start": 30, "char_end": 57, "token_start": 5, "token_end": 9}], "entities_global": [{"text": "kappa B - specific proteins", "type": "ENTITY", "char_start": 5230, "char_end": 5257, "token_start": 5, "token_end": 9, "note": null}]}
+{"sentence_id": 31, "sentence_text": "Novel region within the V kappa gene promoter is responsible for tissue and stage - specific expression of immunoglobulin genes in human lymphoid neoplasms .", "sentence_char_start_global": 5395, "sentence_char_end_global": 5552, "entities": [{"text": "V kappa gene promoter", "type": "ENTITY", "char_start": 24, "char_end": 45, "token_start": 4, "token_end": 7}, {"text": "immunoglobulin genes", "type": "ENTITY", "char_start": 107, "char_end": 127, "token_start": 18, "token_end": 19}], "entities_global": [{"text": "V kappa gene promoter", "type": "ENTITY", "char_start": 5419, "char_end": 5440, "token_start": 4, "token_end": 7, "note": null}, {"text": "immunoglobulin genes", "type": "ENTITY", "char_start": 5502, "char_end": 5522, "token_start": 18, "token_end": 19, "note": null}]}
+{"sentence_id": 32, "sentence_text": "Immunoglobulin gene - specific transacting factors have been shown to play a role in lymphoid tissue - specific expression of immunoglobulin genes .", "sentence_char_start_global": 5553, "sentence_char_end_global": 5701, "entities": [{"text": "Immunoglobulin gene - specific transacting factors", "type": "ENTITY", "char_start": 0, "char_end": 50, "token_start": 0, "token_end": 5}, {"text": "immunoglobulin genes", "type": "ENTITY", "char_start": 126, "char_end": 146, "token_start": 20, "token_end": 21}], "entities_global": [{"text": "Immunoglobulin gene - specific transacting factors", "type": "ENTITY", "char_start": 5553, "char_end": 5603, "token_start": 0, "token_end": 5, "note": null}, {"text": "immunoglobulin genes", "type": "ENTITY", "char_start": 5679, "char_end": 5699, "token_start": 20, "token_end": 21, "note": null}]}
+{"sentence_id": 33, "sentence_text": "The role of these factors in B - cell differentiation and stage - specific expression of these genes is , however , not fully understood .", "sentence_char_start_global": 5702, "sentence_char_end_global": 5840, "entities": [], "entities_global": []}
+{"sentence_id": 34, "sentence_text": "We have used a model of human lymphoid neoplasia to address this question .", "sentence_char_start_global": 5841, "sentence_char_end_global": 5916, "entities": [], "entities_global": []}
+{"sentence_id": 35, "sentence_text": "Different fragments of unrearranged human variable region of immunoglobulin kappa gene ( V kappa ) were used for cell - free in vitro transcription and DNA mobility shift assays .", "sentence_char_start_global": 5917, "sentence_char_end_global": 6096, "entities": [{"text": "unrearranged human variable region", "type": "ENTITY", "char_start": 23, "char_end": 57, "token_start": 3, "token_end": 6}, {"text": "immunoglobulin kappa gene", "type": "ENTITY", "char_start": 61, "char_end": 86, "token_start": 8, "token_end": 10}, {"text": "V kappa", "type": "ENTITY", "char_start": 89, "char_end": 96, "token_start": 12, "token_end": 13}], "entities_global": [{"text": "unrearranged human variable region", "type": "ENTITY", "char_start": 5940, "char_end": 5974, "token_start": 3, "token_end": 6, "note": null}, {"text": "immunoglobulin kappa gene", "type": "ENTITY", "char_start": 5978, "char_end": 6003, "token_start": 8, "token_end": 10, "note": null}, {"text": "V kappa", "type": "ENTITY", "char_start": 6006, "char_end": 6013, "token_start": 12, "token_end": 13, "note": null}]}
+{"sentence_id": 36, "sentence_text": "Previously described enhancement of in vitro transcription that was only seen with nuclear extracts derived from B - cell neoplasms corresponding to the late stages of B - cell differentiation was shown to be dependent on the actions of these factor ( s ) on the DNA region within the V kappa gene promoter .", "sentence_char_start_global": 6097, "sentence_char_end_global": 6405, "entities": [{"text": "V kappa gene promoter", "type": "ENTITY", "char_start": 285, "char_end": 306, "token_start": 50, "token_end": 53}], "entities_global": [{"text": "V kappa gene promoter", "type": "ENTITY", "char_start": 6382, "char_end": 6403, "token_start": 50, "token_end": 53, "note": null}]}
+{"sentence_id": 37, "sentence_text": "This region is located within the 920 bp fragment located 210 bp upstream from the coding region and this fragment represents a possible novel DNA region , which plays a role in the stage - and tissue - specific expression of immunoglobulin genes .", "sentence_char_start_global": 6406, "sentence_char_end_global": 6654, "entities": [{"text": "immunoglobulin genes", "type": "ENTITY", "char_start": 226, "char_end": 246, "token_start": 41, "token_end": 42}], "entities_global": [{"text": "immunoglobulin genes", "type": "ENTITY", "char_start": 6632, "char_end": 6652, "token_start": 41, "token_end": 42, "note": null}]}
+{"sentence_id": 38, "sentence_text": "[ Determination of the sensitivity to glucocorticoids in vitro ]", "sentence_char_start_global": 6655, "sentence_char_end_global": 6719, "entities": [{"text": "glucocorticoids", "type": "ENTITY", "char_start": 38, "char_end": 53, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "glucocorticoids", "type": "ENTITY", "char_start": 6693, "char_end": 6708, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 39, "sentence_text": "A modified method for the determination of glucocorticoid receptors in human lymphocytes is suggested .", "sentence_char_start_global": 6720, "sentence_char_end_global": 6823, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 43, "char_end": 67, "token_start": 7, "token_end": 8}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 6763, "char_end": 6787, "token_start": 7, "token_end": 8, "note": null}]}
+{"sentence_id": 40, "sentence_text": "The principal distinction of the method is standardization by the lymphocyte count in a sample ( 1 mln ) and the labeled hormone concentration .", "sentence_char_start_global": 6824, "sentence_char_end_global": 6968, "entities": [{"text": "hormone", "type": "ENTITY", "char_start": 121, "char_end": 128, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "hormone", "type": "ENTITY", "char_start": 6945, "char_end": 6952, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 41, "sentence_text": "The modification saves time and money , limits the range of the data variations , and makes use of a lesser volume of blood .", "sentence_char_start_global": 6969, "sentence_char_end_global": 7094, "entities": [], "entities_global": []}
+{"sentence_id": 42, "sentence_text": "Examinations of 70 children aged 4 to 15 suffering from the nephrotic form of glomerulonephritis have made it possible to distinguish two groups of patients : with relatively high values of specific binding X = 6820 . 1 + / - 530 . 0 ( n = 30 , p = 0 . 95 , t = 2 . 04 ) , this corresponding to a clinical form of hormone - sensitive glomerulonephritis , and with relatively low values of specific binding X = 1815 . 2 + / - 302 . 8 ( n = 40 , p = 0 . 95 , t = 1 . 96 ) , that corresponds to hormone - resistant glomerulonephritis .", "sentence_char_start_global": 7095, "sentence_char_end_global": 7627, "entities": [{"text": "hormone", "type": "ENTITY", "char_start": 314, "char_end": 321, "token_start": 69, "token_end": 69}, {"text": "hormone", "type": "ENTITY", "char_start": 492, "char_end": 499, "token_start": 114, "token_end": 114}], "entities_global": [{"text": "hormone", "type": "ENTITY", "char_start": 7409, "char_end": 7416, "token_start": 69, "token_end": 69, "note": null}, {"text": "hormone", "type": "ENTITY", "char_start": 7587, "char_end": 7594, "token_start": 114, "token_end": 114, "note": null}]}
+{"sentence_id": 43, "sentence_text": "Dynamic studies have not shown any statistically significant changes in the specific binding values .", "sentence_char_start_global": 7628, "sentence_char_end_global": 7729, "entities": [], "entities_global": []}
+{"sentence_id": 44, "sentence_text": "These results permit regarding the specific binding value as a prognostic criterion in the assessment of corticosteroid therapy ; this allows a wide employment of the described method in practical nephrology .", "sentence_char_start_global": 7730, "sentence_char_end_global": 7939, "entities": [{"text": "corticosteroid", "type": "ENTITY", "char_start": 105, "char_end": 119, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "corticosteroid", "type": "ENTITY", "char_start": 7835, "char_end": 7849, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 45, "sentence_text": "Octamer - binding proteins from B or HeLa cells stimulate transcription of the immunoglobulin heavy - chain promoter in vitro .", "sentence_char_start_global": 7940, "sentence_char_end_global": 8067, "entities": [{"text": "Octamer - binding proteins", "type": "ENTITY", "char_start": 0, "char_end": 26, "token_start": 0, "token_end": 3}, {"text": "immunoglobulin heavy - chain promoter", "type": "ENTITY", "char_start": 79, "char_end": 116, "token_start": 13, "token_end": 17}], "entities_global": [{"text": "Octamer - binding proteins", "type": "ENTITY", "char_start": 7940, "char_end": 7966, "token_start": 0, "token_end": 3, "note": null}, {"text": "immunoglobulin heavy - chain promoter", "type": "ENTITY", "char_start": 8019, "char_end": 8056, "token_start": 13, "token_end": 17, "note": null}]}
+{"sentence_id": 46, "sentence_text": "The B - cell - type specificity of the immunoglobulin ( Ig ) heavy - chain and light - chain promoters is mediated by an octanucleotide ( OCTA ) element , ATGCAAAT , that is also a functional component of other RNA polymerase II promoters , such as snRNA and histone H2B promoters .", "sentence_char_start_global": 8068, "sentence_char_end_global": 8350, "entities": [{"text": "immunoglobulin", "type": "ENTITY", "char_start": 39, "char_end": 53, "token_start": 9, "token_end": 9}, {"text": "Ig", "type": "ENTITY", "char_start": 56, "char_end": 58, "token_start": 11, "token_end": 11}, {"text": "octanucleotide ( OCTA ) element", "type": "ENTITY", "char_start": 121, "char_end": 152, "token_start": 25, "token_end": 29}, {"text": "RNA polymerase II promoters", "type": "ENTITY", "char_start": 211, "char_end": 238, "token_start": 41, "token_end": 44}], "entities_global": [{"text": "immunoglobulin", "type": "ENTITY", "char_start": 8107, "char_end": 8121, "token_start": 9, "token_end": 9, "note": null}, {"text": "Ig", "type": "ENTITY", "char_start": 8124, "char_end": 8126, "token_start": 11, "token_end": 11, "note": null}, {"text": "octanucleotide ( OCTA ) element", "type": "ENTITY", "char_start": 8189, "char_end": 8220, "token_start": 25, "token_end": 29, "note": null}, {"text": "RNA polymerase II promoters", "type": "ENTITY", "char_start": 8279, "char_end": 8306, "token_start": 41, "token_end": 44, "note": null}]}
+{"sentence_id": 47, "sentence_text": "Two nuclear proteins that bind specifically and with high affinity to the OCTA element have been identified .", "sentence_char_start_global": 8351, "sentence_char_end_global": 8460, "entities": [{"text": "nuclear proteins", "type": "ENTITY", "char_start": 4, "char_end": 20, "token_start": 1, "token_end": 2}, {"text": "OCTA element", "type": "ENTITY", "char_start": 74, "char_end": 86, "token_start": 12, "token_end": 13}], "entities_global": [{"text": "nuclear proteins", "type": "ENTITY", "char_start": 8355, "char_end": 8371, "token_start": 1, "token_end": 2, "note": null}, {"text": "OCTA element", "type": "ENTITY", "char_start": 8425, "char_end": 8437, "token_start": 12, "token_end": 13, "note": null}]}
+{"sentence_id": 48, "sentence_text": "NF - A1 is present in a variety of cell types , whereas the presence of NF - A2 is essentially confined to B cells , leading to the hypothesis that NF - A2 activates cell - type - specific transcription of the Ig promoter and NF - A1 mediates the other responses of the OCTA element .", "sentence_char_start_global": 8461, "sentence_char_end_global": 8745, "entities": [{"text": "NF - A1", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 2}, {"text": "NF - A2", "type": "ENTITY", "char_start": 72, "char_end": 79, "token_start": 16, "token_end": 18}, {"text": "NF - A2", "type": "ENTITY", "char_start": 148, "char_end": 155, "token_start": 31, "token_end": 33}, {"text": "Ig promoter", "type": "ENTITY", "char_start": 210, "char_end": 221, "token_start": 43, "token_end": 44}, {"text": "NF - A1", "type": "ENTITY", "char_start": 226, "char_end": 233, "token_start": 46, "token_end": 48}, {"text": "OCTA element", "type": "ENTITY", "char_start": 270, "char_end": 282, "token_start": 55, "token_end": 56}], "entities_global": [{"text": "NF - A1", "type": "ENTITY", "char_start": 8461, "char_end": 8468, "token_start": 0, "token_end": 2, "note": null}, {"text": "NF - A2", "type": "ENTITY", "char_start": 8533, "char_end": 8540, "token_start": 16, "token_end": 18, "note": null}, {"text": "NF - A2", "type": "ENTITY", "char_start": 8609, "char_end": 8616, "token_start": 31, "token_end": 33, "note": null}, {"text": "Ig promoter", "type": "ENTITY", "char_start": 8671, "char_end": 8682, "token_start": 43, "token_end": 44, "note": null}, {"text": "NF - A1", "type": "ENTITY", "char_start": 8687, "char_end": 8694, "token_start": 46, "token_end": 48, "note": null}, {"text": "OCTA element", "type": "ENTITY", "char_start": 8731, "char_end": 8743, "token_start": 55, "token_end": 56, "note": null}]}
+{"sentence_id": 49, "sentence_text": "Extracts of the B - cell line , BJA - B , contain high levels of NF - A2 and specifically transcribe Ig promoters .", "sentence_char_start_global": 8746, "sentence_char_end_global": 8861, "entities": [{"text": "NF - A2", "type": "ENTITY", "char_start": 65, "char_end": 72, "token_start": 16, "token_end": 18}, {"text": "Ig promoters", "type": "ENTITY", "char_start": 101, "char_end": 113, "token_start": 22, "token_end": 23}], "entities_global": [{"text": "NF - A2", "type": "ENTITY", "char_start": 8811, "char_end": 8818, "token_start": 16, "token_end": 18, "note": null}, {"text": "Ig promoters", "type": "ENTITY", "char_start": 8847, "char_end": 8859, "token_start": 22, "token_end": 23, "note": null}]}
+{"sentence_id": 50, "sentence_text": "In contrast , extracts from HeLa cells transcribed the Ig promoter poorly .", "sentence_char_start_global": 8862, "sentence_char_end_global": 8937, "entities": [{"text": "Ig promoter", "type": "ENTITY", "char_start": 55, "char_end": 66, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "Ig promoter", "type": "ENTITY", "char_start": 8917, "char_end": 8928, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 51, "sentence_text": "Surprisingly , addition of either affinity - enriched NF - A2 or NF - A1 to either a HeLa extract or a partially purified reaction system specifically stimulates the Ig promoter .", "sentence_char_start_global": 8938, "sentence_char_end_global": 9117, "entities": [{"text": "Ig promoter", "type": "ENTITY", "char_start": 166, "char_end": 177, "token_start": 29, "token_end": 30}], "entities_global": [{"text": "Ig promoter", "type": "ENTITY", "char_start": 9104, "char_end": 9115, "token_start": 29, "token_end": 30, "note": null}]}
+{"sentence_id": 52, "sentence_text": "This suggests that the constitutive OCTA - binding factor NF - A1 can activate transcription of the Ig promoter and that B - cell - specific transcription of this promoter , at least in vitro , is partially due to a quantitative difference in the amount of OCTA - binding protein .", "sentence_char_start_global": 9118, "sentence_char_end_global": 9399, "entities": [{"text": "OCTA - binding factor NF - A1", "type": "ENTITY", "char_start": 36, "char_end": 65, "token_start": 5, "token_end": 11}, {"text": "Ig promoter", "type": "ENTITY", "char_start": 100, "char_end": 111, "token_start": 17, "token_end": 18}, {"text": "OCTA - binding protein", "type": "ENTITY", "char_start": 257, "char_end": 279, "token_start": 47, "token_end": 50}], "entities_global": [{"text": "OCTA - binding factor NF - A1", "type": "ENTITY", "char_start": 9154, "char_end": 9183, "token_start": 5, "token_end": 11, "note": null}, {"text": "Ig promoter", "type": "ENTITY", "char_start": 9218, "char_end": 9229, "token_start": 17, "token_end": 18, "note": null}, {"text": "OCTA - binding protein", "type": "ENTITY", "char_start": 9375, "char_end": 9397, "token_start": 47, "token_end": 50, "note": null}]}
+{"sentence_id": 53, "sentence_text": "Because NF - A1 can stimulate Ig transcription , the inability of this factor to activate in vivo the Ig promoter to the same degree as the snRNA promoters probably reflects a difference in the context of the OCTA element in these two types of promoters .", "sentence_char_start_global": 9400, "sentence_char_end_global": 9655, "entities": [{"text": "NF - A1", "type": "ENTITY", "char_start": 8, "char_end": 15, "token_start": 1, "token_end": 3}, {"text": "Ig", "type": "ENTITY", "char_start": 30, "char_end": 32, "token_start": 6, "token_end": 6}, {"text": "Ig promoter", "type": "ENTITY", "char_start": 102, "char_end": 113, "token_start": 19, "token_end": 20}, {"text": "snRNA promoters", "type": "ENTITY", "char_start": 140, "char_end": 155, "token_start": 27, "token_end": 28}, {"text": "OCTA element", "type": "ENTITY", "char_start": 209, "char_end": 221, "token_start": 38, "token_end": 39}, {"text": "promoters", "type": "ENTITY", "char_start": 244, "char_end": 253, "token_start": 45, "token_end": 45}], "entities_global": [{"text": "NF - A1", "type": "ENTITY", "char_start": 9408, "char_end": 9415, "token_start": 1, "token_end": 3, "note": null}, {"text": "Ig", "type": "ENTITY", "char_start": 9430, "char_end": 9432, "token_start": 6, "token_end": 6, "note": null}, {"text": "Ig promoter", "type": "ENTITY", "char_start": 9502, "char_end": 9513, "token_start": 19, "token_end": 20, "note": null}, {"text": "snRNA promoters", "type": "ENTITY", "char_start": 9540, "char_end": 9555, "token_start": 27, "token_end": 28, "note": null}, {"text": "OCTA element", "type": "ENTITY", "char_start": 9609, "char_end": 9621, "token_start": 38, "token_end": 39, "note": null}, {"text": "promoters", "type": "ENTITY", "char_start": 9644, "char_end": 9653, "token_start": 45, "token_end": 45, "note": null}]}
+{"sentence_id": 54, "sentence_text": "Identification of a putative regulator of early T cell activation genes .", "sentence_char_start_global": 9656, "sentence_char_end_global": 9729, "entities": [{"text": "early T cell activation genes", "type": "ENTITY", "char_start": 42, "char_end": 71, "token_start": 6, "token_end": 10}], "entities_global": [{"text": "early T cell activation genes", "type": "ENTITY", "char_start": 9698, "char_end": 9727, "token_start": 6, "token_end": 10, "note": null}]}
+{"sentence_id": 55, "sentence_text": "Molecules involved in the antigen receptor - dependent regulation of early T cell activation genes were investigated with the use of functional sequences of the T cell activation - specific enhancer of interleukin - 2 ( IL - 2 ) .", "sentence_char_start_global": 9730, "sentence_char_end_global": 9960, "entities": [{"text": "early T cell activation genes", "type": "ENTITY", "char_start": 69, "char_end": 98, "token_start": 10, "token_end": 14}, {"text": "T cell activation - specific enhancer", "type": "ENTITY", "char_start": 161, "char_end": 198, "token_start": 25, "token_end": 30}, {"text": "interleukin - 2", "type": "ENTITY", "char_start": 202, "char_end": 217, "token_start": 32, "token_end": 34}, {"text": "IL - 2", "type": "ENTITY", "char_start": 220, "char_end": 226, "token_start": 36, "token_end": 38}], "entities_global": [{"text": "early T cell activation genes", "type": "ENTITY", "char_start": 9799, "char_end": 9828, "token_start": 10, "token_end": 14, "note": null}, {"text": "T cell activation - specific enhancer", "type": "ENTITY", "char_start": 9891, "char_end": 9928, "token_start": 25, "token_end": 30, "note": null}, {"text": "interleukin - 2", "type": "ENTITY", "char_start": 9932, "char_end": 9947, "token_start": 32, "token_end": 34, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 9950, "char_end": 9956, "token_start": 36, "token_end": 38, "note": null}]}
+{"sentence_id": 56, "sentence_text": "One of these sequences forms a protein complex , NFAT - 1 , specifically with nuclear extracts of activated T cells .", "sentence_char_start_global": 9961, "sentence_char_end_global": 10078, "entities": [{"text": "NFAT - 1", "type": "ENTITY", "char_start": 49, "char_end": 57, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "NFAT - 1", "type": "ENTITY", "char_start": 10010, "char_end": 10018, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 57, "sentence_text": "This complex appeared 10 to 25 minutes before the activation of the IL - 2 gene .", "sentence_char_start_global": 10079, "sentence_char_end_global": 10160, "entities": [{"text": "IL - 2 gene", "type": "ENTITY", "char_start": 68, "char_end": 79, "token_start": 12, "token_end": 15}], "entities_global": [{"text": "IL - 2 gene", "type": "ENTITY", "char_start": 10147, "char_end": 10158, "token_start": 12, "token_end": 15, "note": null}]}
+{"sentence_id": 58, "sentence_text": "Studies with inhibitors of protein synthesis indicated that the time of synthesis of the activator of the IL - 2 gene in Jurkat T cells corresponds to the time of appearance of NFAT - 1 .", "sentence_char_start_global": 10161, "sentence_char_end_global": 10348, "entities": [{"text": "IL - 2 gene", "type": "ENTITY", "char_start": 106, "char_end": 117, "token_start": 17, "token_end": 20}, {"text": "NFAT - 1", "type": "ENTITY", "char_start": 177, "char_end": 185, "token_start": 32, "token_end": 34}], "entities_global": [{"text": "IL - 2 gene", "type": "ENTITY", "char_start": 10267, "char_end": 10278, "token_start": 17, "token_end": 20, "note": null}, {"text": "NFAT - 1", "type": "ENTITY", "char_start": 10338, "char_end": 10346, "token_start": 32, "token_end": 34, "note": null}]}
+{"sentence_id": 59, "sentence_text": "NFAT - 1 , or a very similar protein , bound functional sequences of the long terminal repeat ( LTR ) of the human immunodeficiency virus type 1 ; the LTR of this virus is known to be stimulated during early T cell activation .", "sentence_char_start_global": 10349, "sentence_char_end_global": 10576, "entities": [{"text": "NFAT - 1", "type": "ENTITY", "char_start": 0, "char_end": 8, "token_start": 0, "token_end": 2}, {"text": "long terminal repeat", "type": "ENTITY", "char_start": 73, "char_end": 93, "token_start": 15, "token_end": 17}, {"text": "LTR", "type": "ENTITY", "char_start": 96, "char_end": 99, "token_start": 19, "token_end": 19}, {"text": "LTR", "type": "ENTITY", "char_start": 151, "char_end": 154, "token_start": 30, "token_end": 30}], "entities_global": [{"text": "NFAT - 1", "type": "ENTITY", "char_start": 10349, "char_end": 10357, "token_start": 0, "token_end": 2, "note": null}, {"text": "long terminal repeat", "type": "ENTITY", "char_start": 10422, "char_end": 10442, "token_start": 15, "token_end": 17, "note": null}, {"text": "LTR", "type": "ENTITY", "char_start": 10445, "char_end": 10448, "token_start": 19, "token_end": 19, "note": null}, {"text": "LTR", "type": "ENTITY", "char_start": 10500, "char_end": 10503, "token_start": 30, "token_end": 30, "note": null}]}
+{"sentence_id": 60, "sentence_text": "The binding site for this complex activated a linked promoter after transfection into antigen receptor - activated T cells but not other cell types .", "sentence_char_start_global": 10577, "sentence_char_end_global": 10726, "entities": [{"text": "binding site", "type": "ENTITY", "char_start": 4, "char_end": 16, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "binding site", "type": "ENTITY", "char_start": 10581, "char_end": 10593, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 61, "sentence_text": "These characteristics suggest that NFAT - 1 transmits signals initiated at the T cell antigen receptor .", "sentence_char_start_global": 10727, "sentence_char_end_global": 10831, "entities": [{"text": "NFAT - 1", "type": "ENTITY", "char_start": 35, "char_end": 43, "token_start": 4, "token_end": 6}, {"text": "T cell antigen receptor", "type": "ENTITY", "char_start": 79, "char_end": 102, "token_start": 12, "token_end": 15}], "entities_global": [{"text": "NFAT - 1", "type": "ENTITY", "char_start": 10762, "char_end": 10770, "token_start": 4, "token_end": 6, "note": null}, {"text": "T cell antigen receptor", "type": "ENTITY", "char_start": 10806, "char_end": 10829, "token_start": 12, "token_end": 15, "note": null}]}
+{"sentence_id": 62, "sentence_text": "Characterization of thyroid hormone receptors in human IM - 9 lymphocytes .", "sentence_char_start_global": 10832, "sentence_char_end_global": 10907, "entities": [{"text": "thyroid hormone receptors", "type": "ENTITY", "char_start": 20, "char_end": 45, "token_start": 2, "token_end": 4}], "entities_global": [{"text": "thyroid hormone receptors", "type": "ENTITY", "char_start": 10852, "char_end": 10877, "token_start": 2, "token_end": 4, "note": null}]}
+{"sentence_id": 63, "sentence_text": "Although putatively identified more than 10 years ago , thyroid hormone receptors in human tissues remain poorly characterized .", "sentence_char_start_global": 10908, "sentence_char_end_global": 11036, "entities": [{"text": "thyroid hormone receptors", "type": "ENTITY", "char_start": 56, "char_end": 81, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "thyroid hormone receptors", "type": "ENTITY", "char_start": 10964, "char_end": 10989, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 64, "sentence_text": "As a first step towards understanding the mechanism of thyroid hormone action in man we have characterized T3 binding sites in nuclei of the human lymphoblastoid line , IM - 9 cells .", "sentence_char_start_global": 11037, "sentence_char_end_global": 11220, "entities": [{"text": "T3 binding sites", "type": "ENTITY", "char_start": 107, "char_end": 123, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "T3 binding sites", "type": "ENTITY", "char_start": 11144, "char_end": 11160, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 65, "sentence_text": "In whole cell experiments at 37 degrees C , nuclear binding of [ 125I ] T3 was saturable ( Kd 34 + / - 6 pmol / l ) and of finite capacity ( approximately equal to 350 sites / cell ) .", "sentence_char_start_global": 11221, "sentence_char_end_global": 11405, "entities": [{"text": "[ 125I ] T3", "type": "ENTITY", "char_start": 63, "char_end": 74, "token_start": 12, "token_end": 15}], "entities_global": [{"text": "[ 125I ] T3", "type": "ENTITY", "char_start": 11284, "char_end": 11295, "token_start": 12, "token_end": 15, "note": null}]}
+{"sentence_id": 66, "sentence_text": "The binding sites were extracted from a nuclear pellet by treatment with 0 . 4 mol / l KCl and sonication .", "sentence_char_start_global": 11406, "sentence_char_end_global": 11513, "entities": [{"text": "binding sites", "type": "ENTITY", "char_start": 4, "char_end": 17, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "binding sites", "type": "ENTITY", "char_start": 11410, "char_end": 11423, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 67, "sentence_text": "Separation of bound from free [ 125I ] T3 in the extracts was achieved using the calcium phosphate matrix , hydroxyapatite at a concentration of 0 . 3 ml of a 150 g / l slurry .", "sentence_char_start_global": 11514, "sentence_char_end_global": 11691, "entities": [{"text": "[ 125I ] T3", "type": "ENTITY", "char_start": 30, "char_end": 41, "token_start": 5, "token_end": 8}], "entities_global": [{"text": "[ 125I ] T3", "type": "ENTITY", "char_start": 11544, "char_end": 11555, "token_start": 5, "token_end": 8, "note": null}]}
+{"sentence_id": 68, "sentence_text": "Rectilinear Scatchard plots were obtained only when the hydroxyapatite was washed with a buffer containing 0 . 5 % Triton X - 100 .", "sentence_char_start_global": 11692, "sentence_char_end_global": 11823, "entities": [], "entities_global": []}
+{"sentence_id": 69, "sentence_text": "Under these conditions T3 binding sites in the nuclear extracts were present at a concentration of 22 . 4 + / - 8 . 6 fmol / mg protein and showed an affinity of ( Kd , room temperature ) 140 + / - 10 pmol / l .", "sentence_char_start_global": 11824, "sentence_char_end_global": 12035, "entities": [{"text": "T3 binding sites", "type": "ENTITY", "char_start": 23, "char_end": 39, "token_start": 3, "token_end": 5}], "entities_global": [{"text": "T3 binding sites", "type": "ENTITY", "char_start": 11847, "char_end": 11863, "token_start": 3, "token_end": 5, "note": null}]}
+{"sentence_id": 70, "sentence_text": "The same assay system was used to determine the hierarchy of affinities for a range of natural and synthetic analogues .", "sentence_char_start_global": 12036, "sentence_char_end_global": 12156, "entities": [], "entities_global": []}
+{"sentence_id": 71, "sentence_text": "Calling T3 100 , the order of potencies observed was : Triac , 500 ; 3 , 5 - diiodo - 3 ' - isopropylthyronine , 89 ; T4 , 32 ; 3 , 5 - dimethyl - 3 ' isopropylthyronine 2 ; 3 , 5 - T2 , 0 . 7 , rT3 , 0 . 4 ; 3 ' 5 ' - T2 , less than 0 . 01 .", "sentence_char_start_global": 12157, "sentence_char_end_global": 12399, "entities": [], "entities_global": []}
+{"sentence_id": 72, "sentence_text": "These results suggest that the T3 binding sites present in human IM - 9 lymphocyte nuclei and extracts thereof are thyroid hormone receptors .", "sentence_char_start_global": 12400, "sentence_char_end_global": 12542, "entities": [{"text": "T3 binding sites", "type": "ENTITY", "char_start": 31, "char_end": 47, "token_start": 5, "token_end": 7}, {"text": "thyroid hormone receptors", "type": "ENTITY", "char_start": 115, "char_end": 140, "token_start": 20, "token_end": 22}], "entities_global": [{"text": "T3 binding sites", "type": "ENTITY", "char_start": 12431, "char_end": 12447, "token_start": 5, "token_end": 7, "note": null}, {"text": "thyroid hormone receptors", "type": "ENTITY", "char_start": 12515, "char_end": 12540, "token_start": 20, "token_end": 22, "note": null}]}
+{"sentence_id": 73, "sentence_text": "These cells may be a useful tool to increase our understanding of human T3 receptors", "sentence_char_start_global": 12543, "sentence_char_end_global": 12627, "entities": [{"text": "human T3 receptors", "type": "ENTITY", "char_start": 66, "char_end": 84, "token_start": 12, "token_end": 14}], "entities_global": [{"text": "human T3 receptors", "type": "ENTITY", "char_start": 12609, "char_end": 12627, "token_start": 12, "token_end": 14, "note": null}]}
+{"sentence_id": 74, "sentence_text": "Definition of T - cell specific DNA - binding factors that interact with a 3 ' - silencer in the CD4 + T - cell gene Rpt - 1 .", "sentence_char_start_global": 12628, "sentence_char_end_global": 12754, "entities": [{"text": "T - cell specific DNA - binding factors", "type": "ENTITY", "char_start": 14, "char_end": 53, "token_start": 2, "token_end": 9}, {"text": "3 ' - silencer", "type": "ENTITY", "char_start": 75, "char_end": 89, "token_start": 14, "token_end": 17}, {"text": "CD4 + T - cell gene Rpt - 1", "type": "ENTITY", "char_start": 97, "char_end": 124, "token_start": 20, "token_end": 28}], "entities_global": [{"text": "T - cell specific DNA - binding factors", "type": "ENTITY", "char_start": 12642, "char_end": 12681, "token_start": 2, "token_end": 9, "note": null}, {"text": "3 ' - silencer", "type": "ENTITY", "char_start": 12703, "char_end": 12717, "token_start": 14, "token_end": 17, "note": null}, {"text": "CD4 + T - cell gene Rpt - 1", "type": "ENTITY", "char_start": 12725, "char_end": 12752, "token_start": 20, "token_end": 28, "note": null}]}
+{"sentence_id": 75, "sentence_text": "Analysis of the region 3 ' to the CD4 + T - cell gene Rpt - 1 ( encoding regulatory protein T - lymphocyte 1 ) led to the definition of a silencer element that inhibits heterologous gene expression in certain CD4 + T - cell lines but not in B - cell or non - lymphoid cell lines .", "sentence_char_start_global": 12755, "sentence_char_end_global": 13035, "entities": [{"text": "CD4 + T - cell gene Rpt - 1", "type": "ENTITY", "char_start": 34, "char_end": 61, "token_start": 8, "token_end": 16}, {"text": "T - lymphocyte 1", "type": "ENTITY", "char_start": 92, "char_end": 108, "token_start": 21, "token_end": 24}, {"text": "silencer element", "type": "ENTITY", "char_start": 138, "char_end": 154, "token_start": 32, "token_end": 33}, {"text": "heterologous gene", "type": "ENTITY", "char_start": 169, "char_end": 186, "token_start": 36, "token_end": 37}], "entities_global": [{"text": "CD4 + T - cell gene Rpt - 1", "type": "ENTITY", "char_start": 12789, "char_end": 12816, "token_start": 8, "token_end": 16, "note": null}, {"text": "T - lymphocyte 1", "type": "ENTITY", "char_start": 12847, "char_end": 12863, "token_start": 21, "token_end": 24, "note": null}, {"text": "silencer element", "type": "ENTITY", "char_start": 12893, "char_end": 12909, "token_start": 32, "token_end": 33, "note": null}, {"text": "heterologous gene", "type": "ENTITY", "char_start": 12924, "char_end": 12941, "token_start": 36, "token_end": 37, "note": null}]}
+{"sentence_id": 76, "sentence_text": "Functional silencer activity in vivo was associated with the presence of a specific silencer - DNA - protein complex in electrophoretic mobility shift assays with T - cell extracts .", "sentence_char_start_global": 13036, "sentence_char_end_global": 13218, "entities": [{"text": "silencer", "type": "ENTITY", "char_start": 11, "char_end": 19, "token_start": 1, "token_end": 1}, {"text": "silencer - DNA - protein complex", "type": "ENTITY", "char_start": 84, "char_end": 116, "token_start": 13, "token_end": 18}], "entities_global": [{"text": "silencer", "type": "ENTITY", "char_start": 13047, "char_end": 13055, "token_start": 1, "token_end": 1, "note": null}, {"text": "silencer - DNA - protein complex", "type": "ENTITY", "char_start": 13120, "char_end": 13152, "token_start": 13, "token_end": 18, "note": null}]}
+{"sentence_id": 77, "sentence_text": "Formation of this complex was selectively inhibited by the region in HIV - 1 containing a silencer element .", "sentence_char_start_global": 13219, "sentence_char_end_global": 13327, "entities": [{"text": "HIV - 1", "type": "ENTITY", "char_start": 69, "char_end": 76, "token_start": 11, "token_end": 13}, {"text": "silencer element", "type": "ENTITY", "char_start": 90, "char_end": 106, "token_start": 16, "token_end": 17}], "entities_global": [{"text": "HIV - 1", "type": "ENTITY", "char_start": 13288, "char_end": 13295, "token_start": 11, "token_end": 13, "note": null}, {"text": "silencer element", "type": "ENTITY", "char_start": 13309, "char_end": 13325, "token_start": 16, "token_end": 17, "note": null}]}
+{"sentence_id": 78, "sentence_text": "We discuss the possibility that DNA - binding factors may coregulate HIV - 1 and Rpt - 1 gene expression through a common transcriptional silencer element .", "sentence_char_start_global": 13328, "sentence_char_end_global": 13484, "entities": [{"text": "DNA - binding factors", "type": "ENTITY", "char_start": 32, "char_end": 53, "token_start": 5, "token_end": 8}, {"text": "transcriptional silencer element", "type": "ENTITY", "char_start": 122, "char_end": 154, "token_start": 23, "token_end": 25}], "entities_global": [{"text": "DNA - binding factors", "type": "ENTITY", "char_start": 13360, "char_end": 13381, "token_start": 5, "token_end": 8, "note": null}, {"text": "transcriptional silencer element", "type": "ENTITY", "char_start": 13450, "char_end": 13482, "token_start": 23, "token_end": 25, "note": null}]}
+{"sentence_id": 79, "sentence_text": "Congenital immunodeficiencies associated with absence of HLA class II antigens on lymphocytes result from distinct mutations in trans - acting factors .", "sentence_char_start_global": 13485, "sentence_char_end_global": 13637, "entities": [{"text": "HLA class II antigens", "type": "ENTITY", "char_start": 57, "char_end": 78, "token_start": 6, "token_end": 9}, {"text": "trans - acting factors", "type": "ENTITY", "char_start": 128, "char_end": 150, "token_start": 17, "token_end": 20}], "entities_global": [{"text": "HLA class II antigens", "type": "ENTITY", "char_start": 13542, "char_end": 13563, "token_start": 6, "token_end": 9, "note": null}, {"text": "trans - acting factors", "type": "ENTITY", "char_start": 13613, "char_end": 13635, "token_start": 17, "token_end": 20, "note": null}]}
+{"sentence_id": 80, "sentence_text": "Coordinate regulation of HLA class II gene expression during development and coinduction of class II genes by soluble factors suggests that common trans - acting factor ( s ) control expression of these genes .", "sentence_char_start_global": 13638, "sentence_char_end_global": 13848, "entities": [{"text": "HLA class II gene", "type": "ENTITY", "char_start": 25, "char_end": 42, "token_start": 3, "token_end": 6}, {"text": "class II genes", "type": "ENTITY", "char_start": 92, "char_end": 106, "token_start": 13, "token_end": 15}, {"text": "soluble factors", "type": "ENTITY", "char_start": 110, "char_end": 125, "token_start": 17, "token_end": 18}, {"text": "trans - acting factor", "type": "ENTITY", "char_start": 147, "char_end": 168, "token_start": 22, "token_end": 25}], "entities_global": [{"text": "HLA class II gene", "type": "ENTITY", "char_start": 13663, "char_end": 13680, "token_start": 3, "token_end": 6, "note": null}, {"text": "class II genes", "type": "ENTITY", "char_start": 13730, "char_end": 13744, "token_start": 13, "token_end": 15, "note": null}, {"text": "soluble factors", "type": "ENTITY", "char_start": 13748, "char_end": 13763, "token_start": 17, "token_end": 18, "note": null}, {"text": "trans - acting factor", "type": "ENTITY", "char_start": 13785, "char_end": 13806, "token_start": 22, "token_end": 25, "note": null}]}
+{"sentence_id": 81, "sentence_text": "In B - lymphoblastoid cell lines derived from two independent class II - deficient bare lymphocyte syndrome patients , we observed a drastic decrease in transcription rates of the class II genes .", "sentence_char_start_global": 13849, "sentence_char_end_global": 14045, "entities": [{"text": "class II genes", "type": "ENTITY", "char_start": 180, "char_end": 194, "token_start": 29, "token_end": 31}], "entities_global": [{"text": "class II genes", "type": "ENTITY", "char_start": 14029, "char_end": 14043, "token_start": 29, "token_end": 31, "note": null}]}
+{"sentence_id": 82, "sentence_text": "When these cell lines are fused , class II genes are reexpressed , indicating that immunodeficiencies in bare lymphocyte syndrome patients are the result of two distinct mutations .", "sentence_char_start_global": 14046, "sentence_char_end_global": 14227, "entities": [{"text": "class II genes", "type": "ENTITY", "char_start": 34, "char_end": 48, "token_start": 7, "token_end": 9}], "entities_global": [{"text": "class II genes", "type": "ENTITY", "char_start": 14080, "char_end": 14094, "token_start": 7, "token_end": 9, "note": null}]}
+{"sentence_id": 83, "sentence_text": "Further studies show that genes governing the expression of class II antigens fall into at least three complementation groups ; two of these were previously unidentified in mutant cell lines generated in vitro .", "sentence_char_start_global": 14228, "sentence_char_end_global": 14439, "entities": [{"text": "class II antigens", "type": "ENTITY", "char_start": 60, "char_end": 77, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "class II antigens", "type": "ENTITY", "char_start": 14288, "char_end": 14305, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 84, "sentence_text": "In addition , we report the identification of two discrete complexes , NFX1 . 1 and NFX1 . 2 , that bind to the DRA X consensus element .", "sentence_char_start_global": 14440, "sentence_char_end_global": 14577, "entities": [{"text": "NFX1 . 1", "type": "ENTITY", "char_start": 71, "char_end": 79, "token_start": 12, "token_end": 14}, {"text": "NFX1 . 2", "type": "ENTITY", "char_start": 84, "char_end": 92, "token_start": 16, "token_end": 18}, {"text": "DRA X consensus element", "type": "ENTITY", "char_start": 112, "char_end": 135, "token_start": 24, "token_end": 27}], "entities_global": [{"text": "NFX1 . 1", "type": "ENTITY", "char_start": 14511, "char_end": 14519, "token_start": 12, "token_end": 14, "note": null}, {"text": "NFX1 . 2", "type": "ENTITY", "char_start": 14524, "char_end": 14532, "token_start": 16, "token_end": 18, "note": null}, {"text": "DRA X consensus element", "type": "ENTITY", "char_start": 14552, "char_end": 14575, "token_start": 24, "token_end": 27, "note": null}]}
+{"sentence_id": 85, "sentence_text": "Though the mutation in at least one mutant line generated in vitro ( RJ2 . 2 . 5 ) affects products functioning via interaction with the X box , clear alterations in either NFX1 . 1 or NFX1 . 2 are not found in any of the mutant cell lines .", "sentence_char_start_global": 14578, "sentence_char_end_global": 14819, "entities": [{"text": "X box", "type": "ENTITY", "char_start": 137, "char_end": 142, "token_start": 26, "token_end": 27}, {"text": "NFX1 . 1", "type": "ENTITY", "char_start": 173, "char_end": 181, "token_start": 33, "token_end": 35}, {"text": "NFX1 . 2", "type": "ENTITY", "char_start": 185, "char_end": 193, "token_start": 37, "token_end": 39}], "entities_global": [{"text": "X box", "type": "ENTITY", "char_start": 14715, "char_end": 14720, "token_start": 26, "token_end": 27, "note": null}, {"text": "NFX1 . 1", "type": "ENTITY", "char_start": 14751, "char_end": 14759, "token_start": 33, "token_end": 35, "note": null}, {"text": "NFX1 . 2", "type": "ENTITY", "char_start": 14763, "char_end": 14771, "token_start": 37, "token_end": 39, "note": null}]}
+{"sentence_id": 86, "sentence_text": "In vivo responsiveness to glucocorticoid correlated with glucocorticoid receptor content in peripheral blood leukocytes in normal humans .", "sentence_char_start_global": 14820, "sentence_char_end_global": 14958, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 57, "char_end": 80, "token_start": 7, "token_end": 8}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 14877, "char_end": 14900, "token_start": 7, "token_end": 8, "note": null}]}
+{"sentence_id": 87, "sentence_text": "Dexamethasone loading tests ( 0 . 1 mg dexamethasone / kg , iv ) were performed in 18 normal males to evaluate the individual responsiveness to glucocorticoid .", "sentence_char_start_global": 14959, "sentence_char_end_global": 15119, "entities": [], "entities_global": []}
+{"sentence_id": 88, "sentence_text": "There were inter - individual differences in increase in peripheral blood polymorphonuclear leukocyte count , decrease in peripheral blood lymphocyte count , and increase in plasma free fatty acids levels after dexamethasone injection .", "sentence_char_start_global": 15120, "sentence_char_end_global": 15356, "entities": [], "entities_global": []}
+{"sentence_id": 89, "sentence_text": "In addition , there was a significant correlation between the maximum increase in polymorphonuclear leukocytes and the maximum decrease in lymphocytes ( r = 0 . 7514 , p less than 0 . 0003 ) .", "sentence_char_start_global": 15357, "sentence_char_end_global": 15549, "entities": [], "entities_global": []}
+{"sentence_id": 90, "sentence_text": "Simultaneous measurements of glucocorticoid receptor content by whole - cell assay revealed that glucocorticoid receptor content in polymorphonuclear leukocytes linearly correlated with that in the corresponding lymphocytes ( r = 0 . 9482 , p less than 0 . 0001 ) .", "sentence_char_start_global": 15550, "sentence_char_end_global": 15815, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 29, "char_end": 52, "token_start": 3, "token_end": 4}, {"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 97, "char_end": 120, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 15579, "char_end": 15602, "token_start": 3, "token_end": 4, "note": null}, {"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 15647, "char_end": 15670, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 91, "sentence_text": "There were also significant correlations between the maximum increase in polymorphonuclear leukocytes and glucocorticoid receptor content in polymorphonuclear leukocytes ( r = 0 . 7239 , p less than 0 . 0007 ) , and between the maximum decrease in lymphocytes and glucocorticoid receptor content in lymphocytes ( r = 0 . 7703 , p less than 0 . 0002 ) .", "sentence_char_start_global": 15816, "sentence_char_end_global": 16168, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 106, "char_end": 129, "token_start": 13, "token_end": 14}, {"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 264, "char_end": 287, "token_start": 42, "token_end": 43}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 15922, "char_end": 15945, "token_start": 13, "token_end": 14, "note": null}, {"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 16080, "char_end": 16103, "token_start": 42, "token_end": 43, "note": null}]}
+{"sentence_id": 92, "sentence_text": "These results suggest that individual differences are preserved both in glucocorticoid responsiveness and in glucocorticoid receptor content in peripheral blood leukocytes in normal humans .", "sentence_char_start_global": 16169, "sentence_char_end_global": 16359, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 109, "char_end": 132, "token_start": 14, "token_end": 15}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 16278, "char_end": 16301, "token_start": 14, "token_end": 15, "note": null}]}
+{"sentence_id": 93, "sentence_text": "Estradiol receptors in the cytosol of peripheral blood mononuclear cells in hepatitis B virus carriers treated with interferon - alpha .", "sentence_char_start_global": 16360, "sentence_char_end_global": 16496, "entities": [{"text": "interferon - alpha", "type": "ENTITY", "char_start": 116, "char_end": 134, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "interferon - alpha", "type": "ENTITY", "char_start": 16476, "char_end": 16494, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 94, "sentence_text": "Estradiol receptors in the cytosol of peripheral blood mononuclear cells and the effects of interferon - alpha ( IFN - alpha ) on estradiol receptors were studied in asymptomatic hepatitis B virus ( HBV ) carriers , patients with chronic hepatitis B and normal controls .", "sentence_char_start_global": 16497, "sentence_char_end_global": 16768, "entities": [{"text": "Estradiol receptors", "type": "ENTITY", "char_start": 0, "char_end": 19, "token_start": 0, "token_end": 1}, {"text": "interferon - alpha", "type": "ENTITY", "char_start": 92, "char_end": 110, "token_start": 14, "token_end": 16}, {"text": "IFN - alpha", "type": "ENTITY", "char_start": 113, "char_end": 124, "token_start": 18, "token_end": 20}, {"text": "estradiol receptors", "type": "ENTITY", "char_start": 130, "char_end": 149, "token_start": 23, "token_end": 24}], "entities_global": [{"text": "Estradiol receptors", "type": "ENTITY", "char_start": 16497, "char_end": 16516, "token_start": 0, "token_end": 1, "note": null}, {"text": "interferon - alpha", "type": "ENTITY", "char_start": 16589, "char_end": 16607, "token_start": 14, "token_end": 16, "note": null}, {"text": "IFN - alpha", "type": "ENTITY", "char_start": 16610, "char_end": 16621, "token_start": 18, "token_end": 20, "note": null}, {"text": "estradiol receptors", "type": "ENTITY", "char_start": 16627, "char_end": 16646, "token_start": 23, "token_end": 24, "note": null}]}
+{"sentence_id": 95, "sentence_text": "The level of estradiol receptors in the cytosol of mononuclear cells was significantly lower in asymptomatic HBV carriers and patients with chronic hepatitis B , compared to normal controls .", "sentence_char_start_global": 16769, "sentence_char_end_global": 16960, "entities": [{"text": "estradiol receptors", "type": "ENTITY", "char_start": 13, "char_end": 32, "token_start": 3, "token_end": 4}], "entities_global": [{"text": "estradiol receptors", "type": "ENTITY", "char_start": 16782, "char_end": 16801, "token_start": 3, "token_end": 4, "note": null}]}
+{"sentence_id": 96, "sentence_text": "This low level of cytosol estradiol receptors in patients with chronic hepatitis B was increased by the administration of IFN - alpha .", "sentence_char_start_global": 16961, "sentence_char_end_global": 17096, "entities": [{"text": "estradiol receptors", "type": "ENTITY", "char_start": 26, "char_end": 45, "token_start": 5, "token_end": 6}, {"text": "IFN - alpha", "type": "ENTITY", "char_start": 122, "char_end": 133, "token_start": 19, "token_end": 21}], "entities_global": [{"text": "estradiol receptors", "type": "ENTITY", "char_start": 16987, "char_end": 17006, "token_start": 5, "token_end": 6, "note": null}, {"text": "IFN - alpha", "type": "ENTITY", "char_start": 17083, "char_end": 17094, "token_start": 19, "token_end": 21, "note": null}]}
+{"sentence_id": 97, "sentence_text": "In addition , when peripheral blood mononuclear cells from patients with chronic hepatitis B were incubated with IFN - alpha in vitro , the level of cytosol estradiol receptors also increased by increasing the concentration of IFN - alpha .", "sentence_char_start_global": 17097, "sentence_char_end_global": 17337, "entities": [{"text": "IFN - alpha", "type": "ENTITY", "char_start": 113, "char_end": 124, "token_start": 17, "token_end": 19}, {"text": "estradiol receptors", "type": "ENTITY", "char_start": 157, "char_end": 176, "token_start": 27, "token_end": 28}, {"text": "IFN - alpha", "type": "ENTITY", "char_start": 227, "char_end": 238, "token_start": 36, "token_end": 38}], "entities_global": [{"text": "IFN - alpha", "type": "ENTITY", "char_start": 17210, "char_end": 17221, "token_start": 17, "token_end": 19, "note": null}, {"text": "estradiol receptors", "type": "ENTITY", "char_start": 17254, "char_end": 17273, "token_start": 27, "token_end": 28, "note": null}, {"text": "IFN - alpha", "type": "ENTITY", "char_start": 17324, "char_end": 17335, "token_start": 36, "token_end": 38, "note": null}]}
+{"sentence_id": 98, "sentence_text": "We previously reported that the response of mononuclear cells to estrogen is impaired in HBV carriers , and our present results suggested that this may be due to the low level of estradiol receptors in the cytosol of mononuclear cells .", "sentence_char_start_global": 17338, "sentence_char_end_global": 17574, "entities": [{"text": "estradiol receptors", "type": "ENTITY", "char_start": 179, "char_end": 198, "token_start": 32, "token_end": 33}], "entities_global": [{"text": "estradiol receptors", "type": "ENTITY", "char_start": 17517, "char_end": 17536, "token_start": 32, "token_end": 33, "note": null}]}
+{"sentence_id": 99, "sentence_text": "Association of increased lytic effector cell function with high estrogen receptor levels in tumor - bearing patients with breast cancer .", "sentence_char_start_global": 17575, "sentence_char_end_global": 17712, "entities": [{"text": "estrogen receptor", "type": "ENTITY", "char_start": 64, "char_end": 81, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "estrogen receptor", "type": "ENTITY", "char_start": 17639, "char_end": 17656, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 100, "sentence_text": "Tumor - bearing patients with breast cancer were assayed for their natural killer ( NK ) cell activity and for the function of activated cytotoxic T - cells , as assessed by lectin - dependent cellular cytotoxicity ( LDCC ) .", "sentence_char_start_global": 17713, "sentence_char_end_global": 17938, "entities": [], "entities_global": []}
+{"sentence_id": 101, "sentence_text": "Tumor - bearing patients with breast cancer had a significant increase in NK activity and in LDCC , as compared with healthy control individuals .", "sentence_char_start_global": 17939, "sentence_char_end_global": 18085, "entities": [], "entities_global": []}
+{"sentence_id": 102, "sentence_text": "Although the enhanced NK cell activity and LDCC were closely associated with high levels ( greater than 31 fmol / mg ) of estrogen receptor ( ER ) content in the primary tumor , no other clinical or histologic correlation between the increase in either parameter of cytotoxic effector cell function could be found .", "sentence_char_start_global": 18086, "sentence_char_end_global": 18401, "entities": [{"text": "estrogen receptor", "type": "ENTITY", "char_start": 122, "char_end": 139, "token_start": 23, "token_end": 24}, {"text": "ER", "type": "ENTITY", "char_start": 142, "char_end": 144, "token_start": 26, "token_end": 26}], "entities_global": [{"text": "estrogen receptor", "type": "ENTITY", "char_start": 18208, "char_end": 18225, "token_start": 23, "token_end": 24, "note": null}, {"text": "ER", "type": "ENTITY", "char_start": 18228, "char_end": 18230, "token_start": 26, "token_end": 26, "note": null}]}
+{"sentence_id": 103, "sentence_text": "Thus , ER levels greater than 31 fmol / mg might be associated with increased cytotoxic effector cell function in tumor - bearing patients with breast cancer .", "sentence_char_start_global": 18402, "sentence_char_end_global": 18561, "entities": [{"text": "ER", "type": "ENTITY", "char_start": 7, "char_end": 9, "token_start": 2, "token_end": 2}], "entities_global": [{"text": "ER", "type": "ENTITY", "char_start": 18409, "char_end": 18411, "token_start": 2, "token_end": 2, "note": null}]}
+{"sentence_id": 104, "sentence_text": "Properties of glucocorticoid receptors in Epstein - Barr virus - transformed lymphocytes from patients with familial cortisol resistance .", "sentence_char_start_global": 18562, "sentence_char_end_global": 18700, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 14, "char_end": 38, "token_start": 2, "token_end": 3}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 18576, "char_end": 18600, "token_start": 2, "token_end": 3, "note": null}]}
+{"sentence_id": 105, "sentence_text": "In a previous report of two patients with familial glucocorticoid resistance due to reduced numbers of glucocorticoid receptors ( GR ) , we have shown decreased numbers of GR in peripheral mononuclear cells and cultured fibroblasts but normal affinity of GR in both patients .", "sentence_char_start_global": 18701, "sentence_char_end_global": 18977, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 103, "char_end": 127, "token_start": 16, "token_end": 17}, {"text": "GR", "type": "ENTITY", "char_start": 130, "char_end": 132, "token_start": 19, "token_end": 19}, {"text": "GR", "type": "ENTITY", "char_start": 172, "char_end": 174, "token_start": 28, "token_end": 28}, {"text": "GR", "type": "ENTITY", "char_start": 255, "char_end": 257, "token_start": 40, "token_end": 40}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 18804, "char_end": 18828, "token_start": 16, "token_end": 17, "note": null}, {"text": "GR", "type": "ENTITY", "char_start": 18831, "char_end": 18833, "token_start": 19, "token_end": 19, "note": null}, {"text": "GR", "type": "ENTITY", "char_start": 18873, "char_end": 18875, "token_start": 28, "token_end": 28, "note": null}, {"text": "GR", "type": "ENTITY", "char_start": 18956, "char_end": 18958, "token_start": 40, "token_end": 40, "note": null}]}
+{"sentence_id": 106, "sentence_text": "In this study , peripheral lymphocytes from these patients , one patient ' s son and daughter , and normal subjects were transformed with Epstein - Barr virus .", "sentence_char_start_global": 18978, "sentence_char_end_global": 19138, "entities": [], "entities_global": []}
+{"sentence_id": 107, "sentence_text": "Reduced numbers and normal affinity of GR were found in the Epstein - Barr virus - transformed lymphocytes from both patients while the son and daughter had normal numbers and affinity of GR .", "sentence_char_start_global": 19139, "sentence_char_end_global": 19331, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 39, "char_end": 41, "token_start": 6, "token_end": 6}, {"text": "GR", "type": "ENTITY", "char_start": 188, "char_end": 190, "token_start": 32, "token_end": 32}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 19178, "char_end": 19180, "token_start": 6, "token_end": 6, "note": null}, {"text": "GR", "type": "ENTITY", "char_start": 19327, "char_end": 19329, "token_start": 32, "token_end": 32, "note": null}]}
+{"sentence_id": 108, "sentence_text": "The thermal stability of GR and thermal activation of cytosolic receptors in both patients were found to be normal .", "sentence_char_start_global": 19332, "sentence_char_end_global": 19448, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 25, "char_end": 27, "token_start": 4, "token_end": 4}, {"text": "cytosolic receptors", "type": "ENTITY", "char_start": 54, "char_end": 73, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 19357, "char_end": 19359, "token_start": 4, "token_end": 4, "note": null}, {"text": "cytosolic receptors", "type": "ENTITY", "char_start": 19386, "char_end": 19405, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 109, "sentence_text": "Although the percentages of nuclear bound GR were similar in both patients and normal controls , the absolute amounts of nuclear bound GR of the patients were about one - half that of normal controls .", "sentence_char_start_global": 19449, "sentence_char_end_global": 19650, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 42, "char_end": 44, "token_start": 6, "token_end": 6}, {"text": "GR", "type": "ENTITY", "char_start": 135, "char_end": 137, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 19491, "char_end": 19493, "token_start": 6, "token_end": 6, "note": null}, {"text": "GR", "type": "ENTITY", "char_start": 19584, "char_end": 19586, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 110, "sentence_text": "These abnormal properties of GR ( reduced numbers of GR ) were preserved in the transformed cells from the patients .", "sentence_char_start_global": 19651, "sentence_char_end_global": 19768, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 29, "char_end": 31, "token_start": 4, "token_end": 4}, {"text": "GR", "type": "ENTITY", "char_start": 53, "char_end": 55, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 19680, "char_end": 19682, "token_start": 4, "token_end": 4, "note": null}, {"text": "GR", "type": "ENTITY", "char_start": 19704, "char_end": 19706, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 111, "sentence_text": "Octamer transcription factors 1 and 2 each bind to two different functional elements in the immunoglobulin heavy - chain promoter .", "sentence_char_start_global": 19769, "sentence_char_end_global": 19900, "entities": [{"text": "functional elements", "type": "ENTITY", "char_start": 65, "char_end": 84, "token_start": 11, "token_end": 12}, {"text": "immunoglobulin heavy - chain promoter", "type": "ENTITY", "char_start": 92, "char_end": 129, "token_start": 15, "token_end": 19}], "entities_global": [{"text": "functional elements", "type": "ENTITY", "char_start": 19834, "char_end": 19853, "token_start": 11, "token_end": 12, "note": null}, {"text": "immunoglobulin heavy - chain promoter", "type": "ENTITY", "char_start": 19861, "char_end": 19898, "token_start": 15, "token_end": 19, "note": null}]}
+{"sentence_id": 112, "sentence_text": "Immunoglobulin heavy - chain genes contain two conserved sequence elements 5 ' to the site of transcription initiation : the octamer ATGCAAAT and the heptamer CTCATGA .", "sentence_char_start_global": 19901, "sentence_char_end_global": 20069, "entities": [{"text": "Immunoglobulin heavy - chain genes", "type": "ENTITY", "char_start": 0, "char_end": 34, "token_start": 0, "token_end": 4}, {"text": "conserved sequence elements", "type": "ENTITY", "char_start": 47, "char_end": 74, "token_start": 7, "token_end": 9}], "entities_global": [{"text": "Immunoglobulin heavy - chain genes", "type": "ENTITY", "char_start": 19901, "char_end": 19935, "token_start": 0, "token_end": 4, "note": null}, {"text": "conserved sequence elements", "type": "ENTITY", "char_start": 19948, "char_end": 19975, "token_start": 7, "token_end": 9, "note": null}]}
+{"sentence_id": 113, "sentence_text": "Both of these elements are required for normal cell - specific promoter function .", "sentence_char_start_global": 20070, "sentence_char_end_global": 20152, "entities": [{"text": "normal cell - specific promoter", "type": "ENTITY", "char_start": 40, "char_end": 71, "token_start": 7, "token_end": 11}], "entities_global": [{"text": "normal cell - specific promoter", "type": "ENTITY", "char_start": 20110, "char_end": 20141, "token_start": 7, "token_end": 11, "note": null}]}
+{"sentence_id": 114, "sentence_text": "The present study demonstrates that both the ubiquitous and lymphoid - cell - specific octamer transcription factors ( OTF - 1 and OTF - 2 , respectively ) interact specifically with each of the two conserved sequence elements , forming either homo - or heterodimeric complexes .", "sentence_char_start_global": 20153, "sentence_char_end_global": 20432, "entities": [{"text": "ubiquitous and lymphoid - cell - specific octamer transcription factors", "type": "ENTITY", "char_start": 45, "char_end": 116, "token_start": 7, "token_end": 16}, {"text": "OTF - 1", "type": "ENTITY", "char_start": 119, "char_end": 126, "token_start": 18, "token_end": 20}, {"text": "OTF - 2", "type": "ENTITY", "char_start": 131, "char_end": 138, "token_start": 22, "token_end": 24}, {"text": "conserved sequence elements", "type": "ENTITY", "char_start": 199, "char_end": 226, "token_start": 35, "token_end": 37}, {"text": "homo - or heterodimeric complexes", "type": "ENTITY", "char_start": 244, "char_end": 277, "token_start": 41, "token_end": 45}], "entities_global": [{"text": "ubiquitous and lymphoid - cell - specific octamer transcription factors", "type": "ENTITY", "char_start": 20198, "char_end": 20269, "token_start": 7, "token_end": 16, "note": null}, {"text": "OTF - 1", "type": "ENTITY", "char_start": 20272, "char_end": 20279, "token_start": 18, "token_end": 20, "note": null}, {"text": "OTF - 2", "type": "ENTITY", "char_start": 20284, "char_end": 20291, "token_start": 22, "token_end": 24, "note": null}, {"text": "conserved sequence elements", "type": "ENTITY", "char_start": 20352, "char_end": 20379, "token_start": 35, "token_end": 37, "note": null}, {"text": "homo - or heterodimeric complexes", "type": "ENTITY", "char_start": 20397, "char_end": 20430, "token_start": 41, "token_end": 45, "note": null}]}
+{"sentence_id": 115, "sentence_text": "This was surprising , since the heptamer and octamer sequence motifs bear no obvious similarity to each other .", "sentence_char_start_global": 20433, "sentence_char_end_global": 20544, "entities": [], "entities_global": []}
+{"sentence_id": 116, "sentence_text": "Binding of either factor to the octamer element occurred independently .", "sentence_char_start_global": 20545, "sentence_char_end_global": 20617, "entities": [{"text": "octamer element", "type": "ENTITY", "char_start": 32, "char_end": 47, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "octamer element", "type": "ENTITY", "char_start": 20577, "char_end": 20592, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 117, "sentence_text": "However , OTF interaction with the heptamer sequence appeared to require the presence of an intact octamer motif and occurred with a spacing of either 2 or 14 base pairs between the two elements , suggesting coordinate binding resulting from protein - protein interactions .", "sentence_char_start_global": 20618, "sentence_char_end_global": 20892, "entities": [{"text": "OTF", "type": "ENTITY", "char_start": 10, "char_end": 13, "token_start": 2, "token_end": 2}, {"text": "heptamer sequence", "type": "ENTITY", "char_start": 35, "char_end": 52, "token_start": 6, "token_end": 7}, {"text": "2 or 14 base pairs", "type": "ENTITY", "char_start": 151, "char_end": 169, "token_start": 25, "token_end": 29}], "entities_global": [{"text": "OTF", "type": "ENTITY", "char_start": 20628, "char_end": 20631, "token_start": 2, "token_end": 2, "note": null}, {"text": "heptamer sequence", "type": "ENTITY", "char_start": 20653, "char_end": 20670, "token_start": 6, "token_end": 7, "note": null}, {"text": "2 or 14 base pairs", "type": "ENTITY", "char_start": 20769, "char_end": 20787, "token_start": 25, "token_end": 29, "note": null}]}
+{"sentence_id": 118, "sentence_text": "The degeneracy in sequences recognized by the OTFs may be important in widening the range over which gene expression can be modulated and in establishing cell type specificity .", "sentence_char_start_global": 20893, "sentence_char_end_global": 21070, "entities": [{"text": "OTFs", "type": "ENTITY", "char_start": 46, "char_end": 50, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "OTFs", "type": "ENTITY", "char_start": 20939, "char_end": 20943, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 119, "sentence_text": "Identification of a novel lymphoid specific octamer binding protein ( OTF - 2B ) by proteolytic clipping bandshift assay ( PCBA ) .", "sentence_char_start_global": 21071, "sentence_char_end_global": 21202, "entities": [{"text": "lymphoid specific octamer binding protein", "type": "ENTITY", "char_start": 26, "char_end": 67, "token_start": 4, "token_end": 8}, {"text": "OTF - 2B", "type": "ENTITY", "char_start": 70, "char_end": 78, "token_start": 10, "token_end": 12}], "entities_global": [{"text": "lymphoid specific octamer binding protein", "type": "ENTITY", "char_start": 21097, "char_end": 21138, "token_start": 4, "token_end": 8, "note": null}, {"text": "OTF - 2B", "type": "ENTITY", "char_start": 21141, "char_end": 21149, "token_start": 10, "token_end": 12, "note": null}]}
+{"sentence_id": 120, "sentence_text": "The octamer sequence ATGCAAAT is found in the promoters of immunoglobulin ( Ig ) heavy and light chain genes and in the heavy chain enhancer and is a major determinant of the cell type specific expression of Ig genes in B cells .", "sentence_char_start_global": 21203, "sentence_char_end_global": 21432, "entities": [{"text": "immunoglobulin ( Ig ) heavy and light chain genes", "type": "ENTITY", "char_start": 59, "char_end": 108, "token_start": 10, "token_end": 18}, {"text": "heavy chain enhancer", "type": "ENTITY", "char_start": 120, "char_end": 140, "token_start": 22, "token_end": 24}, {"text": "Ig genes", "type": "ENTITY", "char_start": 208, "char_end": 216, "token_start": 37, "token_end": 38}], "entities_global": [{"text": "immunoglobulin ( Ig ) heavy and light chain genes", "type": "ENTITY", "char_start": 21262, "char_end": 21311, "token_start": 10, "token_end": 18, "note": null}, {"text": "heavy chain enhancer", "type": "ENTITY", "char_start": 21323, "char_end": 21343, "token_start": 22, "token_end": 24, "note": null}, {"text": "Ig genes", "type": "ENTITY", "char_start": 21411, "char_end": 21419, "token_start": 37, "token_end": 38, "note": null}]}
+{"sentence_id": 121, "sentence_text": "An apparent paradox is that the same sequence serves as an upstream promoter or enhancer element in a variety of housekeeping genes such as the histone H2B and U snRNA genes .", "sentence_char_start_global": 21433, "sentence_char_end_global": 21608, "entities": [{"text": "upstream promoter or enhancer element", "type": "ENTITY", "char_start": 59, "char_end": 96, "token_start": 11, "token_end": 15}, {"text": "housekeeping genes", "type": "ENTITY", "char_start": 113, "char_end": 131, "token_start": 20, "token_end": 21}, {"text": "histone H2B and U snRNA genes", "type": "ENTITY", "char_start": 144, "char_end": 173, "token_start": 25, "token_end": 30}], "entities_global": [{"text": "upstream promoter or enhancer element", "type": "ENTITY", "char_start": 21492, "char_end": 21529, "token_start": 11, "token_end": 15, "note": null}, {"text": "housekeeping genes", "type": "ENTITY", "char_start": 21546, "char_end": 21564, "token_start": 20, "token_end": 21, "note": null}, {"text": "histone H2B and U snRNA genes", "type": "ENTITY", "char_start": 21577, "char_end": 21606, "token_start": 25, "token_end": 30, "note": null}]}
+{"sentence_id": 122, "sentence_text": "The differential usage of this regulatory sequence motif is thought to be mediated by different species of octamer binding proteins .", "sentence_char_start_global": 21609, "sentence_char_end_global": 21742, "entities": [{"text": "octamer binding proteins", "type": "ENTITY", "char_start": 107, "char_end": 131, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "octamer binding proteins", "type": "ENTITY", "char_start": 21716, "char_end": 21740, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 123, "sentence_text": "One species of 100 kd , designated OTF - 1 , is present in all cell types and may exert its activating function only when it can interact with additional adjacent transcription factors .", "sentence_char_start_global": 21743, "sentence_char_end_global": 21929, "entities": [{"text": "OTF - 1", "type": "ENTITY", "char_start": 35, "char_end": 42, "token_start": 7, "token_end": 9}, {"text": "transcription factors", "type": "ENTITY", "char_start": 163, "char_end": 184, "token_start": 31, "token_end": 32}], "entities_global": [{"text": "OTF - 1", "type": "ENTITY", "char_start": 21778, "char_end": 21785, "token_start": 7, "token_end": 9, "note": null}, {"text": "transcription factors", "type": "ENTITY", "char_start": 21906, "char_end": 21927, "token_start": 31, "token_end": 32, "note": null}]}
+{"sentence_id": 124, "sentence_text": "The lymphoid cell specific octamer binding protein of 60 kd ( OTF - 2A ) specifically stimulates Ig promoters which consist essentially of a TATA - box and an octamer sequence upstream of it .", "sentence_char_start_global": 21930, "sentence_char_end_global": 22122, "entities": [{"text": "lymphoid cell specific octamer binding protein", "type": "ENTITY", "char_start": 4, "char_end": 50, "token_start": 1, "token_end": 6}, {"text": "OTF - 2A", "type": "ENTITY", "char_start": 62, "char_end": 70, "token_start": 11, "token_end": 13}, {"text": "Ig promoters", "type": "ENTITY", "char_start": 97, "char_end": 109, "token_start": 17, "token_end": 18}, {"text": "TATA - box", "type": "ENTITY", "char_start": 141, "char_end": 151, "token_start": 24, "token_end": 26}, {"text": "octamer sequence", "type": "ENTITY", "char_start": 159, "char_end": 175, "token_start": 29, "token_end": 30}], "entities_global": [{"text": "lymphoid cell specific octamer binding protein", "type": "ENTITY", "char_start": 21934, "char_end": 21980, "token_start": 1, "token_end": 6, "note": null}, {"text": "OTF - 2A", "type": "ENTITY", "char_start": 21992, "char_end": 22000, "token_start": 11, "token_end": 13, "note": null}, {"text": "Ig promoters", "type": "ENTITY", "char_start": 22027, "char_end": 22039, "token_start": 17, "token_end": 18, "note": null}, {"text": "TATA - box", "type": "ENTITY", "char_start": 22071, "char_end": 22081, "token_start": 24, "token_end": 26, "note": null}, {"text": "octamer sequence", "type": "ENTITY", "char_start": 22089, "char_end": 22105, "token_start": 29, "token_end": 30, "note": null}]}
+{"sentence_id": 125, "sentence_text": "Here we present evidence for yet another B cell specific octamer binding protein of 75 kd ( OTF - 2B ) .", "sentence_char_start_global": 22123, "sentence_char_end_global": 22227, "entities": [{"text": "B cell specific octamer binding protein", "type": "ENTITY", "char_start": 41, "char_end": 80, "token_start": 7, "token_end": 12}, {"text": "OTF - 2B", "type": "ENTITY", "char_start": 92, "char_end": 100, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "B cell specific octamer binding protein", "type": "ENTITY", "char_start": 22164, "char_end": 22203, "token_start": 7, "token_end": 12, "note": null}, {"text": "OTF - 2B", "type": "ENTITY", "char_start": 22215, "char_end": 22223, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 126, "sentence_text": "From several findings , including the absence of OTF - 2B ( but not OTF - 2A ) from a lymphocyte line that can not respond to the IgH enhancer , we propose a role of the novel octamer factor in the long range activation by the IgH enhancer .", "sentence_char_start_global": 22228, "sentence_char_end_global": 22469, "entities": [{"text": "OTF - 2B", "type": "ENTITY", "char_start": 49, "char_end": 57, "token_start": 8, "token_end": 10}, {"text": "OTF - 2A", "type": "ENTITY", "char_start": 68, "char_end": 76, "token_start": 14, "token_end": 16}, {"text": "IgH enhancer", "type": "ENTITY", "char_start": 130, "char_end": 142, "token_start": 28, "token_end": 29}, {"text": "novel octamer factor", "type": "ENTITY", "char_start": 170, "char_end": 190, "token_start": 37, "token_end": 39}, {"text": "IgH enhancer", "type": "ENTITY", "char_start": 227, "char_end": 239, "token_start": 47, "token_end": 48}], "entities_global": [{"text": "OTF - 2B", "type": "ENTITY", "char_start": 22277, "char_end": 22285, "token_start": 8, "token_end": 10, "note": null}, {"text": "OTF - 2A", "type": "ENTITY", "char_start": 22296, "char_end": 22304, "token_start": 14, "token_end": 16, "note": null}, {"text": "IgH enhancer", "type": "ENTITY", "char_start": 22358, "char_end": 22370, "token_start": 28, "token_end": 29, "note": null}, {"text": "novel octamer factor", "type": "ENTITY", "char_start": 22398, "char_end": 22418, "token_start": 37, "token_end": 39, "note": null}, {"text": "IgH enhancer", "type": "ENTITY", "char_start": 22455, "char_end": 22467, "token_start": 47, "token_end": 48, "note": null}]}
+{"sentence_id": 127, "sentence_text": "We have used the proteolytic clipping bandshift assay ( PCBA ) technique to distinguish the three different forms found in B cells .", "sentence_char_start_global": 22470, "sentence_char_end_global": 22602, "entities": [], "entities_global": []}
+{"sentence_id": 128, "sentence_text": "This analysis indicates that the 75 kd - species OTF - 2B is closely related to the 60 kd species OTF - 2A .", "sentence_char_start_global": 22603, "sentence_char_end_global": 22711, "entities": [{"text": "OTF - 2B", "type": "ENTITY", "char_start": 49, "char_end": 57, "token_start": 9, "token_end": 11}, {"text": "60 kd species OTF - 2A", "type": "ENTITY", "char_start": 84, "char_end": 106, "token_start": 17, "token_end": 22}], "entities_global": [{"text": "OTF - 2B", "type": "ENTITY", "char_start": 22652, "char_end": 22660, "token_start": 9, "token_end": 11, "note": null}, {"text": "60 kd species OTF - 2A", "type": "ENTITY", "char_start": 22687, "char_end": 22709, "token_start": 17, "token_end": 22, "note": null}]}
+{"sentence_id": 129, "sentence_text": "Inhibition of interleukin 2 - induced proliferation of cloned murine T cells by glucocorticoids .", "sentence_char_start_global": 22712, "sentence_char_end_global": 22809, "entities": [{"text": "interleukin 2", "type": "ENTITY", "char_start": 14, "char_end": 27, "token_start": 2, "token_end": 3}], "entities_global": [{"text": "interleukin 2", "type": "ENTITY", "char_start": 22726, "char_end": 22739, "token_start": 2, "token_end": 3, "note": null}]}
+{"sentence_id": 130, "sentence_text": "Possible involvement of an inhibitory protein .", "sentence_char_start_global": 22810, "sentence_char_end_global": 22857, "entities": [{"text": "inhibitory protein", "type": "ENTITY", "char_start": 27, "char_end": 45, "token_start": 4, "token_end": 5}], "entities_global": [{"text": "inhibitory protein", "type": "ENTITY", "char_start": 22837, "char_end": 22855, "token_start": 4, "token_end": 5, "note": null}]}
+{"sentence_id": 131, "sentence_text": "The ability of glucocorticoids to inhibit interleukin 2 ( IL 2 ) - induced T cell proliferation in two cytotoxic T cell ( CTL ) clones has been studied .", "sentence_char_start_global": 22858, "sentence_char_end_global": 23011, "entities": [{"text": "interleukin 2", "type": "ENTITY", "char_start": 42, "char_end": 55, "token_start": 6, "token_end": 7}, {"text": "IL 2", "type": "ENTITY", "char_start": 58, "char_end": 62, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "interleukin 2", "type": "ENTITY", "char_start": 22900, "char_end": 22913, "token_start": 6, "token_end": 7, "note": null}, {"text": "IL 2", "type": "ENTITY", "char_start": 22916, "char_end": 22920, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 132, "sentence_text": "A complete inhibition of DNA synthesis by dexamethasone ( Dx ) could be observed when IL 2 - depleted cultures of CTL were either incubated for 6 h with the hormone prior to the addition of IL 2 or treated simultaneously with Dx and a low concentration of IL 2 .", "sentence_char_start_global": 23012, "sentence_char_end_global": 23274, "entities": [{"text": "hormone", "type": "ENTITY", "char_start": 157, "char_end": 164, "token_start": 30, "token_end": 30}, {"text": "IL 2", "type": "ENTITY", "char_start": 190, "char_end": 194, "token_start": 36, "token_end": 37}, {"text": "IL 2", "type": "ENTITY", "char_start": 256, "char_end": 260, "token_start": 48, "token_end": 49}], "entities_global": [{"text": "hormone", "type": "ENTITY", "char_start": 23169, "char_end": 23176, "token_start": 30, "token_end": 30, "note": null}, {"text": "IL 2", "type": "ENTITY", "char_start": 23202, "char_end": 23206, "token_start": 36, "token_end": 37, "note": null}, {"text": "IL 2", "type": "ENTITY", "char_start": 23268, "char_end": 23272, "token_start": 48, "token_end": 49, "note": null}]}
+{"sentence_id": 133, "sentence_text": "No significant reduction in the number and affinity of IL 2 receptors was seen after 6 h incubation with Dx .", "sentence_char_start_global": 23275, "sentence_char_end_global": 23384, "entities": [{"text": "IL 2 receptors", "type": "ENTITY", "char_start": 55, "char_end": 69, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "IL 2 receptors", "type": "ENTITY", "char_start": 23330, "char_end": 23344, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 134, "sentence_text": "The order of potency observed with the different steroids indicated that this inhibitory effect was mediated through binding to a specific glucocorticoid receptor .", "sentence_char_start_global": 23385, "sentence_char_end_global": 23549, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 139, "char_end": 162, "token_start": 21, "token_end": 22}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 23524, "char_end": 23547, "token_start": 21, "token_end": 22, "note": null}]}
+{"sentence_id": 135, "sentence_text": "The action of these hormones possibly involves the synthesis of an inhibitory protein ( s ) , since the presence of cycloheximide during the incubation with Dx prevented the inhibition of DNA synthesis .", "sentence_char_start_global": 23550, "sentence_char_end_global": 23753, "entities": [{"text": "hormones", "type": "ENTITY", "char_start": 20, "char_end": 28, "token_start": 4, "token_end": 4}, {"text": "inhibitory protein", "type": "ENTITY", "char_start": 67, "char_end": 85, "token_start": 11, "token_end": 12}], "entities_global": [{"text": "hormones", "type": "ENTITY", "char_start": 23570, "char_end": 23578, "token_start": 4, "token_end": 4, "note": null}, {"text": "inhibitory protein", "type": "ENTITY", "char_start": 23617, "char_end": 23635, "token_start": 11, "token_end": 12, "note": null}]}
+{"sentence_id": 136, "sentence_text": "Furthermore , supernatant from Dx - treated CTL contained a nondialyzable factor which inhibited DNA synthesis and cell growth of CTL clones induced by IL 2 .", "sentence_char_start_global": 23754, "sentence_char_end_global": 23912, "entities": [{"text": "IL 2", "type": "ENTITY", "char_start": 152, "char_end": 156, "token_start": 24, "token_end": 25}], "entities_global": [{"text": "IL 2", "type": "ENTITY", "char_start": 23906, "char_end": 23910, "token_start": 24, "token_end": 25, "note": null}]}
+{"sentence_id": 137, "sentence_text": "Blocking of IL 2 synthesis and IL 2 receptor formation have been proposed as one of the major mechanisms of glucocorticoid - induced immunosuppression .", "sentence_char_start_global": 23913, "sentence_char_end_global": 24065, "entities": [{"text": "IL 2", "type": "ENTITY", "char_start": 12, "char_end": 16, "token_start": 2, "token_end": 3}, {"text": "IL 2 receptor", "type": "ENTITY", "char_start": 31, "char_end": 44, "token_start": 6, "token_end": 8}], "entities_global": [{"text": "IL 2", "type": "ENTITY", "char_start": 23925, "char_end": 23929, "token_start": 2, "token_end": 3, "note": null}, {"text": "IL 2 receptor", "type": "ENTITY", "char_start": 23944, "char_end": 23957, "token_start": 6, "token_end": 8, "note": null}]}
+{"sentence_id": 138, "sentence_text": "Our results indicate that these hormones may also affect T cell proliferation by inhibiting IL 2 activity .", "sentence_char_start_global": 24066, "sentence_char_end_global": 24173, "entities": [{"text": "hormones", "type": "ENTITY", "char_start": 32, "char_end": 40, "token_start": 5, "token_end": 5}, {"text": "IL 2", "type": "ENTITY", "char_start": 92, "char_end": 96, "token_start": 14, "token_end": 15}], "entities_global": [{"text": "hormones", "type": "ENTITY", "char_start": 24098, "char_end": 24106, "token_start": 5, "token_end": 5, "note": null}, {"text": "IL 2", "type": "ENTITY", "char_start": 24158, "char_end": 24162, "token_start": 14, "token_end": 15, "note": null}]}
+{"sentence_id": 139, "sentence_text": "Identification and purification of a human immunoglobulin - enhancer - binding protein ( NF - kappa B ) that activates transcription from a human immunodeficiency virus type 1 promoter in vitro .", "sentence_char_start_global": 24174, "sentence_char_end_global": 24369, "entities": [{"text": "human immunoglobulin - enhancer - binding protein", "type": "ENTITY", "char_start": 37, "char_end": 86, "token_start": 5, "token_end": 11}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 89, "char_end": 101, "token_start": 13, "token_end": 16}, {"text": "human immunodeficiency virus type 1 promoter", "type": "ENTITY", "char_start": 140, "char_end": 184, "token_start": 23, "token_end": 28}], "entities_global": [{"text": "human immunoglobulin - enhancer - binding protein", "type": "ENTITY", "char_start": 24211, "char_end": 24260, "token_start": 5, "token_end": 11, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 24263, "char_end": 24275, "token_start": 13, "token_end": 16, "note": null}, {"text": "human immunodeficiency virus type 1 promoter", "type": "ENTITY", "char_start": 24314, "char_end": 24358, "token_start": 23, "token_end": 28, "note": null}]}
+{"sentence_id": 140, "sentence_text": "The enhancer - binding factor NF - kappa B , which is found only in cells that transcribe immunoglobulin light chain genes , has been purified from nuclear extracts of Namalwa cells ( human Burkitt lymphoma cells ) by sequence - specific DNA affinity chromatography .", "sentence_char_start_global": 24370, "sentence_char_end_global": 24637, "entities": [{"text": "enhancer - binding factor NF - kappa B", "type": "ENTITY", "char_start": 4, "char_end": 42, "token_start": 1, "token_end": 8}, {"text": "immunoglobulin light chain genes", "type": "ENTITY", "char_start": 90, "char_end": 122, "token_start": 18, "token_end": 21}], "entities_global": [{"text": "enhancer - binding factor NF - kappa B", "type": "ENTITY", "char_start": 24374, "char_end": 24412, "token_start": 1, "token_end": 8, "note": null}, {"text": "immunoglobulin light chain genes", "type": "ENTITY", "char_start": 24460, "char_end": 24492, "token_start": 18, "token_end": 21, "note": null}]}
+{"sentence_id": 141, "sentence_text": "The purified NF - kappa B has been identified as a 51 - kDa polypeptide by UV - crosslinking analysis .", "sentence_char_start_global": 24638, "sentence_char_end_global": 24741, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 13, "char_end": 25, "token_start": 2, "token_end": 5}, {"text": "51 - kDa polypeptide", "type": "ENTITY", "char_start": 51, "char_end": 71, "token_start": 11, "token_end": 14}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 24651, "char_end": 24663, "token_start": 2, "token_end": 5, "note": null}, {"text": "51 - kDa polypeptide", "type": "ENTITY", "char_start": 24689, "char_end": 24709, "token_start": 11, "token_end": 14, "note": null}]}
+{"sentence_id": 142, "sentence_text": "` ` Footprint ' ' and methylation - interference analyses have shown that purified NF - kappa B has a binding activity specific for the kappa light chain enhancer sequence .", "sentence_char_start_global": 24742, "sentence_char_end_global": 24915, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 83, "char_end": 95, "token_start": 14, "token_end": 17}, {"text": "kappa light chain enhancer sequence", "type": "ENTITY", "char_start": 136, "char_end": 171, "token_start": 25, "token_end": 29}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 24825, "char_end": 24837, "token_start": 14, "token_end": 17, "note": null}, {"text": "kappa light chain enhancer sequence", "type": "ENTITY", "char_start": 24878, "char_end": 24913, "token_start": 25, "token_end": 29, "note": null}]}
+{"sentence_id": 143, "sentence_text": "The purified factor activated in vitro transcription of the human immunodeficiency virus type I promoter by binding to an upstream NF - kappa B - binding site", "sentence_char_start_global": 24916, "sentence_char_end_global": 25074, "entities": [{"text": "human immunodeficiency virus type I promoter", "type": "ENTITY", "char_start": 60, "char_end": 104, "token_start": 9, "token_end": 14}, {"text": "upstream NF - kappa B - binding site", "type": "ENTITY", "char_start": 122, "char_end": 158, "token_start": 19, "token_end": 26}], "entities_global": [{"text": "human immunodeficiency virus type I promoter", "type": "ENTITY", "char_start": 24976, "char_end": 25020, "token_start": 9, "token_end": 14, "note": null}, {"text": "upstream NF - kappa B - binding site", "type": "ENTITY", "char_start": 25038, "char_end": 25074, "token_start": 19, "token_end": 26, "note": null}]}
+{"sentence_id": 144, "sentence_text": "Lymphocyte glucocorticoid receptor binding in depression : normal values following recovery .", "sentence_char_start_global": 25075, "sentence_char_end_global": 25168, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 11, "char_end": 34, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 25086, "char_end": 25109, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 145, "sentence_text": "The number of glucocorticoid receptor sites in lymphocytes and plasma cortisol concentrations were measured in 20 patients who had recovered from major depressive disorder and 20 healthy control subjects .", "sentence_char_start_global": 25169, "sentence_char_end_global": 25374, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 14, "char_end": 37, "token_start": 3, "token_end": 4}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 25183, "char_end": 25206, "token_start": 3, "token_end": 4, "note": null}]}
+{"sentence_id": 146, "sentence_text": "The number of glucocorticoid receptor sites in lymphocytes from the recovered depressed group was not significantly different from that of the control group .", "sentence_char_start_global": 25375, "sentence_char_end_global": 25533, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 14, "char_end": 37, "token_start": 3, "token_end": 4}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 25389, "char_end": 25412, "token_start": 3, "token_end": 4, "note": null}]}
+{"sentence_id": 147, "sentence_text": "Although the mean plasma cortisol concentration in recovered depressives was higher than in control subjects , the difference only just reached significance .", "sentence_char_start_global": 25534, "sentence_char_end_global": 25692, "entities": [], "entities_global": []}
+{"sentence_id": 148, "sentence_text": "This study shows that the reduction in glucocorticoid receptor numbers which occurs during acute depressive illness does not persist on recovery and is , therefore , state - dependent .", "sentence_char_start_global": 25693, "sentence_char_end_global": 25878, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 39, "char_end": 62, "token_start": 7, "token_end": 8}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 25732, "char_end": 25755, "token_start": 7, "token_end": 8, "note": null}]}
+{"sentence_id": 149, "sentence_text": "Identification and purification of a human lymphoid - specific octamer - binding protein ( OTF - 2 ) that activates transcription of an immunoglobulin promoter in vitro .", "sentence_char_start_global": 25879, "sentence_char_end_global": 26049, "entities": [{"text": "human lymphoid - specific octamer - binding protein", "type": "ENTITY", "char_start": 37, "char_end": 88, "token_start": 5, "token_end": 12}, {"text": "OTF - 2", "type": "ENTITY", "char_start": 91, "char_end": 98, "token_start": 14, "token_end": 16}, {"text": "immunoglobulin promoter", "type": "ENTITY", "char_start": 136, "char_end": 159, "token_start": 23, "token_end": 24}], "entities_global": [{"text": "human lymphoid - specific octamer - binding protein", "type": "ENTITY", "char_start": 25916, "char_end": 25967, "token_start": 5, "token_end": 12, "note": null}, {"text": "OTF - 2", "type": "ENTITY", "char_start": 25970, "char_end": 25977, "token_start": 14, "token_end": 16, "note": null}, {"text": "immunoglobulin promoter", "type": "ENTITY", "char_start": 26015, "char_end": 26038, "token_start": 23, "token_end": 24, "note": null}]}
+{"sentence_id": 150, "sentence_text": "The octamer sequence 5 ' - ATGCAAAT , in either orientation , serves as an upstream element in a variety of promoters and also occurs as a modular enhancer element .", "sentence_char_start_global": 26050, "sentence_char_end_global": 26215, "entities": [{"text": "upstream element", "type": "ENTITY", "char_start": 75, "char_end": 91, "token_start": 15, "token_end": 16}, {"text": "promoters", "type": "ENTITY", "char_start": 108, "char_end": 117, "token_start": 21, "token_end": 21}, {"text": "modular enhancer element", "type": "ENTITY", "char_start": 139, "char_end": 163, "token_start": 27, "token_end": 29}], "entities_global": [{"text": "upstream element", "type": "ENTITY", "char_start": 26125, "char_end": 26141, "token_start": 15, "token_end": 16, "note": null}, {"text": "promoters", "type": "ENTITY", "char_start": 26158, "char_end": 26167, "token_start": 21, "token_end": 21, "note": null}, {"text": "modular enhancer element", "type": "ENTITY", "char_start": 26189, "char_end": 26213, "token_start": 27, "token_end": 29, "note": null}]}
+{"sentence_id": 151, "sentence_text": "It is of particular interest in immunoglobulin genes since it is found in the upstream regions of all heavy and light chain promoters and in the heavy chain enhancer , both of which are known to be necessary for cell - specific expression .", "sentence_char_start_global": 26216, "sentence_char_end_global": 26456, "entities": [{"text": "immunoglobulin genes", "type": "ENTITY", "char_start": 32, "char_end": 52, "token_start": 6, "token_end": 7}, {"text": "upstream regions", "type": "ENTITY", "char_start": 78, "char_end": 94, "token_start": 14, "token_end": 15}, {"text": "heavy and light chain promoters", "type": "ENTITY", "char_start": 102, "char_end": 133, "token_start": 18, "token_end": 22}, {"text": "heavy chain enhancer", "type": "ENTITY", "char_start": 145, "char_end": 165, "token_start": 26, "token_end": 28}], "entities_global": [{"text": "immunoglobulin genes", "type": "ENTITY", "char_start": 26248, "char_end": 26268, "token_start": 6, "token_end": 7, "note": null}, {"text": "upstream regions", "type": "ENTITY", "char_start": 26294, "char_end": 26310, "token_start": 14, "token_end": 15, "note": null}, {"text": "heavy and light chain promoters", "type": "ENTITY", "char_start": 26318, "char_end": 26349, "token_start": 18, "token_end": 22, "note": null}, {"text": "heavy chain enhancer", "type": "ENTITY", "char_start": 26361, "char_end": 26381, "token_start": 26, "token_end": 28, "note": null}]}
+{"sentence_id": 152, "sentence_text": "We report here the chromatographic separation of ubiquitous and B cell - specific octamer - binding proteins .", "sentence_char_start_global": 26457, "sentence_char_end_global": 26567, "entities": [{"text": "ubiquitous and B cell - specific octamer - binding proteins", "type": "ENTITY", "char_start": 49, "char_end": 108, "token_start": 7, "token_end": 16}], "entities_global": [{"text": "ubiquitous and B cell - specific octamer - binding proteins", "type": "ENTITY", "char_start": 26506, "char_end": 26565, "token_start": 7, "token_end": 16, "note": null}]}
+{"sentence_id": 153, "sentence_text": "The B cell factor was purified to homogeneity using affinity chromatography and consists of three peptides of 62 , 61 , and 58 . 5 + / - 1 . 5 kd .", "sentence_char_start_global": 26568, "sentence_char_end_global": 26715, "entities": [{"text": "B cell factor", "type": "ENTITY", "char_start": 4, "char_end": 17, "token_start": 1, "token_end": 3}], "entities_global": [{"text": "B cell factor", "type": "ENTITY", "char_start": 26572, "char_end": 26585, "token_start": 1, "token_end": 3, "note": null}]}
+{"sentence_id": 154, "sentence_text": "Each of the polypeptides was renatured after SDS - PAGE and shown to bind to the octamer sequence .", "sentence_char_start_global": 26716, "sentence_char_end_global": 26815, "entities": [], "entities_global": []}
+{"sentence_id": 155, "sentence_text": "The specific DNA binding activity of the pure B cell - specific factor was indistinguishable from that of the affinity - purified ubiquitous factor .", "sentence_char_start_global": 26816, "sentence_char_end_global": 26965, "entities": [{"text": "B cell - specific factor", "type": "ENTITY", "char_start": 46, "char_end": 70, "token_start": 8, "token_end": 12}, {"text": "affinity - purified ubiquitous factor", "type": "ENTITY", "char_start": 110, "char_end": 147, "token_start": 19, "token_end": 23}], "entities_global": [{"text": "B cell - specific factor", "type": "ENTITY", "char_start": 26862, "char_end": 26886, "token_start": 8, "token_end": 12, "note": null}, {"text": "affinity - purified ubiquitous factor", "type": "ENTITY", "char_start": 26926, "char_end": 26963, "token_start": 19, "token_end": 23, "note": null}]}
+{"sentence_id": 156, "sentence_text": "This B cell - specific octamer - binding factor , in pure form , activated transcription from a kappa light chain promoter in vitro , thus demonstrating that it is indeed a B cell - specific transcription factor for this gene .", "sentence_char_start_global": 26966, "sentence_char_end_global": 27193, "entities": [{"text": "B cell - specific octamer - binding factor", "type": "ENTITY", "char_start": 5, "char_end": 47, "token_start": 1, "token_end": 8}, {"text": "kappa light chain promoter", "type": "ENTITY", "char_start": 96, "char_end": 122, "token_start": 18, "token_end": 21}, {"text": "B cell - specific transcription factor", "type": "ENTITY", "char_start": 173, "char_end": 211, "token_start": 32, "token_end": 37}], "entities_global": [{"text": "B cell - specific octamer - binding factor", "type": "ENTITY", "char_start": 26971, "char_end": 27013, "token_start": 1, "token_end": 8, "note": null}, {"text": "kappa light chain promoter", "type": "ENTITY", "char_start": 27062, "char_end": 27088, "token_start": 18, "token_end": 21, "note": null}, {"text": "B cell - specific transcription factor", "type": "ENTITY", "char_start": 27139, "char_end": 27177, "token_start": 32, "token_end": 37, "note": null}]}
+{"sentence_id": 157, "sentence_text": "In addition to the ubiquitous and B cell - specific octamer - binding factors , we identified several additional proteins , one of which is B cell - specific , that interact with the kappa promoter .", "sentence_char_start_global": 27194, "sentence_char_end_global": 27393, "entities": [{"text": "ubiquitous and B cell - specific octamer - binding factors", "type": "ENTITY", "char_start": 19, "char_end": 77, "token_start": 4, "token_end": 13}, {"text": "kappa promoter", "type": "ENTITY", "char_start": 183, "char_end": 197, "token_start": 34, "token_end": 35}], "entities_global": [{"text": "ubiquitous and B cell - specific octamer - binding factors", "type": "ENTITY", "char_start": 27213, "char_end": 27271, "token_start": 4, "token_end": 13, "note": null}, {"text": "kappa promoter", "type": "ENTITY", "char_start": 27377, "char_end": 27391, "token_start": 34, "token_end": 35, "note": null}]}
+{"sentence_id": 158, "sentence_text": "Decreased deoxyribonucleic acid binding of glucocorticoid - receptor complex in cultured skin fibroblasts from a patient with the glucocorticoid resistance syndrome .", "sentence_char_start_global": 27394, "sentence_char_end_global": 27560, "entities": [{"text": "glucocorticoid - receptor complex", "type": "ENTITY", "char_start": 43, "char_end": 76, "token_start": 5, "token_end": 8}], "entities_global": [{"text": "glucocorticoid - receptor complex", "type": "ENTITY", "char_start": 27437, "char_end": 27470, "token_start": 5, "token_end": 8, "note": null}]}
+{"sentence_id": 159, "sentence_text": "A patient with the syndrome of glucocorticoid resistance was studied .", "sentence_char_start_global": 27561, "sentence_char_end_global": 27631, "entities": [], "entities_global": []}
+{"sentence_id": 160, "sentence_text": "A 27 - yr - old woman initially was diagnosed as having Cushing ' s disease , based on the findings of high plasma ACTH and serum cortisol levels , increased urinary cortisol secretion , resistance to adrenal suppression with dexamethasone , and bilateral adrenal hyperplasia by computed tomography and scintigraphy of the adrenal glands .", "sentence_char_start_global": 27632, "sentence_char_end_global": 27971, "entities": [], "entities_global": []}
+{"sentence_id": 161, "sentence_text": "However , she had no signs or symptoms of Cushing ' s syndrome .", "sentence_char_start_global": 27972, "sentence_char_end_global": 28036, "entities": [], "entities_global": []}
+{"sentence_id": 162, "sentence_text": "During a 5 - yr follow - up , no clinical abnormalities developed , although hypercortisolism persisted .", "sentence_char_start_global": 28037, "sentence_char_end_global": 28142, "entities": [], "entities_global": []}
+{"sentence_id": 163, "sentence_text": "End - organ resistance to cortisol was suspected .", "sentence_char_start_global": 28143, "sentence_char_end_global": 28193, "entities": [], "entities_global": []}
+{"sentence_id": 164, "sentence_text": "To explain the end - organ resistance to cortisol , the glucocorticoid receptors ( GR ) in peripheral mononuclear leukocytes and cultured skin fibroblasts from a forearm skin biopsy were characterized and compared with the results of similar studies in normal subjects .", "sentence_char_start_global": 28194, "sentence_char_end_global": 28464, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 56, "char_end": 80, "token_start": 11, "token_end": 12}, {"text": "GR", "type": "ENTITY", "char_start": 83, "char_end": 85, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 28250, "char_end": 28274, "token_start": 11, "token_end": 12, "note": null}, {"text": "GR", "type": "ENTITY", "char_start": 28277, "char_end": 28279, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 165, "sentence_text": "The patient ' s GR in whole cell assays had an increased dissociation constant ( Kd ) .", "sentence_char_start_global": 28465, "sentence_char_end_global": 28552, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 16, "char_end": 18, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 28481, "char_end": 28483, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 166, "sentence_text": "In the cytosol of cultured skin fibroblasts from the patient , there was also decreased binding capacity .", "sentence_char_start_global": 28553, "sentence_char_end_global": 28659, "entities": [], "entities_global": []}
+{"sentence_id": 167, "sentence_text": "The thermal stability and the sedimentation coefficient in a sucrose density gradient of the receptors in the cytosol of cultured skin fibroblasts from the patient and normal subjects were similar .", "sentence_char_start_global": 28660, "sentence_char_end_global": 28858, "entities": [], "entities_global": []}
+{"sentence_id": 168, "sentence_text": "GR complex activation , analyzed by DEAE - cellulose chromatography , was decreased in the patient .", "sentence_char_start_global": 28859, "sentence_char_end_global": 28959, "entities": [], "entities_global": []}
+{"sentence_id": 169, "sentence_text": "DNA binding of the GR complex after temperature - induced activation was lower in the patient than in normal subjects .", "sentence_char_start_global": 28960, "sentence_char_end_global": 29079, "entities": [{"text": "DNA", "type": "ENTITY", "char_start": 0, "char_end": 3, "token_start": 0, "token_end": 0}, {"text": "GR complex", "type": "ENTITY", "char_start": 19, "char_end": 29, "token_start": 4, "token_end": 5}], "entities_global": [{"text": "DNA", "type": "ENTITY", "char_start": 28960, "char_end": 28963, "token_start": 0, "token_end": 0, "note": null}, {"text": "GR complex", "type": "ENTITY", "char_start": 28979, "char_end": 28989, "token_start": 4, "token_end": 5, "note": null}]}
+{"sentence_id": 170, "sentence_text": "Nuclear translocation of GR complexes from the patient was also slightly decreased .", "sentence_char_start_global": 29080, "sentence_char_end_global": 29164, "entities": [{"text": "GR complexes", "type": "ENTITY", "char_start": 25, "char_end": 37, "token_start": 3, "token_end": 4}], "entities_global": [{"text": "GR complexes", "type": "ENTITY", "char_start": 29105, "char_end": 29117, "token_start": 3, "token_end": 4, "note": null}]}
+{"sentence_id": 171, "sentence_text": "These results suggest that the patient ' s glucocorticoid resistance was due to a decrease in the affinity of the receptor for glucocorticoids and a decrease in the binding of the GR complex to DNA .", "sentence_char_start_global": 29165, "sentence_char_end_global": 29364, "entities": [{"text": "GR complex", "type": "ENTITY", "char_start": 180, "char_end": 190, "token_start": 31, "token_end": 32}, {"text": "DNA", "type": "ENTITY", "char_start": 194, "char_end": 197, "token_start": 34, "token_end": 34}], "entities_global": [{"text": "GR complex", "type": "ENTITY", "char_start": 29345, "char_end": 29355, "token_start": 31, "token_end": 32, "note": null}, {"text": "DNA", "type": "ENTITY", "char_start": 29359, "char_end": 29362, "token_start": 34, "token_end": 34, "note": null}]}
+{"sentence_id": 172, "sentence_text": "Granulocyte - macrophage colony - stimulating factor .", "sentence_char_start_global": 29365, "sentence_char_end_global": 29419, "entities": [{"text": "Granulocyte - macrophage colony - stimulating factor", "type": "ENTITY", "char_start": 0, "char_end": 52, "token_start": 0, "token_end": 6}], "entities_global": [{"text": "Granulocyte - macrophage colony - stimulating factor", "type": "ENTITY", "char_start": 29365, "char_end": 29417, "token_start": 0, "token_end": 6, "note": null}]}
+{"sentence_id": 173, "sentence_text": "Sensitive and receptor - mediated regulation by 1 , 25 - dihydroxyvitamin D3 in normal human peripheral blood lymphocytes .", "sentence_char_start_global": 29420, "sentence_char_end_global": 29543, "entities": [], "entities_global": []}
+{"sentence_id": 174, "sentence_text": "We show that 1 , 25 - dihydroxyvitamin D3 ( 1 , 25 [ OH ] 2D3 ) , the most hormonally active metabolite of vitamin D3 , modulates sensitively and specifically both the protein and messenger RNA accumulation of the multilineage growth factor granulocyte - macrophage colony - stimulating factor ( GM - CSF ) .", "sentence_char_start_global": 29544, "sentence_char_end_global": 29852, "entities": [{"text": "messenger RNA", "type": "ENTITY", "char_start": 180, "char_end": 193, "token_start": 36, "token_end": 37}, {"text": "multilineage growth factor", "type": "ENTITY", "char_start": 214, "char_end": 240, "token_start": 41, "token_end": 43}, {"text": "granulocyte - macrophage colony - stimulating factor", "type": "ENTITY", "char_start": 241, "char_end": 293, "token_start": 44, "token_end": 50}, {"text": "GM - CSF", "type": "ENTITY", "char_start": 296, "char_end": 304, "token_start": 52, "token_end": 54}], "entities_global": [{"text": "messenger RNA", "type": "ENTITY", "char_start": 29724, "char_end": 29737, "token_start": 36, "token_end": 37, "note": null}, {"text": "multilineage growth factor", "type": "ENTITY", "char_start": 29758, "char_end": 29784, "token_start": 41, "token_end": 43, "note": null}, {"text": "granulocyte - macrophage colony - stimulating factor", "type": "ENTITY", "char_start": 29785, "char_end": 29837, "token_start": 44, "token_end": 50, "note": null}, {"text": "GM - CSF", "type": "ENTITY", "char_start": 29840, "char_end": 29848, "token_start": 52, "token_end": 54, "note": null}]}
+{"sentence_id": 175, "sentence_text": "The regulation of GM - CSF expression is seen in both normal human mitogen - activated T lymphocytes and T lymphocytes from a line ( S - LB1 ) transformed with human T cell lymphotropic virus 1 ( HTLV - 1 ) .", "sentence_char_start_global": 29853, "sentence_char_end_global": 30061, "entities": [{"text": "GM - CSF", "type": "ENTITY", "char_start": 18, "char_end": 26, "token_start": 3, "token_end": 5}], "entities_global": [{"text": "GM - CSF", "type": "ENTITY", "char_start": 29871, "char_end": 29879, "token_start": 3, "token_end": 5, "note": null}]}
+{"sentence_id": 176, "sentence_text": "In contrast , cells from a HTLV - 1 transformed T lymphocyte line ( Ab - VDR ) established from a patient with vitamin D - resistant rickets type II with undetectable 1 , 25 ( OH ) 2D3 cellular receptors are resistant to the action of 1 , 25 ( OH ) 2D3 .", "sentence_char_start_global": 30062, "sentence_char_end_global": 30316, "entities": [{"text": "1 , 25 ( OH ) 2D3 cellular receptors", "type": "ENTITY", "char_start": 167, "char_end": 203, "token_start": 32, "token_end": 40}], "entities_global": [{"text": "1 , 25 ( OH ) 2D3 cellular receptors", "type": "ENTITY", "char_start": 30229, "char_end": 30265, "token_start": 32, "token_end": 40, "note": null}]}
+{"sentence_id": 177, "sentence_text": "Inhibition of GM - CSF expression by 1 , 25 ( OH ) 2D3 can occur independently of interleukin 2 regulation and is probably mediated through cellular 1 , 25 ( OH ) 2D3 receptors .", "sentence_char_start_global": 30317, "sentence_char_end_global": 30495, "entities": [{"text": "GM - CSF", "type": "ENTITY", "char_start": 14, "char_end": 22, "token_start": 2, "token_end": 4}, {"text": "interleukin 2", "type": "ENTITY", "char_start": 82, "char_end": 95, "token_start": 18, "token_end": 19}, {"text": "cellular 1 , 25 ( OH ) 2D3 receptors", "type": "ENTITY", "char_start": 140, "char_end": 176, "token_start": 26, "token_end": 34}], "entities_global": [{"text": "GM - CSF", "type": "ENTITY", "char_start": 30331, "char_end": 30339, "token_start": 2, "token_end": 4, "note": null}, {"text": "interleukin 2", "type": "ENTITY", "char_start": 30399, "char_end": 30412, "token_start": 18, "token_end": 19, "note": null}, {"text": "cellular 1 , 25 ( OH ) 2D3 receptors", "type": "ENTITY", "char_start": 30457, "char_end": 30493, "token_start": 26, "token_end": 34, "note": null}]}
+{"sentence_id": 178, "sentence_text": "We conclude that 1 , 25 ( OH ) 2D3 may be important in the physiology of hematopoiesis .", "sentence_char_start_global": 30496, "sentence_char_end_global": 30584, "entities": [], "entities_global": []}
+{"sentence_id": 179, "sentence_text": "Altered interaction between triiodothyronine and its nuclear receptors in absence of cortisol : a proposed mechanism for increased thyrotropin secretion in corticosteroid deficiency states .", "sentence_char_start_global": 30585, "sentence_char_end_global": 30775, "entities": [{"text": "nuclear receptors", "type": "ENTITY", "char_start": 53, "char_end": 70, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "nuclear receptors", "type": "ENTITY", "char_start": 30638, "char_end": 30655, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 180, "sentence_text": "Thyroid hormones occasionally appear less effective when administered alone to patients with panhypopituitarism , and manifestations suggestive of hypothyroidism have been reported in patients suffering from untreated Addison ' s disease .", "sentence_char_start_global": 30776, "sentence_char_end_global": 31015, "entities": [], "entities_global": []}
+{"sentence_id": 181, "sentence_text": "In the latter condition , thyrotropin secretion is increased : this occurs already after as little as 2 days of temporary withdrawal of therapy with substitution doses of corticosteroids while circulating levels of thyroid hormones remain within normal limits .", "sentence_char_start_global": 31016, "sentence_char_end_global": 31277, "entities": [], "entities_global": []}
+{"sentence_id": 182, "sentence_text": "Therefore , a possible role of cortisol in interaction between triiodothyronine and its nuclear receptors was examined at the level of circulating lymphocytes obtained from patients with primary or secondary adrenocortical failure .", "sentence_char_start_global": 31278, "sentence_char_end_global": 31510, "entities": [{"text": "nuclear receptors", "type": "ENTITY", "char_start": 88, "char_end": 105, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "nuclear receptors", "type": "ENTITY", "char_start": 31366, "char_end": 31383, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 183, "sentence_text": "The affinity of these receptors was found to be decreased , by more than 50 % on average , in the absence of cortisol treatments .", "sentence_char_start_global": 31511, "sentence_char_end_global": 31641, "entities": [], "entities_global": []}
+{"sentence_id": 184, "sentence_text": "This change was promptly corrected upon resumption of therapy .", "sentence_char_start_global": 31642, "sentence_char_end_global": 31705, "entities": [], "entities_global": []}
+{"sentence_id": 185, "sentence_text": "The number of binding sites was not significantly modified .", "sentence_char_start_global": 31706, "sentence_char_end_global": 31766, "entities": [], "entities_global": []}
+{"sentence_id": 186, "sentence_text": "The influence of cortisol on thyroid hormone receptors discussed here might account for the clinical observations mentioned above .", "sentence_char_start_global": 31767, "sentence_char_end_global": 31898, "entities": [{"text": "thyroid hormone receptors", "type": "ENTITY", "char_start": 29, "char_end": 54, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "thyroid hormone receptors", "type": "ENTITY", "char_start": 31796, "char_end": 31821, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 187, "sentence_text": "Inhibition by cortisol of human natural killer ( NK ) cell activity .", "sentence_char_start_global": 31899, "sentence_char_end_global": 31968, "entities": [], "entities_global": []}
+{"sentence_id": 188, "sentence_text": "The effects of cortisol on the natural killer ( NK ) activity of human peripheral blood mononuclear ( PBM ) cells were studied in vitro using a direct 4 - h 51Cr - release assay and K 562 cell line as a target .", "sentence_char_start_global": 31969, "sentence_char_end_global": 32180, "entities": [], "entities_global": []}
+{"sentence_id": 189, "sentence_text": "Preincubation for 20 h of PBM cells drawn from healthy donors with 1 X 10 ( - 8 ) to 1 X 10 ( - 5 ) M cortisol resulted in a significant decrease of NK cell activity .", "sentence_char_start_global": 32181, "sentence_char_end_global": 32348, "entities": [], "entities_global": []}
+{"sentence_id": 190, "sentence_text": "The magnitude of the suppression was directly related to the steroid concentration and inversely related to the number of effector cells .", "sentence_char_start_global": 32349, "sentence_char_end_global": 32487, "entities": [], "entities_global": []}
+{"sentence_id": 191, "sentence_text": "Cortisol was able to minimize the enhancement of NK cytotoxicity obtainable in the presence of immune interferon ( IFN - gamma ) .", "sentence_char_start_global": 32488, "sentence_char_end_global": 32618, "entities": [], "entities_global": []}
+{"sentence_id": 192, "sentence_text": "A significantly higher suppression was achieved after sequential exposure of PBM cells to cortisol and equimolar levels of prostaglandin E2 ( PgE2 ) .", "sentence_char_start_global": 32619, "sentence_char_end_global": 32769, "entities": [], "entities_global": []}
+{"sentence_id": 193, "sentence_text": "The concomitant incubation with theophylline and isobutyl - methylxanthine failed to enhance the cortisol - induced suppression , whereas PgE2 - dependent inhibition significantly increased after exposure of PBM cells to methyl - xanthines .", "sentence_char_start_global": 32770, "sentence_char_end_global": 33011, "entities": [], "entities_global": []}
+{"sentence_id": 194, "sentence_text": "The inhibitory effect of cortisol was partially or totally prevented by the concomitant incubation with equimolar amounts of 11 - deoxycortisol and RU 486 but not of progesterone .", "sentence_char_start_global": 33012, "sentence_char_end_global": 33192, "entities": [], "entities_global": []}
+{"sentence_id": 195, "sentence_text": "Treatment of NK effectors with a monoclonal anti - human corticosteroid - binding globulin ( CBG ) antibody produced an enhancement of the spontaneous NK activity and a partial suppression of cortisol - mediated effects .", "sentence_char_start_global": 33193, "sentence_char_end_global": 33414, "entities": [{"text": "monoclonal anti - human corticosteroid - binding globulin ( CBG ) antibody", "type": "ENTITY", "char_start": 33, "char_end": 107, "token_start": 6, "token_end": 17}], "entities_global": [{"text": "monoclonal anti - human corticosteroid - binding globulin ( CBG ) antibody", "type": "ENTITY", "char_start": 33226, "char_end": 33300, "token_start": 6, "token_end": 17, "note": null}]}
+{"sentence_id": 196, "sentence_text": "Our results suggest that endogenous glucocorticoids play a role in the regulation of NK cell - mediated cytotoxicity .", "sentence_char_start_global": 33415, "sentence_char_end_global": 33533, "entities": [], "entities_global": []}
+{"sentence_id": 197, "sentence_text": "Since the effect of cortisol was additive to that of PgE2 and was not changed by phosphodiesterase inhibitors , it is conceivable that the hormone acts at a level different from the adenylate cyclase - phosphodiesterase system .", "sentence_char_start_global": 33534, "sentence_char_end_global": 33762, "entities": [{"text": "phosphodiesterase", "type": "ENTITY", "char_start": 81, "char_end": 98, "token_start": 16, "token_end": 16}, {"text": "adenylate cyclase", "type": "ENTITY", "char_start": 182, "char_end": 199, "token_start": 32, "token_end": 33}, {"text": "phosphodiesterase", "type": "ENTITY", "char_start": 202, "char_end": 219, "token_start": 35, "token_end": 35}], "entities_global": [{"text": "phosphodiesterase", "type": "ENTITY", "char_start": 33615, "char_end": 33632, "token_start": 16, "token_end": 16, "note": null}, {"text": "adenylate cyclase", "type": "ENTITY", "char_start": 33716, "char_end": 33733, "token_start": 32, "token_end": 33, "note": null}, {"text": "phosphodiesterase", "type": "ENTITY", "char_start": 33736, "char_end": 33753, "token_start": 35, "token_end": 35, "note": null}]}
+{"sentence_id": 198, "sentence_text": "Data obtained with the use of antiglucocorticoids and the anti - CBG antibody are compatible with a role both of high - affinity glucocorticoid receptors and of CBG in mediating cortisol action on the human NK cell activity .", "sentence_char_start_global": 33763, "sentence_char_end_global": 33988, "entities": [{"text": "anti - CBG antibody", "type": "ENTITY", "char_start": 58, "char_end": 77, "token_start": 9, "token_end": 12}, {"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 129, "char_end": 153, "token_start": 23, "token_end": 24}, {"text": "CBG", "type": "ENTITY", "char_start": 161, "char_end": 164, "token_start": 27, "token_end": 27}], "entities_global": [{"text": "anti - CBG antibody", "type": "ENTITY", "char_start": 33821, "char_end": 33840, "token_start": 9, "token_end": 12, "note": null}, {"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 33892, "char_end": 33916, "token_start": 23, "token_end": 24, "note": null}, {"text": "CBG", "type": "ENTITY", "char_start": 33924, "char_end": 33927, "token_start": 27, "token_end": 27, "note": null}]}
+{"sentence_id": 199, "sentence_text": "Interaction of cell - type - specific nuclear proteins with immunoglobulin VH promoter region sequences .", "sentence_char_start_global": 33989, "sentence_char_end_global": 34094, "entities": [{"text": "cell - type - specific nuclear proteins", "type": "ENTITY", "char_start": 15, "char_end": 54, "token_start": 2, "token_end": 8}, {"text": "immunoglobulin VH promoter region sequences", "type": "ENTITY", "char_start": 60, "char_end": 103, "token_start": 10, "token_end": 14}], "entities_global": [{"text": "cell - type - specific nuclear proteins", "type": "ENTITY", "char_start": 34004, "char_end": 34043, "token_start": 2, "token_end": 8, "note": null}, {"text": "immunoglobulin VH promoter region sequences", "type": "ENTITY", "char_start": 34049, "char_end": 34092, "token_start": 10, "token_end": 14, "note": null}]}
+{"sentence_id": 200, "sentence_text": "All human and murine immunoglobulin heavy chain variable region ( VH ) genes contain the sequence ATGCAAAT approximately 70 nucleotides 5 ' from the site of transcription initiation .", "sentence_char_start_global": 34095, "sentence_char_end_global": 34278, "entities": [{"text": "human and murine immunoglobulin heavy chain variable region ( VH ) genes", "type": "ENTITY", "char_start": 4, "char_end": 76, "token_start": 1, "token_end": 12}], "entities_global": [{"text": "human and murine immunoglobulin heavy chain variable region ( VH ) genes", "type": "ENTITY", "char_start": 34099, "char_end": 34171, "token_start": 1, "token_end": 12, "note": null}]}
+{"sentence_id": 201, "sentence_text": "This octanucleotide , in reverse orientation , is also found in all light chain variable region ( VL ) genes , and in the immunoglobulin heavy chain transcriptional enhancer .", "sentence_char_start_global": 34279, "sentence_char_end_global": 34454, "entities": [{"text": "light chain variable region ( VL ) genes", "type": "ENTITY", "char_start": 68, "char_end": 108, "token_start": 12, "token_end": 19}, {"text": "immunoglobulin heavy chain transcriptional enhancer", "type": "ENTITY", "char_start": 122, "char_end": 173, "token_start": 24, "token_end": 28}], "entities_global": [{"text": "light chain variable region ( VL ) genes", "type": "ENTITY", "char_start": 34347, "char_end": 34387, "token_start": 12, "token_end": 19, "note": null}, {"text": "immunoglobulin heavy chain transcriptional enhancer", "type": "ENTITY", "char_start": 34401, "char_end": 34452, "token_start": 24, "token_end": 28, "note": null}]}
+{"sentence_id": 202, "sentence_text": "Transfection studies have established that this octamer is involved in the lymphoid - specific transcription of immunoglobulin genes .", "sentence_char_start_global": 34455, "sentence_char_end_global": 34589, "entities": [{"text": "immunoglobulin genes", "type": "ENTITY", "char_start": 112, "char_end": 132, "token_start": 16, "token_end": 17}], "entities_global": [{"text": "immunoglobulin genes", "type": "ENTITY", "char_start": 34567, "char_end": 34587, "token_start": 16, "token_end": 17, "note": null}]}
+{"sentence_id": 203, "sentence_text": "Octamer - containing fragments have been reported to bind a factor present in nuclear extracts of human cell lines ; however , identical binding activity was detected in both B lymphoid and non - lymphoid cells .", "sentence_char_start_global": 34590, "sentence_char_end_global": 34802, "entities": [{"text": "Octamer - containing fragments", "type": "ENTITY", "char_start": 0, "char_end": 30, "token_start": 0, "token_end": 3}], "entities_global": [{"text": "Octamer - containing fragments", "type": "ENTITY", "char_start": 34590, "char_end": 34620, "token_start": 0, "token_end": 3, "note": null}]}
+{"sentence_id": 204, "sentence_text": "Here we establish that nuclear extracts from distinct cell types differ in their ability to interact with octamer - containing fragments .", "sentence_char_start_global": 34803, "sentence_char_end_global": 34941, "entities": [{"text": "octamer - containing fragments", "type": "ENTITY", "char_start": 106, "char_end": 136, "token_start": 17, "token_end": 20}], "entities_global": [{"text": "octamer - containing fragments", "type": "ENTITY", "char_start": 34909, "char_end": 34939, "token_start": 17, "token_end": 20, "note": null}]}
+{"sentence_id": 205, "sentence_text": "We have also detected a DNA - protein interaction that may be involved in the cell - type specificity of immunoglobulin expression , and we have determined that a sequence upstream of the octamer participates in an interaction with a nuclear protein ( s ) .", "sentence_char_start_global": 34942, "sentence_char_end_global": 35199, "entities": [{"text": "immunoglobulin", "type": "ENTITY", "char_start": 105, "char_end": 119, "token_start": 20, "token_end": 20}, {"text": "nuclear protein", "type": "ENTITY", "char_start": 234, "char_end": 249, "token_start": 40, "token_end": 41}], "entities_global": [{"text": "immunoglobulin", "type": "ENTITY", "char_start": 35047, "char_end": 35061, "token_start": 20, "token_end": 20, "note": null}, {"text": "nuclear protein", "type": "ENTITY", "char_start": 35176, "char_end": 35191, "token_start": 40, "token_end": 41, "note": null}]}
+{"sentence_id": 206, "sentence_text": "Preferential transcription of HTLV - I LTR in cell - free extracts of human T cells producing HTLV - I viral proteins .", "sentence_char_start_global": 35200, "sentence_char_end_global": 35319, "entities": [{"text": "HTLV - I LTR", "type": "ENTITY", "char_start": 30, "char_end": 42, "token_start": 3, "token_end": 6}, {"text": "HTLV - I viral proteins", "type": "ENTITY", "char_start": 94, "char_end": 117, "token_start": 17, "token_end": 21}], "entities_global": [{"text": "HTLV - I LTR", "type": "ENTITY", "char_start": 35230, "char_end": 35242, "token_start": 3, "token_end": 6, "note": null}, {"text": "HTLV - I viral proteins", "type": "ENTITY", "char_start": 35294, "char_end": 35317, "token_start": 17, "token_end": 21, "note": null}]}
+{"sentence_id": 207, "sentence_text": "The promoters of the adenovirus 2 major late gene , the mouse beta - globin gene , the mouse immunoglobulin VH gene and the LTR of the human T - lymphotropic retrovirus type I were tested for their transcription activities in cell - free extracts of four cell lines ; HeLa , CESS ( Epstein - Barr virus - transformed human B cell line ) , MT - 1 ( HTLV - I - infected human T cell line without viral protein synthesis ) , and MT - 2 ( HTLV - I - infected human T cell line producing viral proteins ) .", "sentence_char_start_global": 35320, "sentence_char_end_global": 35821, "entities": [{"text": "promoters", "type": "ENTITY", "char_start": 4, "char_end": 13, "token_start": 1, "token_end": 1}, {"text": "adenovirus 2 major late gene", "type": "ENTITY", "char_start": 21, "char_end": 49, "token_start": 4, "token_end": 8}, {"text": "mouse beta - globin gene", "type": "ENTITY", "char_start": 56, "char_end": 80, "token_start": 11, "token_end": 15}, {"text": "mouse immunoglobulin VH gene", "type": "ENTITY", "char_start": 87, "char_end": 115, "token_start": 18, "token_end": 21}, {"text": "LTR", "type": "ENTITY", "char_start": 124, "char_end": 127, "token_start": 24, "token_end": 24}, {"text": "viral proteins", "type": "ENTITY", "char_start": 483, "char_end": 497, "token_start": 100, "token_end": 101}], "entities_global": [{"text": "promoters", "type": "ENTITY", "char_start": 35324, "char_end": 35333, "token_start": 1, "token_end": 1, "note": null}, {"text": "adenovirus 2 major late gene", "type": "ENTITY", "char_start": 35341, "char_end": 35369, "token_start": 4, "token_end": 8, "note": null}, {"text": "mouse beta - globin gene", "type": "ENTITY", "char_start": 35376, "char_end": 35400, "token_start": 11, "token_end": 15, "note": null}, {"text": "mouse immunoglobulin VH gene", "type": "ENTITY", "char_start": 35407, "char_end": 35435, "token_start": 18, "token_end": 21, "note": null}, {"text": "LTR", "type": "ENTITY", "char_start": 35444, "char_end": 35447, "token_start": 24, "token_end": 24, "note": null}, {"text": "viral proteins", "type": "ENTITY", "char_start": 35803, "char_end": 35817, "token_start": 100, "token_end": 101, "note": null}]}
+{"sentence_id": 208, "sentence_text": "LTR was preferentially transcribed in the extracts of MT - 2 although the other three genes were transcribed with relatively constant efficiencies in different extracts .", "sentence_char_start_global": 35822, "sentence_char_end_global": 35992, "entities": [{"text": "LTR", "type": "ENTITY", "char_start": 0, "char_end": 3, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "LTR", "type": "ENTITY", "char_start": 35822, "char_end": 35825, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 209, "sentence_text": "The results agree well with the previous in vivo studies on the promoter activity of HTLV - I LTR .", "sentence_char_start_global": 35993, "sentence_char_end_global": 36092, "entities": [{"text": "HTLV - I LTR", "type": "ENTITY", "char_start": 85, "char_end": 97, "token_start": 15, "token_end": 18}], "entities_global": [{"text": "HTLV - I LTR", "type": "ENTITY", "char_start": 36078, "char_end": 36090, "token_start": 15, "token_end": 18, "note": null}]}
+{"sentence_id": 210, "sentence_text": "Mixing of HeLa and MT - 2 extracts revealed the presence of a LTR - specific stimulating activity in MT - 2 extracts .", "sentence_char_start_global": 36093, "sentence_char_end_global": 36211, "entities": [], "entities_global": []}
+{"sentence_id": 211, "sentence_text": "A nuclear factor that binds to a conserved sequence motif in transcriptional control elements of immunoglobulin genes .", "sentence_char_start_global": 36212, "sentence_char_end_global": 36331, "entities": [{"text": "nuclear factor", "type": "ENTITY", "char_start": 2, "char_end": 16, "token_start": 1, "token_end": 2}, {"text": "transcriptional control elements", "type": "ENTITY", "char_start": 61, "char_end": 93, "token_start": 11, "token_end": 13}, {"text": "immunoglobulin genes", "type": "ENTITY", "char_start": 97, "char_end": 117, "token_start": 15, "token_end": 16}], "entities_global": [{"text": "nuclear factor", "type": "ENTITY", "char_start": 36214, "char_end": 36228, "token_start": 1, "token_end": 2, "note": null}, {"text": "transcriptional control elements", "type": "ENTITY", "char_start": 36273, "char_end": 36305, "token_start": 11, "token_end": 13, "note": null}, {"text": "immunoglobulin genes", "type": "ENTITY", "char_start": 36309, "char_end": 36329, "token_start": 15, "token_end": 16, "note": null}]}
+{"sentence_id": 212, "sentence_text": "Trans - acting factors that mediate B - cell specific transcription of immunoglobulin genes have been postulated based on an analysis of the expression of exogenously introduced immunoglobulin gene recombinants in lymphoid and non - lymphoid cells .", "sentence_char_start_global": 36332, "sentence_char_end_global": 36581, "entities": [{"text": "Trans - acting factors", "type": "ENTITY", "char_start": 0, "char_end": 22, "token_start": 0, "token_end": 3}, {"text": "immunoglobulin genes", "type": "ENTITY", "char_start": 71, "char_end": 91, "token_start": 12, "token_end": 13}, {"text": "immunoglobulin gene recombinants", "type": "ENTITY", "char_start": 178, "char_end": 210, "token_start": 27, "token_end": 29}], "entities_global": [{"text": "Trans - acting factors", "type": "ENTITY", "char_start": 36332, "char_end": 36354, "token_start": 0, "token_end": 3, "note": null}, {"text": "immunoglobulin genes", "type": "ENTITY", "char_start": 36403, "char_end": 36423, "token_start": 12, "token_end": 13, "note": null}, {"text": "immunoglobulin gene recombinants", "type": "ENTITY", "char_start": 36510, "char_end": 36542, "token_start": 27, "token_end": 29, "note": null}]}
+{"sentence_id": 213, "sentence_text": "Two B - cell - specific , cis - acting transcriptional regulatory elements have been identified .", "sentence_char_start_global": 36582, "sentence_char_end_global": 36679, "entities": [{"text": "cis - acting transcriptional regulatory elements", "type": "ENTITY", "char_start": 26, "char_end": 74, "token_start": 7, "token_end": 12}], "entities_global": [{"text": "cis - acting transcriptional regulatory elements", "type": "ENTITY", "char_start": 36608, "char_end": 36656, "token_start": 7, "token_end": 12, "note": null}]}
+{"sentence_id": 214, "sentence_text": "One element is located in the intron between the variable ( V ) and constant ( C ) regions of both heavy and kappa light - chain genes and acts as a transcriptional enhancer .", "sentence_char_start_global": 36680, "sentence_char_end_global": 36855, "entities": [{"text": "heavy and kappa light - chain genes", "type": "ENTITY", "char_start": 99, "char_end": 134, "token_start": 21, "token_end": 27}], "entities_global": [{"text": "heavy and kappa light - chain genes", "type": "ENTITY", "char_start": 36779, "char_end": 36814, "token_start": 21, "token_end": 27, "note": null}]}
+{"sentence_id": 215, "sentence_text": "The second element is found upstream of both heavy and kappa light - chain gene promoters .", "sentence_char_start_global": 36856, "sentence_char_end_global": 36947, "entities": [{"text": "element", "type": "ENTITY", "char_start": 11, "char_end": 18, "token_start": 2, "token_end": 2}, {"text": "heavy and kappa light - chain gene promoters", "type": "ENTITY", "char_start": 45, "char_end": 89, "token_start": 8, "token_end": 15}], "entities_global": [{"text": "element", "type": "ENTITY", "char_start": 36867, "char_end": 36874, "token_start": 2, "token_end": 2, "note": null}, {"text": "heavy and kappa light - chain gene promoters", "type": "ENTITY", "char_start": 36901, "char_end": 36945, "token_start": 8, "token_end": 15, "note": null}]}
+{"sentence_id": 216, "sentence_text": "This element directs lymphoid - specific transcription even in the presence of viral enhancers .", "sentence_char_start_global": 36948, "sentence_char_end_global": 37044, "entities": [{"text": "viral enhancers", "type": "ENTITY", "char_start": 79, "char_end": 94, "token_start": 12, "token_end": 13}], "entities_global": [{"text": "viral enhancers", "type": "ENTITY", "char_start": 37027, "char_end": 37042, "token_start": 12, "token_end": 13, "note": null}]}
+{"sentence_id": 217, "sentence_text": "We have sought nuclear factors that might bind specifically to these two regulatory elements by application of a modified gel electrophoresis DNA binding assay .", "sentence_char_start_global": 37045, "sentence_char_end_global": 37206, "entities": [{"text": "regulatory elements", "type": "ENTITY", "char_start": 73, "char_end": 92, "token_start": 12, "token_end": 13}], "entities_global": [{"text": "regulatory elements", "type": "ENTITY", "char_start": 37118, "char_end": 37137, "token_start": 12, "token_end": 13, "note": null}]}
+{"sentence_id": 218, "sentence_text": "We report here the identification of a human B - cell nuclear factor ( IgNF - A ) that binds to DNA sequences in the upstream regions of both the mouse heavy and kappa light - chain gene promoters and also to the mouse heavy - chain gene enhancer .", "sentence_char_start_global": 37207, "sentence_char_end_global": 37455, "entities": [{"text": "human B - cell nuclear factor", "type": "ENTITY", "char_start": 39, "char_end": 68, "token_start": 7, "token_end": 12}, {"text": "IgNF - A", "type": "ENTITY", "char_start": 71, "char_end": 79, "token_start": 14, "token_end": 16}, {"text": "DNA sequences", "type": "ENTITY", "char_start": 96, "char_end": 109, "token_start": 21, "token_end": 22}, {"text": "upstream regions", "type": "ENTITY", "char_start": 117, "char_end": 133, "token_start": 25, "token_end": 26}, {"text": "mouse heavy and kappa light - chain gene promoters", "type": "ENTITY", "char_start": 146, "char_end": 196, "token_start": 30, "token_end": 38}, {"text": "mouse heavy - chain gene enhancer", "type": "ENTITY", "char_start": 213, "char_end": 246, "token_start": 43, "token_end": 48}], "entities_global": [{"text": "human B - cell nuclear factor", "type": "ENTITY", "char_start": 37246, "char_end": 37275, "token_start": 7, "token_end": 12, "note": null}, {"text": "IgNF - A", "type": "ENTITY", "char_start": 37278, "char_end": 37286, "token_start": 14, "token_end": 16, "note": null}, {"text": "DNA sequences", "type": "ENTITY", "char_start": 37303, "char_end": 37316, "token_start": 21, "token_end": 22, "note": null}, {"text": "upstream regions", "type": "ENTITY", "char_start": 37324, "char_end": 37340, "token_start": 25, "token_end": 26, "note": null}, {"text": "mouse heavy and kappa light - chain gene promoters", "type": "ENTITY", "char_start": 37353, "char_end": 37403, "token_start": 30, "token_end": 38, "note": null}, {"text": "mouse heavy - chain gene enhancer", "type": "ENTITY", "char_start": 37420, "char_end": 37453, "token_start": 43, "token_end": 48, "note": null}]}
+{"sentence_id": 219, "sentence_text": "This sequence - specific binding is probably mediated by a highly conserved sequence motif , ATTTGCAT , present in all three transcriptional elements .", "sentence_char_start_global": 37456, "sentence_char_end_global": 37607, "entities": [{"text": "transcriptional elements", "type": "ENTITY", "char_start": 125, "char_end": 149, "token_start": 21, "token_end": 22}], "entities_global": [{"text": "transcriptional elements", "type": "ENTITY", "char_start": 37581, "char_end": 37605, "token_start": 21, "token_end": 22, "note": null}]}
+{"sentence_id": 220, "sentence_text": "Interestingly , a factor showing similar binding specificity to IgNF - A is also present in human HeLa cells .", "sentence_char_start_global": 37608, "sentence_char_end_global": 37718, "entities": [{"text": "IgNF - A", "type": "ENTITY", "char_start": 64, "char_end": 72, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "IgNF - A", "type": "ENTITY", "char_start": 37672, "char_end": 37680, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 221, "sentence_text": "The new world primates as animal models of glucocorticoid resistance .", "sentence_char_start_global": 37719, "sentence_char_end_global": 37789, "entities": [], "entities_global": []}
+{"sentence_id": 222, "sentence_text": "Many New World primate species have greatly increased plasma cortisol concentrations , decreased plasma cortisol binding globulin capacity and affinity , marked resistance of the hypothalamic - pituitary - adrenal axis to suppression by dexamethasone , and no biological evidence of glucocorticoid excess .", "sentence_char_start_global": 37790, "sentence_char_end_global": 38096, "entities": [], "entities_global": []}
+{"sentence_id": 223, "sentence_text": "These primates also have high levels of circulating progesterone , estrogen , mineralocorticoid , androgen and vitamin D .", "sentence_char_start_global": 38097, "sentence_char_end_global": 38219, "entities": [], "entities_global": []}
+{"sentence_id": 224, "sentence_text": "The glucocorticoid target tissues that have been examined ( circulating mononuclear lymphocytes and cultured skin fibroblasts ) have normal concentrations of glucocorticoid receptors with decreased affinity for dexamethasone .", "sentence_char_start_global": 38220, "sentence_char_end_global": 38446, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 158, "char_end": 182, "token_start": 21, "token_end": 22}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 38378, "char_end": 38402, "token_start": 21, "token_end": 22, "note": null}]}
+{"sentence_id": 225, "sentence_text": "Transformation of B - lymphocytes with the Epstein - Barr virus leads to glucocorticoid receptor induction that is less than that observed with cells from Old World primates .", "sentence_char_start_global": 38447, "sentence_char_end_global": 38622, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 73, "char_end": 96, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 38520, "char_end": 38543, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 226, "sentence_text": "The receptor in these cells has a low affinity for dexamethasone .", "sentence_char_start_global": 38623, "sentence_char_end_global": 38689, "entities": [], "entities_global": []}
+{"sentence_id": 227, "sentence_text": "The low affinity leads to an increased loss of specific bound ligand during thermal activation .", "sentence_char_start_global": 38690, "sentence_char_end_global": 38786, "entities": [], "entities_global": []}
+{"sentence_id": 228, "sentence_text": "Meroreceptor generation is normal .", "sentence_char_start_global": 38787, "sentence_char_end_global": 38822, "entities": [], "entities_global": []}
+{"sentence_id": 229, "sentence_text": "The molecular weight of the receptor , determined by SDS - PAGE , is similar to that of Old World primates ( approximately 92 , 000 ) and the activation pattern per se , examined in vitro by heating cytosol and performing phosphocellulose chromatography , appears similar to that of human controls .", "sentence_char_start_global": 38823, "sentence_char_end_global": 39122, "entities": [], "entities_global": []}
+{"sentence_id": 230, "sentence_text": "The ratios of nuclear to cytosolic hormone - receptor - complexes and of cytosolic activated to unactivated receptor complexes in intact cells are similar to Old World primates .", "sentence_char_start_global": 39123, "sentence_char_end_global": 39301, "entities": [{"text": "cytosolic hormone - receptor - complexes", "type": "ENTITY", "char_start": 25, "char_end": 65, "token_start": 5, "token_end": 10}, {"text": "unactivated receptor complexes", "type": "ENTITY", "char_start": 96, "char_end": 126, "token_start": 16, "token_end": 18}], "entities_global": [{"text": "cytosolic hormone - receptor - complexes", "type": "ENTITY", "char_start": 39148, "char_end": 39188, "token_start": 5, "token_end": 10, "note": null}, {"text": "unactivated receptor complexes", "type": "ENTITY", "char_start": 39219, "char_end": 39249, "token_start": 16, "token_end": 18, "note": null}]}
+{"sentence_id": 231, "sentence_text": "Results from mixing studies do not support the hypothesis that a binding inhibitor ( s ) or a deficient cytosolic positive modifier ( s ) of binding underlies the findings in these primates .", "sentence_char_start_global": 39302, "sentence_char_end_global": 39493, "entities": [], "entities_global": []}
+{"sentence_id": 232, "sentence_text": "The New World primates , unlike men with the syndrome of primary cortisol resistance , have compensated for their condition with intra - adrenal and mineralocorticoid receptor adaptations .", "sentence_char_start_global": 39494, "sentence_char_end_global": 39683, "entities": [], "entities_global": []}
+{"sentence_id": 233, "sentence_text": "Thus , unlike Old World primates , cortisol in New World primates has only weak sodium - retaining potency because the aldosterone receptor has a low affinity for cortisol .", "sentence_char_start_global": 39684, "sentence_char_end_global": 39857, "entities": [{"text": "aldosterone receptor", "type": "ENTITY", "char_start": 119, "char_end": 139, "token_start": 21, "token_end": 22}], "entities_global": [{"text": "aldosterone receptor", "type": "ENTITY", "char_start": 39803, "char_end": 39823, "token_start": 21, "token_end": 22, "note": null}]}
+{"sentence_id": 234, "sentence_text": "The common element that would explain the apparent resistance to six steroid hormones in New World primates", "sentence_char_start_global": 39858, "sentence_char_end_global": 39965, "entities": [], "entities_global": []}
+{"sentence_id": 235, "sentence_text": "Acetylation and modulation of erythroid Kruppel - like factor ( EKLF ) activity by interaction with histone acetyltransferases .", "sentence_char_start_global": 39966, "sentence_char_end_global": 40094, "entities": [{"text": "erythroid Kruppel - like factor", "type": "ENTITY", "char_start": 30, "char_end": 61, "token_start": 4, "token_end": 8}, {"text": "EKLF", "type": "ENTITY", "char_start": 64, "char_end": 68, "token_start": 10, "token_end": 10}, {"text": "histone acetyltransferases", "type": "ENTITY", "char_start": 100, "char_end": 126, "token_start": 16, "token_end": 17}], "entities_global": [{"text": "erythroid Kruppel - like factor", "type": "ENTITY", "char_start": 39996, "char_end": 40027, "token_start": 4, "token_end": 8, "note": null}, {"text": "EKLF", "type": "ENTITY", "char_start": 40030, "char_end": 40034, "token_start": 10, "token_end": 10, "note": null}, {"text": "histone acetyltransferases", "type": "ENTITY", "char_start": 40066, "char_end": 40092, "token_start": 16, "token_end": 17, "note": null}]}
+{"sentence_id": 236, "sentence_text": "Erythroid Kruppel - like factor ( EKLF ) is a red cell - specific transcriptional activator that is crucial for consolidating the switch to high levels of adult beta - globin expression during erythroid ontogeny .", "sentence_char_start_global": 40095, "sentence_char_end_global": 40308, "entities": [{"text": "Erythroid Kruppel - like factor", "type": "ENTITY", "char_start": 0, "char_end": 31, "token_start": 0, "token_end": 4}, {"text": "EKLF", "type": "ENTITY", "char_start": 34, "char_end": 38, "token_start": 6, "token_end": 6}, {"text": "red cell - specific transcriptional activator", "type": "ENTITY", "char_start": 46, "char_end": 91, "token_start": 10, "token_end": 15}], "entities_global": [{"text": "Erythroid Kruppel - like factor", "type": "ENTITY", "char_start": 40095, "char_end": 40126, "token_start": 0, "token_end": 4, "note": null}, {"text": "EKLF", "type": "ENTITY", "char_start": 40129, "char_end": 40133, "token_start": 6, "token_end": 6, "note": null}, {"text": "red cell - specific transcriptional activator", "type": "ENTITY", "char_start": 40141, "char_end": 40186, "token_start": 10, "token_end": 15, "note": null}]}
+{"sentence_id": 237, "sentence_text": "EKLF is required for integrity of the chromatin structure at the beta - like globin locus , and it interacts with a positive - acting factor in vivo .", "sentence_char_start_global": 40309, "sentence_char_end_global": 40459, "entities": [{"text": "EKLF", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}, {"text": "beta - like globin locus", "type": "ENTITY", "char_start": 65, "char_end": 89, "token_start": 11, "token_end": 15}, {"text": "positive - acting factor", "type": "ENTITY", "char_start": 116, "char_end": 140, "token_start": 22, "token_end": 25}], "entities_global": [{"text": "EKLF", "type": "ENTITY", "char_start": 40309, "char_end": 40313, "token_start": 0, "token_end": 0, "note": null}, {"text": "beta - like globin locus", "type": "ENTITY", "char_start": 40374, "char_end": 40398, "token_start": 11, "token_end": 15, "note": null}, {"text": "positive - acting factor", "type": "ENTITY", "char_start": 40425, "char_end": 40449, "token_start": 22, "token_end": 25, "note": null}]}
+{"sentence_id": 238, "sentence_text": "We find that EKLF is an acetylated transcription factor , and that it interacts in vivo with CBP , p300 , and P / CAF .", "sentence_char_start_global": 40460, "sentence_char_end_global": 40579, "entities": [{"text": "EKLF", "type": "ENTITY", "char_start": 13, "char_end": 17, "token_start": 3, "token_end": 3}, {"text": "acetylated transcription factor", "type": "ENTITY", "char_start": 24, "char_end": 55, "token_start": 6, "token_end": 8}, {"text": "CBP", "type": "ENTITY", "char_start": 93, "char_end": 96, "token_start": 17, "token_end": 17}, {"text": "p300", "type": "ENTITY", "char_start": 99, "char_end": 103, "token_start": 19, "token_end": 19}, {"text": "P / CAF", "type": "ENTITY", "char_start": 110, "char_end": 117, "token_start": 22, "token_end": 24}], "entities_global": [{"text": "EKLF", "type": "ENTITY", "char_start": 40473, "char_end": 40477, "token_start": 3, "token_end": 3, "note": null}, {"text": "acetylated transcription factor", "type": "ENTITY", "char_start": 40484, "char_end": 40515, "token_start": 6, "token_end": 8, "note": null}, {"text": "CBP", "type": "ENTITY", "char_start": 40553, "char_end": 40556, "token_start": 17, "token_end": 17, "note": null}, {"text": "p300", "type": "ENTITY", "char_start": 40559, "char_end": 40563, "token_start": 19, "token_end": 19, "note": null}, {"text": "P / CAF", "type": "ENTITY", "char_start": 40570, "char_end": 40577, "token_start": 22, "token_end": 24, "note": null}]}
+{"sentence_id": 239, "sentence_text": "However , its interactions with these histone acetyltransferases are not equivalent , as CBP and p300 , but not P / CAF , utilize EKLF as a substrate for in vitro acetylation within its trans - activation region .", "sentence_char_start_global": 40580, "sentence_char_end_global": 40793, "entities": [{"text": "histone acetyltransferases", "type": "ENTITY", "char_start": 38, "char_end": 64, "token_start": 6, "token_end": 7}, {"text": "CBP", "type": "ENTITY", "char_start": 89, "char_end": 92, "token_start": 13, "token_end": 13}, {"text": "p300", "type": "ENTITY", "char_start": 97, "char_end": 101, "token_start": 15, "token_end": 15}, {"text": "P / CAF", "type": "ENTITY", "char_start": 112, "char_end": 119, "token_start": 19, "token_end": 21}, {"text": "EKLF", "type": "ENTITY", "char_start": 130, "char_end": 134, "token_start": 24, "token_end": 24}], "entities_global": [{"text": "histone acetyltransferases", "type": "ENTITY", "char_start": 40618, "char_end": 40644, "token_start": 6, "token_end": 7, "note": null}, {"text": "CBP", "type": "ENTITY", "char_start": 40669, "char_end": 40672, "token_start": 13, "token_end": 13, "note": null}, {"text": "p300", "type": "ENTITY", "char_start": 40677, "char_end": 40681, "token_start": 15, "token_end": 15, "note": null}, {"text": "P / CAF", "type": "ENTITY", "char_start": 40692, "char_end": 40699, "token_start": 19, "token_end": 21, "note": null}, {"text": "EKLF", "type": "ENTITY", "char_start": 40710, "char_end": 40714, "token_start": 24, "token_end": 24, "note": null}]}
+{"sentence_id": 240, "sentence_text": "The functional effects of these interactions are that CBP and p300 , but not P / CAF , enhance EKLF ' s transcriptional activation of the beta - globin promoter in erythroid cells .", "sentence_char_start_global": 40794, "sentence_char_end_global": 40975, "entities": [{"text": "CBP", "type": "ENTITY", "char_start": 54, "char_end": 57, "token_start": 8, "token_end": 8}, {"text": "p300", "type": "ENTITY", "char_start": 62, "char_end": 66, "token_start": 10, "token_end": 10}, {"text": "P / CAF", "type": "ENTITY", "char_start": 77, "char_end": 84, "token_start": 14, "token_end": 16}, {"text": "EKLF", "type": "ENTITY", "char_start": 95, "char_end": 99, "token_start": 19, "token_end": 19}, {"text": "beta - globin promoter", "type": "ENTITY", "char_start": 138, "char_end": 160, "token_start": 26, "token_end": 29}], "entities_global": [{"text": "CBP", "type": "ENTITY", "char_start": 40848, "char_end": 40851, "token_start": 8, "token_end": 8, "note": null}, {"text": "p300", "type": "ENTITY", "char_start": 40856, "char_end": 40860, "token_start": 10, "token_end": 10, "note": null}, {"text": "P / CAF", "type": "ENTITY", "char_start": 40871, "char_end": 40878, "token_start": 14, "token_end": 16, "note": null}, {"text": "EKLF", "type": "ENTITY", "char_start": 40889, "char_end": 40893, "token_start": 19, "token_end": 19, "note": null}, {"text": "beta - globin promoter", "type": "ENTITY", "char_start": 40932, "char_end": 40954, "token_start": 26, "token_end": 29, "note": null}]}
+{"sentence_id": 241, "sentence_text": "These results establish EKLF as a tissue - specific transcription factor that undergoes post - translational acetylation and suggest a mechanism by which EKLF is able to alter chromatin structure and induce beta - globin expression within the beta - like globin cluster .", "sentence_char_start_global": 40976, "sentence_char_end_global": 41247, "entities": [{"text": "EKLF", "type": "ENTITY", "char_start": 24, "char_end": 28, "token_start": 3, "token_end": 3}, {"text": "tissue - specific transcription factor", "type": "ENTITY", "char_start": 34, "char_end": 72, "token_start": 6, "token_end": 10}, {"text": "EKLF", "type": "ENTITY", "char_start": 154, "char_end": 158, "token_start": 23, "token_end": 23}, {"text": "beta - like globin cluster", "type": "ENTITY", "char_start": 243, "char_end": 269, "token_start": 38, "token_end": 42}], "entities_global": [{"text": "EKLF", "type": "ENTITY", "char_start": 41000, "char_end": 41004, "token_start": 3, "token_end": 3, "note": null}, {"text": "tissue - specific transcription factor", "type": "ENTITY", "char_start": 41010, "char_end": 41048, "token_start": 6, "token_end": 10, "note": null}, {"text": "EKLF", "type": "ENTITY", "char_start": 41130, "char_end": 41134, "token_start": 23, "token_end": 23, "note": null}, {"text": "beta - like globin cluster", "type": "ENTITY", "char_start": 41219, "char_end": 41245, "token_start": 38, "token_end": 42, "note": null}]}
+{"sentence_id": 242, "sentence_text": "Recognition of herpes simplex virus type 2 tegument proteins by CD4 T cells infiltrating human genital herpes lesions .", "sentence_char_start_global": 41248, "sentence_char_end_global": 41367, "entities": [{"text": "herpes simplex virus type 2 tegument proteins", "type": "ENTITY", "char_start": 15, "char_end": 60, "token_start": 2, "token_end": 8}], "entities_global": [{"text": "herpes simplex virus type 2 tegument proteins", "type": "ENTITY", "char_start": 41263, "char_end": 41308, "token_start": 2, "token_end": 8, "note": null}]}
+{"sentence_id": 243, "sentence_text": "The local cellular immune response to herpes simplex virus ( HSV ) is important in the control of recurrent HSV infection .", "sentence_char_start_global": 41368, "sentence_char_end_global": 41491, "entities": [], "entities_global": []}
+{"sentence_id": 244, "sentence_text": "The antiviral functions of infiltrating CD4 - bearing T cells may include cytotoxicity , inhibition of viral growth , lymphokine secretion , and support of humoral and CD8 responses .", "sentence_char_start_global": 41492, "sentence_char_end_global": 41675, "entities": [], "entities_global": []}
+{"sentence_id": 245, "sentence_text": "The antigens recognized by many HSV - specific CD4 T cells localizing to genital HSV - 2 lesions are unknown .", "sentence_char_start_global": 41676, "sentence_char_end_global": 41786, "entities": [], "entities_global": []}
+{"sentence_id": 246, "sentence_text": "T cells recognizing antigens encoded within map units 0 . 67 to 0 . 73 of HSV DNA are frequently recovered from herpetic lesions .", "sentence_char_start_global": 41787, "sentence_char_end_global": 41917, "entities": [{"text": "HSV DNA", "type": "ENTITY", "char_start": 74, "char_end": 81, "token_start": 16, "token_end": 17}], "entities_global": [{"text": "HSV DNA", "type": "ENTITY", "char_start": 41861, "char_end": 41868, "token_start": 16, "token_end": 17, "note": null}]}
+{"sentence_id": 247, "sentence_text": "Expression cloning with this region of DNA now shows that tegument protein VP22 and the viral dUTPase , encoded by genes UL49 and UL50 , respectively , are T - cell antigens .", "sentence_char_start_global": 41918, "sentence_char_end_global": 42093, "entities": [{"text": "tegument protein", "type": "ENTITY", "char_start": 58, "char_end": 74, "token_start": 10, "token_end": 11}, {"text": "VP22", "type": "ENTITY", "char_start": 75, "char_end": 79, "token_start": 12, "token_end": 12}, {"text": "viral dUTPase", "type": "ENTITY", "char_start": 88, "char_end": 101, "token_start": 15, "token_end": 16}, {"text": "genes UL49 and UL50", "type": "ENTITY", "char_start": 115, "char_end": 134, "token_start": 20, "token_end": 23}, {"text": "T - cell antigens", "type": "ENTITY", "char_start": 156, "char_end": 173, "token_start": 28, "token_end": 31}], "entities_global": [{"text": "tegument protein", "type": "ENTITY", "char_start": 41976, "char_end": 41992, "token_start": 10, "token_end": 11, "note": null}, {"text": "VP22", "type": "ENTITY", "char_start": 41993, "char_end": 41997, "token_start": 12, "token_end": 12, "note": null}, {"text": "viral dUTPase", "type": "ENTITY", "char_start": 42006, "char_end": 42019, "token_start": 15, "token_end": 16, "note": null}, {"text": "genes UL49 and UL50", "type": "ENTITY", "char_start": 42033, "char_end": 42052, "token_start": 20, "token_end": 23, "note": null}, {"text": "T - cell antigens", "type": "ENTITY", "char_start": 42074, "char_end": 42091, "token_start": 28, "token_end": 31, "note": null}]}
+{"sentence_id": 248, "sentence_text": "Separate epitopes in VP22 were defined for T - cell clones from each of three patients .", "sentence_char_start_global": 42094, "sentence_char_end_global": 42182, "entities": [{"text": "epitopes", "type": "ENTITY", "char_start": 9, "char_end": 17, "token_start": 1, "token_end": 1}, {"text": "VP22", "type": "ENTITY", "char_start": 21, "char_end": 25, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "epitopes", "type": "ENTITY", "char_start": 42103, "char_end": 42111, "token_start": 1, "token_end": 1, "note": null}, {"text": "VP22", "type": "ENTITY", "char_start": 42115, "char_end": 42119, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 249, "sentence_text": "Reactivity with the tegument protein encoded by UL21 was identified for an additional patient .", "sentence_char_start_global": 42183, "sentence_char_end_global": 42278, "entities": [{"text": "tegument protein", "type": "ENTITY", "char_start": 20, "char_end": 36, "token_start": 3, "token_end": 4}, {"text": "UL21", "type": "ENTITY", "char_start": 48, "char_end": 52, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "tegument protein", "type": "ENTITY", "char_start": 42203, "char_end": 42219, "token_start": 3, "token_end": 4, "note": null}, {"text": "UL21", "type": "ENTITY", "char_start": 42231, "char_end": 42235, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 250, "sentence_text": "Three new epitopes were identified in VP16 , a tegument protein associated with VP22 .", "sentence_char_start_global": 42279, "sentence_char_end_global": 42365, "entities": [{"text": "VP16", "type": "ENTITY", "char_start": 38, "char_end": 42, "token_start": 6, "token_end": 6}, {"text": "tegument protein", "type": "ENTITY", "char_start": 47, "char_end": 63, "token_start": 9, "token_end": 10}, {"text": "VP22", "type": "ENTITY", "char_start": 80, "char_end": 84, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "VP16", "type": "ENTITY", "char_start": 42317, "char_end": 42321, "token_start": 6, "token_end": 6, "note": null}, {"text": "tegument protein", "type": "ENTITY", "char_start": 42326, "char_end": 42342, "token_start": 9, "token_end": 10, "note": null}, {"text": "VP22", "type": "ENTITY", "char_start": 42359, "char_end": 42363, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 251, "sentence_text": "Some tegument - specific CD4 T - cell clones exhibited cytotoxic activity against HSV - infected cells .", "sentence_char_start_global": 42366, "sentence_char_end_global": 42470, "entities": [], "entities_global": []}
+{"sentence_id": 252, "sentence_text": "These results suggest that herpes simplex tegument proteins are processed for antigen presentation in vivo and are possible candidate compounds for herpes simplex vaccines .", "sentence_char_start_global": 42471, "sentence_char_end_global": 42644, "entities": [{"text": "herpes simplex tegument proteins", "type": "ENTITY", "char_start": 27, "char_end": 59, "token_start": 4, "token_end": 7}], "entities_global": [{"text": "herpes simplex tegument proteins", "type": "ENTITY", "char_start": 42498, "char_end": 42530, "token_start": 4, "token_end": 7, "note": null}]}
+{"sentence_id": 253, "sentence_text": "Fibrinogen activates NF - kappa B transcription factors in mononuclear phagocytes .", "sentence_char_start_global": 42645, "sentence_char_end_global": 42728, "entities": [{"text": "Fibrinogen", "type": "ENTITY", "char_start": 0, "char_end": 10, "token_start": 0, "token_end": 0}, {"text": "NF - kappa B transcription factors", "type": "ENTITY", "char_start": 21, "char_end": 55, "token_start": 2, "token_end": 7}], "entities_global": [{"text": "Fibrinogen", "type": "ENTITY", "char_start": 42645, "char_end": 42655, "token_start": 0, "token_end": 0, "note": null}, {"text": "NF - kappa B transcription factors", "type": "ENTITY", "char_start": 42666, "char_end": 42700, "token_start": 2, "token_end": 7, "note": null}]}
+{"sentence_id": 254, "sentence_text": "Adhesion to extracellular matrices is known to modulate leukocyte activation , although the mechanisms are not fully understood .", "sentence_char_start_global": 42729, "sentence_char_end_global": 42858, "entities": [], "entities_global": []}
+{"sentence_id": 255, "sentence_text": "Mononuclear phagocytes are exposed to fibrinous provisional matrix throughout migration into inflammatory foci , so this study was undertaken to determine whether fibrinogen triggers activation of NF - kappa B transcription factors .", "sentence_char_start_global": 42859, "sentence_char_end_global": 43092, "entities": [{"text": "NF - kappa B transcription factors", "type": "ENTITY", "char_start": 197, "char_end": 231, "token_start": 26, "token_end": 31}], "entities_global": [{"text": "NF - kappa B transcription factors", "type": "ENTITY", "char_start": 43056, "char_end": 43090, "token_start": 26, "token_end": 31, "note": null}]}
+{"sentence_id": 256, "sentence_text": "U937 cells differentiated with PMA in nonadherent culture were shown to express two fibrinogen - binding integrins , predominately CD11b / CD18 , and to a lesser extent , CD11c / CD18 .", "sentence_char_start_global": 43093, "sentence_char_end_global": 43278, "entities": [{"text": "fibrinogen - binding integrins", "type": "ENTITY", "char_start": 84, "char_end": 114, "token_start": 13, "token_end": 16}, {"text": "CD11b / CD18", "type": "ENTITY", "char_start": 131, "char_end": 143, "token_start": 19, "token_end": 21}, {"text": "CD11c / CD18", "type": "ENTITY", "char_start": 171, "char_end": 183, "token_start": 29, "token_end": 31}], "entities_global": [{"text": "fibrinogen - binding integrins", "type": "ENTITY", "char_start": 43177, "char_end": 43207, "token_start": 13, "token_end": 16, "note": null}, {"text": "CD11b / CD18", "type": "ENTITY", "char_start": 43224, "char_end": 43236, "token_start": 19, "token_end": 21, "note": null}, {"text": "CD11c / CD18", "type": "ENTITY", "char_start": 43264, "char_end": 43276, "token_start": 29, "token_end": 31, "note": null}]}
+{"sentence_id": 257, "sentence_text": "Cells stimulated with fibrinogen ( 10 - 100 microg / ml ) / Mn2 + ( 50 microM ) for 2 h were examined by electrophoretic mobility shift assay .", "sentence_char_start_global": 43279, "sentence_char_end_global": 43422, "entities": [{"text": "fibrinogen", "type": "ENTITY", "char_start": 22, "char_end": 32, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "fibrinogen", "type": "ENTITY", "char_start": 43301, "char_end": 43311, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 258, "sentence_text": "NF - kappa B activation , minimal in unstimulated cells , was substantially up - regulated by fibrinogen .", "sentence_char_start_global": 43423, "sentence_char_end_global": 43529, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 0, "char_end": 12, "token_start": 0, "token_end": 3}, {"text": "fibrinogen", "type": "ENTITY", "char_start": 94, "char_end": 104, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 43423, "char_end": 43435, "token_start": 0, "token_end": 3, "note": null}, {"text": "fibrinogen", "type": "ENTITY", "char_start": 43517, "char_end": 43527, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 259, "sentence_text": "Fibrinogen also caused activation of AP - 1 , but not SP1 or cAMP response element - binding protein ( CREB ) factors .", "sentence_char_start_global": 43530, "sentence_char_end_global": 43649, "entities": [{"text": "Fibrinogen", "type": "ENTITY", "char_start": 0, "char_end": 10, "token_start": 0, "token_end": 0}, {"text": "AP - 1", "type": "ENTITY", "char_start": 37, "char_end": 43, "token_start": 5, "token_end": 7}, {"text": "SP1", "type": "ENTITY", "char_start": 54, "char_end": 57, "token_start": 11, "token_end": 11}, {"text": "cAMP response element - binding protein ( CREB ) factors", "type": "ENTITY", "char_start": 61, "char_end": 117, "token_start": 13, "token_end": 22}], "entities_global": [{"text": "Fibrinogen", "type": "ENTITY", "char_start": 43530, "char_end": 43540, "token_start": 0, "token_end": 0, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 43567, "char_end": 43573, "token_start": 5, "token_end": 7, "note": null}, {"text": "SP1", "type": "ENTITY", "char_start": 43584, "char_end": 43587, "token_start": 11, "token_end": 11, "note": null}, {"text": "cAMP response element - binding protein ( CREB ) factors", "type": "ENTITY", "char_start": 43591, "char_end": 43647, "token_start": 13, "token_end": 22, "note": null}]}
+{"sentence_id": 260, "sentence_text": "Blocking mAbs against CD18 and CD11b abrogated fibrinogen - induced NF - kappa B activation .", "sentence_char_start_global": 43650, "sentence_char_end_global": 43743, "entities": [{"text": "mAbs", "type": "ENTITY", "char_start": 9, "char_end": 13, "token_start": 1, "token_end": 1}, {"text": "CD18", "type": "ENTITY", "char_start": 22, "char_end": 26, "token_start": 3, "token_end": 3}, {"text": "CD11b", "type": "ENTITY", "char_start": 31, "char_end": 36, "token_start": 5, "token_end": 5}, {"text": "fibrinogen", "type": "ENTITY", "char_start": 47, "char_end": 57, "token_start": 7, "token_end": 7}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 68, "char_end": 80, "token_start": 10, "token_end": 13}], "entities_global": [{"text": "mAbs", "type": "ENTITY", "char_start": 43659, "char_end": 43663, "token_start": 1, "token_end": 1, "note": null}, {"text": "CD18", "type": "ENTITY", "char_start": 43672, "char_end": 43676, "token_start": 3, "token_end": 3, "note": null}, {"text": "CD11b", "type": "ENTITY", "char_start": 43681, "char_end": 43686, "token_start": 5, "token_end": 5, "note": null}, {"text": "fibrinogen", "type": "ENTITY", "char_start": 43697, "char_end": 43707, "token_start": 7, "token_end": 7, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 43718, "char_end": 43730, "token_start": 10, "token_end": 13, "note": null}]}
+{"sentence_id": 261, "sentence_text": "To determine the effects on transcriptional regulation , U937 cells were transfected with a plasmid containing the HIV - 1 enhancer ( bearing two NF - kappa B sites ) coupled to a chloramphenicol acetyltransferase ( CAT ) reporter .", "sentence_char_start_global": 43744, "sentence_char_end_global": 43976, "entities": [{"text": "HIV - 1 enhancer", "type": "ENTITY", "char_start": 115, "char_end": 131, "token_start": 17, "token_end": 20}, {"text": "NF - kappa B sites", "type": "ENTITY", "char_start": 146, "char_end": 164, "token_start": 24, "token_end": 28}, {"text": "chloramphenicol acetyltransferase ( CAT ) reporter", "type": "ENTITY", "char_start": 180, "char_end": 230, "token_start": 33, "token_end": 38}], "entities_global": [{"text": "HIV - 1 enhancer", "type": "ENTITY", "char_start": 43859, "char_end": 43875, "token_start": 17, "token_end": 20, "note": null}, {"text": "NF - kappa B sites", "type": "ENTITY", "char_start": 43890, "char_end": 43908, "token_start": 24, "token_end": 28, "note": null}, {"text": "chloramphenicol acetyltransferase ( CAT ) reporter", "type": "ENTITY", "char_start": 43924, "char_end": 43974, "token_start": 33, "token_end": 38, "note": null}]}
+{"sentence_id": 262, "sentence_text": "Cells were subsequently stimulated with 1 ) PMA for 24 h , inducing CAT activity by 2 . 6 - fold , 2 ) fibrinogen / Mn2 + for 2 h , inducing CAT activity by 3 . 2 - fold , or 3 ) costimulation with fibrinogen and PMA , inducing 5 . 7 - fold the CAT activity induced by PMA alone .", "sentence_char_start_global": 43977, "sentence_char_end_global": 44257, "entities": [{"text": "fibrinogen", "type": "ENTITY", "char_start": 103, "char_end": 113, "token_start": 24, "token_end": 24}, {"text": "fibrinogen", "type": "ENTITY", "char_start": 198, "char_end": 208, "token_start": 47, "token_end": 47}], "entities_global": [{"text": "fibrinogen", "type": "ENTITY", "char_start": 44080, "char_end": 44090, "token_start": 24, "token_end": 24, "note": null}, {"text": "fibrinogen", "type": "ENTITY", "char_start": 44175, "char_end": 44185, "token_start": 47, "token_end": 47, "note": null}]}
+{"sentence_id": 263, "sentence_text": "We conclude that contact with fibrinogen - derived proteins may contribute to mononuclear phagocyte activation by signaling through CD11b / CD18 , resulting in selective activation of transcriptional regulatory factors , including NF - kappa B .", "sentence_char_start_global": 44258, "sentence_char_end_global": 44503, "entities": [{"text": "fibrinogen - derived proteins", "type": "ENTITY", "char_start": 30, "char_end": 59, "token_start": 5, "token_end": 8}, {"text": "CD11b / CD18", "type": "ENTITY", "char_start": 132, "char_end": 144, "token_start": 18, "token_end": 20}, {"text": "transcriptional regulatory factors", "type": "ENTITY", "char_start": 184, "char_end": 218, "token_start": 27, "token_end": 29}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 231, "char_end": 243, "token_start": 32, "token_end": 35}], "entities_global": [{"text": "fibrinogen - derived proteins", "type": "ENTITY", "char_start": 44288, "char_end": 44317, "token_start": 5, "token_end": 8, "note": null}, {"text": "CD11b / CD18", "type": "ENTITY", "char_start": 44390, "char_end": 44402, "token_start": 18, "token_end": 20, "note": null}, {"text": "transcriptional regulatory factors", "type": "ENTITY", "char_start": 44442, "char_end": 44476, "token_start": 27, "token_end": 29, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 44489, "char_end": 44501, "token_start": 32, "token_end": 35, "note": null}]}
+{"sentence_id": 264, "sentence_text": "Peripheral blood T cells and monocytes and B cell lines derived from patients with lupus express estrogen receptor transcripts similar to those of normal cells .", "sentence_char_start_global": 44504, "sentence_char_end_global": 44665, "entities": [], "entities_global": []}
+{"sentence_id": 265, "sentence_text": "OBJECTIVE : To identify and characterize estrogen receptor ( ER ) transcripts expressed in immune cells of patients with systemic lupus erythematosus ( SLE ) and healthy donors .", "sentence_char_start_global": 44666, "sentence_char_end_global": 44844, "entities": [{"text": "estrogen receptor ( ER ) transcripts", "type": "ENTITY", "char_start": 41, "char_end": 77, "token_start": 6, "token_end": 11}], "entities_global": [{"text": "estrogen receptor ( ER ) transcripts", "type": "ENTITY", "char_start": 44707, "char_end": 44743, "token_start": 6, "token_end": 11, "note": null}]}
+{"sentence_id": 266, "sentence_text": "METHODS : Peripheral blood monocytes and T cells were prepared from patients with SLE ( n = 6 ) and healthy donors ( n = 8 ) .", "sentence_char_start_global": 44845, "sentence_char_end_global": 44971, "entities": [], "entities_global": []}
+{"sentence_id": 267, "sentence_text": "T cells were separated into CD4 and CD8 .", "sentence_char_start_global": 44972, "sentence_char_end_global": 45013, "entities": [], "entities_global": []}
+{"sentence_id": 268, "sentence_text": "Some monocytes and T cells were stimulated with estradiol , PMA , and ionomycin .", "sentence_char_start_global": 45014, "sentence_char_end_global": 45095, "entities": [], "entities_global": []}
+{"sentence_id": 269, "sentence_text": "Epstein - Barr virus - transformed B cell lines ( n = 7 ) and B cell hybridomas ( n = 2 ) established from patients with SLE and a healthy individual were used as a B cell source .", "sentence_char_start_global": 45096, "sentence_char_end_global": 45276, "entities": [], "entities_global": []}
+{"sentence_id": 270, "sentence_text": "These cells were examined for ER mRNA by reverse transcription nested polymerase chain reaction .", "sentence_char_start_global": 45277, "sentence_char_end_global": 45374, "entities": [{"text": "ER mRNA", "type": "ENTITY", "char_start": 30, "char_end": 37, "token_start": 5, "token_end": 6}], "entities_global": [{"text": "ER mRNA", "type": "ENTITY", "char_start": 45307, "char_end": 45314, "token_start": 5, "token_end": 6, "note": null}]}
+{"sentence_id": 271, "sentence_text": "Amplified cDNA were sequenced by standard methods .", "sentence_char_start_global": 45375, "sentence_char_end_global": 45426, "entities": [{"text": "cDNA", "type": "ENTITY", "char_start": 10, "char_end": 14, "token_start": 1, "token_end": 1}], "entities_global": [{"text": "cDNA", "type": "ENTITY", "char_start": 45385, "char_end": 45389, "token_start": 1, "token_end": 1, "note": null}]}
+{"sentence_id": 272, "sentence_text": "RESULTS : In all cells tested , ER mRNA was expressed without prior in vitro stimulation .", "sentence_char_start_global": 45427, "sentence_char_end_global": 45517, "entities": [{"text": "ER mRNA", "type": "ENTITY", "char_start": 32, "char_end": 39, "token_start": 7, "token_end": 8}], "entities_global": [{"text": "ER mRNA", "type": "ENTITY", "char_start": 45459, "char_end": 45466, "token_start": 7, "token_end": 8, "note": null}]}
+{"sentence_id": 273, "sentence_text": "Partial sequences from exons 1 - 8 were nearly identical to the published sequence of the human ER mRNA .", "sentence_char_start_global": 45518, "sentence_char_end_global": 45623, "entities": [{"text": "exons 1 - 8", "type": "ENTITY", "char_start": 23, "char_end": 34, "token_start": 3, "token_end": 6}, {"text": "human ER mRNA", "type": "ENTITY", "char_start": 90, "char_end": 103, "token_start": 16, "token_end": 18}], "entities_global": [{"text": "exons 1 - 8", "type": "ENTITY", "char_start": 45541, "char_end": 45552, "token_start": 3, "token_end": 6, "note": null}, {"text": "human ER mRNA", "type": "ENTITY", "char_start": 45608, "char_end": 45621, "token_start": 16, "token_end": 18, "note": null}]}
+{"sentence_id": 274, "sentence_text": "There were no notable differences in the ER transcripts between patients and healthy controls .", "sentence_char_start_global": 45624, "sentence_char_end_global": 45719, "entities": [{"text": "ER transcripts", "type": "ENTITY", "char_start": 41, "char_end": 55, "token_start": 7, "token_end": 8}], "entities_global": [{"text": "ER transcripts", "type": "ENTITY", "char_start": 45665, "char_end": 45679, "token_start": 7, "token_end": 8, "note": null}]}
+{"sentence_id": 275, "sentence_text": "Variant receptor transcripts lacking exon 5 or exon 7 , which encodes the hormone binding domain , were identified in the majority of the cells .", "sentence_char_start_global": 45720, "sentence_char_end_global": 45865, "entities": [{"text": "exon 5", "type": "ENTITY", "char_start": 37, "char_end": 43, "token_start": 4, "token_end": 5}, {"text": "exon 7", "type": "ENTITY", "char_start": 47, "char_end": 53, "token_start": 7, "token_end": 8}, {"text": "hormone binding domain", "type": "ENTITY", "char_start": 74, "char_end": 96, "token_start": 13, "token_end": 15}], "entities_global": [{"text": "exon 5", "type": "ENTITY", "char_start": 45757, "char_end": 45763, "token_start": 4, "token_end": 5, "note": null}, {"text": "exon 7", "type": "ENTITY", "char_start": 45767, "char_end": 45773, "token_start": 7, "token_end": 8, "note": null}, {"text": "hormone binding domain", "type": "ENTITY", "char_start": 45794, "char_end": 45816, "token_start": 13, "token_end": 15, "note": null}]}
+{"sentence_id": 276, "sentence_text": "Precise deletion of the exons suggests that they are alternatively spliced transcripts .", "sentence_char_start_global": 45866, "sentence_char_end_global": 45954, "entities": [], "entities_global": []}
+{"sentence_id": 277, "sentence_text": "Whether the detected transcripts are translated into functional receptor proteins remains to be determined .", "sentence_char_start_global": 45955, "sentence_char_end_global": 46063, "entities": [{"text": "functional receptor proteins", "type": "ENTITY", "char_start": 53, "char_end": 81, "token_start": 7, "token_end": 9}], "entities_global": [{"text": "functional receptor proteins", "type": "ENTITY", "char_start": 46008, "char_end": 46036, "token_start": 7, "token_end": 9, "note": null}]}
+{"sentence_id": 278, "sentence_text": "In vitro stimulation did not affect ER mRNA expression .", "sentence_char_start_global": 46064, "sentence_char_end_global": 46120, "entities": [{"text": "ER mRNA", "type": "ENTITY", "char_start": 36, "char_end": 43, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "ER mRNA", "type": "ENTITY", "char_start": 46100, "char_end": 46107, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 279, "sentence_text": "The presence of variants did not correlate with disease activity or medication .", "sentence_char_start_global": 46121, "sentence_char_end_global": 46201, "entities": [], "entities_global": []}
+{"sentence_id": 280, "sentence_text": "CONCLUSION : Monocytes , T cells , and B cells in patients express transcripts of the normal wild type ER and the hormone binding domain variants in vivo .", "sentence_char_start_global": 46202, "sentence_char_end_global": 46357, "entities": [{"text": "wild type ER", "type": "ENTITY", "char_start": 93, "char_end": 105, "token_start": 17, "token_end": 19}, {"text": "hormone binding domain variants", "type": "ENTITY", "char_start": 114, "char_end": 145, "token_start": 22, "token_end": 25}], "entities_global": [{"text": "wild type ER", "type": "ENTITY", "char_start": 46295, "char_end": 46307, "token_start": 17, "token_end": 19, "note": null}, {"text": "hormone binding domain variants", "type": "ENTITY", "char_start": 46316, "char_end": 46347, "token_start": 22, "token_end": 25, "note": null}]}
+{"sentence_id": 281, "sentence_text": "DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF - kappa B and AP - 1 .", "sentence_char_start_global": 46358, "sentence_char_end_global": 46499, "entities": [{"text": "Fas ligand", "type": "ENTITY", "char_start": 41, "char_end": 51, "token_start": 6, "token_end": 7}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 116, "char_end": 128, "token_start": 18, "token_end": 21}, {"text": "AP - 1", "type": "ENTITY", "char_start": 133, "char_end": 139, "token_start": 23, "token_end": 25}], "entities_global": [{"text": "Fas ligand", "type": "ENTITY", "char_start": 46399, "char_end": 46409, "token_start": 6, "token_end": 7, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 46474, "char_end": 46486, "token_start": 18, "token_end": 21, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 46491, "char_end": 46497, "token_start": 23, "token_end": 25, "note": null}]}
+{"sentence_id": 282, "sentence_text": "Apoptosis induced by DNA damage and other stresses can proceed via expression of Fas ligand ( FasL ) and ligation of its receptor , Fas ( CD95 ) .", "sentence_char_start_global": 46500, "sentence_char_end_global": 46646, "entities": [{"text": "Fas ligand", "type": "ENTITY", "char_start": 81, "char_end": 91, "token_start": 13, "token_end": 14}, {"text": "FasL", "type": "ENTITY", "char_start": 94, "char_end": 98, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "Fas ligand", "type": "ENTITY", "char_start": 46581, "char_end": 46591, "token_start": 13, "token_end": 14, "note": null}, {"text": "FasL", "type": "ENTITY", "char_start": 46594, "char_end": 46598, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 283, "sentence_text": "We report that activation of the two transcription factors NF - kappa B and AP - 1 is crucially involved in FasL expression induced by etoposide , teniposide , and UV irradiation .", "sentence_char_start_global": 46647, "sentence_char_end_global": 46827, "entities": [{"text": "transcription factors NF - kappa B and AP - 1", "type": "ENTITY", "char_start": 37, "char_end": 82, "token_start": 7, "token_end": 16}, {"text": "FasL", "type": "ENTITY", "char_start": 108, "char_end": 112, "token_start": 21, "token_end": 21}], "entities_global": [{"text": "transcription factors NF - kappa B and AP - 1", "type": "ENTITY", "char_start": 46684, "char_end": 46729, "token_start": 7, "token_end": 16, "note": null}, {"text": "FasL", "type": "ENTITY", "char_start": 46755, "char_end": 46759, "token_start": 21, "token_end": 21, "note": null}]}
+{"sentence_id": 284, "sentence_text": "A nondegradable mutant of I kappa B blocked both FasL expression and apoptosis induced by DNA damage but not Fas ligation .", "sentence_char_start_global": 46828, "sentence_char_end_global": 46951, "entities": [{"text": "nondegradable mutant", "type": "ENTITY", "char_start": 2, "char_end": 22, "token_start": 1, "token_end": 2}, {"text": "I kappa B", "type": "ENTITY", "char_start": 26, "char_end": 35, "token_start": 4, "token_end": 6}, {"text": "FasL", "type": "ENTITY", "char_start": 49, "char_end": 53, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "nondegradable mutant", "type": "ENTITY", "char_start": 46830, "char_end": 46850, "token_start": 1, "token_end": 2, "note": null}, {"text": "I kappa B", "type": "ENTITY", "char_start": 46854, "char_end": 46863, "token_start": 4, "token_end": 6, "note": null}, {"text": "FasL", "type": "ENTITY", "char_start": 46877, "char_end": 46881, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 285, "sentence_text": "These stimuli also induced the stress - activated kinase pathway ( SAPK / JNK ) , which was required for the maximal induction of apoptosis .", "sentence_char_start_global": 46952, "sentence_char_end_global": 47093, "entities": [], "entities_global": []}
+{"sentence_id": 286, "sentence_text": "A 1 . 2 kb FasL promoter responded to DNA damage , as well as coexpression with p65 Rel or Fos / Jun .", "sentence_char_start_global": 47094, "sentence_char_end_global": 47196, "entities": [{"text": "FasL promoter", "type": "ENTITY", "char_start": 11, "char_end": 24, "token_start": 5, "token_end": 6}, {"text": "p65 Rel", "type": "ENTITY", "char_start": 80, "char_end": 87, "token_start": 17, "token_end": 18}, {"text": "Fos / Jun", "type": "ENTITY", "char_start": 91, "char_end": 100, "token_start": 20, "token_end": 22}], "entities_global": [{"text": "FasL promoter", "type": "ENTITY", "char_start": 47105, "char_end": 47118, "token_start": 5, "token_end": 6, "note": null}, {"text": "p65 Rel", "type": "ENTITY", "char_start": 47174, "char_end": 47181, "token_start": 17, "token_end": 18, "note": null}, {"text": "Fos / Jun", "type": "ENTITY", "char_start": 47185, "char_end": 47194, "token_start": 20, "token_end": 22, "note": null}]}
+{"sentence_id": 287, "sentence_text": "Mutations in the relevant NF - kappa B and AP - 1 binding sites eliminated these responses .", "sentence_char_start_global": 47197, "sentence_char_end_global": 47289, "entities": [{"text": "NF - kappa B and AP - 1 binding sites", "type": "ENTITY", "char_start": 26, "char_end": 63, "token_start": 4, "token_end": 13}], "entities_global": [{"text": "NF - kappa B and AP - 1 binding sites", "type": "ENTITY", "char_start": 47223, "char_end": 47260, "token_start": 4, "token_end": 13, "note": null}]}
+{"sentence_id": 288, "sentence_text": "Thus , activation of NF - kappa B and AP - 1 contributes to stress - induced apoptosis via the expression of FasL .", "sentence_char_start_global": 47290, "sentence_char_end_global": 47405, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 21, "char_end": 33, "token_start": 4, "token_end": 7}, {"text": "AP - 1", "type": "ENTITY", "char_start": 38, "char_end": 44, "token_start": 9, "token_end": 11}, {"text": "FasL", "type": "ENTITY", "char_start": 109, "char_end": 113, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 47311, "char_end": 47323, "token_start": 4, "token_end": 7, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 47328, "char_end": 47334, "token_start": 9, "token_end": 11, "note": null}, {"text": "FasL", "type": "ENTITY", "char_start": 47399, "char_end": 47403, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 289, "sentence_text": "A small , nonpeptidyl mimic of granulocyte - colony - stimulating factor [ see commetns ]", "sentence_char_start_global": 47406, "sentence_char_end_global": 47495, "entities": [{"text": "granulocyte - colony - stimulating factor", "type": "ENTITY", "char_start": 31, "char_end": 72, "token_start": 6, "token_end": 11}], "entities_global": [{"text": "granulocyte - colony - stimulating factor", "type": "ENTITY", "char_start": 47437, "char_end": 47478, "token_start": 6, "token_end": 11, "note": null}]}
+{"sentence_id": 290, "sentence_text": "A nonpeptidyl small molecule SB 247464 , capable of activating granulocyte - colony - stimulating factor ( G - CSF ) signal transduction pathways , was identified in a high - throughput assay in cultured cells .", "sentence_char_start_global": 47496, "sentence_char_end_global": 47707, "entities": [{"text": "granulocyte - colony - stimulating factor", "type": "ENTITY", "char_start": 63, "char_end": 104, "token_start": 10, "token_end": 15}, {"text": "G - CSF", "type": "ENTITY", "char_start": 107, "char_end": 114, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "granulocyte - colony - stimulating factor", "type": "ENTITY", "char_start": 47559, "char_end": 47600, "token_start": 10, "token_end": 15, "note": null}, {"text": "G - CSF", "type": "ENTITY", "char_start": 47603, "char_end": 47610, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 291, "sentence_text": "Like G - CSF , SB 247464 induced tyrosine phosphorylation of multiple signaling proteins and stimulated primary murine bone marrow cells to form granulocytic colonies in vitro .", "sentence_char_start_global": 47708, "sentence_char_end_global": 47885, "entities": [{"text": "G - CSF", "type": "ENTITY", "char_start": 5, "char_end": 12, "token_start": 1, "token_end": 3}, {"text": "multiple signaling proteins", "type": "ENTITY", "char_start": 61, "char_end": 88, "token_start": 11, "token_end": 13}], "entities_global": [{"text": "G - CSF", "type": "ENTITY", "char_start": 47713, "char_end": 47720, "token_start": 1, "token_end": 3, "note": null}, {"text": "multiple signaling proteins", "type": "ENTITY", "char_start": 47769, "char_end": 47796, "token_start": 11, "token_end": 13, "note": null}]}
+{"sentence_id": 292, "sentence_text": "It also elevated peripheral blood neutrophil counts in mice .", "sentence_char_start_global": 47886, "sentence_char_end_global": 47947, "entities": [], "entities_global": []}
+{"sentence_id": 293, "sentence_text": "The extracellular domain of the murine G - CSF receptor was required for the activity of SB 247464 , suggesting that the compound acts by oligomerizing receptor chains .", "sentence_char_start_global": 47948, "sentence_char_end_global": 48117, "entities": [{"text": "murine G - CSF receptor", "type": "ENTITY", "char_start": 32, "char_end": 55, "token_start": 5, "token_end": 9}, {"text": "oligomerizing receptor chains", "type": "ENTITY", "char_start": 138, "char_end": 167, "token_start": 25, "token_end": 27}], "entities_global": [{"text": "murine G - CSF receptor", "type": "ENTITY", "char_start": 47980, "char_end": 48003, "token_start": 5, "token_end": 9, "note": null}, {"text": "oligomerizing receptor chains", "type": "ENTITY", "char_start": 48086, "char_end": 48115, "token_start": 25, "token_end": 27, "note": null}]}
+{"sentence_id": 294, "sentence_text": "The results indicate that a small molecule can activate a receptor that normally binds a relatively large protein ligand .", "sentence_char_start_global": 48118, "sentence_char_end_global": 48240, "entities": [], "entities_global": []}
+{"sentence_id": 295, "sentence_text": "Minimal residual disease in acute myelogenous leukemia with PML / RAR alpha or AML1 / ETO mRNA and phenotypic analysis of possible T and natural killer cells in bone marrow .", "sentence_char_start_global": 48241, "sentence_char_end_global": 48415, "entities": [{"text": "PML / RAR alpha", "type": "ENTITY", "char_start": 60, "char_end": 75, "token_start": 8, "token_end": 11}, {"text": "AML1 / ETO mRNA", "type": "ENTITY", "char_start": 79, "char_end": 94, "token_start": 13, "token_end": 16}], "entities_global": [{"text": "PML / RAR alpha", "type": "ENTITY", "char_start": 48301, "char_end": 48316, "token_start": 8, "token_end": 11, "note": null}, {"text": "AML1 / ETO mRNA", "type": "ENTITY", "char_start": 48320, "char_end": 48335, "token_start": 13, "token_end": 16, "note": null}]}
+{"sentence_id": 296, "sentence_text": "Here we studied minimal residual disease ( MRD ) of patients with acute myeloid leukemia ( AML ) who have PML / RAR alpha or AML1 / ETO as well as the phenotypic analysis of lymphocyte subsets involved in antitumor immunity .", "sentence_char_start_global": 48416, "sentence_char_end_global": 48641, "entities": [{"text": "PML / RAR alpha", "type": "ENTITY", "char_start": 106, "char_end": 121, "token_start": 20, "token_end": 23}, {"text": "AML1 / ETO", "type": "ENTITY", "char_start": 125, "char_end": 135, "token_start": 25, "token_end": 27}], "entities_global": [{"text": "PML / RAR alpha", "type": "ENTITY", "char_start": 48522, "char_end": 48537, "token_start": 20, "token_end": 23, "note": null}, {"text": "AML1 / ETO", "type": "ENTITY", "char_start": 48541, "char_end": 48551, "token_start": 25, "token_end": 27, "note": null}]}
+{"sentence_id": 297, "sentence_text": "Eight patients in long - term ( LT ; 3 to 15 years ) and 15 patients in short - term ( ST ; up to 3 years ) remission were studied .", "sentence_char_start_global": 48642, "sentence_char_end_global": 48774, "entities": [], "entities_global": []}
+{"sentence_id": 298, "sentence_text": "Using the reverse transcription - polymerase chain reaction ( RT ) assay , the limit of detection was 10 ( - 5 ) to 10 ( - 6 ) for PML / RAR alpha transcript and 10 ( - 4 ) to 10 ( - 5 ) for the AML1 / ETO transcript .", "sentence_char_start_global": 48775, "sentence_char_end_global": 48993, "entities": [{"text": "PML / RAR alpha transcript", "type": "ENTITY", "char_start": 131, "char_end": 157, "token_start": 30, "token_end": 34}, {"text": "AML1 / ETO transcript", "type": "ENTITY", "char_start": 195, "char_end": 216, "token_start": 49, "token_end": 52}], "entities_global": [{"text": "PML / RAR alpha transcript", "type": "ENTITY", "char_start": 48906, "char_end": 48932, "token_start": 30, "token_end": 34, "note": null}, {"text": "AML1 / ETO transcript", "type": "ENTITY", "char_start": 48970, "char_end": 48991, "token_start": 49, "token_end": 52, "note": null}]}
+{"sentence_id": 299, "sentence_text": "Simultaneously , T lymphocyte subsets and NK cells from the peripheral blood ( PB ) and bone marrow ( BM ) were investigated by flow cytometric analysis .", "sentence_char_start_global": 48994, "sentence_char_end_global": 49148, "entities": [], "entities_global": []}
+{"sentence_id": 300, "sentence_text": "Four of the eight patients in LT and 7 of the 15 patients in ST remission were MRD - positive .", "sentence_char_start_global": 49149, "sentence_char_end_global": 49244, "entities": [], "entities_global": []}
+{"sentence_id": 301, "sentence_text": "Although all MRD - positive patients in LT remission are still until now event - free , 3 of the 7 MRD - positive ( MRD + ) patients in ST remission soon relapsed .", "sentence_char_start_global": 49245, "sentence_char_end_global": 49409, "entities": [], "entities_global": []}
+{"sentence_id": 302, "sentence_text": "The total populations of CD4 + , CD8 + and CD56 + [ possible T - cell and natural killer ( T / NK ) populations ] in the BM of ST patients and MRD + / LT patients were significantly ( p < . 01 ) low .", "sentence_char_start_global": 49410, "sentence_char_end_global": 49610, "entities": [{"text": "CD4", "type": "ENTITY", "char_start": 25, "char_end": 28, "token_start": 4, "token_end": 4}, {"text": "CD8", "type": "ENTITY", "char_start": 33, "char_end": 36, "token_start": 7, "token_end": 7}, {"text": "CD56", "type": "ENTITY", "char_start": 43, "char_end": 47, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "CD4", "type": "ENTITY", "char_start": 49435, "char_end": 49438, "token_start": 4, "token_end": 4, "note": null}, {"text": "CD8", "type": "ENTITY", "char_start": 49443, "char_end": 49446, "token_start": 7, "token_end": 7, "note": null}, {"text": "CD56", "type": "ENTITY", "char_start": 49453, "char_end": 49457, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 303, "sentence_text": "The CD8 + CD28 + population showed the same tendency ( p < . 01 - . 02 ) .", "sentence_char_start_global": 49611, "sentence_char_end_global": 49685, "entities": [], "entities_global": []}
+{"sentence_id": 304, "sentence_text": "The T / NK subsets in the BM of MRD - negative ( MRD - ) LT ( MRD - / LT ) patients showed similar numbers of cells as normal volunteers .", "sentence_char_start_global": 49686, "sentence_char_end_global": 49824, "entities": [], "entities_global": []}
+{"sentence_id": 305, "sentence_text": "Basically , the total percentage of the CD4 + , CD8 + and CD56 + cell populations in the BM was increased and in the following order : MRD - / LT patients , normal volunteers , MRD + / LT patients and MRD + or - / ST patients .", "sentence_char_start_global": 49825, "sentence_char_end_global": 50052, "entities": [], "entities_global": []}
+{"sentence_id": 306, "sentence_text": "The percentages of the T / NK - cell subsets in the PB were not significantly different among these groups .", "sentence_char_start_global": 50053, "sentence_char_end_global": 50161, "entities": [], "entities_global": []}
+{"sentence_id": 307, "sentence_text": "Thus , the difference of the possible T / NK - cell phenotype in the BM may strongly influence clinical and molecular remission .", "sentence_char_start_global": 50162, "sentence_char_end_global": 50291, "entities": [], "entities_global": []}
+{"sentence_id": 308, "sentence_text": "These results still remain to be confirmed by further studies of the functional anti - tumor immunity of T / NK cells of AML in remission .", "sentence_char_start_global": 50292, "sentence_char_end_global": 50431, "entities": [], "entities_global": []}
+{"sentence_id": 309, "sentence_text": "Mycobacterium tuberculosis mannose - capped lipoarabinomannan can induce NF - kappaB - dependent activation of human immunodeficiency virus type 1 long terminal repeat in T cells .", "sentence_char_start_global": 50432, "sentence_char_end_global": 50612, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 73, "char_end": 84, "token_start": 8, "token_end": 10}, {"text": "human immunodeficiency virus type 1 long terminal repeat", "type": "ENTITY", "char_start": 111, "char_end": 167, "token_start": 15, "token_end": 22}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 50505, "char_end": 50516, "token_start": 8, "token_end": 10, "note": null}, {"text": "human immunodeficiency virus type 1 long terminal repeat", "type": "ENTITY", "char_start": 50543, "char_end": 50599, "token_start": 15, "token_end": 22, "note": null}]}
+{"sentence_id": 310, "sentence_text": "Tuberculosis has emerged as an epidemic , extended by the large number of individuals infected with human immunodeficiency virus type 1 ( HIV - 1 ) .", "sentence_char_start_global": 50613, "sentence_char_end_global": 50762, "entities": [], "entities_global": []}
+{"sentence_id": 311, "sentence_text": "The major goal of this study was to determine whether the mycobacterial cell wall component mannose - capped lipoarabinomannan ( ManLAM ) of Mycobacterium tuberculosis ( M . tuberculosis ) could activate transcription of HIV - 1 in T cells with the use of an in vitro cell culture system .", "sentence_char_start_global": 50763, "sentence_char_end_global": 51052, "entities": [], "entities_global": []}
+{"sentence_id": 312, "sentence_text": "These experiments are of prime importance considering that CD4 - expressing T lymphocytes represent the major virus reservoir in the peripheral blood of infected individuals .", "sentence_char_start_global": 51053, "sentence_char_end_global": 51228, "entities": [{"text": "CD4", "type": "ENTITY", "char_start": 59, "char_end": 62, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "CD4", "type": "ENTITY", "char_start": 51112, "char_end": 51115, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 313, "sentence_text": "Using the 1G5 cell line harbouring the luciferase reporter gene under the control of the HIV - 1 LTR , it was first found that culture protein filtrates ( CFP ) from M . tuberculosis or purified ManLAM could activate HIV - 1 LTR - dependent gene expression unlike similarly prepared CFP extracts devoid of ManLAM .", "sentence_char_start_global": 51229, "sentence_char_end_global": 51543, "entities": [{"text": "HIV - 1 LTR", "type": "ENTITY", "char_start": 89, "char_end": 100, "token_start": 15, "token_end": 18}, {"text": "HIV - 1 LTR - dependent gene", "type": "ENTITY", "char_start": 217, "char_end": 245, "token_start": 40, "token_end": 46}], "entities_global": [{"text": "HIV - 1 LTR", "type": "ENTITY", "char_start": 51318, "char_end": 51329, "token_start": 15, "token_end": 18, "note": null}, {"text": "HIV - 1 LTR - dependent gene", "type": "ENTITY", "char_start": 51446, "char_end": 51474, "token_start": 40, "token_end": 46, "note": null}]}
+{"sentence_id": 314, "sentence_text": "The implication of protein tyrosine kinase ( s ) , protein kinase A and / or protein kinase C was highlighted by the abrogation of the ManLAM - mediated activation of HIV - 1 LTR - driven gene expression using herbimycin A and H7 .", "sentence_char_start_global": 51544, "sentence_char_end_global": 51775, "entities": [{"text": "protein tyrosine kinase ( s )", "type": "ENTITY", "char_start": 19, "char_end": 48, "token_start": 3, "token_end": 8}, {"text": "protein kinase A", "type": "ENTITY", "char_start": 51, "char_end": 67, "token_start": 10, "token_end": 12}, {"text": "protein kinase C", "type": "ENTITY", "char_start": 77, "char_end": 93, "token_start": 16, "token_end": 18}], "entities_global": [{"text": "protein tyrosine kinase ( s )", "type": "ENTITY", "char_start": 51563, "char_end": 51592, "token_start": 3, "token_end": 8, "note": null}, {"text": "protein kinase A", "type": "ENTITY", "char_start": 51595, "char_end": 51611, "token_start": 10, "token_end": 12, "note": null}, {"text": "protein kinase C", "type": "ENTITY", "char_start": 51621, "char_end": 51637, "token_start": 16, "token_end": 18, "note": null}]}
+{"sentence_id": 315, "sentence_text": "It was also determined , using electrophoresis mobility shift assays , that M . tuberculosis ManLAM led to the nuclear translocation of the transcription factor NF - kappaB .", "sentence_char_start_global": 51776, "sentence_char_end_global": 51950, "entities": [{"text": "transcription factor NF - kappaB", "type": "ENTITY", "char_start": 140, "char_end": 172, "token_start": 23, "token_end": 27}], "entities_global": [{"text": "transcription factor NF - kappaB", "type": "ENTITY", "char_start": 51916, "char_end": 51948, "token_start": 23, "token_end": 27, "note": null}]}
+{"sentence_id": 316, "sentence_text": "M . tuberculosis ManLAM resulted in clear induction of the luciferase gene placed under the control of the wild - type , but not the kappaB - mutated , HIV - 1 LTR region .", "sentence_char_start_global": 51951, "sentence_char_end_global": 52123, "entities": [{"text": "luciferase gene", "type": "ENTITY", "char_start": 59, "char_end": 74, "token_start": 10, "token_end": 11}, {"text": "wild - type , but not the kappaB - mutated , HIV - 1 LTR region", "type": "ENTITY", "char_start": 107, "char_end": 170, "token_start": 18, "token_end": 33}], "entities_global": [{"text": "luciferase gene", "type": "ENTITY", "char_start": 52010, "char_end": 52025, "token_start": 10, "token_end": 11, "note": null}, {"text": "wild - type , but not the kappaB - mutated , HIV - 1 LTR region", "type": "ENTITY", "char_start": 52058, "char_end": 52121, "token_start": 18, "token_end": 33, "note": null}]}
+{"sentence_id": 317, "sentence_text": "Finally , the ManLAM - mediated activation of HIV - 1 LTR transcription was found to be independent of the autocrine or paracrine action of endogenous TNF - alpha .", "sentence_char_start_global": 52124, "sentence_char_end_global": 52288, "entities": [{"text": "endogenous TNF - alpha", "type": "ENTITY", "char_start": 140, "char_end": 162, "token_start": 25, "token_end": 28}], "entities_global": [{"text": "endogenous TNF - alpha", "type": "ENTITY", "char_start": 52264, "char_end": 52286, "token_start": 25, "token_end": 28, "note": null}]}
+{"sentence_id": 318, "sentence_text": "The results suggest that M . tuberculosis can upregulate HIV - 1 expression in T cells and could thus have the potential to influence the pathogenesis of HIV - 1 infection .", "sentence_char_start_global": 52289, "sentence_char_end_global": 52462, "entities": [], "entities_global": []}
+{"sentence_id": 319, "sentence_text": "Human immunodeficiency virus type 1 long terminal repeat quasispecies differ in basal transcription and nuclear factor recruitment in human glial cells and lymphocytes .", "sentence_char_start_global": 52463, "sentence_char_end_global": 52632, "entities": [{"text": "Human immunodeficiency virus type 1 long terminal repeat", "type": "ENTITY", "char_start": 0, "char_end": 56, "token_start": 0, "token_end": 7}], "entities_global": [{"text": "Human immunodeficiency virus type 1 long terminal repeat", "type": "ENTITY", "char_start": 52463, "char_end": 52519, "token_start": 0, "token_end": 7, "note": null}]}
+{"sentence_id": 320, "sentence_text": "The generation of genomic diversity during the course of infection has the potential to affect all aspects of HIV - 1 replication , including expression of the proviral genome .", "sentence_char_start_global": 52633, "sentence_char_end_global": 52810, "entities": [], "entities_global": []}
+{"sentence_id": 321, "sentence_text": "To gain a better understanding of the impact of long terminal repeat ( LTR ) sequence diversity on LTR - directed gene expression in cells of the central nervous system ( CNS ) and immune system , we amplified and cloned LTRs from proviral DNA in HIV - 1 - infected peripheral blood .", "sentence_char_start_global": 52811, "sentence_char_end_global": 53095, "entities": [{"text": "long terminal repeat", "type": "ENTITY", "char_start": 48, "char_end": 68, "token_start": 9, "token_end": 11}, {"text": "LTR", "type": "ENTITY", "char_start": 71, "char_end": 74, "token_start": 13, "token_end": 13}, {"text": "LTR - directed gene", "type": "ENTITY", "char_start": 99, "char_end": 118, "token_start": 18, "token_end": 21}, {"text": "LTRs", "type": "ENTITY", "char_start": 221, "char_end": 225, "token_start": 41, "token_end": 41}], "entities_global": [{"text": "long terminal repeat", "type": "ENTITY", "char_start": 52859, "char_end": 52879, "token_start": 9, "token_end": 11, "note": null}, {"text": "LTR", "type": "ENTITY", "char_start": 52882, "char_end": 52885, "token_start": 13, "token_end": 13, "note": null}, {"text": "LTR - directed gene", "type": "ENTITY", "char_start": 52910, "char_end": 52929, "token_start": 18, "token_end": 21, "note": null}, {"text": "LTRs", "type": "ENTITY", "char_start": 53032, "char_end": 53036, "token_start": 41, "token_end": 41, "note": null}]}
+{"sentence_id": 322, "sentence_text": "Sequence analysis of nineteen LTRs cloned from 2 adult and 3 pediatric patients revealed an average of 33 nucleotide changes ( with respect to the sequence of the LAI LTR ) within the 455 - bp U3 region .", "sentence_char_start_global": 53096, "sentence_char_end_global": 53300, "entities": [{"text": "LTRs", "type": "ENTITY", "char_start": 30, "char_end": 34, "token_start": 4, "token_end": 4}, {"text": "LAI LTR", "type": "ENTITY", "char_start": 163, "char_end": 170, "token_start": 28, "token_end": 29}, {"text": "455 - bp U3 region", "type": "ENTITY", "char_start": 184, "char_end": 202, "token_start": 33, "token_end": 37}], "entities_global": [{"text": "LTRs", "type": "ENTITY", "char_start": 53126, "char_end": 53130, "token_start": 4, "token_end": 4, "note": null}, {"text": "LAI LTR", "type": "ENTITY", "char_start": 53259, "char_end": 53266, "token_start": 28, "token_end": 29, "note": null}, {"text": "455 - bp U3 region", "type": "ENTITY", "char_start": 53280, "char_end": 53298, "token_start": 33, "token_end": 37, "note": null}]}
+{"sentence_id": 323, "sentence_text": "Transient expression analyses in cells of neuroglial and lymphocytic origin demonstrated that some of these LTRs had activities which varied significantly from the LAI LTR in U - 373 MG cells ( an astrocytoma cell line ) as well as in Jurkat cells ( a CD4 - positive lymphocyte cell line ) .", "sentence_char_start_global": 53301, "sentence_char_end_global": 53592, "entities": [{"text": "LTRs", "type": "ENTITY", "char_start": 108, "char_end": 112, "token_start": 15, "token_end": 15}, {"text": "LAI LTR", "type": "ENTITY", "char_start": 164, "char_end": 171, "token_start": 23, "token_end": 24}], "entities_global": [{"text": "LTRs", "type": "ENTITY", "char_start": 53409, "char_end": 53413, "token_start": 15, "token_end": 15, "note": null}, {"text": "LAI LTR", "type": "ENTITY", "char_start": 53465, "char_end": 53472, "token_start": 23, "token_end": 24, "note": null}]}
+{"sentence_id": 324, "sentence_text": "While LTRs which demonstrated the highest activities in U - 373 MG cells also yielded high activities in Jurkat cells , the LTRs were generally more active in Jurkat cells when compared to the LAI LTR .", "sentence_char_start_global": 53593, "sentence_char_end_global": 53795, "entities": [{"text": "LTRs", "type": "ENTITY", "char_start": 6, "char_end": 10, "token_start": 1, "token_end": 1}, {"text": "LTRs", "type": "ENTITY", "char_start": 124, "char_end": 128, "token_start": 22, "token_end": 22}, {"text": "LAI LTR", "type": "ENTITY", "char_start": 193, "char_end": 200, "token_start": 34, "token_end": 35}], "entities_global": [{"text": "LTRs", "type": "ENTITY", "char_start": 53599, "char_end": 53603, "token_start": 1, "token_end": 1, "note": null}, {"text": "LTRs", "type": "ENTITY", "char_start": 53717, "char_end": 53721, "token_start": 22, "token_end": 22, "note": null}, {"text": "LAI LTR", "type": "ENTITY", "char_start": 53786, "char_end": 53793, "token_start": 34, "token_end": 35, "note": null}]}
+{"sentence_id": 325, "sentence_text": "Differences in LTR sequence also resulted in differences in transcription factor recruitment to cis - acting sites within the U3 region of the LTR , as demonstrated by electrophoretic mobility shift assays .", "sentence_char_start_global": 53796, "sentence_char_end_global": 54003, "entities": [{"text": "LTR sequence", "type": "ENTITY", "char_start": 15, "char_end": 27, "token_start": 2, "token_end": 3}, {"text": "cis - acting sites", "type": "ENTITY", "char_start": 96, "char_end": 114, "token_start": 13, "token_end": 16}, {"text": "U3 region", "type": "ENTITY", "char_start": 126, "char_end": 135, "token_start": 19, "token_end": 20}, {"text": "LTR", "type": "ENTITY", "char_start": 143, "char_end": 146, "token_start": 23, "token_end": 23}], "entities_global": [{"text": "LTR sequence", "type": "ENTITY", "char_start": 53811, "char_end": 53823, "token_start": 2, "token_end": 3, "note": null}, {"text": "cis - acting sites", "type": "ENTITY", "char_start": 53892, "char_end": 53910, "token_start": 13, "token_end": 16, "note": null}, {"text": "U3 region", "type": "ENTITY", "char_start": 53922, "char_end": 53931, "token_start": 19, "token_end": 20, "note": null}, {"text": "LTR", "type": "ENTITY", "char_start": 53939, "char_end": 53942, "token_start": 23, "token_end": 23, "note": null}]}
+{"sentence_id": 326, "sentence_text": "In particular , naturally occurring sequence variation impacted transcription factor binding to an activating transcription factor / cAMP response element binding ( ATF / CREB ) binding site ( located between the LEF - 1 and distal NF - kappaB transcription factor binding sites ) that we identified in previous studies of the HIV - 1 LTR .", "sentence_char_start_global": 54004, "sentence_char_end_global": 54344, "entities": [{"text": "transcription factor", "type": "ENTITY", "char_start": 64, "char_end": 84, "token_start": 8, "token_end": 9}, {"text": "activating transcription factor", "type": "ENTITY", "char_start": 99, "char_end": 130, "token_start": 13, "token_end": 15}, {"text": "cAMP response element binding", "type": "ENTITY", "char_start": 133, "char_end": 162, "token_start": 17, "token_end": 20}, {"text": "ATF", "type": "ENTITY", "char_start": 165, "char_end": 168, "token_start": 22, "token_end": 22}, {"text": "CREB", "type": "ENTITY", "char_start": 171, "char_end": 175, "token_start": 24, "token_end": 24}, {"text": "LEF - 1 and distal NF - kappaB transcription factor binding sites", "type": "ENTITY", "char_start": 213, "char_end": 278, "token_start": 32, "token_end": 43}, {"text": "HIV - 1 LTR", "type": "ENTITY", "char_start": 327, "char_end": 338, "token_start": 53, "token_end": 56}], "entities_global": [{"text": "transcription factor", "type": "ENTITY", "char_start": 54068, "char_end": 54088, "token_start": 8, "token_end": 9, "note": null}, {"text": "activating transcription factor", "type": "ENTITY", "char_start": 54103, "char_end": 54134, "token_start": 13, "token_end": 15, "note": null}, {"text": "cAMP response element binding", "type": "ENTITY", "char_start": 54137, "char_end": 54166, "token_start": 17, "token_end": 20, "note": null}, {"text": "ATF", "type": "ENTITY", "char_start": 54169, "char_end": 54172, "token_start": 22, "token_end": 22, "note": null}, {"text": "CREB", "type": "ENTITY", "char_start": 54175, "char_end": 54179, "token_start": 24, "token_end": 24, "note": null}, {"text": "LEF - 1 and distal NF - kappaB transcription factor binding sites", "type": "ENTITY", "char_start": 54217, "char_end": 54282, "token_start": 32, "token_end": 43, "note": null}, {"text": "HIV - 1 LTR", "type": "ENTITY", "char_start": 54331, "char_end": 54342, "token_start": 53, "token_end": 56, "note": null}]}
+{"sentence_id": 327, "sentence_text": "These findings suggest that LTR sequence changes can significantly affect basal LTR function and transcription factor recruitment , which may , in turn , alter the course of viral replication in cells of CNS and immune system origin .", "sentence_char_start_global": 54345, "sentence_char_end_global": 54579, "entities": [{"text": "LTR sequence", "type": "ENTITY", "char_start": 28, "char_end": 40, "token_start": 4, "token_end": 5}], "entities_global": [{"text": "LTR sequence", "type": "ENTITY", "char_start": 54373, "char_end": 54385, "token_start": 4, "token_end": 5, "note": null}]}
+{"sentence_id": 328, "sentence_text": "HMG box containing transcription factors in lymphocyte differentiation .", "sentence_char_start_global": 54580, "sentence_char_end_global": 54652, "entities": [{"text": "HMG box containing transcription factors", "type": "ENTITY", "char_start": 0, "char_end": 40, "token_start": 0, "token_end": 4}], "entities_global": [{"text": "HMG box containing transcription factors", "type": "ENTITY", "char_start": 54580, "char_end": 54620, "token_start": 0, "token_end": 4, "note": null}]}
+{"sentence_id": 329, "sentence_text": "The identification of the mammalian sex - determining gene Sry has led to the discovery of a large family of related ( ' HMG box ' ) transcription factors that control developmental events in yeast , C . elegans , Drosophila and vertebrates .", "sentence_char_start_global": 54653, "sentence_char_end_global": 54895, "entities": [{"text": "mammalian sex - determining gene Sry", "type": "ENTITY", "char_start": 26, "char_end": 62, "token_start": 4, "token_end": 9}, {"text": "HMG box", "type": "ENTITY", "char_start": 121, "char_end": 128, "token_start": 23, "token_end": 24}, {"text": "transcription factors", "type": "ENTITY", "char_start": 133, "char_end": 154, "token_start": 27, "token_end": 28}], "entities_global": [{"text": "mammalian sex - determining gene Sry", "type": "ENTITY", "char_start": 54679, "char_end": 54715, "token_start": 4, "token_end": 9, "note": null}, {"text": "HMG box", "type": "ENTITY", "char_start": 54774, "char_end": 54781, "token_start": 23, "token_end": 24, "note": null}, {"text": "transcription factors", "type": "ENTITY", "char_start": 54786, "char_end": 54807, "token_start": 27, "token_end": 28, "note": null}]}
+{"sentence_id": 330, "sentence_text": "In lymphocyte differentiation , several HMG box proteins play a decisive role .", "sentence_char_start_global": 54896, "sentence_char_end_global": 54975, "entities": [{"text": "HMG box proteins", "type": "ENTITY", "char_start": 40, "char_end": 56, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "HMG box proteins", "type": "ENTITY", "char_start": 54936, "char_end": 54952, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 331, "sentence_text": "Sox - 4 is important for very early B - cell differentiation , while TCF - 1 / LEF - 1 play a crucial role in early thymocyte development .", "sentence_char_start_global": 54976, "sentence_char_end_global": 55115, "entities": [{"text": "Sox - 4", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 2}, {"text": "TCF - 1", "type": "ENTITY", "char_start": 69, "char_end": 76, "token_start": 14, "token_end": 16}, {"text": "LEF - 1", "type": "ENTITY", "char_start": 79, "char_end": 86, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "Sox - 4", "type": "ENTITY", "char_start": 54976, "char_end": 54983, "token_start": 0, "token_end": 2, "note": null}, {"text": "TCF - 1", "type": "ENTITY", "char_start": 55045, "char_end": 55052, "token_start": 14, "token_end": 16, "note": null}, {"text": "LEF - 1", "type": "ENTITY", "char_start": 55055, "char_end": 55062, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 332, "sentence_text": "TCF / LEF proteins have recently been found to constitute a downstream component of the Wingless / Wnt signal transduction pathway .", "sentence_char_start_global": 55116, "sentence_char_end_global": 55248, "entities": [{"text": "TCF / LEF proteins", "type": "ENTITY", "char_start": 0, "char_end": 18, "token_start": 0, "token_end": 3}], "entities_global": [{"text": "TCF / LEF proteins", "type": "ENTITY", "char_start": 55116, "char_end": 55134, "token_start": 0, "token_end": 3, "note": null}]}
+{"sentence_id": 333, "sentence_text": "In flies , this pathway controls segment polarity ; in Xenopus it controls the definition of the body axis .", "sentence_char_start_global": 55249, "sentence_char_end_global": 55357, "entities": [], "entities_global": []}
+{"sentence_id": 334, "sentence_text": "Deregulation of the pathway occurs in several human tumors .", "sentence_char_start_global": 55358, "sentence_char_end_global": 55418, "entities": [], "entities_global": []}
+{"sentence_id": 335, "sentence_text": "These insights in the molecular events that are involved in TCF / LEF function in these organisms may eventually lead to the understanding of the function of these HMG box proteins in lymphoid development", "sentence_char_start_global": 55419, "sentence_char_end_global": 55623, "entities": [{"text": "TCF / LEF", "type": "ENTITY", "char_start": 60, "char_end": 69, "token_start": 10, "token_end": 12}, {"text": "HMG box proteins", "type": "ENTITY", "char_start": 164, "char_end": 180, "token_start": 28, "token_end": 30}], "entities_global": [{"text": "TCF / LEF", "type": "ENTITY", "char_start": 55479, "char_end": 55488, "token_start": 10, "token_end": 12, "note": null}, {"text": "HMG box proteins", "type": "ENTITY", "char_start": 55583, "char_end": 55599, "token_start": 28, "token_end": 30, "note": null}]}
+{"sentence_id": 336, "sentence_text": "Transcriptional regulation by C / EBP alpha and - beta in the expression of the gene for the MRP14 myeloid calcium binding protein .", "sentence_char_start_global": 55624, "sentence_char_end_global": 55756, "entities": [{"text": "C / EBP alpha and - beta", "type": "ENTITY", "char_start": 30, "char_end": 54, "token_start": 3, "token_end": 9}, {"text": "MRP14 myeloid calcium binding protein", "type": "ENTITY", "char_start": 93, "char_end": 130, "token_start": 18, "token_end": 22}], "entities_global": [{"text": "C / EBP alpha and - beta", "type": "ENTITY", "char_start": 55654, "char_end": 55678, "token_start": 3, "token_end": 9, "note": null}, {"text": "MRP14 myeloid calcium binding protein", "type": "ENTITY", "char_start": 55717, "char_end": 55754, "token_start": 18, "token_end": 22, "note": null}]}
+{"sentence_id": 337, "sentence_text": "Transcriptional regulation of the gene for the myeloid calcium binding protein , MRP14 , was investigated in human monocytic leukemia cell lines .", "sentence_char_start_global": 55757, "sentence_char_end_global": 55903, "entities": [{"text": "myeloid calcium binding protein", "type": "ENTITY", "char_start": 47, "char_end": 78, "token_start": 7, "token_end": 10}, {"text": "MRP14", "type": "ENTITY", "char_start": 81, "char_end": 86, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "myeloid calcium binding protein", "type": "ENTITY", "char_start": 55804, "char_end": 55835, "token_start": 7, "token_end": 10, "note": null}, {"text": "MRP14", "type": "ENTITY", "char_start": 55838, "char_end": 55843, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 338, "sentence_text": "The MRP14 gene was not expressed in monoblastic ML - 1 cells , promonocytic U - 937 cells , or promyelocytic HL - 60 cells .", "sentence_char_start_global": 55904, "sentence_char_end_global": 56028, "entities": [{"text": "MRP14 gene", "type": "ENTITY", "char_start": 4, "char_end": 14, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "MRP14 gene", "type": "ENTITY", "char_start": 55908, "char_end": 55918, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 339, "sentence_text": "On the other hand , the gene was expressed in monocytic THP - 1 cells and in the HL - 60 cells treated with 1 , 25 - dihydroxyvitamin D3 ( VD3 ) .", "sentence_char_start_global": 56029, "sentence_char_end_global": 56175, "entities": [], "entities_global": []}
+{"sentence_id": 340, "sentence_text": "The level of MRP14 in VD3 - treated HL - 60 cells was two - fold higher than that in THP - 1 cells .", "sentence_char_start_global": 56176, "sentence_char_end_global": 56276, "entities": [{"text": "MRP14", "type": "ENTITY", "char_start": 13, "char_end": 18, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "MRP14", "type": "ENTITY", "char_start": 56189, "char_end": 56194, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 341, "sentence_text": "Among several known transcription factor binding motifs , nuclear protein ( s ) of VD3 - treated HL - 60 cells and THP - 1 cells bound to the CCAAT / enhancer binding protein ( C / EBP ) - binding motif that was located in the upstream region of the MRP14 gene ( - 81 ) , as evidenced by the competitive gel mobility - shift assay .", "sentence_char_start_global": 56277, "sentence_char_end_global": 56609, "entities": [{"text": "transcription factor binding motifs", "type": "ENTITY", "char_start": 20, "char_end": 55, "token_start": 3, "token_end": 6}, {"text": "nuclear protein ( s )", "type": "ENTITY", "char_start": 58, "char_end": 79, "token_start": 8, "token_end": 12}, {"text": "CCAAT / enhancer binding protein ( C / EBP ) - binding motif", "type": "ENTITY", "char_start": 142, "char_end": 202, "token_start": 29, "token_end": 41}, {"text": "upstream region", "type": "ENTITY", "char_start": 227, "char_end": 242, "token_start": 47, "token_end": 48}, {"text": "MRP14 gene", "type": "ENTITY", "char_start": 250, "char_end": 260, "token_start": 51, "token_end": 52}], "entities_global": [{"text": "transcription factor binding motifs", "type": "ENTITY", "char_start": 56297, "char_end": 56332, "token_start": 3, "token_end": 6, "note": null}, {"text": "nuclear protein ( s )", "type": "ENTITY", "char_start": 56335, "char_end": 56356, "token_start": 8, "token_end": 12, "note": null}, {"text": "CCAAT / enhancer binding protein ( C / EBP ) - binding motif", "type": "ENTITY", "char_start": 56419, "char_end": 56479, "token_start": 29, "token_end": 41, "note": null}, {"text": "upstream region", "type": "ENTITY", "char_start": 56504, "char_end": 56519, "token_start": 47, "token_end": 48, "note": null}, {"text": "MRP14 gene", "type": "ENTITY", "char_start": 56527, "char_end": 56537, "token_start": 51, "token_end": 52, "note": null}]}
+{"sentence_id": 342, "sentence_text": "An antibody for C / EBP alpha super - shifted the nucleoprotein complex in THP - 1 cells but not in the VD3 - treated HL - 60 cells , whereas an antibody for C / EBP beta blocked the formation of the complex with the nuclear factor of the HL - 60 cells but not with that of THP - 1 cells .", "sentence_char_start_global": 56610, "sentence_char_end_global": 56899, "entities": [{"text": "C / EBP alpha", "type": "ENTITY", "char_start": 16, "char_end": 29, "token_start": 3, "token_end": 6}, {"text": "nucleoprotein complex", "type": "ENTITY", "char_start": 50, "char_end": 71, "token_start": 11, "token_end": 12}, {"text": "C / EBP beta", "type": "ENTITY", "char_start": 158, "char_end": 170, "token_start": 34, "token_end": 37}, {"text": "nuclear factor", "type": "ENTITY", "char_start": 217, "char_end": 231, "token_start": 46, "token_end": 47}], "entities_global": [{"text": "C / EBP alpha", "type": "ENTITY", "char_start": 56626, "char_end": 56639, "token_start": 3, "token_end": 6, "note": null}, {"text": "nucleoprotein complex", "type": "ENTITY", "char_start": 56660, "char_end": 56681, "token_start": 11, "token_end": 12, "note": null}, {"text": "C / EBP beta", "type": "ENTITY", "char_start": 56768, "char_end": 56780, "token_start": 34, "token_end": 37, "note": null}, {"text": "nuclear factor", "type": "ENTITY", "char_start": 56827, "char_end": 56841, "token_start": 46, "token_end": 47, "note": null}]}
+{"sentence_id": 343, "sentence_text": "An anti - C / EBP delta antibody had no effect on the complex in either cell .", "sentence_char_start_global": 56900, "sentence_char_end_global": 56978, "entities": [{"text": "anti - C / EBP delta antibody", "type": "ENTITY", "char_start": 3, "char_end": 32, "token_start": 1, "token_end": 7}], "entities_global": [{"text": "anti - C / EBP delta antibody", "type": "ENTITY", "char_start": 56903, "char_end": 56932, "token_start": 1, "token_end": 7, "note": null}]}
+{"sentence_id": 344, "sentence_text": "Thus , it was concluded that C / EBP alpha and - beta were able to bind to the C / EBP motif , and that C / EBP alpha bound to the motif in THP - 1 cells and C / EBP beta bound to that in the VD3 - treated HL - 60 cells .", "sentence_char_start_global": 56979, "sentence_char_end_global": 57200, "entities": [{"text": "C / EBP alpha and - beta", "type": "ENTITY", "char_start": 29, "char_end": 53, "token_start": 6, "token_end": 12}, {"text": "C / EBP motif", "type": "ENTITY", "char_start": 79, "char_end": 92, "token_start": 19, "token_end": 22}, {"text": "C / EBP alpha", "type": "ENTITY", "char_start": 104, "char_end": 117, "token_start": 26, "token_end": 29}, {"text": "C / EBP beta", "type": "ENTITY", "char_start": 158, "char_end": 170, "token_start": 40, "token_end": 43}], "entities_global": [{"text": "C / EBP alpha and - beta", "type": "ENTITY", "char_start": 57008, "char_end": 57032, "token_start": 6, "token_end": 12, "note": null}, {"text": "C / EBP motif", "type": "ENTITY", "char_start": 57058, "char_end": 57071, "token_start": 19, "token_end": 22, "note": null}, {"text": "C / EBP alpha", "type": "ENTITY", "char_start": 57083, "char_end": 57096, "token_start": 26, "token_end": 29, "note": null}, {"text": "C / EBP beta", "type": "ENTITY", "char_start": 57137, "char_end": 57149, "token_start": 40, "token_end": 43, "note": null}]}
+{"sentence_id": 345, "sentence_text": "Furthermore , to examine the transcriptional activity of the C / EBP motif , we transfected several constructed luciferase reporter DNAs into HL - 60 cells and THP - 1 cells .", "sentence_char_start_global": 57201, "sentence_char_end_global": 57376, "entities": [{"text": "C / EBP motif", "type": "ENTITY", "char_start": 61, "char_end": 74, "token_start": 9, "token_end": 12}, {"text": "luciferase reporter DNAs", "type": "ENTITY", "char_start": 112, "char_end": 136, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "C / EBP motif", "type": "ENTITY", "char_start": 57262, "char_end": 57275, "token_start": 9, "token_end": 12, "note": null}, {"text": "luciferase reporter DNAs", "type": "ENTITY", "char_start": 57313, "char_end": 57337, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 346, "sentence_text": "The luciferase activity of the C / EBP motif in HL - 60 cells was increased by VD3 treatment .", "sentence_char_start_global": 57377, "sentence_char_end_global": 57471, "entities": [{"text": "C / EBP motif", "type": "ENTITY", "char_start": 31, "char_end": 44, "token_start": 5, "token_end": 8}], "entities_global": [{"text": "C / EBP motif", "type": "ENTITY", "char_start": 57408, "char_end": 57421, "token_start": 5, "token_end": 8, "note": null}]}
+{"sentence_id": 347, "sentence_text": "The C / EBP motif in the MRP14 gene was confirmed to function as a regulatory region in VD3 - treated HL - 60 cells and THP - 1 cells by the assay .", "sentence_char_start_global": 57472, "sentence_char_end_global": 57620, "entities": [{"text": "C / EBP motif", "type": "ENTITY", "char_start": 4, "char_end": 17, "token_start": 1, "token_end": 4}, {"text": "MRP14 gene", "type": "ENTITY", "char_start": 25, "char_end": 35, "token_start": 7, "token_end": 8}], "entities_global": [{"text": "C / EBP motif", "type": "ENTITY", "char_start": 57476, "char_end": 57489, "token_start": 1, "token_end": 4, "note": null}, {"text": "MRP14 gene", "type": "ENTITY", "char_start": 57497, "char_end": 57507, "token_start": 7, "token_end": 8, "note": null}]}
+{"sentence_id": 348, "sentence_text": "Since C / EBP beta was also detected in VD3 - untreated HL - 60 cells by immunoblotting , VD3 activated C / EBP beta to bind to the motif , probably through post - translational modification .", "sentence_char_start_global": 57621, "sentence_char_end_global": 57813, "entities": [{"text": "C / EBP beta", "type": "ENTITY", "char_start": 6, "char_end": 18, "token_start": 1, "token_end": 4}, {"text": "C / EBP beta", "type": "ENTITY", "char_start": 104, "char_end": 116, "token_start": 21, "token_end": 24}], "entities_global": [{"text": "C / EBP beta", "type": "ENTITY", "char_start": 57627, "char_end": 57639, "token_start": 1, "token_end": 4, "note": null}, {"text": "C / EBP beta", "type": "ENTITY", "char_start": 57725, "char_end": 57737, "token_start": 21, "token_end": 24, "note": null}]}
+{"sentence_id": 349, "sentence_text": "Patients with high - risk myelodysplastic syndrome can have polyclonal or clonal haemopoiesis in complete haematological remission .", "sentence_char_start_global": 57814, "sentence_char_end_global": 57946, "entities": [], "entities_global": []}
+{"sentence_id": 350, "sentence_text": "The clonality of mature peripheral blood - derived myeloid and lymphoid cells and bone marrow haemopoietic progenitors from 18 females with myelodysplasia ( MDS ) ( five refractory anaemia , RA ; one RA with ringed sideroblasts , RARS ; three chronic myelomonocytic leukaemia , CMML ; four RA with excess of blasts , RAEB ; five RAEB in transformation , RAEB - t ) was studied by X - chromosome inactivation analysis .", "sentence_char_start_global": 57947, "sentence_char_end_global": 58365, "entities": [{"text": "X - chromosome", "type": "ENTITY", "char_start": 380, "char_end": 394, "token_start": 68, "token_end": 70}], "entities_global": [{"text": "X - chromosome", "type": "ENTITY", "char_start": 58327, "char_end": 58341, "token_start": 68, "token_end": 70, "note": null}]}
+{"sentence_id": 351, "sentence_text": "Using the human androgen - receptor ( HUMARA ) assay , we analysed the clonal patterns of highly purified immature CD34 + 38 - and committed CD34 + 38 + marrow - derived progenitors , and CD16 + 14 - granulocytes , CD14 + monocytes , CD3 + T and CD19 + B lymphocytes from peripheral blood .", "sentence_char_start_global": 58366, "sentence_char_end_global": 58656, "entities": [], "entities_global": []}
+{"sentence_id": 352, "sentence_text": "In high - risk patients ( RAEB , RAEB - t ) , clonality analysis was performed before and after intensive remission - induction treatment .", "sentence_char_start_global": 58657, "sentence_char_end_global": 58796, "entities": [], "entities_global": []}
+{"sentence_id": 353, "sentence_text": "All patients , except one with RA , had predominance of a single clone in their granulocytes and monocytes .", "sentence_char_start_global": 58797, "sentence_char_end_global": 58905, "entities": [], "entities_global": []}
+{"sentence_id": 354, "sentence_text": "The same clonal pattern was found in CD34 + progenitor cells .", "sentence_char_start_global": 58906, "sentence_char_end_global": 58968, "entities": [], "entities_global": []}
+{"sentence_id": 355, "sentence_text": "In contrast , CD3 + T lymphocytes were polyclonal or oligoclonal in 14 / 18 patients .", "sentence_char_start_global": 58969, "sentence_char_end_global": 59055, "entities": [], "entities_global": []}
+{"sentence_id": 356, "sentence_text": "X - chromosome inactivation patterns of CD19 + B cells were highly concordant with CD3 + T cells except for two patients ( one RA , one CMML ) with monoclonal B and polyclonal T lymphocytes , therefore suggesting a clonal mutation in a progenitor common to the myeloid and B - lymphoid lineages or the coexistence of MDS and a B - cell disorder in these particular patients .", "sentence_char_start_global": 59056, "sentence_char_end_global": 59431, "entities": [{"text": "X - chromosome", "type": "ENTITY", "char_start": 0, "char_end": 14, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "X - chromosome", "type": "ENTITY", "char_start": 59056, "char_end": 59070, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 357, "sentence_text": "After high - dose non - myeloablative chemotherapy , polyclonal haemopoiesis was reinstalled in the mature myeloid cells and immature and committed marrow progenitors in three of four patients achieving complete haematological remission .", "sentence_char_start_global": 59432, "sentence_char_end_global": 59670, "entities": [], "entities_global": []}
+{"sentence_id": 358, "sentence_text": "Therefore we conclude that most haematological remissions in MDS are associated with restoration of polyclonal haemopoiesis .", "sentence_char_start_global": 59671, "sentence_char_end_global": 59796, "entities": [], "entities_global": []}
+{"sentence_id": 359, "sentence_text": "Prominent sex steroid metabolism in human lymphocytes .", "sentence_char_start_global": 59797, "sentence_char_end_global": 59852, "entities": [], "entities_global": []}
+{"sentence_id": 360, "sentence_text": "Steroid metabolism was investigated in cultured human B - lymphoblastoid cells ( B - LCL ) , and peripheral blood T and B cells .", "sentence_char_start_global": 59853, "sentence_char_end_global": 59982, "entities": [], "entities_global": []}
+{"sentence_id": 361, "sentence_text": "Gene expression was examined by reverse - transcription polymerase chain reaction amplification ( RT - PCR ) .", "sentence_char_start_global": 59983, "sentence_char_end_global": 60093, "entities": [], "entities_global": []}
+{"sentence_id": 362, "sentence_text": "Appropriate sized transcripts were detected in both cultured and fresh peripheral lymphocytes for CYP11A , CYP17 , HSD11L ( 11beta - hydroxysteroid dehydrogenase I ) , HSD17B1 ( 17beta - hydroxysteroid dehydrogenase type I ) and SRD5A1 ( 5alpha - reductase I ) .", "sentence_char_start_global": 60094, "sentence_char_end_global": 60356, "entities": [{"text": "transcripts", "type": "ENTITY", "char_start": 18, "char_end": 29, "token_start": 2, "token_end": 2}, {"text": "CYP11A", "type": "ENTITY", "char_start": 98, "char_end": 104, "token_start": 13, "token_end": 13}, {"text": "CYP17", "type": "ENTITY", "char_start": 107, "char_end": 112, "token_start": 15, "token_end": 15}, {"text": "HSD11L", "type": "ENTITY", "char_start": 115, "char_end": 121, "token_start": 17, "token_end": 17}, {"text": "11beta - hydroxysteroid dehydrogenase I", "type": "ENTITY", "char_start": 124, "char_end": 163, "token_start": 19, "token_end": 23}, {"text": "HSD17B1", "type": "ENTITY", "char_start": 168, "char_end": 175, "token_start": 26, "token_end": 26}, {"text": "17beta - hydroxysteroid dehydrogenase type I", "type": "ENTITY", "char_start": 178, "char_end": 222, "token_start": 28, "token_end": 33}, {"text": "SRD5A1", "type": "ENTITY", "char_start": 229, "char_end": 235, "token_start": 36, "token_end": 36}, {"text": "5alpha - reductase I", "type": "ENTITY", "char_start": 238, "char_end": 258, "token_start": 38, "token_end": 41}], "entities_global": [{"text": "transcripts", "type": "ENTITY", "char_start": 60112, "char_end": 60123, "token_start": 2, "token_end": 2, "note": null}, {"text": "CYP11A", "type": "ENTITY", "char_start": 60192, "char_end": 60198, "token_start": 13, "token_end": 13, "note": null}, {"text": "CYP17", "type": "ENTITY", "char_start": 60201, "char_end": 60206, "token_start": 15, "token_end": 15, "note": null}, {"text": "HSD11L", "type": "ENTITY", "char_start": 60209, "char_end": 60215, "token_start": 17, "token_end": 17, "note": null}, {"text": "11beta - hydroxysteroid dehydrogenase I", "type": "ENTITY", "char_start": 60218, "char_end": 60257, "token_start": 19, "token_end": 23, "note": null}, {"text": "HSD17B1", "type": "ENTITY", "char_start": 60262, "char_end": 60269, "token_start": 26, "token_end": 26, "note": null}, {"text": "17beta - hydroxysteroid dehydrogenase type I", "type": "ENTITY", "char_start": 60272, "char_end": 60316, "token_start": 28, "token_end": 33, "note": null}, {"text": "SRD5A1", "type": "ENTITY", "char_start": 60323, "char_end": 60329, "token_start": 36, "token_end": 36, "note": null}, {"text": "5alpha - reductase I", "type": "ENTITY", "char_start": 60332, "char_end": 60352, "token_start": 38, "token_end": 41, "note": null}]}
+{"sentence_id": 363, "sentence_text": "B - LCL , but not T and B cells , expressed CYP11B .", "sentence_char_start_global": 60357, "sentence_char_end_global": 60409, "entities": [{"text": "CYP11B", "type": "ENTITY", "char_start": 44, "char_end": 50, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "CYP11B", "type": "ENTITY", "char_start": 60401, "char_end": 60407, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 364, "sentence_text": "There was minimal expression of HSD3B1 and HSD3B2 ( 3beta - hydroxysteroid dehydrogenase I and II ) in B - LCL and T cells .", "sentence_char_start_global": 60410, "sentence_char_end_global": 60534, "entities": [{"text": "HSD3B1", "type": "ENTITY", "char_start": 32, "char_end": 38, "token_start": 5, "token_end": 5}, {"text": "HSD3B2", "type": "ENTITY", "char_start": 43, "char_end": 49, "token_start": 7, "token_end": 7}, {"text": "3beta - hydroxysteroid dehydrogenase I and II", "type": "ENTITY", "char_start": 52, "char_end": 97, "token_start": 9, "token_end": 15}], "entities_global": [{"text": "HSD3B1", "type": "ENTITY", "char_start": 60442, "char_end": 60448, "token_start": 5, "token_end": 5, "note": null}, {"text": "HSD3B2", "type": "ENTITY", "char_start": 60453, "char_end": 60459, "token_start": 7, "token_end": 7, "note": null}, {"text": "3beta - hydroxysteroid dehydrogenase I and II", "type": "ENTITY", "char_start": 60462, "char_end": 60507, "token_start": 9, "token_end": 15, "note": null}]}
+{"sentence_id": 365, "sentence_text": "Transcripts for CYP19 and HSD11K were not detected .", "sentence_char_start_global": 60535, "sentence_char_end_global": 60587, "entities": [{"text": "CYP19", "type": "ENTITY", "char_start": 16, "char_end": 21, "token_start": 2, "token_end": 2}, {"text": "HSD11K", "type": "ENTITY", "char_start": 26, "char_end": 32, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "CYP19", "type": "ENTITY", "char_start": 60551, "char_end": 60556, "token_start": 2, "token_end": 2, "note": null}, {"text": "HSD11K", "type": "ENTITY", "char_start": 60561, "char_end": 60567, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 366, "sentence_text": "Corresponding enzymatic activity was detectable only for 17 - hydroxysteroid dehydrogenase and 5alpha - reductase , respectively producing testosterone and 5alpha - dihydrotestosterone .", "sentence_char_start_global": 60588, "sentence_char_end_global": 60774, "entities": [{"text": "17 - hydroxysteroid dehydrogenase", "type": "ENTITY", "char_start": 57, "char_end": 90, "token_start": 7, "token_end": 10}, {"text": "5alpha - reductase", "type": "ENTITY", "char_start": 95, "char_end": 113, "token_start": 12, "token_end": 14}], "entities_global": [{"text": "17 - hydroxysteroid dehydrogenase", "type": "ENTITY", "char_start": 60645, "char_end": 60678, "token_start": 7, "token_end": 10, "note": null}, {"text": "5alpha - reductase", "type": "ENTITY", "char_start": 60683, "char_end": 60701, "token_start": 12, "token_end": 14, "note": null}]}
+{"sentence_id": 367, "sentence_text": "Steroid identities were confirmed by gas chromatography / mass spectrometry ( GC / MS ) .", "sentence_char_start_global": 60775, "sentence_char_end_global": 60864, "entities": [], "entities_global": []}
+{"sentence_id": 368, "sentence_text": "One metabolite thought to be deoxycorticosterone was identified by GC / MS as 6alpha - hydroxypregnanolone .", "sentence_char_start_global": 60865, "sentence_char_end_global": 60973, "entities": [], "entities_global": []}
+{"sentence_id": 369, "sentence_text": "It was concluded that sex hormone metabolism , including androgen synthesis , occurs in lymphocytes , and may modulate immune response .", "sentence_char_start_global": 60974, "sentence_char_end_global": 61110, "entities": [], "entities_global": []}
+{"sentence_id": 370, "sentence_text": "Human white blood cells and hair follicles are good sources of mRNA for the pterin carbinolamine dehydratase / dimerization cofactor of HNF1 for mutation detection .", "sentence_char_start_global": 61111, "sentence_char_end_global": 61276, "entities": [{"text": "mRNA", "type": "ENTITY", "char_start": 63, "char_end": 67, "token_start": 11, "token_end": 11}, {"text": "pterin carbinolamine dehydratase / dimerization cofactor", "type": "ENTITY", "char_start": 76, "char_end": 132, "token_start": 14, "token_end": 19}, {"text": "HNF1", "type": "ENTITY", "char_start": 136, "char_end": 140, "token_start": 21, "token_end": 21}], "entities_global": [{"text": "mRNA", "type": "ENTITY", "char_start": 61174, "char_end": 61178, "token_start": 11, "token_end": 11, "note": null}, {"text": "pterin carbinolamine dehydratase / dimerization cofactor", "type": "ENTITY", "char_start": 61187, "char_end": 61243, "token_start": 14, "token_end": 19, "note": null}, {"text": "HNF1", "type": "ENTITY", "char_start": 61247, "char_end": 61251, "token_start": 21, "token_end": 21, "note": null}]}
+{"sentence_id": 371, "sentence_text": "Pterin carbinolamine dehydratase / dimerization cofactor of HNF1 ( PCD / DCoH ) is a protein that has a dual function .", "sentence_char_start_global": 61277, "sentence_char_end_global": 61396, "entities": [{"text": "Pterin carbinolamine dehydratase / dimerization cofactor", "type": "ENTITY", "char_start": 0, "char_end": 56, "token_start": 0, "token_end": 5}, {"text": "HNF1", "type": "ENTITY", "char_start": 60, "char_end": 64, "token_start": 7, "token_end": 7}, {"text": "PCD / DCoH", "type": "ENTITY", "char_start": 67, "char_end": 77, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "Pterin carbinolamine dehydratase / dimerization cofactor", "type": "ENTITY", "char_start": 61277, "char_end": 61333, "token_start": 0, "token_end": 5, "note": null}, {"text": "HNF1", "type": "ENTITY", "char_start": 61337, "char_end": 61341, "token_start": 7, "token_end": 7, "note": null}, {"text": "PCD / DCoH", "type": "ENTITY", "char_start": 61344, "char_end": 61354, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 372, "sentence_text": "It is a pterin 4alpha - carbinolamine dehydratase that is involved in the regeneration of the cofactor tetrahydrobiopterin during the phenylalanine hydroxylase - catalyzed hydroxylation of phenylalanine .", "sentence_char_start_global": 61397, "sentence_char_end_global": 61601, "entities": [{"text": "pterin 4alpha - carbinolamine dehydratase", "type": "ENTITY", "char_start": 8, "char_end": 49, "token_start": 3, "token_end": 7}, {"text": "cofactor tetrahydrobiopterin", "type": "ENTITY", "char_start": 94, "char_end": 122, "token_start": 16, "token_end": 17}], "entities_global": [{"text": "pterin 4alpha - carbinolamine dehydratase", "type": "ENTITY", "char_start": 61405, "char_end": 61446, "token_start": 3, "token_end": 7, "note": null}, {"text": "cofactor tetrahydrobiopterin", "type": "ENTITY", "char_start": 61491, "char_end": 61519, "token_start": 16, "token_end": 17, "note": null}]}
+{"sentence_id": 373, "sentence_text": "In addition , it is the dimerization cofactor of HNF1 that is able to activate the transcriptional activity of HNF1 .", "sentence_char_start_global": 61602, "sentence_char_end_global": 61719, "entities": [{"text": "HNF1", "type": "ENTITY", "char_start": 49, "char_end": 53, "token_start": 9, "token_end": 9}, {"text": "HNF1", "type": "ENTITY", "char_start": 111, "char_end": 115, "token_start": 19, "token_end": 19}], "entities_global": [{"text": "HNF1", "type": "ENTITY", "char_start": 61651, "char_end": 61655, "token_start": 9, "token_end": 9, "note": null}, {"text": "HNF1", "type": "ENTITY", "char_start": 61713, "char_end": 61717, "token_start": 19, "token_end": 19, "note": null}]}
+{"sentence_id": 374, "sentence_text": "Deficiencies in the gene for this dual functional protein result in hyperphenylalaninemi .", "sentence_char_start_global": 61720, "sentence_char_end_global": 61810, "entities": [{"text": "dual functional protein", "type": "ENTITY", "char_start": 34, "char_end": 57, "token_start": 6, "token_end": 8}], "entities_global": [{"text": "dual functional protein", "type": "ENTITY", "char_start": 61754, "char_end": 61777, "token_start": 6, "token_end": 8, "note": null}]}
+{"sentence_id": 375, "sentence_text": "Here we report for the first time that the PCD / DCoH mRNA is present in human white blood cells and hair follicles .", "sentence_char_start_global": 61811, "sentence_char_end_global": 61928, "entities": [{"text": "PCD / DCoH mRNA", "type": "ENTITY", "char_start": 43, "char_end": 58, "token_start": 9, "token_end": 12}], "entities_global": [{"text": "PCD / DCoH mRNA", "type": "ENTITY", "char_start": 61854, "char_end": 61869, "token_start": 9, "token_end": 12, "note": null}]}
+{"sentence_id": 376, "sentence_text": "Taking advantage of this finding , a sensitive , rapid and convenient method for screening mutations occurring in the coding region of this gene has been described .", "sentence_char_start_global": 61929, "sentence_char_end_global": 62094, "entities": [], "entities_global": []}
+{"sentence_id": 377, "sentence_text": "Copyright 1998 Academic Press .", "sentence_char_start_global": 62095, "sentence_char_end_global": 62126, "entities": [], "entities_global": []}
+{"sentence_id": 378, "sentence_text": "Biochemical characterization of the NF - Y transcription factor complex during B lymphocyte development .", "sentence_char_start_global": 62127, "sentence_char_end_global": 62232, "entities": [{"text": "NF - Y transcription factor complex", "type": "ENTITY", "char_start": 36, "char_end": 71, "token_start": 4, "token_end": 9}], "entities_global": [{"text": "NF - Y transcription factor complex", "type": "ENTITY", "char_start": 62163, "char_end": 62198, "token_start": 4, "token_end": 9, "note": null}]}
+{"sentence_id": 379, "sentence_text": "The transcription factor , NF - Y , plays a critical role in tissue - specific major histocompatibility complex class II gene transcription .", "sentence_char_start_global": 62233, "sentence_char_end_global": 62374, "entities": [{"text": "transcription factor", "type": "ENTITY", "char_start": 4, "char_end": 24, "token_start": 1, "token_end": 2}, {"text": "NF - Y", "type": "ENTITY", "char_start": 27, "char_end": 33, "token_start": 4, "token_end": 6}, {"text": "major histocompatibility complex class II gene", "type": "ENTITY", "char_start": 79, "char_end": 125, "token_start": 16, "token_end": 21}], "entities_global": [{"text": "transcription factor", "type": "ENTITY", "char_start": 62237, "char_end": 62257, "token_start": 1, "token_end": 2, "note": null}, {"text": "NF - Y", "type": "ENTITY", "char_start": 62260, "char_end": 62266, "token_start": 4, "token_end": 6, "note": null}, {"text": "major histocompatibility complex class II gene", "type": "ENTITY", "char_start": 62312, "char_end": 62358, "token_start": 16, "token_end": 21, "note": null}]}
+{"sentence_id": 380, "sentence_text": "In this report the biochemical properties of the heterotrimeric NF - Y complex have been characterized during stage - specific B - cell development , and in several class II - mutant B - cell lines , which represent distinct bare lymphocyte syndrome class II genetic complementation groups .", "sentence_char_start_global": 62375, "sentence_char_end_global": 62666, "entities": [{"text": "heterotrimeric NF - Y complex", "type": "ENTITY", "char_start": 49, "char_end": 78, "token_start": 8, "token_end": 12}], "entities_global": [{"text": "heterotrimeric NF - Y complex", "type": "ENTITY", "char_start": 62424, "char_end": 62453, "token_start": 8, "token_end": 12, "note": null}]}
+{"sentence_id": 381, "sentence_text": "The NF - Y complex derived from class II + mature B - cells bound with high affinity to anion exchangers , and eluted as an intact trimeric complex , whereas , NF - Y derived from class II - plasma B - cells , and from bare lymphocyte syndrome group II cell lines , RJ2 . 2 . 5 and RM3 , dissociated into discrete NF - YA and NF - YB : C subunit fractions .", "sentence_char_start_global": 62667, "sentence_char_end_global": 63024, "entities": [{"text": "NF - Y complex", "type": "ENTITY", "char_start": 4, "char_end": 18, "token_start": 1, "token_end": 4}, {"text": "anion exchangers", "type": "ENTITY", "char_start": 88, "char_end": 104, "token_start": 19, "token_end": 20}, {"text": "trimeric complex", "type": "ENTITY", "char_start": 131, "char_end": 147, "token_start": 27, "token_end": 28}, {"text": "NF - Y", "type": "ENTITY", "char_start": 160, "char_end": 166, "token_start": 32, "token_end": 34}, {"text": "NF - YA", "type": "ENTITY", "char_start": 314, "char_end": 321, "token_start": 66, "token_end": 68}, {"text": "NF - YB : C", "type": "ENTITY", "char_start": 326, "char_end": 337, "token_start": 70, "token_end": 74}, {"text": "subunit fractions", "type": "ENTITY", "char_start": 338, "char_end": 355, "token_start": 75, "token_end": 76}], "entities_global": [{"text": "NF - Y complex", "type": "ENTITY", "char_start": 62671, "char_end": 62685, "token_start": 1, "token_end": 4, "note": null}, {"text": "anion exchangers", "type": "ENTITY", "char_start": 62755, "char_end": 62771, "token_start": 19, "token_end": 20, "note": null}, {"text": "trimeric complex", "type": "ENTITY", "char_start": 62798, "char_end": 62814, "token_start": 27, "token_end": 28, "note": null}, {"text": "NF - Y", "type": "ENTITY", "char_start": 62827, "char_end": 62833, "token_start": 32, "token_end": 34, "note": null}, {"text": "NF - YA", "type": "ENTITY", "char_start": 62981, "char_end": 62988, "token_start": 66, "token_end": 68, "note": null}, {"text": "NF - YB : C", "type": "ENTITY", "char_start": 62993, "char_end": 63004, "token_start": 70, "token_end": 74, "note": null}, {"text": "subunit fractions", "type": "ENTITY", "char_start": 63005, "char_end": 63022, "token_start": 75, "token_end": 76, "note": null}]}
+{"sentence_id": 382, "sentence_text": "Recombination of the MPC11 plasma B - cell derived NF - Y A : B : C complex with the low molecular mass protein fraction , NF - Y - associated factors ( YAFs ) , derived from mature A20 B - cell nuclei , conferred high affinity anion exchange binding to NF - Y as an intact trimeric complex .", "sentence_char_start_global": 63025, "sentence_char_end_global": 63317, "entities": [{"text": "MPC11 plasma B - cell derived NF - Y A : B : C complex", "type": "ENTITY", "char_start": 21, "char_end": 75, "token_start": 3, "token_end": 17}, {"text": "NF - Y - associated factors", "type": "ENTITY", "char_start": 123, "char_end": 150, "token_start": 26, "token_end": 31}, {"text": "YAFs", "type": "ENTITY", "char_start": 153, "char_end": 157, "token_start": 33, "token_end": 33}, {"text": "NF - Y", "type": "ENTITY", "char_start": 254, "char_end": 260, "token_start": 52, "token_end": 54}, {"text": "intact trimeric complex", "type": "ENTITY", "char_start": 267, "char_end": 290, "token_start": 57, "token_end": 59}], "entities_global": [{"text": "MPC11 plasma B - cell derived NF - Y A : B : C complex", "type": "ENTITY", "char_start": 63046, "char_end": 63100, "token_start": 3, "token_end": 17, "note": null}, {"text": "NF - Y - associated factors", "type": "ENTITY", "char_start": 63148, "char_end": 63175, "token_start": 26, "token_end": 31, "note": null}, {"text": "YAFs", "type": "ENTITY", "char_start": 63178, "char_end": 63182, "token_start": 33, "token_end": 33, "note": null}, {"text": "NF - Y", "type": "ENTITY", "char_start": 63279, "char_end": 63285, "token_start": 52, "token_end": 54, "note": null}, {"text": "intact trimeric complex", "type": "ENTITY", "char_start": 63292, "char_end": 63315, "token_start": 57, "token_end": 59, "note": null}]}
+{"sentence_id": 383, "sentence_text": "Recombination of the native NF - YA : B : C complex with the transcriptional cofactor , PC4 , likewise conferred high affinity NF - Y binding to anion exchangers , and stabilized NF - Y interaction with CCAAT - box DNA motifs in vitro .", "sentence_char_start_global": 63318, "sentence_char_end_global": 63554, "entities": [{"text": "native NF - YA : B : C complex", "type": "ENTITY", "char_start": 21, "char_end": 51, "token_start": 3, "token_end": 11}, {"text": "transcriptional cofactor", "type": "ENTITY", "char_start": 61, "char_end": 85, "token_start": 14, "token_end": 15}, {"text": "PC4", "type": "ENTITY", "char_start": 88, "char_end": 91, "token_start": 17, "token_end": 17}, {"text": "high affinity NF - Y", "type": "ENTITY", "char_start": 113, "char_end": 133, "token_start": 21, "token_end": 25}, {"text": "anion exchangers", "type": "ENTITY", "char_start": 145, "char_end": 161, "token_start": 28, "token_end": 29}, {"text": "NF - Y", "type": "ENTITY", "char_start": 179, "char_end": 185, "token_start": 33, "token_end": 35}, {"text": "CCAAT - box DNA motifs", "type": "ENTITY", "char_start": 203, "char_end": 225, "token_start": 38, "token_end": 42}], "entities_global": [{"text": "native NF - YA : B : C complex", "type": "ENTITY", "char_start": 63339, "char_end": 63369, "token_start": 3, "token_end": 11, "note": null}, {"text": "transcriptional cofactor", "type": "ENTITY", "char_start": 63379, "char_end": 63403, "token_start": 14, "token_end": 15, "note": null}, {"text": "PC4", "type": "ENTITY", "char_start": 63406, "char_end": 63409, "token_start": 17, "token_end": 17, "note": null}, {"text": "high affinity NF - Y", "type": "ENTITY", "char_start": 63431, "char_end": 63451, "token_start": 21, "token_end": 25, "note": null}, {"text": "anion exchangers", "type": "ENTITY", "char_start": 63463, "char_end": 63479, "token_start": 28, "token_end": 29, "note": null}, {"text": "NF - Y", "type": "ENTITY", "char_start": 63497, "char_end": 63503, "token_start": 33, "token_end": 35, "note": null}, {"text": "CCAAT - box DNA motifs", "type": "ENTITY", "char_start": 63521, "char_end": 63543, "token_start": 38, "token_end": 42, "note": null}]}
+{"sentence_id": 384, "sentence_text": "Interaction between PC4 and NF - Y was mapped to the C - terminal region of PC4 , and the subunit interaction subdomain of the highly conserved DNA binding - subunit interaction domain ( DBD ) of NF - YA .", "sentence_char_start_global": 63555, "sentence_char_end_global": 63760, "entities": [{"text": "PC4", "type": "ENTITY", "char_start": 20, "char_end": 23, "token_start": 2, "token_end": 2}, {"text": "NF - Y", "type": "ENTITY", "char_start": 28, "char_end": 34, "token_start": 4, "token_end": 6}, {"text": "C - terminal region", "type": "ENTITY", "char_start": 53, "char_end": 72, "token_start": 11, "token_end": 14}, {"text": "PC4", "type": "ENTITY", "char_start": 76, "char_end": 79, "token_start": 16, "token_end": 16}, {"text": "subunit interaction subdomain", "type": "ENTITY", "char_start": 90, "char_end": 119, "token_start": 20, "token_end": 22}, {"text": "highly conserved DNA binding - subunit interaction domain", "type": "ENTITY", "char_start": 127, "char_end": 184, "token_start": 25, "token_end": 32}, {"text": "DBD", "type": "ENTITY", "char_start": 187, "char_end": 190, "token_start": 34, "token_end": 34}, {"text": "NF - YA", "type": "ENTITY", "char_start": 196, "char_end": 203, "token_start": 37, "token_end": 39}], "entities_global": [{"text": "PC4", "type": "ENTITY", "char_start": 63575, "char_end": 63578, "token_start": 2, "token_end": 2, "note": null}, {"text": "NF - Y", "type": "ENTITY", "char_start": 63583, "char_end": 63589, "token_start": 4, "token_end": 6, "note": null}, {"text": "C - terminal region", "type": "ENTITY", "char_start": 63608, "char_end": 63627, "token_start": 11, "token_end": 14, "note": null}, {"text": "PC4", "type": "ENTITY", "char_start": 63631, "char_end": 63634, "token_start": 16, "token_end": 16, "note": null}, {"text": "subunit interaction subdomain", "type": "ENTITY", "char_start": 63645, "char_end": 63674, "token_start": 20, "token_end": 22, "note": null}, {"text": "highly conserved DNA binding - subunit interaction domain", "type": "ENTITY", "char_start": 63682, "char_end": 63739, "token_start": 25, "token_end": 32, "note": null}, {"text": "DBD", "type": "ENTITY", "char_start": 63742, "char_end": 63745, "token_start": 34, "token_end": 34, "note": null}, {"text": "NF - YA", "type": "ENTITY", "char_start": 63751, "char_end": 63758, "token_start": 37, "token_end": 39, "note": null}]}
+{"sentence_id": 385, "sentence_text": "These results suggest that in class II + mature B - cells NF - Y is associated with the protein cofactor , PC4 , which may play an important role in NF - Y - mediated transcriptional control of class II genes .", "sentence_char_start_global": 63761, "sentence_char_end_global": 63971, "entities": [{"text": "NF - Y", "type": "ENTITY", "char_start": 58, "char_end": 64, "token_start": 12, "token_end": 14}, {"text": "PC4", "type": "ENTITY", "char_start": 107, "char_end": 110, "token_start": 22, "token_end": 22}, {"text": "class II genes", "type": "ENTITY", "char_start": 194, "char_end": 208, "token_start": 39, "token_end": 41}], "entities_global": [{"text": "NF - Y", "type": "ENTITY", "char_start": 63819, "char_end": 63825, "token_start": 12, "token_end": 14, "note": null}, {"text": "PC4", "type": "ENTITY", "char_start": 63868, "char_end": 63871, "token_start": 22, "token_end": 22, "note": null}, {"text": "class II genes", "type": "ENTITY", "char_start": 63955, "char_end": 63969, "token_start": 39, "token_end": 41, "note": null}]}
+{"sentence_id": 386, "sentence_text": "Arrest of B lymphocyte terminal differentiation by CD40 signaling : mechanism for lack of antibody - secreting cells in germinal centers .", "sentence_char_start_global": 63972, "sentence_char_end_global": 64110, "entities": [], "entities_global": []}
+{"sentence_id": 387, "sentence_text": "Despite extensive research , the role of CD40 signaling in B cell terminal differentiation remains controversial .", "sentence_char_start_global": 64111, "sentence_char_end_global": 64225, "entities": [{"text": "CD40", "type": "ENTITY", "char_start": 41, "char_end": 45, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "CD40", "type": "ENTITY", "char_start": 64152, "char_end": 64156, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 388, "sentence_text": "Here we show that CD40 engagement arrests B cell differentiation prior to plasma cell formation .", "sentence_char_start_global": 64226, "sentence_char_end_global": 64323, "entities": [{"text": "CD40", "type": "ENTITY", "char_start": 18, "char_end": 22, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "CD40", "type": "ENTITY", "char_start": 64244, "char_end": 64248, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 389, "sentence_text": "This arrest is manifested at a molecular level as a reduction in mRNA levels of secretory immunoglobulin gene products such as mu ( s ) and J chain as well as the loss of the transcriptional regulator BLIMP - 1 .", "sentence_char_start_global": 64324, "sentence_char_end_global": 64536, "entities": [{"text": "transcriptional regulator", "type": "ENTITY", "char_start": 175, "char_end": 200, "token_start": 35, "token_end": 36}, {"text": "BLIMP - 1", "type": "ENTITY", "char_start": 201, "char_end": 210, "token_start": 37, "token_end": 39}], "entities_global": [{"text": "transcriptional regulator", "type": "ENTITY", "char_start": 64499, "char_end": 64524, "token_start": 35, "token_end": 36, "note": null}, {"text": "BLIMP - 1", "type": "ENTITY", "char_start": 64525, "char_end": 64534, "token_start": 37, "token_end": 39, "note": null}]}
+{"sentence_id": 390, "sentence_text": "Furthermore , the inhibition of B cell differentiation by CD40 engagement could not be overcome by either mitogens or cytokines , but could be reversed by antibodies that interfere with the CD40 / gp39 interaction .", "sentence_char_start_global": 64537, "sentence_char_end_global": 64752, "entities": [{"text": "CD40", "type": "ENTITY", "char_start": 58, "char_end": 62, "token_start": 9, "token_end": 9}, {"text": "mitogens", "type": "ENTITY", "char_start": 106, "char_end": 114, "token_start": 17, "token_end": 17}, {"text": "cytokines", "type": "ENTITY", "char_start": 118, "char_end": 127, "token_start": 19, "token_end": 19}, {"text": "CD40", "type": "ENTITY", "char_start": 190, "char_end": 194, "token_start": 31, "token_end": 31}, {"text": "gp39", "type": "ENTITY", "char_start": 197, "char_end": 201, "token_start": 33, "token_end": 33}], "entities_global": [{"text": "CD40", "type": "ENTITY", "char_start": 64595, "char_end": 64599, "token_start": 9, "token_end": 9, "note": null}, {"text": "mitogens", "type": "ENTITY", "char_start": 64643, "char_end": 64651, "token_start": 17, "token_end": 17, "note": null}, {"text": "cytokines", "type": "ENTITY", "char_start": 64655, "char_end": 64664, "token_start": 19, "token_end": 19, "note": null}, {"text": "CD40", "type": "ENTITY", "char_start": 64727, "char_end": 64731, "token_start": 31, "token_end": 31, "note": null}, {"text": "gp39", "type": "ENTITY", "char_start": 64734, "char_end": 64738, "token_start": 33, "token_end": 33, "note": null}]}
+{"sentence_id": 391, "sentence_text": "These data suggest that secretory immunoglobulin is not produced by B cells that are actively engaged by gp39 - expressing T cells .", "sentence_char_start_global": 64753, "sentence_char_end_global": 64885, "entities": [], "entities_global": []}
+{"sentence_id": 392, "sentence_text": "A positively charged alpha - lipoic acid analogue with increased cellular uptake and more potent immunomodulatory activity .", "sentence_char_start_global": 64886, "sentence_char_end_global": 65010, "entities": [], "entities_global": []}
+{"sentence_id": 393, "sentence_text": "alpha - Lipoic acid ( LA ) is taken up by cells and reduced to its potent dithiol form , dihydrolipoate ( DHLA ) , much of which is rapidly effluxed out from cells .", "sentence_char_start_global": 65011, "sentence_char_end_global": 65176, "entities": [], "entities_global": []}
+{"sentence_id": 394, "sentence_text": "To improve retention in cells , the LA molecule was modified to confer a positive charge at physiological pH .", "sentence_char_start_global": 65177, "sentence_char_end_global": 65287, "entities": [], "entities_global": []}
+{"sentence_id": 395, "sentence_text": "N , N - dimethyl , N ' - 2 - amidoethyl - lipoate was synthesized .", "sentence_char_start_global": 65288, "sentence_char_end_global": 65355, "entities": [], "entities_global": []}
+{"sentence_id": 396, "sentence_text": "The protonated form of the new molecule is referred to as LA - Plus .", "sentence_char_start_global": 65356, "sentence_char_end_global": 65425, "entities": [], "entities_global": []}
+{"sentence_id": 397, "sentence_text": "The uptake of LA - Plus by human Wurzburg T cells was higher compared to that of LA .", "sentence_char_start_global": 65426, "sentence_char_end_global": 65511, "entities": [], "entities_global": []}
+{"sentence_id": 398, "sentence_text": "Several - fold higher amounts of DHLA - Plus , the corresponding reduced form of LA - Plus , were detected in LA - Plus treated cells compared to the amount of DHLA found in cells treated with LA .", "sentence_char_start_global": 65512, "sentence_char_end_global": 65709, "entities": [], "entities_global": []}
+{"sentence_id": 399, "sentence_text": "At 100 microM , LA did not but LA - Plus inhibited H2O2 induced NF - kappaB activation and NF - kappaB directed IL - 2 receptor expression .", "sentence_char_start_global": 65710, "sentence_char_end_global": 65850, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 64, "char_end": 75, "token_start": 14, "token_end": 16}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 91, "char_end": 102, "token_start": 19, "token_end": 21}, {"text": "IL - 2 receptor", "type": "ENTITY", "char_start": 112, "char_end": 127, "token_start": 23, "token_end": 26}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 65774, "char_end": 65785, "token_start": 14, "token_end": 16, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 65801, "char_end": 65812, "token_start": 19, "token_end": 21, "note": null}, {"text": "IL - 2 receptor", "type": "ENTITY", "char_start": 65822, "char_end": 65837, "token_start": 23, "token_end": 26, "note": null}]}
+{"sentence_id": 400, "sentence_text": "Both LA and LA - Plus synergised with selenium in inhibiting H2O2 induced NF - kappaB activation .", "sentence_char_start_global": 65851, "sentence_char_end_global": 65949, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 74, "char_end": 85, "token_start": 13, "token_end": 15}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 65925, "char_end": 65936, "token_start": 13, "token_end": 15, "note": null}]}
+{"sentence_id": 401, "sentence_text": "At 150 microM LA - Plus , but not LA , inhibited TNFalpha induced NF - kappaB activation .", "sentence_char_start_global": 65950, "sentence_char_end_global": 66040, "entities": [{"text": "TNFalpha", "type": "ENTITY", "char_start": 49, "char_end": 57, "token_start": 12, "token_end": 12}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 66, "char_end": 77, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "TNFalpha", "type": "ENTITY", "char_start": 65999, "char_end": 66007, "token_start": 12, "token_end": 12, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 66016, "char_end": 66027, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 402, "sentence_text": "At 5 microM LA - Plus , but not LA , protected against both spontaneous and etoposide induced apoptosis in rat thymocytes .", "sentence_char_start_global": 66041, "sentence_char_end_global": 66164, "entities": [], "entities_global": []}
+{"sentence_id": 403, "sentence_text": "LA - Plus is thus an improved form of LA with increased therapeutic potential .", "sentence_char_start_global": 66165, "sentence_char_end_global": 66244, "entities": [], "entities_global": []}
+{"sentence_id": 404, "sentence_text": "Copyright 1998 Academic Press .", "sentence_char_start_global": 66245, "sentence_char_end_global": 66276, "entities": [], "entities_global": []}
+{"sentence_id": 405, "sentence_text": "Carrier identification in X - linked immunodeficiency diseases .", "sentence_char_start_global": 66277, "sentence_char_end_global": 66341, "entities": [], "entities_global": []}
+{"sentence_id": 406, "sentence_text": "OBJECTIVE : Carrier identification in X - linked immunodeficiency disorders can be based on the demonstration of non - random X inactivation ( NRXI ) in affected blood cell lineages when growth is impaired in cells expressing the abnormal gene .", "sentence_char_start_global": 66342, "sentence_char_end_global": 66587, "entities": [{"text": "abnormal gene", "type": "ENTITY", "char_start": 230, "char_end": 243, "token_start": 38, "token_end": 39}], "entities_global": [{"text": "abnormal gene", "type": "ENTITY", "char_start": 66572, "char_end": 66585, "token_start": 38, "token_end": 39, "note": null}]}
+{"sentence_id": 407, "sentence_text": "We examined the utility of seeking evidence of NRXI to test the carrier status of women in families affected by X - linked severe combined immunodeficiency ( XSCID ) and X - linked hypogammaglobulinaem ( XLH ) , to identify as carriers the mothers of boys with SCID or hypogammaglobulinaem whose phenotype suggested X - linkage and to infer X - linkage in boys with SCID or hypogammaglobulinaem whose disease was not clearly X - linked on the basis either of family history or clinical and immunological characteristics .", "sentence_char_start_global": 66588, "sentence_char_end_global": 67109, "entities": [], "entities_global": []}
+{"sentence_id": 408, "sentence_text": "METHODOLOGY : A polymerase chain reaction - based method was used to amplify a polymorphic CAG repeat in the first exon of the androgen receptor gene after selective digestion of the active X chromosome with a methylation - sensitive enzyme , HpaII to distinguish between the paternal and maternal alleles and to identify their methylation status .", "sentence_char_start_global": 67110, "sentence_char_end_global": 67458, "entities": [{"text": "CAG repeat", "type": "ENTITY", "char_start": 91, "char_end": 101, "token_start": 15, "token_end": 16}, {"text": "first exon", "type": "ENTITY", "char_start": 109, "char_end": 119, "token_start": 19, "token_end": 20}, {"text": "androgen receptor gene", "type": "ENTITY", "char_start": 127, "char_end": 149, "token_start": 23, "token_end": 25}, {"text": "active X chromosome", "type": "ENTITY", "char_start": 183, "char_end": 202, "token_start": 31, "token_end": 33}, {"text": "methylation - sensitive enzyme", "type": "ENTITY", "char_start": 210, "char_end": 240, "token_start": 36, "token_end": 39}, {"text": "HpaII", "type": "ENTITY", "char_start": 243, "char_end": 248, "token_start": 41, "token_end": 41}, {"text": "paternal and maternal alleles", "type": "ENTITY", "char_start": 276, "char_end": 305, "token_start": 46, "token_end": 49}], "entities_global": [{"text": "CAG repeat", "type": "ENTITY", "char_start": 67201, "char_end": 67211, "token_start": 15, "token_end": 16, "note": null}, {"text": "first exon", "type": "ENTITY", "char_start": 67219, "char_end": 67229, "token_start": 19, "token_end": 20, "note": null}, {"text": "androgen receptor gene", "type": "ENTITY", "char_start": 67237, "char_end": 67259, "token_start": 23, "token_end": 25, "note": null}, {"text": "active X chromosome", "type": "ENTITY", "char_start": 67293, "char_end": 67312, "token_start": 31, "token_end": 33, "note": null}, {"text": "methylation - sensitive enzyme", "type": "ENTITY", "char_start": 67320, "char_end": 67350, "token_start": 36, "token_end": 39, "note": null}, {"text": "HpaII", "type": "ENTITY", "char_start": 67353, "char_end": 67358, "token_start": 41, "token_end": 41, "note": null}, {"text": "paternal and maternal alleles", "type": "ENTITY", "char_start": 67386, "char_end": 67415, "token_start": 46, "token_end": 49, "note": null}]}
+{"sentence_id": 409, "sentence_text": "RESULTS : Heterozygosity was found in 24 of 31 female subjects ( 77 % ) .", "sentence_char_start_global": 67459, "sentence_char_end_global": 67532, "entities": [], "entities_global": []}
+{"sentence_id": 410, "sentence_text": "As anticipated , NRXI could be demonstrated in all lymphoid cells studied from obligate carriers of XSCID and an obligate carrier of XLH but not on a carrier of X - linked immunodeficiency with hyper - IgM .", "sentence_char_start_global": 67533, "sentence_char_end_global": 67740, "entities": [{"text": "hyper - IgM", "type": "ENTITY", "char_start": 194, "char_end": 205, "token_start": 34, "token_end": 36}], "entities_global": [{"text": "hyper - IgM", "type": "ENTITY", "char_start": 67727, "char_end": 67738, "token_start": 34, "token_end": 36, "note": null}]}
+{"sentence_id": 411, "sentence_text": "The finding of NRXI in the mother of a boy with a SCID variant showed her to be a carrier of XSCID and establishes that her son has XSCID , not otherwise evident from available data .", "sentence_char_start_global": 67741, "sentence_char_end_global": 67924, "entities": [], "entities_global": []}
+{"sentence_id": 412, "sentence_text": "CONCLUSIONS : This PCR assay provides a rapid method for carrier detection of X - linked immunodeficiencies , and has allowed us to expand the phenotype of XSCID", "sentence_char_start_global": 67925, "sentence_char_end_global": 68086, "entities": [], "entities_global": []}
+{"sentence_id": 413, "sentence_text": "Leukocyte - endothelial interaction is augmented by high glucose concentrations and hyperglycemia in a NF - kB - dependent fashion .", "sentence_char_start_global": 68087, "sentence_char_end_global": 68219, "entities": [], "entities_global": []}
+{"sentence_id": 414, "sentence_text": "We addressed the role of hyperglycemia in leukocyte - endothelium interaction under flow conditions by exposing human umbilical vein endothelial cells for 24 h to normal ( 5 mM ) , high concentration of glucose ( 30 mM ) , advanced glycosylation end product - albumin ( 100 microg / ml ) , or hyperglycemic ( 174 - 316 mg / dl ) sera from patients with diabetes and abnormal hemoglobin A1c ( 8 . 1 + / - 1 . 4 % ) .", "sentence_char_start_global": 68220, "sentence_char_end_global": 68635, "entities": [{"text": "product - albumin", "type": "ENTITY", "char_start": 250, "char_end": 267, "token_start": 43, "token_end": 45}], "entities_global": [{"text": "product - albumin", "type": "ENTITY", "char_start": 68470, "char_end": 68487, "token_start": 43, "token_end": 45, "note": null}]}
+{"sentence_id": 415, "sentence_text": "At the end of incubation endothelial cells were perfused with total leukocyte suspension in a parallel plate flow chamber under laminar flow ( 1 . 5 dyn / cm2 ) .", "sentence_char_start_global": 68636, "sentence_char_end_global": 68798, "entities": [], "entities_global": []}
+{"sentence_id": 416, "sentence_text": "Rolling and adherent cells were evaluated by digital image processing .", "sentence_char_start_global": 68799, "sentence_char_end_global": 68870, "entities": [], "entities_global": []}
+{"sentence_id": 417, "sentence_text": "Results showed that 30 mM glucose significantly ( P < 0 . 01 ) increased the number of adherent leukocytes to endothelial cells in respect to control ( 5 mM glucose ; 151 + / - 19 versus 33 + / - 8 cells / mm2 ) .", "sentence_char_start_global": 68871, "sentence_char_end_global": 69084, "entities": [], "entities_global": []}
+{"sentence_id": 418, "sentence_text": "A similar response was induced by endothelial stimulation with IL - 1beta , here used as positive control ( 195 + / - 20 cells / mm2 ) .", "sentence_char_start_global": 69085, "sentence_char_end_global": 69221, "entities": [{"text": "IL - 1beta", "type": "ENTITY", "char_start": 63, "char_end": 73, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "IL - 1beta", "type": "ENTITY", "char_start": 69148, "char_end": 69158, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 419, "sentence_text": "The number of rolling cells on endothelial surface was not affected by high glucose level .", "sentence_char_start_global": 69222, "sentence_char_end_global": 69313, "entities": [], "entities_global": []}
+{"sentence_id": 420, "sentence_text": "Stable adhesion of leukocytes to glucose - treated as well as to IL - 1beta - stimulated endothelial cells was preceded by short interaction of leukocytes with the endothelial surface .", "sentence_char_start_global": 69314, "sentence_char_end_global": 69499, "entities": [], "entities_global": []}
+{"sentence_id": 421, "sentence_text": "The distance travelled by leukocytes before arrest on 30 mM glucose , or on IL - 1beta - treated endothelial cells , was significantly ( P < 0 . 01 ) higher than that observed for leukocytes adhering on control endothelium ( 30 mM glucose : 76 . 7 + / - 3 . 5 ; IL1beta : 69 . 7 + / - 4 versus 5 mM glucose : 21 . 5 + / - 5 microm ) .", "sentence_char_start_global": 69500, "sentence_char_end_global": 69834, "entities": [], "entities_global": []}
+{"sentence_id": 422, "sentence_text": "Functional blocking of E - selectin , intercellular cell adhesion molecule - 1 , and vascular cell adhesion molecule - 1 on endothelial cells with the corresponding mouse mAb significantly inhibited glucose - induced increase in leukocyte adhesion ( 67 + / - 16 , 83 + / - 12 , 62 + / - 8 versus 144 + / - 21 cells / mm2 ) .", "sentence_char_start_global": 69835, "sentence_char_end_global": 70159, "entities": [{"text": "E - selectin", "type": "ENTITY", "char_start": 23, "char_end": 35, "token_start": 3, "token_end": 5}, {"text": "intercellular cell adhesion molecule - 1", "type": "ENTITY", "char_start": 38, "char_end": 78, "token_start": 7, "token_end": 12}, {"text": "vascular cell adhesion molecule - 1", "type": "ENTITY", "char_start": 85, "char_end": 120, "token_start": 15, "token_end": 20}, {"text": "mouse mAb", "type": "ENTITY", "char_start": 165, "char_end": 174, "token_start": 27, "token_end": 28}], "entities_global": [{"text": "E - selectin", "type": "ENTITY", "char_start": 69858, "char_end": 69870, "token_start": 3, "token_end": 5, "note": null}, {"text": "intercellular cell adhesion molecule - 1", "type": "ENTITY", "char_start": 69873, "char_end": 69913, "token_start": 7, "token_end": 12, "note": null}, {"text": "vascular cell adhesion molecule - 1", "type": "ENTITY", "char_start": 69920, "char_end": 69955, "token_start": 15, "token_end": 20, "note": null}, {"text": "mouse mAb", "type": "ENTITY", "char_start": 70000, "char_end": 70009, "token_start": 27, "token_end": 28, "note": null}]}
+{"sentence_id": 423, "sentence_text": "Confocal fluorescence microscopy studies showed that 30 mM glucose induced an increase in endothelial surface expression of E - selectin , intercellular cell adhesion molecule - 1 , and vascular cell adhesion molecule - 1 .", "sentence_char_start_global": 70160, "sentence_char_end_global": 70383, "entities": [{"text": "E - selectin", "type": "ENTITY", "char_start": 124, "char_end": 136, "token_start": 17, "token_end": 19}, {"text": "intercellular cell adhesion molecule - 1", "type": "ENTITY", "char_start": 139, "char_end": 179, "token_start": 21, "token_end": 26}, {"text": "vascular cell adhesion molecule - 1", "type": "ENTITY", "char_start": 186, "char_end": 221, "token_start": 29, "token_end": 34}], "entities_global": [{"text": "E - selectin", "type": "ENTITY", "char_start": 70284, "char_end": 70296, "token_start": 17, "token_end": 19, "note": null}, {"text": "intercellular cell adhesion molecule - 1", "type": "ENTITY", "char_start": 70299, "char_end": 70339, "token_start": 21, "token_end": 26, "note": null}, {"text": "vascular cell adhesion molecule - 1", "type": "ENTITY", "char_start": 70346, "char_end": 70381, "token_start": 29, "token_end": 34, "note": null}]}
+{"sentence_id": 424, "sentence_text": "Electrophoretic mobility shift assay of nuclear extracts of human umbilical vein endothelial cells ( HUVEC ) exposed for 1 h to 30 mM glucose revealed an intense NF - kB activation .", "sentence_char_start_global": 70384, "sentence_char_end_global": 70566, "entities": [{"text": "NF - kB", "type": "ENTITY", "char_start": 162, "char_end": 169, "token_start": 27, "token_end": 29}], "entities_global": [{"text": "NF - kB", "type": "ENTITY", "char_start": 70546, "char_end": 70553, "token_start": 27, "token_end": 29, "note": null}]}
+{"sentence_id": 425, "sentence_text": "Treatment of HUVEC exposed to high glucose with the NF - kB inhibitors pyrrolidinedithiocar ( 100 microM ) and tosyl - phe - chloromethylketone ( 25 microM ) significantly reduced ( P < 0 . 05 ) leukocyte adhesion in respect to HUVEC treated with glucose alone .", "sentence_char_start_global": 70567, "sentence_char_end_global": 70829, "entities": [{"text": "NF - kB inhibitors", "type": "ENTITY", "char_start": 52, "char_end": 70, "token_start": 9, "token_end": 12}], "entities_global": [{"text": "NF - kB inhibitors", "type": "ENTITY", "char_start": 70619, "char_end": 70637, "token_start": 9, "token_end": 12, "note": null}]}
+{"sentence_id": 426, "sentence_text": "A significant ( P < 0 . 01 ) inhibitory effect on glucose - induced leukocyte adhesion was observed after blocking protein kinase C activity with staurosporine ( 5 nM ) .", "sentence_char_start_global": 70830, "sentence_char_end_global": 71000, "entities": [{"text": "protein kinase C", "type": "ENTITY", "char_start": 115, "char_end": 131, "token_start": 21, "token_end": 23}], "entities_global": [{"text": "protein kinase C", "type": "ENTITY", "char_start": 70945, "char_end": 70961, "token_start": 21, "token_end": 23, "note": null}]}
+{"sentence_id": 427, "sentence_text": "When HUVEC were treated with specific antisense oligodesoxynucleotid against PKCalpha and PKCepsilon isoforms before the addition of 30 mM glucose , a significant ( P < 0 . 05 ) reduction in the adhesion was also seen .", "sentence_char_start_global": 71001, "sentence_char_end_global": 71220, "entities": [{"text": "PKCalpha and PKCepsilon isoforms", "type": "ENTITY", "char_start": 77, "char_end": 109, "token_start": 9, "token_end": 12}], "entities_global": [{"text": "PKCalpha and PKCepsilon isoforms", "type": "ENTITY", "char_start": 71078, "char_end": 71110, "token_start": 9, "token_end": 12, "note": null}]}
+{"sentence_id": 428, "sentence_text": "Advanced glycosylation end product - albumin significantly increased the number of adhering leukocytes in respect to native albumin used as control ( 110 + / - 16 versus 66 + / - 7 , P < 0 . 01 ) .", "sentence_char_start_global": 71221, "sentence_char_end_global": 71418, "entities": [{"text": "product - albumin", "type": "ENTITY", "char_start": 27, "char_end": 44, "token_start": 3, "token_end": 5}, {"text": "native albumin", "type": "ENTITY", "char_start": 117, "char_end": 131, "token_start": 16, "token_end": 17}], "entities_global": [{"text": "product - albumin", "type": "ENTITY", "char_start": 71248, "char_end": 71265, "token_start": 3, "token_end": 5, "note": null}, {"text": "native albumin", "type": "ENTITY", "char_start": 71338, "char_end": 71352, "token_start": 16, "token_end": 17, "note": null}]}
+{"sentence_id": 429, "sentence_text": "Sera from diabetic patients significantly ( P < 0 . 01 ) enhanced leukocyte adhesion as compared with controls , despite normal levels of IL - 1beta and TNFalpha in these sera .", "sentence_char_start_global": 71419, "sentence_char_end_global": 71596, "entities": [{"text": "IL - 1beta", "type": "ENTITY", "char_start": 138, "char_end": 148, "token_start": 24, "token_end": 26}, {"text": "TNFalpha", "type": "ENTITY", "char_start": 153, "char_end": 161, "token_start": 28, "token_end": 28}], "entities_global": [{"text": "IL - 1beta", "type": "ENTITY", "char_start": 71557, "char_end": 71567, "token_start": 24, "token_end": 26, "note": null}, {"text": "TNFalpha", "type": "ENTITY", "char_start": 71572, "char_end": 71580, "token_start": 28, "token_end": 28, "note": null}]}
+{"sentence_id": 430, "sentence_text": "These data indicate that high glucose concentration and hyperglycemia promote leukocyte adhesion to the endothelium through upregulation of cell surface expression of adhesive proteins , possibly depending on NF - kB activation .", "sentence_char_start_global": 71597, "sentence_char_end_global": 71826, "entities": [{"text": "NF - kB", "type": "ENTITY", "char_start": 209, "char_end": 216, "token_start": 28, "token_end": 30}], "entities_global": [{"text": "NF - kB", "type": "ENTITY", "char_start": 71806, "char_end": 71813, "token_start": 28, "token_end": 30, "note": null}]}
+{"sentence_id": 431, "sentence_text": "Ikaros in hemopoietic lineage determination and homeostasis .", "sentence_char_start_global": 71827, "sentence_char_end_global": 71888, "entities": [{"text": "Ikaros", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "Ikaros", "type": "ENTITY", "char_start": 71827, "char_end": 71833, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 432, "sentence_text": "Studies on the molecular mechanisms that control hemopoietic differentiation have focused on signaling cascades and nuclear effectors that drive this complex developmental system in a regulated fashion .", "sentence_char_start_global": 71889, "sentence_char_end_global": 72092, "entities": [], "entities_global": []}
+{"sentence_id": 433, "sentence_text": "Here we review the role of Ikaros , the founding member of a unique family of zinc finger transcription factors in this developmental process .", "sentence_char_start_global": 72093, "sentence_char_end_global": 72236, "entities": [{"text": "Ikaros", "type": "ENTITY", "char_start": 27, "char_end": 33, "token_start": 6, "token_end": 6}, {"text": "zinc finger transcription factors", "type": "ENTITY", "char_start": 78, "char_end": 111, "token_start": 16, "token_end": 19}], "entities_global": [{"text": "Ikaros", "type": "ENTITY", "char_start": 72120, "char_end": 72126, "token_start": 6, "token_end": 6, "note": null}, {"text": "zinc finger transcription factors", "type": "ENTITY", "char_start": 72171, "char_end": 72204, "token_start": 16, "token_end": 19, "note": null}]}
+{"sentence_id": 434, "sentence_text": "Studies on an Ikaros null mutation have revealed an essential role for this factor in lymphoid cell fate determination and at subsequent branch points of the T cell differentiation pathway .", "sentence_char_start_global": 72237, "sentence_char_end_global": 72427, "entities": [{"text": "Ikaros", "type": "ENTITY", "char_start": 14, "char_end": 20, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "Ikaros", "type": "ENTITY", "char_start": 72251, "char_end": 72257, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 435, "sentence_text": "Differences in the phenotypes of a null and a dominant negative ( DN ) Ikaros mutation provide insight into a regulatory network through which Ikaros proteins exert their effects in development .", "sentence_char_start_global": 72428, "sentence_char_end_global": 72623, "entities": [{"text": "dominant negative ( DN ) Ikaros mutation", "type": "ENTITY", "char_start": 46, "char_end": 86, "token_start": 9, "token_end": 15}, {"text": "Ikaros proteins", "type": "ENTITY", "char_start": 143, "char_end": 158, "token_start": 24, "token_end": 25}], "entities_global": [{"text": "dominant negative ( DN ) Ikaros mutation", "type": "ENTITY", "char_start": 72474, "char_end": 72514, "token_start": 9, "token_end": 15, "note": null}, {"text": "Ikaros proteins", "type": "ENTITY", "char_start": 72571, "char_end": 72586, "token_start": 24, "token_end": 25, "note": null}]}
+{"sentence_id": 436, "sentence_text": "In addition a comparative analysis of the hemopoietic stem cell and precursor compartment resulting from the two Ikaros mutations reveals a profound yet not absolute requirement for Ikaros", "sentence_char_start_global": 72624, "sentence_char_end_global": 72812, "entities": [{"text": "Ikaros mutations", "type": "ENTITY", "char_start": 113, "char_end": 129, "token_start": 17, "token_end": 18}, {"text": "Ikaros", "type": "ENTITY", "char_start": 182, "char_end": 188, "token_start": 27, "token_end": 27}], "entities_global": [{"text": "Ikaros mutations", "type": "ENTITY", "char_start": 72737, "char_end": 72753, "token_start": 17, "token_end": 18, "note": null}, {"text": "Ikaros", "type": "ENTITY", "char_start": 72806, "char_end": 72812, "token_start": 27, "token_end": 27, "note": null}]}
+{"sentence_id": 437, "sentence_text": "Induction of early B cell factor ( EBF ) and multiple B lineage genes by the basic helix - loop - helix transcription factor E12 .", "sentence_char_start_global": 72813, "sentence_char_end_global": 72943, "entities": [{"text": "early B cell factor", "type": "ENTITY", "char_start": 13, "char_end": 32, "token_start": 2, "token_end": 5}, {"text": "EBF", "type": "ENTITY", "char_start": 35, "char_end": 38, "token_start": 7, "token_end": 7}, {"text": "multiple B lineage genes", "type": "ENTITY", "char_start": 45, "char_end": 69, "token_start": 10, "token_end": 13}, {"text": "basic helix - loop - helix transcription factor", "type": "ENTITY", "char_start": 77, "char_end": 124, "token_start": 16, "token_end": 23}, {"text": "E12", "type": "ENTITY", "char_start": 125, "char_end": 128, "token_start": 24, "token_end": 24}], "entities_global": [{"text": "early B cell factor", "type": "ENTITY", "char_start": 72826, "char_end": 72845, "token_start": 2, "token_end": 5, "note": null}, {"text": "EBF", "type": "ENTITY", "char_start": 72848, "char_end": 72851, "token_start": 7, "token_end": 7, "note": null}, {"text": "multiple B lineage genes", "type": "ENTITY", "char_start": 72858, "char_end": 72882, "token_start": 10, "token_end": 13, "note": null}, {"text": "basic helix - loop - helix transcription factor", "type": "ENTITY", "char_start": 72890, "char_end": 72937, "token_start": 16, "token_end": 23, "note": null}, {"text": "E12", "type": "ENTITY", "char_start": 72938, "char_end": 72941, "token_start": 24, "token_end": 24, "note": null}]}
+{"sentence_id": 438, "sentence_text": "The transcription factors encoded by the E2A and early B cell factor ( EBF ) genes are required for the proper development of B lymphocytes .", "sentence_char_start_global": 72944, "sentence_char_end_global": 73085, "entities": [{"text": "transcription factors", "type": "ENTITY", "char_start": 4, "char_end": 25, "token_start": 1, "token_end": 2}, {"text": "E2A", "type": "ENTITY", "char_start": 41, "char_end": 44, "token_start": 6, "token_end": 6}, {"text": "early B cell factor", "type": "ENTITY", "char_start": 49, "char_end": 68, "token_start": 8, "token_end": 11}, {"text": "EBF", "type": "ENTITY", "char_start": 71, "char_end": 74, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "transcription factors", "type": "ENTITY", "char_start": 72948, "char_end": 72969, "token_start": 1, "token_end": 2, "note": null}, {"text": "E2A", "type": "ENTITY", "char_start": 72985, "char_end": 72988, "token_start": 6, "token_end": 6, "note": null}, {"text": "early B cell factor", "type": "ENTITY", "char_start": 72993, "char_end": 73012, "token_start": 8, "token_end": 11, "note": null}, {"text": "EBF", "type": "ENTITY", "char_start": 73015, "char_end": 73018, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 439, "sentence_text": "However , the absence of B lineage cells in E2A - and EBF - deficient mice has made it difficult to determine the function or relationship between these proteins .", "sentence_char_start_global": 73086, "sentence_char_end_global": 73249, "entities": [], "entities_global": []}
+{"sentence_id": 440, "sentence_text": "We report the identification of a novel model system in which the role of E2A and EBF in the regulation of multiple B lineage traits can be studied .", "sentence_char_start_global": 73250, "sentence_char_end_global": 73399, "entities": [{"text": "E2A", "type": "ENTITY", "char_start": 74, "char_end": 77, "token_start": 14, "token_end": 14}, {"text": "EBF", "type": "ENTITY", "char_start": 82, "char_end": 85, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "E2A", "type": "ENTITY", "char_start": 73324, "char_end": 73327, "token_start": 14, "token_end": 14, "note": null}, {"text": "EBF", "type": "ENTITY", "char_start": 73332, "char_end": 73335, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 441, "sentence_text": "We found that the conversion of 70Z / 3 pre - B lymphocytes to cells with a macrophage - like phenotype is associated with the loss of E2A and EBF .", "sentence_char_start_global": 73400, "sentence_char_end_global": 73548, "entities": [{"text": "E2A", "type": "ENTITY", "char_start": 135, "char_end": 138, "token_start": 27, "token_end": 27}, {"text": "EBF", "type": "ENTITY", "char_start": 143, "char_end": 146, "token_start": 29, "token_end": 29}], "entities_global": [{"text": "E2A", "type": "ENTITY", "char_start": 73535, "char_end": 73538, "token_start": 27, "token_end": 27, "note": null}, {"text": "EBF", "type": "ENTITY", "char_start": 73543, "char_end": 73546, "token_start": 29, "token_end": 29, "note": null}]}
+{"sentence_id": 442, "sentence_text": "Moreover , we show that ectopic expression of the E2A protein E12 in this macrophage line results in the induction of many B lineage genes , including EBF , IL7Ralpha , lambda5 , and Rag - 1 , and the ability to induce kappa light chain in response to mitogen .", "sentence_char_start_global": 73549, "sentence_char_end_global": 73810, "entities": [{"text": "E2A", "type": "ENTITY", "char_start": 50, "char_end": 53, "token_start": 9, "token_end": 9}, {"text": "E12", "type": "ENTITY", "char_start": 62, "char_end": 65, "token_start": 11, "token_end": 11}, {"text": "many B lineage genes", "type": "ENTITY", "char_start": 118, "char_end": 138, "token_start": 21, "token_end": 24}, {"text": "EBF", "type": "ENTITY", "char_start": 151, "char_end": 154, "token_start": 27, "token_end": 27}, {"text": "IL7Ralpha", "type": "ENTITY", "char_start": 157, "char_end": 166, "token_start": 29, "token_end": 29}, {"text": "lambda5", "type": "ENTITY", "char_start": 169, "char_end": 176, "token_start": 31, "token_end": 31}, {"text": "kappa light chain", "type": "ENTITY", "char_start": 219, "char_end": 236, "token_start": 43, "token_end": 45}], "entities_global": [{"text": "E2A", "type": "ENTITY", "char_start": 73599, "char_end": 73602, "token_start": 9, "token_end": 9, "note": null}, {"text": "E12", "type": "ENTITY", "char_start": 73611, "char_end": 73614, "token_start": 11, "token_end": 11, "note": null}, {"text": "many B lineage genes", "type": "ENTITY", "char_start": 73667, "char_end": 73687, "token_start": 21, "token_end": 24, "note": null}, {"text": "EBF", "type": "ENTITY", "char_start": 73700, "char_end": 73703, "token_start": 27, "token_end": 27, "note": null}, {"text": "IL7Ralpha", "type": "ENTITY", "char_start": 73706, "char_end": 73715, "token_start": 29, "token_end": 29, "note": null}, {"text": "lambda5", "type": "ENTITY", "char_start": 73718, "char_end": 73725, "token_start": 31, "token_end": 31, "note": null}, {"text": "kappa light chain", "type": "ENTITY", "char_start": 73768, "char_end": 73785, "token_start": 43, "token_end": 45, "note": null}]}
+{"sentence_id": 443, "sentence_text": "Activation of EBF may be one of the critical functions of E12 in regulating the B lineage phenotype since expression of EBF alone leads to the activation of a subset of E12 - inducible traits .", "sentence_char_start_global": 73811, "sentence_char_end_global": 74004, "entities": [{"text": "EBF", "type": "ENTITY", "char_start": 14, "char_end": 17, "token_start": 2, "token_end": 2}, {"text": "E12", "type": "ENTITY", "char_start": 58, "char_end": 61, "token_start": 11, "token_end": 11}, {"text": "EBF", "type": "ENTITY", "char_start": 120, "char_end": 123, "token_start": 21, "token_end": 21}, {"text": "E12", "type": "ENTITY", "char_start": 169, "char_end": 172, "token_start": 31, "token_end": 31}], "entities_global": [{"text": "EBF", "type": "ENTITY", "char_start": 73825, "char_end": 73828, "token_start": 2, "token_end": 2, "note": null}, {"text": "E12", "type": "ENTITY", "char_start": 73869, "char_end": 73872, "token_start": 11, "token_end": 11, "note": null}, {"text": "EBF", "type": "ENTITY", "char_start": 73931, "char_end": 73934, "token_start": 21, "token_end": 21, "note": null}, {"text": "E12", "type": "ENTITY", "char_start": 73980, "char_end": 73983, "token_start": 31, "token_end": 31, "note": null}]}
+{"sentence_id": 444, "sentence_text": "Our data demonstrate that , in the context of this macrophage line , E12 induces expression of EBF and together these transcription factors coordinately regulate numerous B lineage - associated genes .", "sentence_char_start_global": 74005, "sentence_char_end_global": 74206, "entities": [{"text": "E12", "type": "ENTITY", "char_start": 69, "char_end": 72, "token_start": 13, "token_end": 13}, {"text": "EBF", "type": "ENTITY", "char_start": 95, "char_end": 98, "token_start": 17, "token_end": 17}, {"text": "transcription factors", "type": "ENTITY", "char_start": 118, "char_end": 139, "token_start": 21, "token_end": 22}, {"text": "B lineage - associated genes", "type": "ENTITY", "char_start": 171, "char_end": 199, "token_start": 26, "token_end": 30}], "entities_global": [{"text": "E12", "type": "ENTITY", "char_start": 74074, "char_end": 74077, "token_start": 13, "token_end": 13, "note": null}, {"text": "EBF", "type": "ENTITY", "char_start": 74100, "char_end": 74103, "token_start": 17, "token_end": 17, "note": null}, {"text": "transcription factors", "type": "ENTITY", "char_start": 74123, "char_end": 74144, "token_start": 21, "token_end": 22, "note": null}, {"text": "B lineage - associated genes", "type": "ENTITY", "char_start": 74176, "char_end": 74204, "token_start": 26, "token_end": 30, "note": null}]}
+{"sentence_id": 445, "sentence_text": "Activation - induced down - regulation of retinoid receptor RXRalpha expression in human T lymphocytes .", "sentence_char_start_global": 74207, "sentence_char_end_global": 74311, "entities": [{"text": "retinoid receptor RXRalpha", "type": "ENTITY", "char_start": 42, "char_end": 68, "token_start": 7, "token_end": 9}], "entities_global": [{"text": "retinoid receptor RXRalpha", "type": "ENTITY", "char_start": 74249, "char_end": 74275, "token_start": 7, "token_end": 9, "note": null}]}
+{"sentence_id": 446, "sentence_text": "Role of cell cycle regulation .", "sentence_char_start_global": 74312, "sentence_char_end_global": 74343, "entities": [], "entities_global": []}
+{"sentence_id": 447, "sentence_text": "A 5 . 4 - kilobase mRNA , the expression of which is down - regulated after treatment of human peripheral blood mononuclear cells ( PBMCs ) with various T cell - activating agents , was isolated using an mRNA differential display method .", "sentence_char_start_global": 74344, "sentence_char_end_global": 74582, "entities": [{"text": "5 . 4 - kilobase mRNA", "type": "ENTITY", "char_start": 2, "char_end": 23, "token_start": 1, "token_end": 6}], "entities_global": [{"text": "5 . 4 - kilobase mRNA", "type": "ENTITY", "char_start": 74346, "char_end": 74367, "token_start": 1, "token_end": 6, "note": null}]}
+{"sentence_id": 448, "sentence_text": "Nucleotide sequence analysis identified the 5 ' end of this RNA as human retinoid receptor RXRalpha mRNA .", "sentence_char_start_global": 74583, "sentence_char_end_global": 74689, "entities": [{"text": "5 ' end", "type": "ENTITY", "char_start": 44, "char_end": 51, "token_start": 5, "token_end": 7}, {"text": "RNA", "type": "ENTITY", "char_start": 60, "char_end": 63, "token_start": 10, "token_end": 10}, {"text": "human retinoid receptor RXRalpha mRNA", "type": "ENTITY", "char_start": 67, "char_end": 104, "token_start": 12, "token_end": 16}], "entities_global": [{"text": "5 ' end", "type": "ENTITY", "char_start": 74627, "char_end": 74634, "token_start": 5, "token_end": 7, "note": null}, {"text": "RNA", "type": "ENTITY", "char_start": 74643, "char_end": 74646, "token_start": 10, "token_end": 10, "note": null}, {"text": "human retinoid receptor RXRalpha mRNA", "type": "ENTITY", "char_start": 74650, "char_end": 74687, "token_start": 12, "token_end": 16, "note": null}]}
+{"sentence_id": 449, "sentence_text": "Here , we report the nucleotide sequence of 3 . 6 kilobases of this RNA , which represents the 3 ' end of RXRalpha mRNA , the sequence of which has not been previously described .", "sentence_char_start_global": 74690, "sentence_char_end_global": 74869, "entities": [{"text": "3 . 6 kilobases", "type": "ENTITY", "char_start": 44, "char_end": 59, "token_start": 8, "token_end": 11}, {"text": "3 ' end", "type": "ENTITY", "char_start": 95, "char_end": 102, "token_start": 19, "token_end": 21}, {"text": "RXRalpha mRNA", "type": "ENTITY", "char_start": 106, "char_end": 119, "token_start": 23, "token_end": 24}], "entities_global": [{"text": "3 . 6 kilobases", "type": "ENTITY", "char_start": 74734, "char_end": 74749, "token_start": 8, "token_end": 11, "note": null}, {"text": "3 ' end", "type": "ENTITY", "char_start": 74785, "char_end": 74792, "token_start": 19, "token_end": 21, "note": null}, {"text": "RXRalpha mRNA", "type": "ENTITY", "char_start": 74796, "char_end": 74809, "token_start": 23, "token_end": 24, "note": null}]}
+{"sentence_id": 450, "sentence_text": "Activated PBMCs also expressed lower levels of RXRalpha protein , and a DNA binding assay showed that the activation - induced loss of RXRalpha mRNA and protein expression correlated with the loss of DNA binding activity of this protein .", "sentence_char_start_global": 74870, "sentence_char_end_global": 75108, "entities": [{"text": "RXRalpha", "type": "ENTITY", "char_start": 47, "char_end": 55, "token_start": 7, "token_end": 7}, {"text": "RXRalpha mRNA", "type": "ENTITY", "char_start": 135, "char_end": 148, "token_start": 23, "token_end": 24}], "entities_global": [{"text": "RXRalpha", "type": "ENTITY", "char_start": 74917, "char_end": 74925, "token_start": 7, "token_end": 7, "note": null}, {"text": "RXRalpha mRNA", "type": "ENTITY", "char_start": 75005, "char_end": 75018, "token_start": 23, "token_end": 24, "note": null}]}
+{"sentence_id": 451, "sentence_text": "We present evidence that the transition from G0 / G1 to S phase of the cell cycle results in the down - regulation of RXRalpha expression and that cell cycle inhibitors , which block the cells in G1 phase , prevent this down - regulation .", "sentence_char_start_global": 75109, "sentence_char_end_global": 75348, "entities": [{"text": "RXRalpha", "type": "ENTITY", "char_start": 118, "char_end": 126, "token_start": 24, "token_end": 24}], "entities_global": [{"text": "RXRalpha", "type": "ENTITY", "char_start": 75227, "char_end": 75235, "token_start": 24, "token_end": 24, "note": null}]}
+{"sentence_id": 452, "sentence_text": "The decrease in the levels of RXRalpha mRNA was found to be regulated at the post - transcriptional level and involved new protein synthesis .", "sentence_char_start_global": 75349, "sentence_char_end_global": 75491, "entities": [{"text": "RXRalpha mRNA", "type": "ENTITY", "char_start": 30, "char_end": 43, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "RXRalpha mRNA", "type": "ENTITY", "char_start": 75379, "char_end": 75392, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 453, "sentence_text": "These observations indicate that the levels of RXRalpha expression in T lymphocytes are coupled to cell cycle progression , and there is tight regulatory control of RXRalpha expression during the transition from G0 / G1 to S phase of the cell cycle .", "sentence_char_start_global": 75492, "sentence_char_end_global": 75742, "entities": [{"text": "RXRalpha", "type": "ENTITY", "char_start": 47, "char_end": 55, "token_start": 7, "token_end": 7}, {"text": "RXRalpha", "type": "ENTITY", "char_start": 165, "char_end": 173, "token_start": 26, "token_end": 26}], "entities_global": [{"text": "RXRalpha", "type": "ENTITY", "char_start": 75539, "char_end": 75547, "token_start": 7, "token_end": 7, "note": null}, {"text": "RXRalpha", "type": "ENTITY", "char_start": 75657, "char_end": 75665, "token_start": 26, "token_end": 26, "note": null}]}
+{"sentence_id": 454, "sentence_text": "Epidemiology and pathogenesis of AIDS - related lymphomas .", "sentence_char_start_global": 75743, "sentence_char_end_global": 75802, "entities": [], "entities_global": []}
+{"sentence_id": 455, "sentence_text": "Among patients with congenital and acquired immunodeficiencies , non - Hodgkin ' s lymphoma ( NHLs ) are the most common tumors of the immune system .", "sentence_char_start_global": 75803, "sentence_char_end_global": 75953, "entities": [], "entities_global": []}
+{"sentence_id": 456, "sentence_text": "In the setting of human immunodeficiency virus ( HIV ) infection , as many as 10 % to 20 % of people ultimately developed NHLs .", "sentence_char_start_global": 75954, "sentence_char_end_global": 76082, "entities": [], "entities_global": []}
+{"sentence_id": 457, "sentence_text": "These tumors are clinically aggressive , frequently involve extranodal sites , and often exhibit unique features that distinguish them from NHL arising in individuals with other forms of immunosuppression .", "sentence_char_start_global": 76083, "sentence_char_end_global": 76289, "entities": [], "entities_global": []}
+{"sentence_id": 458, "sentence_text": "Important in the development of HIV - associated NHL are cytokines and other factors that induce B - cell proliferation and increase the likelihood of mutations of c - myc , bcl - 6 , and other tumor - suppressor genes with carcinogenic potential .", "sentence_char_start_global": 76290, "sentence_char_end_global": 76538, "entities": [{"text": "cytokines", "type": "ENTITY", "char_start": 57, "char_end": 66, "token_start": 10, "token_end": 10}, {"text": "c - myc", "type": "ENTITY", "char_start": 164, "char_end": 171, "token_start": 27, "token_end": 29}, {"text": "bcl - 6", "type": "ENTITY", "char_start": 174, "char_end": 181, "token_start": 31, "token_end": 33}, {"text": "tumor - suppressor genes", "type": "ENTITY", "char_start": 194, "char_end": 218, "token_start": 37, "token_end": 40}], "entities_global": [{"text": "cytokines", "type": "ENTITY", "char_start": 76347, "char_end": 76356, "token_start": 10, "token_end": 10, "note": null}, {"text": "c - myc", "type": "ENTITY", "char_start": 76454, "char_end": 76461, "token_start": 27, "token_end": 29, "note": null}, {"text": "bcl - 6", "type": "ENTITY", "char_start": 76464, "char_end": 76471, "token_start": 31, "token_end": 33, "note": null}, {"text": "tumor - suppressor genes", "type": "ENTITY", "char_start": 76484, "char_end": 76508, "token_start": 37, "token_end": 40, "note": null}]}
+{"sentence_id": 459, "sentence_text": "Specific forms of HIV - associated NHL are linked to expression of Epstein - Barr virus ( EBV ) - latent proteins ; the newly described DNA virus , Karposi ' s sarcoma - associated herpesvirus / human herpesvirus - 8 ( KSHV / HHV - 8 ) ; and perhaps HIV .", "sentence_char_start_global": 76539, "sentence_char_end_global": 76794, "entities": [{"text": "Epstein - Barr virus ( EBV ) - latent proteins", "type": "ENTITY", "char_start": 67, "char_end": 113, "token_start": 12, "token_end": 21}], "entities_global": [{"text": "Epstein - Barr virus ( EBV ) - latent proteins", "type": "ENTITY", "char_start": 76606, "char_end": 76652, "token_start": 12, "token_end": 21, "note": null}]}
+{"sentence_id": 460, "sentence_text": "Elucidation of the factors that contribute to the high incidence of NHL among patients infected with HIV provides insights into important elements of lymphomagenesis .", "sentence_char_start_global": 76795, "sentence_char_end_global": 76962, "entities": [], "entities_global": []}
+{"sentence_id": 461, "sentence_text": "Matrix metalloproteinase expression in human breast cancer : an immunohistochemical study including correlation with cathepsin D , type IV collagen , laminin , fibronectin , EGFR , c - erbB - 2 oncoprotein , p53 , steroid receptors status and proliferative indices .", "sentence_char_start_global": 76963, "sentence_char_end_global": 77229, "entities": [{"text": "Matrix metalloproteinase", "type": "ENTITY", "char_start": 0, "char_end": 24, "token_start": 0, "token_end": 1}, {"text": "cathepsin D", "type": "ENTITY", "char_start": 117, "char_end": 128, "token_start": 14, "token_end": 15}, {"text": "type IV collagen", "type": "ENTITY", "char_start": 131, "char_end": 147, "token_start": 17, "token_end": 19}, {"text": "laminin", "type": "ENTITY", "char_start": 150, "char_end": 157, "token_start": 21, "token_end": 21}, {"text": "fibronectin", "type": "ENTITY", "char_start": 160, "char_end": 171, "token_start": 23, "token_end": 23}, {"text": "EGFR", "type": "ENTITY", "char_start": 174, "char_end": 178, "token_start": 25, "token_end": 25}, {"text": "c - erbB - 2 oncoprotein", "type": "ENTITY", "char_start": 181, "char_end": 205, "token_start": 27, "token_end": 32}, {"text": "p53", "type": "ENTITY", "char_start": 208, "char_end": 211, "token_start": 34, "token_end": 34}], "entities_global": [{"text": "Matrix metalloproteinase", "type": "ENTITY", "char_start": 76963, "char_end": 76987, "token_start": 0, "token_end": 1, "note": null}, {"text": "cathepsin D", "type": "ENTITY", "char_start": 77080, "char_end": 77091, "token_start": 14, "token_end": 15, "note": null}, {"text": "type IV collagen", "type": "ENTITY", "char_start": 77094, "char_end": 77110, "token_start": 17, "token_end": 19, "note": null}, {"text": "laminin", "type": "ENTITY", "char_start": 77113, "char_end": 77120, "token_start": 21, "token_end": 21, "note": null}, {"text": "fibronectin", "type": "ENTITY", "char_start": 77123, "char_end": 77134, "token_start": 23, "token_end": 23, "note": null}, {"text": "EGFR", "type": "ENTITY", "char_start": 77137, "char_end": 77141, "token_start": 25, "token_end": 25, "note": null}, {"text": "c - erbB - 2 oncoprotein", "type": "ENTITY", "char_start": 77144, "char_end": 77168, "token_start": 27, "token_end": 32, "note": null}, {"text": "p53", "type": "ENTITY", "char_start": 77171, "char_end": 77174, "token_start": 34, "token_end": 34, "note": null}]}
+{"sentence_id": 462, "sentence_text": "Matrix metalloproteinase s ( MMPs ) are a group of enzymes thought to be responsible for both normal connective tissue matrix remodelling and accelerated breakdown associated with tumour development .", "sentence_char_start_global": 77230, "sentence_char_end_global": 77430, "entities": [{"text": "Matrix metalloproteinase", "type": "ENTITY", "char_start": 0, "char_end": 24, "token_start": 0, "token_end": 1}, {"text": "MMPs", "type": "ENTITY", "char_start": 29, "char_end": 33, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "Matrix metalloproteinase", "type": "ENTITY", "char_start": 77230, "char_end": 77254, "token_start": 0, "token_end": 1, "note": null}, {"text": "MMPs", "type": "ENTITY", "char_start": 77259, "char_end": 77263, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 463, "sentence_text": "The current study aimed to investigate the immunohistochemical expression of matrix metalloproteinase 3 ( MMP - 3 , stromelysin - 1 ) in correlation with the expression of Basement Membrane ( BM ) antigen ( type IV collagen , laminin ) , fibronectin , cathepsin D , p53 , c - erbB - 2 , proliferative activity ( Ki - 67 , PCNA ) , steroid receptor content as well as to the other conventional clinicopathological parameters in breast cancer .", "sentence_char_start_global": 77431, "sentence_char_end_global": 77873, "entities": [{"text": "matrix metalloproteinase 3", "type": "ENTITY", "char_start": 77, "char_end": 103, "token_start": 10, "token_end": 12}, {"text": "MMP - 3", "type": "ENTITY", "char_start": 106, "char_end": 113, "token_start": 14, "token_end": 16}, {"text": "stromelysin - 1", "type": "ENTITY", "char_start": 116, "char_end": 131, "token_start": 18, "token_end": 20}, {"text": "Basement Membrane ( BM ) antigen", "type": "ENTITY", "char_start": 172, "char_end": 204, "token_start": 28, "token_end": 33}, {"text": "type IV collagen", "type": "ENTITY", "char_start": 207, "char_end": 223, "token_start": 35, "token_end": 37}, {"text": "laminin", "type": "ENTITY", "char_start": 226, "char_end": 233, "token_start": 39, "token_end": 39}, {"text": "fibronectin", "type": "ENTITY", "char_start": 238, "char_end": 249, "token_start": 42, "token_end": 42}, {"text": "cathepsin D", "type": "ENTITY", "char_start": 252, "char_end": 263, "token_start": 44, "token_end": 45}, {"text": "p53", "type": "ENTITY", "char_start": 266, "char_end": 269, "token_start": 47, "token_end": 47}, {"text": "c - erbB - 2", "type": "ENTITY", "char_start": 272, "char_end": 284, "token_start": 49, "token_end": 53}, {"text": "Ki - 67", "type": "ENTITY", "char_start": 312, "char_end": 319, "token_start": 58, "token_end": 60}, {"text": "PCNA", "type": "ENTITY", "char_start": 322, "char_end": 326, "token_start": 62, "token_end": 62}], "entities_global": [{"text": "matrix metalloproteinase 3", "type": "ENTITY", "char_start": 77508, "char_end": 77534, "token_start": 10, "token_end": 12, "note": null}, {"text": "MMP - 3", "type": "ENTITY", "char_start": 77537, "char_end": 77544, "token_start": 14, "token_end": 16, "note": null}, {"text": "stromelysin - 1", "type": "ENTITY", "char_start": 77547, "char_end": 77562, "token_start": 18, "token_end": 20, "note": null}, {"text": "Basement Membrane ( BM ) antigen", "type": "ENTITY", "char_start": 77603, "char_end": 77635, "token_start": 28, "token_end": 33, "note": null}, {"text": "type IV collagen", "type": "ENTITY", "char_start": 77638, "char_end": 77654, "token_start": 35, "token_end": 37, "note": null}, {"text": "laminin", "type": "ENTITY", "char_start": 77657, "char_end": 77664, "token_start": 39, "token_end": 39, "note": null}, {"text": "fibronectin", "type": "ENTITY", "char_start": 77669, "char_end": 77680, "token_start": 42, "token_end": 42, "note": null}, {"text": "cathepsin D", "type": "ENTITY", "char_start": 77683, "char_end": 77694, "token_start": 44, "token_end": 45, "note": null}, {"text": "p53", "type": "ENTITY", "char_start": 77697, "char_end": 77700, "token_start": 47, "token_end": 47, "note": null}, {"text": "c - erbB - 2", "type": "ENTITY", "char_start": 77703, "char_end": 77715, "token_start": 49, "token_end": 53, "note": null}, {"text": "Ki - 67", "type": "ENTITY", "char_start": 77743, "char_end": 77750, "token_start": 58, "token_end": 60, "note": null}, {"text": "PCNA", "type": "ENTITY", "char_start": 77753, "char_end": 77757, "token_start": 62, "token_end": 62, "note": null}]}
+{"sentence_id": 464, "sentence_text": "This study was performed on a series of frozen and paraffin sections from 84 breast cancer specimens by immunohistochemistry using the monoclonal antibody MMP - 3 ( Ab - 1 ) .", "sentence_char_start_global": 77874, "sentence_char_end_global": 78049, "entities": [{"text": "monoclonal antibody MMP - 3", "type": "ENTITY", "char_start": 135, "char_end": 162, "token_start": 21, "token_end": 25}, {"text": "Ab - 1", "type": "ENTITY", "char_start": 165, "char_end": 171, "token_start": 27, "token_end": 29}], "entities_global": [{"text": "monoclonal antibody MMP - 3", "type": "ENTITY", "char_start": 78009, "char_end": 78036, "token_start": 21, "token_end": 25, "note": null}, {"text": "Ab - 1", "type": "ENTITY", "char_start": 78039, "char_end": 78045, "token_start": 27, "token_end": 29, "note": null}]}
+{"sentence_id": 465, "sentence_text": "Stromelysin - 1 ( ST1 ) was observed in about 10 % of epithelial cells in the control groups ( cases of fibrocystic and benign proliferative breast disease ) , while expression ( > 10 % of expression ) was detected in 89 . 7 % of tumours .", "sentence_char_start_global": 78050, "sentence_char_end_global": 78289, "entities": [{"text": "Stromelysin - 1", "type": "ENTITY", "char_start": 0, "char_end": 15, "token_start": 0, "token_end": 2}, {"text": "ST1", "type": "ENTITY", "char_start": 18, "char_end": 21, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "Stromelysin - 1", "type": "ENTITY", "char_start": 78050, "char_end": 78065, "token_start": 0, "token_end": 2, "note": null}, {"text": "ST1", "type": "ENTITY", "char_start": 78068, "char_end": 78071, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 466, "sentence_text": "The expression of ST1 in carcinoma cells was strongly associated with its presence in the stroma ( p < 0 . 001 ) .", "sentence_char_start_global": 78290, "sentence_char_end_global": 78404, "entities": [{"text": "ST1", "type": "ENTITY", "char_start": 18, "char_end": 21, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "ST1", "type": "ENTITY", "char_start": 78308, "char_end": 78311, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 467, "sentence_text": "A significantly positive correlation was found between ST1 expression , and p53 tumour suppressor gene product ( p = 0 . 004 ) , and a relationship with c - erbB - 2 protein and progesterone receptor status was also indicated .", "sentence_char_start_global": 78405, "sentence_char_end_global": 78632, "entities": [{"text": "ST1", "type": "ENTITY", "char_start": 55, "char_end": 58, "token_start": 7, "token_end": 7}, {"text": "p53", "type": "ENTITY", "char_start": 76, "char_end": 79, "token_start": 11, "token_end": 11}, {"text": "c - erbB - 2", "type": "ENTITY", "char_start": 153, "char_end": 165, "token_start": 28, "token_end": 32}], "entities_global": [{"text": "ST1", "type": "ENTITY", "char_start": 78460, "char_end": 78463, "token_start": 7, "token_end": 7, "note": null}, {"text": "p53", "type": "ENTITY", "char_start": 78481, "char_end": 78484, "token_start": 11, "token_end": 11, "note": null}, {"text": "c - erbB - 2", "type": "ENTITY", "char_start": 78558, "char_end": 78570, "token_start": 28, "token_end": 32, "note": null}]}
+{"sentence_id": 468, "sentence_text": "These findings suggest that ST1 expression in breast cancer tissue is irrespective of the expression of the extracellular matrix component , the proteolytic enzyme cathepsin D and the growth fraction of the tumour , and that it could be a potential new prognostic marker in breast cancer .", "sentence_char_start_global": 78633, "sentence_char_end_global": 78922, "entities": [{"text": "ST1", "type": "ENTITY", "char_start": 28, "char_end": 31, "token_start": 4, "token_end": 4}, {"text": "proteolytic enzyme", "type": "ENTITY", "char_start": 145, "char_end": 163, "token_start": 22, "token_end": 23}, {"text": "cathepsin D", "type": "ENTITY", "char_start": 164, "char_end": 175, "token_start": 24, "token_end": 25}], "entities_global": [{"text": "ST1", "type": "ENTITY", "char_start": 78661, "char_end": 78664, "token_start": 4, "token_end": 4, "note": null}, {"text": "proteolytic enzyme", "type": "ENTITY", "char_start": 78778, "char_end": 78796, "token_start": 22, "token_end": 23, "note": null}, {"text": "cathepsin D", "type": "ENTITY", "char_start": 78797, "char_end": 78808, "token_start": 24, "token_end": 25, "note": null}]}
+{"sentence_id": 469, "sentence_text": "Use of transfected liver cells to evaluate potential mechanisms of alcohol - induced liver injury [ see comments ]", "sentence_char_start_global": 78923, "sentence_char_end_global": 79037, "entities": [], "entities_global": []}
+{"sentence_id": 470, "sentence_text": "There is increased activity of the proinflammatory cytokine , tumor necrosis factor ( TNF ) in alcoholic liver disease ( ALD ) .", "sentence_char_start_global": 79038, "sentence_char_end_global": 79166, "entities": [{"text": "proinflammatory cytokine", "type": "ENTITY", "char_start": 35, "char_end": 59, "token_start": 6, "token_end": 7}, {"text": "tumor necrosis factor", "type": "ENTITY", "char_start": 62, "char_end": 83, "token_start": 9, "token_end": 11}, {"text": "TNF", "type": "ENTITY", "char_start": 86, "char_end": 89, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "proinflammatory cytokine", "type": "ENTITY", "char_start": 79073, "char_end": 79097, "token_start": 6, "token_end": 7, "note": null}, {"text": "tumor necrosis factor", "type": "ENTITY", "char_start": 79100, "char_end": 79121, "token_start": 9, "token_end": 11, "note": null}, {"text": "TNF", "type": "ENTITY", "char_start": 79124, "char_end": 79127, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 471, "sentence_text": "Hepatic neutrophil infiltration is a principal injurious manifestation of ALD .", "sentence_char_start_global": 79167, "sentence_char_end_global": 79246, "entities": [], "entities_global": []}
+{"sentence_id": 472, "sentence_text": "TNF can induce cellular oxidative injury directly , and indirectly by inducing neutrophil chemotactic factor ( IL - 8 ) production by hepatocytes .", "sentence_char_start_global": 79247, "sentence_char_end_global": 79394, "entities": [{"text": "TNF", "type": "ENTITY", "char_start": 0, "char_end": 3, "token_start": 0, "token_end": 0}, {"text": "IL - 8", "type": "ENTITY", "char_start": 111, "char_end": 117, "token_start": 16, "token_end": 18}], "entities_global": [{"text": "TNF", "type": "ENTITY", "char_start": 79247, "char_end": 79250, "token_start": 0, "token_end": 0, "note": null}, {"text": "IL - 8", "type": "ENTITY", "char_start": 79358, "char_end": 79364, "token_start": 16, "token_end": 18, "note": null}]}
+{"sentence_id": 473, "sentence_text": "IL - 8 activates and chemotactically attracts neutrophils to the liver where they release oxidizing substances .", "sentence_char_start_global": 79395, "sentence_char_end_global": 79507, "entities": [{"text": "IL - 8", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "IL - 8", "type": "ENTITY", "char_start": 79395, "char_end": 79401, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 474, "sentence_text": "Patients with ALD also have decreased protective factors for cellular oxidative injury .", "sentence_char_start_global": 79508, "sentence_char_end_global": 79596, "entities": [{"text": "protective factors", "type": "ENTITY", "char_start": 38, "char_end": 56, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "protective factors", "type": "ENTITY", "char_start": 79546, "char_end": 79564, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 475, "sentence_text": "Manganous superoxide dismutase ( MnSOD ) is an antioxidant protective factor .", "sentence_char_start_global": 79597, "sentence_char_end_global": 79675, "entities": [{"text": "Manganous superoxide dismutase", "type": "ENTITY", "char_start": 0, "char_end": 30, "token_start": 0, "token_end": 2}, {"text": "MnSOD", "type": "ENTITY", "char_start": 33, "char_end": 38, "token_start": 4, "token_end": 4}, {"text": "antioxidant protective factor", "type": "ENTITY", "char_start": 47, "char_end": 76, "token_start": 8, "token_end": 10}], "entities_global": [{"text": "Manganous superoxide dismutase", "type": "ENTITY", "char_start": 79597, "char_end": 79627, "token_start": 0, "token_end": 2, "note": null}, {"text": "MnSOD", "type": "ENTITY", "char_start": 79630, "char_end": 79635, "token_start": 4, "token_end": 4, "note": null}, {"text": "antioxidant protective factor", "type": "ENTITY", "char_start": 79644, "char_end": 79673, "token_start": 8, "token_end": 10, "note": null}]}
+{"sentence_id": 476, "sentence_text": "The objectives of these studies were to investigate mechanisms for induction of an injurious factor ( IL - 8 ) and a protective factor ( MnSOD ) in the HepG2 human hepatoma cell line .", "sentence_char_start_global": 79676, "sentence_char_end_global": 79860, "entities": [{"text": "injurious factor", "type": "ENTITY", "char_start": 83, "char_end": 99, "token_start": 13, "token_end": 14}, {"text": "IL - 8", "type": "ENTITY", "char_start": 102, "char_end": 108, "token_start": 16, "token_end": 18}, {"text": "protective factor", "type": "ENTITY", "char_start": 117, "char_end": 134, "token_start": 22, "token_end": 23}, {"text": "MnSOD", "type": "ENTITY", "char_start": 137, "char_end": 142, "token_start": 25, "token_end": 25}], "entities_global": [{"text": "injurious factor", "type": "ENTITY", "char_start": 79759, "char_end": 79775, "token_start": 13, "token_end": 14, "note": null}, {"text": "IL - 8", "type": "ENTITY", "char_start": 79778, "char_end": 79784, "token_start": 16, "token_end": 18, "note": null}, {"text": "protective factor", "type": "ENTITY", "char_start": 79793, "char_end": 79810, "token_start": 22, "token_end": 23, "note": null}, {"text": "MnSOD", "type": "ENTITY", "char_start": 79813, "char_end": 79818, "token_start": 25, "token_end": 25, "note": null}]}
+{"sentence_id": 477, "sentence_text": "In the first set of experiments , IL - 8 gene reporter constructs were used to transiently transfect a derivative ( MVh2E1 - 9 ) of the HepG2 cell line which expresses P - 4502E1 and metabolizes ethanol .", "sentence_char_start_global": 79861, "sentence_char_end_global": 80065, "entities": [{"text": "IL - 8 gene reporter constructs", "type": "ENTITY", "char_start": 34, "char_end": 65, "token_start": 7, "token_end": 12}, {"text": "P - 4502E1", "type": "ENTITY", "char_start": 168, "char_end": 178, "token_start": 32, "token_end": 34}], "entities_global": [{"text": "IL - 8 gene reporter constructs", "type": "ENTITY", "char_start": 79895, "char_end": 79926, "token_start": 7, "token_end": 12, "note": null}, {"text": "P - 4502E1", "type": "ENTITY", "char_start": 80029, "char_end": 80039, "token_start": 32, "token_end": 34, "note": null}]}
+{"sentence_id": 478, "sentence_text": "Inactivation of the NF - kappaB and 3 ' NF - IL - 6 DNA binding sites decreased IL - 8 gene transcriptional activation in response to TNF while inactivation of the 5 ' NF - IL - 6 binding site increased IL - 8 gene transcriptional activity in response to TNF .", "sentence_char_start_global": 80066, "sentence_char_end_global": 80326, "entities": [{"text": "NF - kappaB and 3 ' NF - IL - 6 DNA binding sites", "type": "ENTITY", "char_start": 20, "char_end": 69, "token_start": 3, "token_end": 16}, {"text": "IL - 8 gene", "type": "ENTITY", "char_start": 80, "char_end": 91, "token_start": 18, "token_end": 21}, {"text": "TNF", "type": "ENTITY", "char_start": 134, "char_end": 137, "token_start": 27, "token_end": 27}, {"text": "5 ' NF - IL - 6 binding site", "type": "ENTITY", "char_start": 164, "char_end": 192, "token_start": 32, "token_end": 40}, {"text": "IL - 8 gene", "type": "ENTITY", "char_start": 203, "char_end": 214, "token_start": 42, "token_end": 45}, {"text": "TNF", "type": "ENTITY", "char_start": 255, "char_end": 258, "token_start": 51, "token_end": 51}], "entities_global": [{"text": "NF - kappaB and 3 ' NF - IL - 6 DNA binding sites", "type": "ENTITY", "char_start": 80086, "char_end": 80135, "token_start": 3, "token_end": 16, "note": null}, {"text": "IL - 8 gene", "type": "ENTITY", "char_start": 80146, "char_end": 80157, "token_start": 18, "token_end": 21, "note": null}, {"text": "TNF", "type": "ENTITY", "char_start": 80200, "char_end": 80203, "token_start": 27, "token_end": 27, "note": null}, {"text": "5 ' NF - IL - 6 binding site", "type": "ENTITY", "char_start": 80230, "char_end": 80258, "token_start": 32, "token_end": 40, "note": null}, {"text": "IL - 8 gene", "type": "ENTITY", "char_start": 80269, "char_end": 80280, "token_start": 42, "token_end": 45, "note": null}, {"text": "TNF", "type": "ENTITY", "char_start": 80321, "char_end": 80324, "token_start": 51, "token_end": 51, "note": null}]}
+{"sentence_id": 479, "sentence_text": "This system may be useful to assess the effects of ethanol on TNF - induced hepatocyte IL - 8 production .", "sentence_char_start_global": 80327, "sentence_char_end_global": 80433, "entities": [{"text": "TNF", "type": "ENTITY", "char_start": 62, "char_end": 65, "token_start": 12, "token_end": 12}, {"text": "IL - 8", "type": "ENTITY", "char_start": 87, "char_end": 93, "token_start": 16, "token_end": 18}], "entities_global": [{"text": "TNF", "type": "ENTITY", "char_start": 80389, "char_end": 80392, "token_start": 12, "token_end": 12, "note": null}, {"text": "IL - 8", "type": "ENTITY", "char_start": 80414, "char_end": 80420, "token_start": 16, "token_end": 18, "note": null}]}
+{"sentence_id": 480, "sentence_text": "In the second set of experiments , HepG2 cells were cultured in 25 to 100 mmol concentrations of ethanol .", "sentence_char_start_global": 80434, "sentence_char_end_global": 80540, "entities": [], "entities_global": []}
+{"sentence_id": 481, "sentence_text": "Both TNF and ethanol increased HepG2 cell MnSOD activity in short - term ( 72 hr ) cultures with ethanol .", "sentence_char_start_global": 80541, "sentence_char_end_global": 80647, "entities": [{"text": "TNF", "type": "ENTITY", "char_start": 5, "char_end": 8, "token_start": 1, "token_end": 1}, {"text": "MnSOD", "type": "ENTITY", "char_start": 42, "char_end": 47, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "TNF", "type": "ENTITY", "char_start": 80546, "char_end": 80549, "token_start": 1, "token_end": 1, "note": null}, {"text": "MnSOD", "type": "ENTITY", "char_start": 80583, "char_end": 80588, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 482, "sentence_text": "However , after long - term ( 10 weeks ) culture with ethanol , there was no induction of MnSOD by ethanol and there was a diminished induction of MnSOD in response to TNF .", "sentence_char_start_global": 80648, "sentence_char_end_global": 80821, "entities": [{"text": "MnSOD", "type": "ENTITY", "char_start": 90, "char_end": 95, "token_start": 19, "token_end": 19}, {"text": "MnSOD", "type": "ENTITY", "char_start": 147, "char_end": 152, "token_start": 29, "token_end": 29}, {"text": "TNF", "type": "ENTITY", "char_start": 168, "char_end": 171, "token_start": 33, "token_end": 33}], "entities_global": [{"text": "MnSOD", "type": "ENTITY", "char_start": 80738, "char_end": 80743, "token_start": 19, "token_end": 19, "note": null}, {"text": "MnSOD", "type": "ENTITY", "char_start": 80795, "char_end": 80800, "token_start": 29, "token_end": 29, "note": null}, {"text": "TNF", "type": "ENTITY", "char_start": 80816, "char_end": 80819, "token_start": 33, "token_end": 33, "note": null}]}
+{"sentence_id": 483, "sentence_text": "Further studies are needed to assess the effect of this diminished induction of MnSOD with chronic ethanol culture on HepG2 cell susceptibility to TNF cytotoxicity .", "sentence_char_start_global": 80822, "sentence_char_end_global": 80987, "entities": [{"text": "MnSOD", "type": "ENTITY", "char_start": 80, "char_end": 85, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "MnSOD", "type": "ENTITY", "char_start": 80902, "char_end": 80907, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 484, "sentence_text": "We conclude that transfected liver cell lines can be used to evaluate mechanisms for increased injurious factors and decreased protective factors in alcoholic liver injury .", "sentence_char_start_global": 80988, "sentence_char_end_global": 81161, "entities": [{"text": "injurious factors", "type": "ENTITY", "char_start": 95, "char_end": 112, "token_start": 15, "token_end": 16}, {"text": "protective factors", "type": "ENTITY", "char_start": 127, "char_end": 145, "token_start": 19, "token_end": 20}], "entities_global": [{"text": "injurious factors", "type": "ENTITY", "char_start": 81083, "char_end": 81100, "token_start": 15, "token_end": 16, "note": null}, {"text": "protective factors", "type": "ENTITY", "char_start": 81115, "char_end": 81133, "token_start": 19, "token_end": 20, "note": null}]}
+{"sentence_id": 485, "sentence_text": "Tissue factor transcription driven by Egr - 1 is a critical mechanism of murine pulmonary fibrin deposition in hypoxia .", "sentence_char_start_global": 81162, "sentence_char_end_global": 81282, "entities": [{"text": "Egr - 1", "type": "ENTITY", "char_start": 38, "char_end": 45, "token_start": 5, "token_end": 7}, {"text": "murine pulmonary fibrin", "type": "ENTITY", "char_start": 73, "char_end": 96, "token_start": 13, "token_end": 15}], "entities_global": [{"text": "Egr - 1", "type": "ENTITY", "char_start": 81200, "char_end": 81207, "token_start": 5, "token_end": 7, "note": null}, {"text": "murine pulmonary fibrin", "type": "ENTITY", "char_start": 81235, "char_end": 81258, "token_start": 13, "token_end": 15, "note": null}]}
+{"sentence_id": 486, "sentence_text": "Local hypoxemia and stasis trigger thrombosis .", "sentence_char_start_global": 81283, "sentence_char_end_global": 81330, "entities": [], "entities_global": []}
+{"sentence_id": 487, "sentence_text": "We have demonstrated previously that in a murine model of normobaric hypoxia pulmonary fibrin deposition is a result of expression of tissue factor , especially in oxygen - deprived mononuclear phagocytes ( MPs ) .", "sentence_char_start_global": 81331, "sentence_char_end_global": 81545, "entities": [{"text": "fibrin", "type": "ENTITY", "char_start": 87, "char_end": 93, "token_start": 13, "token_end": 13}, {"text": "tissue factor", "type": "ENTITY", "char_start": 134, "char_end": 147, "token_start": 21, "token_end": 22}, {"text": "oxygen - deprived mononuclear phagocytes", "type": "ENTITY", "char_start": 164, "char_end": 204, "token_start": 26, "token_end": 30}, {"text": "MPs", "type": "ENTITY", "char_start": 207, "char_end": 210, "token_start": 32, "token_end": 32}], "entities_global": [{"text": "fibrin", "type": "ENTITY", "char_start": 81418, "char_end": 81424, "token_start": 13, "token_end": 13, "note": null}, {"text": "tissue factor", "type": "ENTITY", "char_start": 81465, "char_end": 81478, "token_start": 21, "token_end": 22, "note": null}, {"text": "oxygen - deprived mononuclear phagocytes", "type": "ENTITY", "char_start": 81495, "char_end": 81535, "token_start": 26, "token_end": 30, "note": null}, {"text": "MPs", "type": "ENTITY", "char_start": 81538, "char_end": 81541, "token_start": 32, "token_end": 32, "note": null}]}
+{"sentence_id": 488, "sentence_text": "We now show that transcription factor early - growth - response gene product ( Egr - 1 ) is rapidly activated in hypoxia , both in vitro and in vivo , and is responsible for transcription and expression of tissue factor in hypoxic lung .", "sentence_char_start_global": 81546, "sentence_char_end_global": 81783, "entities": [{"text": "transcription factor early - growth - response gene product", "type": "ENTITY", "char_start": 17, "char_end": 76, "token_start": 4, "token_end": 12}, {"text": "Egr - 1", "type": "ENTITY", "char_start": 79, "char_end": 86, "token_start": 14, "token_end": 16}, {"text": "tissue factor", "type": "ENTITY", "char_start": 206, "char_end": 219, "token_start": 39, "token_end": 40}], "entities_global": [{"text": "transcription factor early - growth - response gene product", "type": "ENTITY", "char_start": 81563, "char_end": 81622, "token_start": 4, "token_end": 12, "note": null}, {"text": "Egr - 1", "type": "ENTITY", "char_start": 81625, "char_end": 81632, "token_start": 14, "token_end": 16, "note": null}, {"text": "tissue factor", "type": "ENTITY", "char_start": 81752, "char_end": 81765, "token_start": 39, "token_end": 40, "note": null}]}
+{"sentence_id": 489, "sentence_text": "MPs and HeLa cells subjected to hypoxia ( pO2 approximately 13 torr ) had increased levels of tissue factor transcripts ( approximately 18 - fold ) and an increased rate of transcription ( approximately 15 - fold ) , based on nuclear run - on analysis .", "sentence_char_start_global": 81784, "sentence_char_end_global": 82037, "entities": [{"text": "MPs", "type": "ENTITY", "char_start": 0, "char_end": 3, "token_start": 0, "token_end": 0}, {"text": "tissue factor transcripts", "type": "ENTITY", "char_start": 94, "char_end": 119, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "MPs", "type": "ENTITY", "char_start": 81784, "char_end": 81787, "token_start": 0, "token_end": 0, "note": null}, {"text": "tissue factor transcripts", "type": "ENTITY", "char_start": 81878, "char_end": 81903, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 490, "sentence_text": "Gel - shift analysis of nuclear extracts from hypoxic MPs and HeLa cells demonstrated increased DNA - binding activity at the serum response region ( SRR ; - 111 / + 14 bp ) of the tissue factor promoter at Egr - 1 motifs .", "sentence_char_start_global": 82038, "sentence_char_end_global": 82261, "entities": [{"text": "hypoxic MPs", "type": "ENTITY", "char_start": 46, "char_end": 57, "token_start": 8, "token_end": 9}, {"text": "serum response region", "type": "ENTITY", "char_start": 126, "char_end": 147, "token_start": 21, "token_end": 23}, {"text": "tissue factor promoter", "type": "ENTITY", "char_start": 181, "char_end": 203, "token_start": 36, "token_end": 38}, {"text": "Egr - 1 motifs", "type": "ENTITY", "char_start": 207, "char_end": 221, "token_start": 40, "token_end": 43}], "entities_global": [{"text": "hypoxic MPs", "type": "ENTITY", "char_start": 82084, "char_end": 82095, "token_start": 8, "token_end": 9, "note": null}, {"text": "serum response region", "type": "ENTITY", "char_start": 82164, "char_end": 82185, "token_start": 21, "token_end": 23, "note": null}, {"text": "tissue factor promoter", "type": "ENTITY", "char_start": 82219, "char_end": 82241, "token_start": 36, "token_end": 38, "note": null}, {"text": "Egr - 1 motifs", "type": "ENTITY", "char_start": 82245, "char_end": 82259, "token_start": 40, "token_end": 43, "note": null}]}
+{"sentence_id": 491, "sentence_text": "Using 32P - labeled Egr consensus oligonucleotide , we observed induction of DNA - binding activity in nuclear extracts from hypoxic lung and HeLa cells because of activation of Egr - 1 , by means of supershift analysis .", "sentence_char_start_global": 82262, "sentence_char_end_global": 82483, "entities": [{"text": "Egr - 1", "type": "ENTITY", "char_start": 178, "char_end": 185, "token_start": 29, "token_end": 31}], "entities_global": [{"text": "Egr - 1", "type": "ENTITY", "char_start": 82440, "char_end": 82447, "token_start": 29, "token_end": 31, "note": null}]}
+{"sentence_id": 492, "sentence_text": "Transient transfection of HeLa cells with chimeric plasmids containing wild - type or mutant SRR from the tissue factor promoter showed that intact Sp1 sites are necessary for basal promoter activity , whereas the integrity of Egr - 1 sites was required for hypoxia - enhanced expression .", "sentence_char_start_global": 82484, "sentence_char_end_global": 82773, "entities": [{"text": "chimeric plasmids", "type": "ENTITY", "char_start": 42, "char_end": 59, "token_start": 6, "token_end": 7}, {"text": "wild - type or mutant SRR", "type": "ENTITY", "char_start": 71, "char_end": 96, "token_start": 9, "token_end": 14}, {"text": "tissue factor promoter", "type": "ENTITY", "char_start": 106, "char_end": 128, "token_start": 17, "token_end": 19}, {"text": "intact Sp1 sites", "type": "ENTITY", "char_start": 141, "char_end": 157, "token_start": 22, "token_end": 24}, {"text": "Egr - 1 sites", "type": "ENTITY", "char_start": 227, "char_end": 240, "token_start": 36, "token_end": 39}], "entities_global": [{"text": "chimeric plasmids", "type": "ENTITY", "char_start": 82526, "char_end": 82543, "token_start": 6, "token_end": 7, "note": null}, {"text": "wild - type or mutant SRR", "type": "ENTITY", "char_start": 82555, "char_end": 82580, "token_start": 9, "token_end": 14, "note": null}, {"text": "tissue factor promoter", "type": "ENTITY", "char_start": 82590, "char_end": 82612, "token_start": 17, "token_end": 19, "note": null}, {"text": "intact Sp1 sites", "type": "ENTITY", "char_start": 82625, "char_end": 82641, "token_start": 22, "token_end": 24, "note": null}, {"text": "Egr - 1 sites", "type": "ENTITY", "char_start": 82711, "char_end": 82724, "token_start": 36, "token_end": 39, "note": null}]}
+{"sentence_id": 493, "sentence_text": "A central role for Egr - 1 in hypoxia - mediated tissue factor expression was confirmed by experiments with homozygous Egr - 1 null mice ; wild - type mice subjected to oxygen deprivation expressed tissue factor and showed fibrin deposition , but hypoxic homozygous Egr - 1 null mice displayed neither tissue factor nor fibrin .", "sentence_char_start_global": 82774, "sentence_char_end_global": 83102, "entities": [{"text": "Egr - 1", "type": "ENTITY", "char_start": 19, "char_end": 26, "token_start": 4, "token_end": 6}, {"text": "Egr - 1", "type": "ENTITY", "char_start": 119, "char_end": 126, "token_start": 20, "token_end": 22}, {"text": "oxygen deprivation expressed tissue factor", "type": "ENTITY", "char_start": 169, "char_end": 211, "token_start": 32, "token_end": 36}, {"text": "fibrin", "type": "ENTITY", "char_start": 223, "char_end": 229, "token_start": 39, "token_end": 39}, {"text": "Egr - 1", "type": "ENTITY", "char_start": 266, "char_end": 273, "token_start": 45, "token_end": 47}, {"text": "tissue factor", "type": "ENTITY", "char_start": 302, "char_end": 315, "token_start": 52, "token_end": 53}, {"text": "fibrin", "type": "ENTITY", "char_start": 320, "char_end": 326, "token_start": 55, "token_end": 55}], "entities_global": [{"text": "Egr - 1", "type": "ENTITY", "char_start": 82793, "char_end": 82800, "token_start": 4, "token_end": 6, "note": null}, {"text": "Egr - 1", "type": "ENTITY", "char_start": 82893, "char_end": 82900, "token_start": 20, "token_end": 22, "note": null}, {"text": "oxygen deprivation expressed tissue factor", "type": "ENTITY", "char_start": 82943, "char_end": 82985, "token_start": 32, "token_end": 36, "note": null}, {"text": "fibrin", "type": "ENTITY", "char_start": 82997, "char_end": 83003, "token_start": 39, "token_end": 39, "note": null}, {"text": "Egr - 1", "type": "ENTITY", "char_start": 83040, "char_end": 83047, "token_start": 45, "token_end": 47, "note": null}, {"text": "tissue factor", "type": "ENTITY", "char_start": 83076, "char_end": 83089, "token_start": 52, "token_end": 53, "note": null}, {"text": "fibrin", "type": "ENTITY", "char_start": 83094, "char_end": 83100, "token_start": 55, "token_end": 55, "note": null}]}
+{"sentence_id": 494, "sentence_text": "These data delineate a novel biology for hypoxia - induced fibrin deposition , in which oxygen deprivation - induced activation of Egr - 1 , resulting in expression of tissue factor , has an unexpected and central role .", "sentence_char_start_global": 83103, "sentence_char_end_global": 83323, "entities": [{"text": "fibrin", "type": "ENTITY", "char_start": 59, "char_end": 65, "token_start": 10, "token_end": 10}, {"text": "Egr - 1", "type": "ENTITY", "char_start": 131, "char_end": 138, "token_start": 21, "token_end": 23}, {"text": "tissue factor", "type": "ENTITY", "char_start": 168, "char_end": 181, "token_start": 29, "token_end": 30}], "entities_global": [{"text": "fibrin", "type": "ENTITY", "char_start": 83162, "char_end": 83168, "token_start": 10, "token_end": 10, "note": null}, {"text": "Egr - 1", "type": "ENTITY", "char_start": 83234, "char_end": 83241, "token_start": 21, "token_end": 23, "note": null}, {"text": "tissue factor", "type": "ENTITY", "char_start": 83271, "char_end": 83284, "token_start": 29, "token_end": 30, "note": null}]}
+{"sentence_id": 495, "sentence_text": "Kinetics of cytokine and NFAT gene expression in human interleukin - 2 - dependent T lymphoblasts stimulated via T - cell receptor .", "sentence_char_start_global": 83324, "sentence_char_end_global": 83456, "entities": [{"text": "T - cell receptor", "type": "ENTITY", "char_start": 113, "char_end": 130, "token_start": 18, "token_end": 21}], "entities_global": [{"text": "T - cell receptor", "type": "ENTITY", "char_start": 83437, "char_end": 83454, "token_start": 18, "token_end": 21, "note": null}]}
+{"sentence_id": 496, "sentence_text": "T cells respond to mitogenic or antigenic stimulation by proliferation and by turning on cytokine gene expression .", "sentence_char_start_global": 83457, "sentence_char_end_global": 83572, "entities": [], "entities_global": []}
+{"sentence_id": 497, "sentence_text": "Here we have analysed the kinetics and nature of cytokine production in human peripheral blood - derived T lymphoblasts stimulated with anti - CD3 antibodies or Lens culinaris lectin ( LCL ) .", "sentence_char_start_global": 83573, "sentence_char_end_global": 83765, "entities": [{"text": "anti - CD3 antibodies", "type": "ENTITY", "char_start": 136, "char_end": 157, "token_start": 21, "token_end": 24}, {"text": "Lens culinaris lectin", "type": "ENTITY", "char_start": 161, "char_end": 182, "token_start": 26, "token_end": 28}, {"text": "LCL", "type": "ENTITY", "char_start": 185, "char_end": 188, "token_start": 30, "token_end": 30}], "entities_global": [{"text": "anti - CD3 antibodies", "type": "ENTITY", "char_start": 83709, "char_end": 83730, "token_start": 21, "token_end": 24, "note": null}, {"text": "Lens culinaris lectin", "type": "ENTITY", "char_start": 83734, "char_end": 83755, "token_start": 26, "token_end": 28, "note": null}, {"text": "LCL", "type": "ENTITY", "char_start": 83758, "char_end": 83761, "token_start": 30, "token_end": 30, "note": null}]}
+{"sentence_id": 498, "sentence_text": "T cells were purified from peripheral blood mononuclear cells ( PBMC ) and primarily activated with anti - CD3 antibodies and cultured in the presence of interleukin - 2 ( IL - 2 ) .", "sentence_char_start_global": 83766, "sentence_char_end_global": 83948, "entities": [{"text": "anti - CD3 antibodies", "type": "ENTITY", "char_start": 100, "char_end": 121, "token_start": 16, "token_end": 19}, {"text": "interleukin - 2", "type": "ENTITY", "char_start": 154, "char_end": 169, "token_start": 26, "token_end": 28}, {"text": "IL - 2", "type": "ENTITY", "char_start": 172, "char_end": 178, "token_start": 30, "token_end": 32}], "entities_global": [{"text": "anti - CD3 antibodies", "type": "ENTITY", "char_start": 83866, "char_end": 83887, "token_start": 16, "token_end": 19, "note": null}, {"text": "interleukin - 2", "type": "ENTITY", "char_start": 83920, "char_end": 83935, "token_start": 26, "token_end": 28, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 83938, "char_end": 83944, "token_start": 30, "token_end": 32, "note": null}]}
+{"sentence_id": 499, "sentence_text": "Anti - CD3 - restimulated T cells ( mainly CD8 + ) produced IL - 2 , interferon - gamma ( IFN - gamma ) and tumour necrosis factor - alpha ( TNF - alpha ) and low levels of IL - 4 and IL - 10 transcripts and proteins .", "sentence_char_start_global": 83949, "sentence_char_end_global": 84167, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 60, "char_end": 66, "token_start": 13, "token_end": 15}, {"text": "interferon - gamma", "type": "ENTITY", "char_start": 69, "char_end": 87, "token_start": 17, "token_end": 19}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 90, "char_end": 101, "token_start": 21, "token_end": 23}, {"text": "tumour necrosis factor - alpha", "type": "ENTITY", "char_start": 108, "char_end": 138, "token_start": 26, "token_end": 30}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 141, "char_end": 152, "token_start": 32, "token_end": 34}, {"text": "IL - 4 and IL - 10 transcripts", "type": "ENTITY", "char_start": 173, "char_end": 203, "token_start": 40, "token_end": 47}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 84009, "char_end": 84015, "token_start": 13, "token_end": 15, "note": null}, {"text": "interferon - gamma", "type": "ENTITY", "char_start": 84018, "char_end": 84036, "token_start": 17, "token_end": 19, "note": null}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 84039, "char_end": 84050, "token_start": 21, "token_end": 23, "note": null}, {"text": "tumour necrosis factor - alpha", "type": "ENTITY", "char_start": 84057, "char_end": 84087, "token_start": 26, "token_end": 30, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 84090, "char_end": 84101, "token_start": 32, "token_end": 34, "note": null}, {"text": "IL - 4 and IL - 10 transcripts", "type": "ENTITY", "char_start": 84122, "char_end": 84152, "token_start": 40, "token_end": 47, "note": null}]}
+{"sentence_id": 500, "sentence_text": "No IL - 6 gene expression was observed .", "sentence_char_start_global": 84168, "sentence_char_end_global": 84208, "entities": [{"text": "IL - 6 gene", "type": "ENTITY", "char_start": 3, "char_end": 14, "token_start": 1, "token_end": 4}], "entities_global": [{"text": "IL - 6 gene", "type": "ENTITY", "char_start": 84171, "char_end": 84182, "token_start": 1, "token_end": 4, "note": null}]}
+{"sentence_id": 501, "sentence_text": "In LCL - stimulated cells the cytokine production pattern was very similar .", "sentence_char_start_global": 84209, "sentence_char_end_global": 84285, "entities": [], "entities_global": []}
+{"sentence_id": 502, "sentence_text": "Steady - state mRNA levels of IL - 2 , IL - 10 and IFN - gamma peaked at 3 hr after anti - CD3 stimulation and declined rapidly thereafter .", "sentence_char_start_global": 84286, "sentence_char_end_global": 84426, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 30, "char_end": 36, "token_start": 6, "token_end": 8}, {"text": "IL - 10", "type": "ENTITY", "char_start": 39, "char_end": 46, "token_start": 10, "token_end": 12}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 51, "char_end": 62, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 84316, "char_end": 84322, "token_start": 6, "token_end": 8, "note": null}, {"text": "IL - 10", "type": "ENTITY", "char_start": 84325, "char_end": 84332, "token_start": 10, "token_end": 12, "note": null}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 84337, "char_end": 84348, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 503, "sentence_text": "The kinetics of TNF - alpha mRNA expression was faster , being at its peak level 1 hr after stimulation .", "sentence_char_start_global": 84427, "sentence_char_end_global": 84532, "entities": [{"text": "TNF - alpha mRNA", "type": "ENTITY", "char_start": 16, "char_end": 32, "token_start": 3, "token_end": 6}], "entities_global": [{"text": "TNF - alpha mRNA", "type": "ENTITY", "char_start": 84443, "char_end": 84459, "token_start": 3, "token_end": 6, "note": null}]}
+{"sentence_id": 504, "sentence_text": "Anti - CD3 - stimulated IL - 2 gene expression was down - regulated by protein synthesis inhibitor , whereas IL - 10 , IFN - gamma and TNF - alpha genes were readily induced independent of ongoing protein synthesis .", "sentence_char_start_global": 84533, "sentence_char_end_global": 84749, "entities": [{"text": "IL - 2 gene", "type": "ENTITY", "char_start": 24, "char_end": 35, "token_start": 5, "token_end": 8}, {"text": "IL - 10 , IFN - gamma and TNF - alpha genes", "type": "ENTITY", "char_start": 109, "char_end": 152, "token_start": 20, "token_end": 31}], "entities_global": [{"text": "IL - 2 gene", "type": "ENTITY", "char_start": 84557, "char_end": 84568, "token_start": 5, "token_end": 8, "note": null}, {"text": "IL - 10 , IFN - gamma and TNF - alpha genes", "type": "ENTITY", "char_start": 84642, "char_end": 84685, "token_start": 20, "token_end": 31, "note": null}]}
+{"sentence_id": 505, "sentence_text": "T - cell receptor stimulation also induced a very rapid expression of c - jun , c - fos and NFATc1 ( NFATc ) genes , the gene products of which are involved in cytokine gene expression .", "sentence_char_start_global": 84750, "sentence_char_end_global": 84936, "entities": [{"text": "T - cell receptor", "type": "ENTITY", "char_start": 0, "char_end": 17, "token_start": 0, "token_end": 3}, {"text": "c - jun , c - fos and NFATc1 ( NFATc ) genes", "type": "ENTITY", "char_start": 70, "char_end": 114, "token_start": 12, "token_end": 24}], "entities_global": [{"text": "T - cell receptor", "type": "ENTITY", "char_start": 84750, "char_end": 84767, "token_start": 0, "token_end": 3, "note": null}, {"text": "c - jun , c - fos and NFATc1 ( NFATc ) genes", "type": "ENTITY", "char_start": 84820, "char_end": 84864, "token_start": 12, "token_end": 24, "note": null}]}
+{"sentence_id": 506, "sentence_text": "In conclusion , the cytokines synthesized by IL - 2 - dependent T cells were predominantly IL - 2 , IFN - gamma and TNF - alpha .", "sentence_char_start_global": 84937, "sentence_char_end_global": 85066, "entities": [{"text": "cytokines", "type": "ENTITY", "char_start": 20, "char_end": 29, "token_start": 4, "token_end": 4}, {"text": "IL - 2", "type": "ENTITY", "char_start": 91, "char_end": 97, "token_start": 16, "token_end": 18}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 100, "char_end": 111, "token_start": 20, "token_end": 22}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 116, "char_end": 127, "token_start": 24, "token_end": 26}], "entities_global": [{"text": "cytokines", "type": "ENTITY", "char_start": 84957, "char_end": 84966, "token_start": 4, "token_end": 4, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 85028, "char_end": 85034, "token_start": 16, "token_end": 18, "note": null}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 85037, "char_end": 85048, "token_start": 20, "token_end": 22, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 85053, "char_end": 85064, "token_start": 24, "token_end": 26, "note": null}]}
+{"sentence_id": 507, "sentence_text": "An animal model to study local oxidation of LDL and its biological effects in the arterial wall .", "sentence_char_start_global": 85067, "sentence_char_end_global": 85164, "entities": [], "entities_global": []}
+{"sentence_id": 508, "sentence_text": "Oxidized LDL ( oxLDL ) is present in atherosclerotic lesions and is believed to play a key role in atherogenesis .", "sentence_char_start_global": 85165, "sentence_char_end_global": 85279, "entities": [], "entities_global": []}
+{"sentence_id": 509, "sentence_text": "Mainly on the basis of cell culture studies , oxLDL has been shown to produce many biological effects that influence the atherosclerotic process .", "sentence_char_start_global": 85280, "sentence_char_end_global": 85426, "entities": [], "entities_global": []}
+{"sentence_id": 510, "sentence_text": "To study LDL oxidation in vivo , we have established a model in which Sprague - Dawley rats are given a single injection of unmodified human LDL ( > or = 4 mg / kg body weight ) .", "sentence_char_start_global": 85427, "sentence_char_end_global": 85606, "entities": [], "entities_global": []}
+{"sentence_id": 511, "sentence_text": "Within 6 hours , an accumulation of apolipoprotein B and epitopes present on oxLDL are detected in the arterial endothelium and media .", "sentence_char_start_global": 85607, "sentence_char_end_global": 85742, "entities": [{"text": "epitopes", "type": "ENTITY", "char_start": 57, "char_end": 65, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "epitopes", "type": "ENTITY", "char_start": 85664, "char_end": 85672, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 512, "sentence_text": "The presence of oxLDL is associated with activation of the transcription factor nuclear factor - kappaB in the endothelium as well as endothelial expression of intercellular adhesion molecule - 1 .", "sentence_char_start_global": 85743, "sentence_char_end_global": 85940, "entities": [{"text": "transcription factor", "type": "ENTITY", "char_start": 59, "char_end": 79, "token_start": 10, "token_end": 11}, {"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 80, "char_end": 103, "token_start": 12, "token_end": 15}, {"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 160, "char_end": 195, "token_start": 25, "token_end": 29}], "entities_global": [{"text": "transcription factor", "type": "ENTITY", "char_start": 85802, "char_end": 85822, "token_start": 10, "token_end": 11, "note": null}, {"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 85823, "char_end": 85846, "token_start": 12, "token_end": 15, "note": null}, {"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 85903, "char_end": 85938, "token_start": 25, "token_end": 29, "note": null}]}
+{"sentence_id": 513, "sentence_text": "Injection of LDL enriched with the antioxidant probucol resulted in arterial accumulation of apolipoprotein B , but the expression of oxLDL - specific epitopes was reduced at 24 hours .", "sentence_char_start_global": 85941, "sentence_char_end_global": 86126, "entities": [], "entities_global": []}
+{"sentence_id": 514, "sentence_text": "Thus , this simple model has the potential to analyze the mechanisms behind and biological effects of LDL oxidation in vivo .", "sentence_char_start_global": 86127, "sentence_char_end_global": 86252, "entities": [], "entities_global": []}
+{"sentence_id": 515, "sentence_text": "Molecular mechanisms of promoter regulation of the gp34 gene that is trans - activated by an oncoprotein Tax of human T cell leukemia virus type I .", "sentence_char_start_global": 86253, "sentence_char_end_global": 86401, "entities": [{"text": "gp34 gene", "type": "ENTITY", "char_start": 51, "char_end": 60, "token_start": 7, "token_end": 8}, {"text": "oncoprotein Tax", "type": "ENTITY", "char_start": 93, "char_end": 108, "token_start": 16, "token_end": 17}], "entities_global": [{"text": "gp34 gene", "type": "ENTITY", "char_start": 86304, "char_end": 86313, "token_start": 7, "token_end": 8, "note": null}, {"text": "oncoprotein Tax", "type": "ENTITY", "char_start": 86346, "char_end": 86361, "token_start": 16, "token_end": 17, "note": null}]}
+{"sentence_id": 516, "sentence_text": "We investigated the molecular mechanism of transcriptional activation of the gp34 gene by the Tax oncoprotein of human T cell leukemia virus type I ( HTLV - I ) .", "sentence_char_start_global": 86402, "sentence_char_end_global": 86564, "entities": [{"text": "gp34 gene", "type": "ENTITY", "char_start": 77, "char_end": 86, "token_start": 10, "token_end": 11}, {"text": "Tax oncoprotein", "type": "ENTITY", "char_start": 94, "char_end": 109, "token_start": 14, "token_end": 15}], "entities_global": [{"text": "gp34 gene", "type": "ENTITY", "char_start": 86479, "char_end": 86488, "token_start": 10, "token_end": 11, "note": null}, {"text": "Tax oncoprotein", "type": "ENTITY", "char_start": 86496, "char_end": 86511, "token_start": 14, "token_end": 15, "note": null}]}
+{"sentence_id": 517, "sentence_text": "gp34 is a type II transmembrane molecule belonging to the tumor necrosis factor family and is constitutively expressed on HTLV - I - producing cells but not normal resting T cells .", "sentence_char_start_global": 86565, "sentence_char_end_global": 86746, "entities": [{"text": "gp34", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}, {"text": "type II transmembrane molecule", "type": "ENTITY", "char_start": 10, "char_end": 40, "token_start": 3, "token_end": 6}], "entities_global": [{"text": "gp34", "type": "ENTITY", "char_start": 86565, "char_end": 86569, "token_start": 0, "token_end": 0, "note": null}, {"text": "type II transmembrane molecule", "type": "ENTITY", "char_start": 86575, "char_end": 86605, "token_start": 3, "token_end": 6, "note": null}]}
+{"sentence_id": 518, "sentence_text": "The transcriptional regulatory region of the gp34 gene was activated by HTLV - I Tax in the human T cell line Jurkat , in which endogenous gp34 is induced by Tax .", "sentence_char_start_global": 86747, "sentence_char_end_global": 86910, "entities": [{"text": "gp34 gene", "type": "ENTITY", "char_start": 45, "char_end": 54, "token_start": 6, "token_end": 7}, {"text": "Tax", "type": "ENTITY", "char_start": 81, "char_end": 84, "token_start": 14, "token_end": 14}, {"text": "gp34", "type": "ENTITY", "char_start": 139, "char_end": 143, "token_start": 26, "token_end": 26}, {"text": "Tax", "type": "ENTITY", "char_start": 158, "char_end": 161, "token_start": 30, "token_end": 30}], "entities_global": [{"text": "gp34 gene", "type": "ENTITY", "char_start": 86792, "char_end": 86801, "token_start": 6, "token_end": 7, "note": null}, {"text": "Tax", "type": "ENTITY", "char_start": 86828, "char_end": 86831, "token_start": 14, "token_end": 14, "note": null}, {"text": "gp34", "type": "ENTITY", "char_start": 86886, "char_end": 86890, "token_start": 26, "token_end": 26, "note": null}, {"text": "Tax", "type": "ENTITY", "char_start": 86905, "char_end": 86908, "token_start": 30, "token_end": 30, "note": null}]}
+{"sentence_id": 519, "sentence_text": "Sequence analysis demonstrated that two NF - kappaB - like elements ( 1 and 2 ) were present in the regulatory region .", "sentence_char_start_global": 86911, "sentence_char_end_global": 87030, "entities": [{"text": "NF - kappaB - like elements", "type": "ENTITY", "char_start": 40, "char_end": 67, "token_start": 5, "token_end": 10}, {"text": "regulatory region", "type": "ENTITY", "char_start": 100, "char_end": 117, "token_start": 20, "token_end": 21}], "entities_global": [{"text": "NF - kappaB - like elements", "type": "ENTITY", "char_start": 86951, "char_end": 86978, "token_start": 5, "token_end": 10, "note": null}, {"text": "regulatory region", "type": "ENTITY", "char_start": 87011, "char_end": 87028, "token_start": 20, "token_end": 21, "note": null}]}
+{"sentence_id": 520, "sentence_text": "Both NF - kappaB - like elements were able to bind to NF - kappaB or its related factor ( s ) in a Tax - dependent manner .", "sentence_char_start_global": 87031, "sentence_char_end_global": 87154, "entities": [{"text": "NF - kappaB - like elements", "type": "ENTITY", "char_start": 5, "char_end": 32, "token_start": 1, "token_end": 6}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 54, "char_end": 65, "token_start": 12, "token_end": 14}, {"text": "Tax", "type": "ENTITY", "char_start": 99, "char_end": 102, "token_start": 24, "token_end": 24}], "entities_global": [{"text": "NF - kappaB - like elements", "type": "ENTITY", "char_start": 87036, "char_end": 87063, "token_start": 1, "token_end": 6, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 87085, "char_end": 87096, "token_start": 12, "token_end": 14, "note": null}, {"text": "Tax", "type": "ENTITY", "char_start": 87130, "char_end": 87133, "token_start": 24, "token_end": 24, "note": null}]}
+{"sentence_id": 521, "sentence_text": "Chloramphenicol acetyltransferase assays indicated that NF - kappaB - like element 1 was Tax - responsive , although the activity was lower than that the native promoter .", "sentence_char_start_global": 87155, "sentence_char_end_global": 87326, "entities": [{"text": "Chloramphenicol acetyltransferase", "type": "ENTITY", "char_start": 0, "char_end": 33, "token_start": 0, "token_end": 1}, {"text": "NF - kappaB - like element 1", "type": "ENTITY", "char_start": 56, "char_end": 84, "token_start": 5, "token_end": 11}, {"text": "Tax", "type": "ENTITY", "char_start": 89, "char_end": 92, "token_start": 13, "token_end": 13}, {"text": "native promoter", "type": "ENTITY", "char_start": 154, "char_end": 169, "token_start": 25, "token_end": 26}], "entities_global": [{"text": "Chloramphenicol acetyltransferase", "type": "ENTITY", "char_start": 87155, "char_end": 87188, "token_start": 0, "token_end": 1, "note": null}, {"text": "NF - kappaB - like element 1", "type": "ENTITY", "char_start": 87211, "char_end": 87239, "token_start": 5, "token_end": 11, "note": null}, {"text": "Tax", "type": "ENTITY", "char_start": 87244, "char_end": 87247, "token_start": 13, "token_end": 13, "note": null}, {"text": "native promoter", "type": "ENTITY", "char_start": 87309, "char_end": 87324, "token_start": 25, "token_end": 26, "note": null}]}
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+{"sentence_id": 523, "sentence_text": "Unlike typical NF - kappaB elements , the NF - kappaB - like elements in gp34 were not activated by treatment of Jurkat cells with phorbol ester despite induction of the NF - kappaB - like binding activity .", "sentence_char_start_global": 87513, "sentence_char_end_global": 87720, "entities": [{"text": "NF - kappaB elements", "type": "ENTITY", "char_start": 15, "char_end": 35, "token_start": 2, "token_end": 5}, {"text": "NF - kappaB - like elements", "type": "ENTITY", "char_start": 42, "char_end": 69, "token_start": 8, "token_end": 13}, {"text": "gp34", "type": "ENTITY", "char_start": 73, "char_end": 77, "token_start": 15, "token_end": 15}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 170, "char_end": 181, "token_start": 31, "token_end": 33}], "entities_global": [{"text": "NF - kappaB elements", "type": "ENTITY", "char_start": 87528, "char_end": 87548, "token_start": 2, "token_end": 5, "note": null}, {"text": "NF - kappaB - like elements", "type": "ENTITY", "char_start": 87555, "char_end": 87582, "token_start": 8, "token_end": 13, "note": null}, {"text": "gp34", "type": "ENTITY", "char_start": 87586, "char_end": 87590, "token_start": 15, "token_end": 15, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 87683, "char_end": 87694, "token_start": 31, "token_end": 33, "note": null}]}
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+{"sentence_id": 525, "sentence_text": "Our results imply complex regulation of expression of the gp34 gene and suggest implication of gp34 in proliferation of HTLV - I infected T cells .", "sentence_char_start_global": 87964, "sentence_char_end_global": 88111, "entities": [{"text": "gp34 gene", "type": "ENTITY", "char_start": 58, "char_end": 67, "token_start": 9, "token_end": 10}, {"text": "gp34", "type": "ENTITY", "char_start": 95, "char_end": 99, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "gp34 gene", "type": "ENTITY", "char_start": 88022, "char_end": 88031, "token_start": 9, "token_end": 10, "note": null}, {"text": "gp34", "type": "ENTITY", "char_start": 88059, "char_end": 88063, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 526, "sentence_text": "beta - Amyloid fibrils activate parallel mitogen - activated protein kinase pathways in microglia and THP1 monocytes .", "sentence_char_start_global": 88112, "sentence_char_end_global": 88230, "entities": [{"text": "beta - Amyloid fibrils", "type": "ENTITY", "char_start": 0, "char_end": 22, "token_start": 0, "token_end": 3}, {"text": "mitogen - activated protein kinase", "type": "ENTITY", "char_start": 41, "char_end": 75, "token_start": 6, "token_end": 10}], "entities_global": [{"text": "beta - Amyloid fibrils", "type": "ENTITY", "char_start": 88112, "char_end": 88134, "token_start": 0, "token_end": 3, "note": null}, {"text": "mitogen - activated protein kinase", "type": "ENTITY", "char_start": 88153, "char_end": 88187, "token_start": 6, "token_end": 10, "note": null}]}
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+{"sentence_id": 530, "sentence_text": "We report that exposure of primary rat microglia and human THP1 monocytes to fibrillar Abeta results in the tyrosine kinase - dependent activation of two parallel signal transduction cascades involving members of the mitogen - activated protein kinase ( MAPK ) superfamily .", "sentence_char_start_global": 88752, "sentence_char_end_global": 89026, "entities": [{"text": "fibrillar Abeta", "type": "ENTITY", "char_start": 77, "char_end": 92, "token_start": 13, "token_end": 14}, {"text": "tyrosine kinase", "type": "ENTITY", "char_start": 108, "char_end": 123, "token_start": 18, "token_end": 19}, {"text": "mitogen - activated protein kinase ( MAPK ) superfamily", "type": "ENTITY", "char_start": 217, "char_end": 272, "token_start": 33, "token_end": 41}], "entities_global": [{"text": "fibrillar Abeta", "type": "ENTITY", "char_start": 88829, "char_end": 88844, "token_start": 13, "token_end": 14, "note": null}, {"text": "tyrosine kinase", "type": "ENTITY", "char_start": 88860, "char_end": 88875, "token_start": 18, "token_end": 19, "note": null}, {"text": "mitogen - activated protein kinase ( MAPK ) superfamily", "type": "ENTITY", "char_start": 88969, "char_end": 89024, "token_start": 33, "token_end": 41, "note": null}]}
+{"sentence_id": 531, "sentence_text": "Abeta stimulated the rapid , transient activation of extracellular signal - regulated kinase 1 ( ERK1 ) and ERK2 in microglia and ERK2 in THP1 monocytes .", "sentence_char_start_global": 89027, "sentence_char_end_global": 89181, "entities": [{"text": "Abeta", "type": "ENTITY", "char_start": 0, "char_end": 5, "token_start": 0, "token_end": 0}, {"text": "extracellular signal - regulated kinase 1", "type": "ENTITY", "char_start": 53, "char_end": 94, "token_start": 8, "token_end": 13}, {"text": "ERK1", "type": "ENTITY", "char_start": 97, "char_end": 101, "token_start": 15, "token_end": 15}, {"text": "ERK2", "type": "ENTITY", "char_start": 108, "char_end": 112, "token_start": 18, "token_end": 18}, {"text": "ERK2", "type": "ENTITY", "char_start": 130, "char_end": 134, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "Abeta", "type": "ENTITY", "char_start": 89027, "char_end": 89032, "token_start": 0, "token_end": 0, "note": null}, {"text": "extracellular signal - regulated kinase 1", "type": "ENTITY", "char_start": 89080, "char_end": 89121, "token_start": 8, "token_end": 13, "note": null}, {"text": "ERK1", "type": "ENTITY", "char_start": 89124, "char_end": 89128, "token_start": 15, "token_end": 15, "note": null}, {"text": "ERK2", "type": "ENTITY", "char_start": 89135, "char_end": 89139, "token_start": 18, "token_end": 18, "note": null}, {"text": "ERK2", "type": "ENTITY", "char_start": 89157, "char_end": 89161, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 532, "sentence_text": "A second superfamily member , p38 MAPK , was also activated with similar kinetics .", "sentence_char_start_global": 89182, "sentence_char_end_global": 89265, "entities": [{"text": "superfamily member", "type": "ENTITY", "char_start": 9, "char_end": 27, "token_start": 2, "token_end": 3}, {"text": "p38 MAPK", "type": "ENTITY", "char_start": 30, "char_end": 38, "token_start": 5, "token_end": 6}], "entities_global": [{"text": "superfamily member", "type": "ENTITY", "char_start": 89191, "char_end": 89209, "token_start": 2, "token_end": 3, "note": null}, {"text": "p38 MAPK", "type": "ENTITY", "char_start": 89212, "char_end": 89220, "token_start": 5, "token_end": 6, "note": null}]}
+{"sentence_id": 533, "sentence_text": "Scavenger receptor and receptor for advanced glycated end products ( RAGE ) ligands failed to activate ERK and p38 MAPK in the absence of significant increases in protein tyrosine phosphorylation , demonstrating that scavenger receptors and RAGE are not linked to these pathways .", "sentence_char_start_global": 89266, "sentence_char_end_global": 89546, "entities": [{"text": "Scavenger receptor", "type": "ENTITY", "char_start": 0, "char_end": 18, "token_start": 0, "token_end": 1}, {"text": "receptor for advanced glycated end products", "type": "ENTITY", "char_start": 23, "char_end": 66, "token_start": 3, "token_end": 8}, {"text": "RAGE", "type": "ENTITY", "char_start": 69, "char_end": 73, "token_start": 10, "token_end": 10}, {"text": "ERK", "type": "ENTITY", "char_start": 103, "char_end": 106, "token_start": 16, "token_end": 16}, {"text": "p38 MAPK", "type": "ENTITY", "char_start": 111, "char_end": 119, "token_start": 18, "token_end": 19}, {"text": "scavenger receptors", "type": "ENTITY", "char_start": 217, "char_end": 236, "token_start": 33, "token_end": 34}, {"text": "RAGE", "type": "ENTITY", "char_start": 241, "char_end": 245, "token_start": 36, "token_end": 36}], "entities_global": [{"text": "Scavenger receptor", "type": "ENTITY", "char_start": 89266, "char_end": 89284, "token_start": 0, "token_end": 1, "note": null}, {"text": "receptor for advanced glycated end products", "type": "ENTITY", "char_start": 89289, "char_end": 89332, "token_start": 3, "token_end": 8, "note": null}, {"text": "RAGE", "type": "ENTITY", "char_start": 89335, "char_end": 89339, "token_start": 10, "token_end": 10, "note": null}, {"text": "ERK", "type": "ENTITY", "char_start": 89369, "char_end": 89372, "token_start": 16, "token_end": 16, "note": null}, {"text": "p38 MAPK", "type": "ENTITY", "char_start": 89377, "char_end": 89385, "token_start": 18, "token_end": 19, "note": null}, {"text": "scavenger receptors", "type": "ENTITY", "char_start": 89483, "char_end": 89502, "token_start": 33, "token_end": 34, "note": null}, {"text": "RAGE", "type": "ENTITY", "char_start": 89507, "char_end": 89511, "token_start": 36, "token_end": 36, "note": null}]}
+{"sentence_id": 534, "sentence_text": "Importantly , the stress - activated protein kinases ( SAPKs ) were not significantly activated in response to Abeta .", "sentence_char_start_global": 89547, "sentence_char_end_global": 89665, "entities": [{"text": "stress - activated protein kinases", "type": "ENTITY", "char_start": 18, "char_end": 52, "token_start": 3, "token_end": 7}, {"text": "SAPKs", "type": "ENTITY", "char_start": 55, "char_end": 60, "token_start": 9, "token_end": 9}, {"text": "Abeta", "type": "ENTITY", "char_start": 111, "char_end": 116, "token_start": 18, "token_end": 18}], "entities_global": [{"text": "stress - activated protein kinases", "type": "ENTITY", "char_start": 89565, "char_end": 89599, "token_start": 3, "token_end": 7, "note": null}, {"text": "SAPKs", "type": "ENTITY", "char_start": 89602, "char_end": 89607, "token_start": 9, "token_end": 9, "note": null}, {"text": "Abeta", "type": "ENTITY", "char_start": 89658, "char_end": 89663, "token_start": 18, "token_end": 18, "note": null}]}
+{"sentence_id": 535, "sentence_text": "Downstream effectors of the MAPK signal transduction cascades include MAPKAP kinases , such as RSK1 and RSK2 , as well as transcription factors .", "sentence_char_start_global": 89666, "sentence_char_end_global": 89811, "entities": [{"text": "MAPKAP kinases", "type": "ENTITY", "char_start": 70, "char_end": 84, "token_start": 9, "token_end": 10}, {"text": "RSK1", "type": "ENTITY", "char_start": 95, "char_end": 99, "token_start": 14, "token_end": 14}, {"text": "RSK2", "type": "ENTITY", "char_start": 104, "char_end": 108, "token_start": 16, "token_end": 16}, {"text": "transcription factors", "type": "ENTITY", "char_start": 122, "char_end": 143, "token_start": 21, "token_end": 22}], "entities_global": [{"text": "MAPKAP kinases", "type": "ENTITY", "char_start": 89736, "char_end": 89750, "token_start": 9, "token_end": 10, "note": null}, {"text": "RSK1", "type": "ENTITY", "char_start": 89761, "char_end": 89765, "token_start": 14, "token_end": 14, "note": null}, {"text": "RSK2", "type": "ENTITY", "char_start": 89770, "char_end": 89774, "token_start": 16, "token_end": 16, "note": null}, {"text": "transcription factors", "type": "ENTITY", "char_start": 89788, "char_end": 89809, "token_start": 21, "token_end": 22, "note": null}]}
+{"sentence_id": 536, "sentence_text": "Exposure of microglia and THP1 monocytes to Abeta resulted in the activation of RSK1 and RSK2 and phosphorylation of cAMP response element - binding protein at Ser133 , providing a mechanism for Abeta - induced changes in gene expression", "sentence_char_start_global": 89812, "sentence_char_end_global": 90049, "entities": [{"text": "Abeta", "type": "ENTITY", "char_start": 44, "char_end": 49, "token_start": 7, "token_end": 7}, {"text": "RSK1", "type": "ENTITY", "char_start": 80, "char_end": 84, "token_start": 13, "token_end": 13}, {"text": "RSK2", "type": "ENTITY", "char_start": 89, "char_end": 93, "token_start": 15, "token_end": 15}, {"text": "cAMP response element - binding protein", "type": "ENTITY", "char_start": 117, "char_end": 156, "token_start": 19, "token_end": 24}, {"text": "Abeta", "type": "ENTITY", "char_start": 195, "char_end": 200, "token_start": 32, "token_end": 32}], "entities_global": [{"text": "Abeta", "type": "ENTITY", "char_start": 89856, "char_end": 89861, "token_start": 7, "token_end": 7, "note": null}, {"text": "RSK1", "type": "ENTITY", "char_start": 89892, "char_end": 89896, "token_start": 13, "token_end": 13, "note": null}, {"text": "RSK2", "type": "ENTITY", "char_start": 89901, "char_end": 89905, "token_start": 15, "token_end": 15, "note": null}, {"text": "cAMP response element - binding protein", "type": "ENTITY", "char_start": 89929, "char_end": 89968, "token_start": 19, "token_end": 24, "note": null}, {"text": "Abeta", "type": "ENTITY", "char_start": 90007, "char_end": 90012, "token_start": 32, "token_end": 32, "note": null}]}
+{"sentence_id": 537, "sentence_text": "Regulation of cellular retinoic acid binding protein ( CRABP II ) during human monocyte differentiation in vitro .", "sentence_char_start_global": 90050, "sentence_char_end_global": 90164, "entities": [{"text": "cellular retinoic acid binding protein", "type": "ENTITY", "char_start": 14, "char_end": 52, "token_start": 2, "token_end": 6}, {"text": "CRABP II", "type": "ENTITY", "char_start": 55, "char_end": 63, "token_start": 8, "token_end": 9}], "entities_global": [{"text": "cellular retinoic acid binding protein", "type": "ENTITY", "char_start": 90064, "char_end": 90102, "token_start": 2, "token_end": 6, "note": null}, {"text": "CRABP II", "type": "ENTITY", "char_start": 90105, "char_end": 90113, "token_start": 8, "token_end": 9, "note": null}]}
+{"sentence_id": 538, "sentence_text": "Cellular retinoic acid binding proteins ( CRABP ) are low molecular weight proteins whose precise function remains unknown .", "sentence_char_start_global": 90165, "sentence_char_end_global": 90289, "entities": [{"text": "Cellular retinoic acid binding proteins", "type": "ENTITY", "char_start": 0, "char_end": 39, "token_start": 0, "token_end": 4}, {"text": "CRABP", "type": "ENTITY", "char_start": 42, "char_end": 47, "token_start": 6, "token_end": 6}, {"text": "low molecular weight proteins", "type": "ENTITY", "char_start": 54, "char_end": 83, "token_start": 9, "token_end": 12}], "entities_global": [{"text": "Cellular retinoic acid binding proteins", "type": "ENTITY", "char_start": 90165, "char_end": 90204, "token_start": 0, "token_end": 4, "note": null}, {"text": "CRABP", "type": "ENTITY", "char_start": 90207, "char_end": 90212, "token_start": 6, "token_end": 6, "note": null}, {"text": "low molecular weight proteins", "type": "ENTITY", "char_start": 90219, "char_end": 90248, "token_start": 9, "token_end": 12, "note": null}]}
+{"sentence_id": 539, "sentence_text": "They bind retinoids and may thereby modulate the intracellular steady - state concentration of retinoids .", "sentence_char_start_global": 90290, "sentence_char_end_global": 90396, "entities": [], "entities_global": []}
+{"sentence_id": 540, "sentence_text": "Whereas CRABP I is ubiquitously expressed , CRABP II is mainly detected in various cell types of the skin .", "sentence_char_start_global": 90397, "sentence_char_end_global": 90504, "entities": [{"text": "CRABP I", "type": "ENTITY", "char_start": 8, "char_end": 15, "token_start": 1, "token_end": 2}, {"text": "CRABP II", "type": "ENTITY", "char_start": 44, "char_end": 52, "token_start": 7, "token_end": 8}], "entities_global": [{"text": "CRABP I", "type": "ENTITY", "char_start": 90405, "char_end": 90412, "token_start": 1, "token_end": 2, "note": null}, {"text": "CRABP II", "type": "ENTITY", "char_start": 90441, "char_end": 90449, "token_start": 7, "token_end": 8, "note": null}]}
+{"sentence_id": 541, "sentence_text": "By representative difference analysis we found that CRABP II is also strongly expressed in human monocyte - derived macrophages ( MAC ) but not in freshly isolated monocytes ( MO ) .", "sentence_char_start_global": 90505, "sentence_char_end_global": 90687, "entities": [{"text": "CRABP II", "type": "ENTITY", "char_start": 52, "char_end": 60, "token_start": 7, "token_end": 8}], "entities_global": [{"text": "CRABP II", "type": "ENTITY", "char_start": 90557, "char_end": 90565, "token_start": 7, "token_end": 8, "note": null}]}
+{"sentence_id": 542, "sentence_text": "The CRABP II mRNA was gradually upregulated during differentiation from MO to MAC in the presence of 2 % serum .", "sentence_char_start_global": 90688, "sentence_char_end_global": 90800, "entities": [{"text": "CRABP II mRNA", "type": "ENTITY", "char_start": 4, "char_end": 17, "token_start": 1, "token_end": 3}], "entities_global": [{"text": "CRABP II mRNA", "type": "ENTITY", "char_start": 90692, "char_end": 90705, "token_start": 1, "token_end": 3, "note": null}]}
+{"sentence_id": 543, "sentence_text": "Adherence , which is important for MO differentiation , induced CRABP II expression , but the addition of 10 ( - 7 ) M retinoic acid inhibited the upregulation of CRABP II expression during MO / MAC differentiation .", "sentence_char_start_global": 90801, "sentence_char_end_global": 91017, "entities": [{"text": "CRABP II", "type": "ENTITY", "char_start": 64, "char_end": 72, "token_start": 10, "token_end": 11}, {"text": "CRABP II", "type": "ENTITY", "char_start": 163, "char_end": 171, "token_start": 30, "token_end": 31}], "entities_global": [{"text": "CRABP II", "type": "ENTITY", "char_start": 90865, "char_end": 90873, "token_start": 10, "token_end": 11, "note": null}, {"text": "CRABP II", "type": "ENTITY", "char_start": 90964, "char_end": 90972, "token_start": 30, "token_end": 31, "note": null}]}
+{"sentence_id": 544, "sentence_text": "As MO can differentiate along the classical pathway not only to MAC but also to dendritic cells we analyzed the expression of CRABP II in MO - derived dendritic cells cultured with 10 % FCS , IL - 4 , and GM - CSF .", "sentence_char_start_global": 91018, "sentence_char_end_global": 91233, "entities": [{"text": "CRABP II", "type": "ENTITY", "char_start": 126, "char_end": 134, "token_start": 22, "token_end": 23}, {"text": "FCS", "type": "ENTITY", "char_start": 186, "char_end": 189, "token_start": 34, "token_end": 34}, {"text": "IL - 4", "type": "ENTITY", "char_start": 192, "char_end": 198, "token_start": 36, "token_end": 38}, {"text": "GM - CSF", "type": "ENTITY", "char_start": 205, "char_end": 213, "token_start": 41, "token_end": 43}], "entities_global": [{"text": "CRABP II", "type": "ENTITY", "char_start": 91144, "char_end": 91152, "token_start": 22, "token_end": 23, "note": null}, {"text": "FCS", "type": "ENTITY", "char_start": 91204, "char_end": 91207, "token_start": 34, "token_end": 34, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 91210, "char_end": 91216, "token_start": 36, "token_end": 38, "note": null}, {"text": "GM - CSF", "type": "ENTITY", "char_start": 91223, "char_end": 91231, "token_start": 41, "token_end": 43, "note": null}]}
+{"sentence_id": 545, "sentence_text": "In contrast to MAC , MO - derived dendritic cells showed an extremely low expression of CRABP II .", "sentence_char_start_global": 91234, "sentence_char_end_global": 91332, "entities": [{"text": "CRABP II", "type": "ENTITY", "char_start": 88, "char_end": 96, "token_start": 16, "token_end": 17}], "entities_global": [{"text": "CRABP II", "type": "ENTITY", "char_start": 91322, "char_end": 91330, "token_start": 16, "token_end": 17, "note": null}]}
+{"sentence_id": 546, "sentence_text": "From these results we conclude ( 1 ) that the availability and the metabolism of retinoids may be different in MAC compared to MO and dendritic cells and ( 2 ) that this may influence differentiation and activation of those cells .", "sentence_char_start_global": 91333, "sentence_char_end_global": 91564, "entities": [], "entities_global": []}
+{"sentence_id": 547, "sentence_text": "Transcription factor B - cell - specific activator protein ( BSAP ) is differentially expressed in B cells and in subsets of B - cell lymphomas .", "sentence_char_start_global": 91565, "sentence_char_end_global": 91710, "entities": [{"text": "Transcription factor B - cell - specific activator protein", "type": "ENTITY", "char_start": 0, "char_end": 58, "token_start": 0, "token_end": 8}, {"text": "BSAP", "type": "ENTITY", "char_start": 61, "char_end": 65, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "Transcription factor B - cell - specific activator protein", "type": "ENTITY", "char_start": 91565, "char_end": 91623, "token_start": 0, "token_end": 8, "note": null}, {"text": "BSAP", "type": "ENTITY", "char_start": 91626, "char_end": 91630, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 548, "sentence_text": "The paired box containing gene PAX - 5 encodes the transcription factor BSAP ( B - cell - specific activator protein ) , which plays a key role in B - lymphocyte development .", "sentence_char_start_global": 91711, "sentence_char_end_global": 91886, "entities": [{"text": "paired box containing gene", "type": "ENTITY", "char_start": 4, "char_end": 30, "token_start": 1, "token_end": 4}, {"text": "PAX - 5", "type": "ENTITY", "char_start": 31, "char_end": 38, "token_start": 5, "token_end": 7}, {"text": "transcription factor", "type": "ENTITY", "char_start": 51, "char_end": 71, "token_start": 10, "token_end": 11}, {"text": "BSAP", "type": "ENTITY", "char_start": 72, "char_end": 76, "token_start": 12, "token_end": 12}, {"text": "B - cell - specific activator protein", "type": "ENTITY", "char_start": 79, "char_end": 116, "token_start": 14, "token_end": 20}], "entities_global": [{"text": "paired box containing gene", "type": "ENTITY", "char_start": 91715, "char_end": 91741, "token_start": 1, "token_end": 4, "note": null}, {"text": "PAX - 5", "type": "ENTITY", "char_start": 91742, "char_end": 91749, "token_start": 5, "token_end": 7, "note": null}, {"text": "transcription factor", "type": "ENTITY", "char_start": 91762, "char_end": 91782, "token_start": 10, "token_end": 11, "note": null}, {"text": "BSAP", "type": "ENTITY", "char_start": 91783, "char_end": 91787, "token_start": 12, "token_end": 12, "note": null}, {"text": "B - cell - specific activator protein", "type": "ENTITY", "char_start": 91790, "char_end": 91827, "token_start": 14, "token_end": 20, "note": null}]}
+{"sentence_id": 549, "sentence_text": "Despite its known involvement in a rare subtype of non - Hodgkin ' s lymphoma ( NHL ) , a detailed examination of BSAP expression in NHL has not been previously reported .", "sentence_char_start_global": 91887, "sentence_char_end_global": 92058, "entities": [{"text": "BSAP", "type": "ENTITY", "char_start": 114, "char_end": 118, "token_start": 23, "token_end": 23}], "entities_global": [{"text": "BSAP", "type": "ENTITY", "char_start": 92001, "char_end": 92005, "token_start": 23, "token_end": 23, "note": null}]}
+{"sentence_id": 550, "sentence_text": "In this study , we analyzed normal and malignant lymphoid tissues and cell lines , including 102 cases of B - cell NHL , 23 cases of T - and null - cell NHL , and 18 cases of Hodgkin ' s disease .", "sentence_char_start_global": 92059, "sentence_char_end_global": 92255, "entities": [], "entities_global": []}
+{"sentence_id": 551, "sentence_text": "Normal lymphoid tissues showed strong nuclear BSAP expression in mantle zone B cells , less intense reactivity in follicular center B cells , and no expression in cells of the T - cell - rich zones .", "sentence_char_start_global": 92256, "sentence_char_end_global": 92455, "entities": [{"text": "BSAP", "type": "ENTITY", "char_start": 46, "char_end": 50, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "BSAP", "type": "ENTITY", "char_start": 92302, "char_end": 92306, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 552, "sentence_text": "Monocytoid B cells showed weak expression , whereas plasma cells and extrafollicular large transformed B cells were negative .", "sentence_char_start_global": 92456, "sentence_char_end_global": 92582, "entities": [], "entities_global": []}
+{"sentence_id": 553, "sentence_text": "Of the 102 B - cell NHLs , 83 ( 81 % ) demonstrated BSAP expression .", "sentence_char_start_global": 92583, "sentence_char_end_global": 92652, "entities": [{"text": "BSAP", "type": "ENTITY", "char_start": 52, "char_end": 56, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "BSAP", "type": "ENTITY", "char_start": 92635, "char_end": 92639, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 554, "sentence_text": "All of the 13 ( 100 % ) B - cell chronic lymphocytic leukemias ( B - CLLs ) , 21 of ( 100 % ) mantle cells ( MCLs ) , and 20 of 21 ( 95 % ) follicular lymphomas ( FLs ) were positive .", "sentence_char_start_global": 92653, "sentence_char_end_global": 92837, "entities": [], "entities_global": []}
+{"sentence_id": 555, "sentence_text": "Moderate staining intensities were found in most B - CLL and FL cases , whereas most MCLs showed strong reactions , paralleling the strong reactivity of nonmalignant mantle cells .", "sentence_char_start_global": 92838, "sentence_char_end_global": 93018, "entities": [], "entities_global": []}
+{"sentence_id": 556, "sentence_text": "Eight of 12 ( 67 % ) marginal zone lymphoma cases showed negative or low BSAP levels , and 17 of 24 ( 71 % ) large B - cell lymphomas displayed moderate to strong expression .", "sentence_char_start_global": 93019, "sentence_char_end_global": 93194, "entities": [{"text": "BSAP", "type": "ENTITY", "char_start": 73, "char_end": 77, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "BSAP", "type": "ENTITY", "char_start": 93092, "char_end": 93096, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 557, "sentence_text": "None of the 23 T - and null - cell lymphomas reacted with the BSAP antisera , whereas in Hodgkin ' s disease , 2 of 4 ( 50 % ) nodular lymphocytic predominance and 5 of 14 ( 36 % ) classical cases showed weak nuclear or nucleolar BSAP reactions in a fraction of the tumor cells .", "sentence_char_start_global": 93195, "sentence_char_end_global": 93474, "entities": [{"text": "BSAP", "type": "ENTITY", "char_start": 62, "char_end": 66, "token_start": 14, "token_end": 14}, {"text": "BSAP", "type": "ENTITY", "char_start": 230, "char_end": 234, "token_start": 49, "token_end": 49}], "entities_global": [{"text": "BSAP", "type": "ENTITY", "char_start": 93257, "char_end": 93261, "token_start": 14, "token_end": 14, "note": null}, {"text": "BSAP", "type": "ENTITY", "char_start": 93425, "char_end": 93429, "token_start": 49, "token_end": 49, "note": null}]}
+{"sentence_id": 558, "sentence_text": "Western blot analysis showed a 52 - kD BSAP band in B - cell lines , but not in non - B - cell or plasma cell lines .", "sentence_char_start_global": 93475, "sentence_char_end_global": 93592, "entities": [{"text": "BSAP", "type": "ENTITY", "char_start": 39, "char_end": 43, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "BSAP", "type": "ENTITY", "char_start": 93514, "char_end": 93518, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 559, "sentence_text": "We conclude that BSAP expression is largely restricted to lymphomas of B - cell lineage and that BSAP expression varies in B - cell subsets and subtypes of B - cell NHL .", "sentence_char_start_global": 93593, "sentence_char_end_global": 93763, "entities": [{"text": "BSAP", "type": "ENTITY", "char_start": 17, "char_end": 21, "token_start": 3, "token_end": 3}, {"text": "BSAP", "type": "ENTITY", "char_start": 97, "char_end": 101, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "BSAP", "type": "ENTITY", "char_start": 93610, "char_end": 93614, "token_start": 3, "token_end": 3, "note": null}, {"text": "BSAP", "type": "ENTITY", "char_start": 93690, "char_end": 93694, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 560, "sentence_text": "The high levels of BSAP , especially those found in large - cell lymphomas and in some follicular lymphomas , may be a consequence of deregulated gene expression and suggest a possible involvement of PAX - 5 in certain B - cell malignancies .", "sentence_char_start_global": 93764, "sentence_char_end_global": 94006, "entities": [{"text": "BSAP", "type": "ENTITY", "char_start": 19, "char_end": 23, "token_start": 4, "token_end": 4}, {"text": "PAX - 5", "type": "ENTITY", "char_start": 200, "char_end": 207, "token_start": 34, "token_end": 36}], "entities_global": [{"text": "BSAP", "type": "ENTITY", "char_start": 93783, "char_end": 93787, "token_start": 4, "token_end": 4, "note": null}, {"text": "PAX - 5", "type": "ENTITY", "char_start": 93964, "char_end": 93971, "token_start": 34, "token_end": 36, "note": null}]}
+{"sentence_id": 561, "sentence_text": "This is a US government work .", "sentence_char_start_global": 94007, "sentence_char_end_global": 94037, "entities": [], "entities_global": []}
+{"sentence_id": 562, "sentence_text": "There are no restrictions on its use .", "sentence_char_start_global": 94038, "sentence_char_end_global": 94076, "entities": [], "entities_global": []}
+{"sentence_id": 563, "sentence_text": "Mitogen and growth factor - induced activation of a STAT - like molecule in channel catfish lymphoid cells .", "sentence_char_start_global": 94077, "sentence_char_end_global": 94185, "entities": [{"text": "STAT - like molecule", "type": "ENTITY", "char_start": 52, "char_end": 72, "token_start": 9, "token_end": 12}], "entities_global": [{"text": "STAT - like molecule", "type": "ENTITY", "char_start": 94129, "char_end": 94149, "token_start": 9, "token_end": 12, "note": null}]}
+{"sentence_id": 564, "sentence_text": "This article describes the identification of a putative STAT molecule in the channel catfish ( Ictalurus punctatus ) , the first report of such a molecule in a ' lower ' vertebrate .", "sentence_char_start_global": 94186, "sentence_char_end_global": 94368, "entities": [{"text": "putative STAT molecule", "type": "ENTITY", "char_start": 47, "char_end": 69, "token_start": 7, "token_end": 9}], "entities_global": [{"text": "putative STAT molecule", "type": "ENTITY", "char_start": 94233, "char_end": 94255, "token_start": 7, "token_end": 9, "note": null}]}
+{"sentence_id": 565, "sentence_text": "A monoclonal antibody against human STAT6 recognizes an approximately 100 kDa molecule that becomes activated and translocates to the nucleus upon both growth factor and mitogen stimulation of catfish leukocytes .", "sentence_char_start_global": 94369, "sentence_char_end_global": 94582, "entities": [{"text": "monoclonal antibody", "type": "ENTITY", "char_start": 2, "char_end": 21, "token_start": 1, "token_end": 2}, {"text": "human STAT6", "type": "ENTITY", "char_start": 30, "char_end": 41, "token_start": 4, "token_end": 5}, {"text": "100 kDa molecule", "type": "ENTITY", "char_start": 70, "char_end": 86, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "monoclonal antibody", "type": "ENTITY", "char_start": 94371, "char_end": 94390, "token_start": 1, "token_end": 2, "note": null}, {"text": "human STAT6", "type": "ENTITY", "char_start": 94399, "char_end": 94410, "token_start": 4, "token_end": 5, "note": null}, {"text": "100 kDa molecule", "type": "ENTITY", "char_start": 94439, "char_end": 94455, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 566, "sentence_text": "This presumed catfish STAT binds the mammalian interferon - gamma activation site , a known motif of mammalian STAT binding , as shown by electromobility shift assays .", "sentence_char_start_global": 94583, "sentence_char_end_global": 94751, "entities": [{"text": "catfish STAT", "type": "ENTITY", "char_start": 14, "char_end": 26, "token_start": 2, "token_end": 3}, {"text": "mammalian interferon - gamma activation site", "type": "ENTITY", "char_start": 37, "char_end": 81, "token_start": 6, "token_end": 11}], "entities_global": [{"text": "catfish STAT", "type": "ENTITY", "char_start": 94597, "char_end": 94609, "token_start": 2, "token_end": 3, "note": null}, {"text": "mammalian interferon - gamma activation site", "type": "ENTITY", "char_start": 94620, "char_end": 94664, "token_start": 6, "token_end": 11, "note": null}]}
+{"sentence_id": 567, "sentence_text": "Purification of the proteins present in these DNA complexes confirms that the catfish reactive molecule binds to the interferon - gamma activation site sequence .", "sentence_char_start_global": 94752, "sentence_char_end_global": 94914, "entities": [{"text": "DNA complexes", "type": "ENTITY", "char_start": 46, "char_end": 59, "token_start": 7, "token_end": 8}, {"text": "interferon - gamma activation site sequence", "type": "ENTITY", "char_start": 117, "char_end": 160, "token_start": 18, "token_end": 23}], "entities_global": [{"text": "DNA complexes", "type": "ENTITY", "char_start": 94798, "char_end": 94811, "token_start": 7, "token_end": 8, "note": null}, {"text": "interferon - gamma activation site sequence", "type": "ENTITY", "char_start": 94869, "char_end": 94912, "token_start": 18, "token_end": 23, "note": null}]}
+{"sentence_id": 568, "sentence_text": "These results suggest that STAT molecules have been highly conserved in vertebrate evolution .", "sentence_char_start_global": 94915, "sentence_char_end_global": 95009, "entities": [{"text": "STAT molecules", "type": "ENTITY", "char_start": 27, "char_end": 41, "token_start": 4, "token_end": 5}], "entities_global": [{"text": "STAT molecules", "type": "ENTITY", "char_start": 94942, "char_end": 94956, "token_start": 4, "token_end": 5, "note": null}]}
+{"sentence_id": 569, "sentence_text": "Isolation and analysis of a T cell clone variant exhibiting constitutively phosphorylated Ser133 cAMP response element - binding protein .", "sentence_char_start_global": 95010, "sentence_char_end_global": 95148, "entities": [{"text": "phosphorylated Ser133 cAMP response element - binding protein", "type": "ENTITY", "char_start": 75, "char_end": 136, "token_start": 11, "token_end": 18}], "entities_global": [{"text": "phosphorylated Ser133 cAMP response element - binding protein", "type": "ENTITY", "char_start": 95085, "char_end": 95146, "token_start": 11, "token_end": 18, "note": null}]}
+{"sentence_id": 570, "sentence_text": "In driving T cell proliferation , IL - 2 stimulates a new program of gene expression that includes proliferating cell nuclear antigen ( PCNA ) , a requisite processivity factor for DNA polymerase delta .", "sentence_char_start_global": 95149, "sentence_char_end_global": 95352, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 34, "char_end": 40, "token_start": 6, "token_end": 8}, {"text": "proliferating cell nuclear antigen", "type": "ENTITY", "char_start": 99, "char_end": 133, "token_start": 18, "token_end": 21}, {"text": "PCNA", "type": "ENTITY", "char_start": 136, "char_end": 140, "token_start": 23, "token_end": 23}, {"text": "DNA polymerase delta", "type": "ENTITY", "char_start": 181, "char_end": 201, "token_start": 31, "token_end": 33}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 95183, "char_end": 95189, "token_start": 6, "token_end": 8, "note": null}, {"text": "proliferating cell nuclear antigen", "type": "ENTITY", "char_start": 95248, "char_end": 95282, "token_start": 18, "token_end": 21, "note": null}, {"text": "PCNA", "type": "ENTITY", "char_start": 95285, "char_end": 95289, "token_start": 23, "token_end": 23, "note": null}, {"text": "DNA polymerase delta", "type": "ENTITY", "char_start": 95330, "char_end": 95350, "token_start": 31, "token_end": 33, "note": null}]}
+{"sentence_id": 571, "sentence_text": "PCNA transcription is regulated in part through tandem CRE sequences in the promoter and CRE binding proteins ; IL - 2 stimulates CREB phosphorylation in the resting cloned T lymphocyte , L2 .", "sentence_char_start_global": 95353, "sentence_char_end_global": 95545, "entities": [{"text": "PCNA", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}, {"text": "CRE sequences", "type": "ENTITY", "char_start": 55, "char_end": 68, "token_start": 8, "token_end": 9}, {"text": "promoter and CRE binding proteins", "type": "ENTITY", "char_start": 76, "char_end": 109, "token_start": 12, "token_end": 16}, {"text": "IL - 2", "type": "ENTITY", "char_start": 112, "char_end": 118, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "PCNA", "type": "ENTITY", "char_start": 95353, "char_end": 95357, "token_start": 0, "token_end": 0, "note": null}, {"text": "CRE sequences", "type": "ENTITY", "char_start": 95408, "char_end": 95421, "token_start": 8, "token_end": 9, "note": null}, {"text": "promoter and CRE binding proteins", "type": "ENTITY", "char_start": 95429, "char_end": 95462, "token_start": 12, "token_end": 16, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 95465, "char_end": 95471, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 572, "sentence_text": "After culturing L2 cells for greater than 91 days , we consistently isolate a stable variant that exhibits constitutive CREB phosphorylation .", "sentence_char_start_global": 95546, "sentence_char_end_global": 95688, "entities": [], "entities_global": []}
+{"sentence_id": 573, "sentence_text": "L2 and L2 variant cells were tested for IL - 2 responsiveness and rapamycin sensitivity with respect to specific kinase activity , PCNA expression and proliferation .", "sentence_char_start_global": 95689, "sentence_char_end_global": 95855, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 40, "char_end": 46, "token_start": 8, "token_end": 10}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 95729, "char_end": 95735, "token_start": 8, "token_end": 10, "note": null}]}
+{"sentence_id": 574, "sentence_text": "In L2 cells , IL - 2 stimulated and rapamycin inhibited the following : cAMP - independent CREB kinase activity , PCNA expression and proliferation .", "sentence_char_start_global": 95856, "sentence_char_end_global": 96005, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 14, "char_end": 20, "token_start": 4, "token_end": 6}, {"text": "CREB kinase", "type": "ENTITY", "char_start": 91, "char_end": 102, "token_start": 17, "token_end": 18}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 95870, "char_end": 95876, "token_start": 4, "token_end": 6, "note": null}, {"text": "CREB kinase", "type": "ENTITY", "char_start": 95947, "char_end": 95958, "token_start": 17, "token_end": 18, "note": null}]}
+{"sentence_id": 575, "sentence_text": "In L2 variant cells , CREB kinase activity was constitutively high ; IL - 2 stimulated and rapamycin blocked PCNA expression and proliferation .", "sentence_char_start_global": 96006, "sentence_char_end_global": 96150, "entities": [{"text": "CREB kinase", "type": "ENTITY", "char_start": 22, "char_end": 33, "token_start": 5, "token_end": 6}, {"text": "IL - 2", "type": "ENTITY", "char_start": 69, "char_end": 75, "token_start": 12, "token_end": 14}], "entities_global": [{"text": "CREB kinase", "type": "ENTITY", "char_start": 96028, "char_end": 96039, "token_start": 5, "token_end": 6, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 96075, "char_end": 96081, "token_start": 12, "token_end": 14, "note": null}]}
+{"sentence_id": 576, "sentence_text": "These results indicate that IL - 2 induces a rapamycin - sensitive , cAMP - independent CREB kinase activity in L2 cells .", "sentence_char_start_global": 96151, "sentence_char_end_global": 96273, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 28, "char_end": 34, "token_start": 4, "token_end": 6}, {"text": "CREB kinase", "type": "ENTITY", "char_start": 88, "char_end": 99, "token_start": 16, "token_end": 17}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 96179, "char_end": 96185, "token_start": 4, "token_end": 6, "note": null}, {"text": "CREB kinase", "type": "ENTITY", "char_start": 96239, "char_end": 96250, "token_start": 16, "token_end": 17, "note": null}]}
+{"sentence_id": 577, "sentence_text": "However , phosphorylation of CREB alone is not sufficient to drive PCNA expression and L2 cell proliferation in the absence of IL - 2 .", "sentence_char_start_global": 96274, "sentence_char_end_global": 96409, "entities": [{"text": "CREB", "type": "ENTITY", "char_start": 29, "char_end": 33, "token_start": 4, "token_end": 4}, {"text": "PCNA", "type": "ENTITY", "char_start": 67, "char_end": 71, "token_start": 11, "token_end": 11}, {"text": "IL - 2", "type": "ENTITY", "char_start": 127, "char_end": 133, "token_start": 21, "token_end": 23}], "entities_global": [{"text": "CREB", "type": "ENTITY", "char_start": 96303, "char_end": 96307, "token_start": 4, "token_end": 4, "note": null}, {"text": "PCNA", "type": "ENTITY", "char_start": 96341, "char_end": 96345, "token_start": 11, "token_end": 11, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 96401, "char_end": 96407, "token_start": 21, "token_end": 23, "note": null}]}
+{"sentence_id": 578, "sentence_text": "Serotonin derivative , N - ( p - coumaroyl ) serotonin , inhibits the production of TNF - alpha , IL - 1alpha , IL - 1beta , and IL - 6 by endotoxin - stimulated human blood monocytes .", "sentence_char_start_global": 96410, "sentence_char_end_global": 96595, "entities": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 84, "char_end": 95, "token_start": 16, "token_end": 18}, {"text": "IL - 1alpha", "type": "ENTITY", "char_start": 98, "char_end": 109, "token_start": 20, "token_end": 22}, {"text": "IL - 1beta", "type": "ENTITY", "char_start": 112, "char_end": 122, "token_start": 24, "token_end": 26}, {"text": "IL - 6", "type": "ENTITY", "char_start": 129, "char_end": 135, "token_start": 29, "token_end": 31}], "entities_global": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 96494, "char_end": 96505, "token_start": 16, "token_end": 18, "note": null}, {"text": "IL - 1alpha", "type": "ENTITY", "char_start": 96508, "char_end": 96519, "token_start": 20, "token_end": 22, "note": null}, {"text": "IL - 1beta", "type": "ENTITY", "char_start": 96522, "char_end": 96532, "token_start": 24, "token_end": 26, "note": null}, {"text": "IL - 6", "type": "ENTITY", "char_start": 96539, "char_end": 96545, "token_start": 29, "token_end": 31, "note": null}]}
+{"sentence_id": 579, "sentence_text": "We have reported that N - ( p - coumaroyl ) serotonin ( CS ) and its derivatives with antioxidative activity are present in safflower seeds .", "sentence_char_start_global": 96596, "sentence_char_end_global": 96737, "entities": [], "entities_global": []}
+{"sentence_id": 580, "sentence_text": "As reactive oxygen species ( ROS ) are implicated in the signaling of lipopolysaccharide ( LPS ) , we examined whether CS has a suppressive effect on inflammatory cytokine generation from human monocyte s in vitro .", "sentence_char_start_global": 96738, "sentence_char_end_global": 96953, "entities": [{"text": "inflammatory cytokine", "type": "ENTITY", "char_start": 150, "char_end": 171, "token_start": 27, "token_end": 28}], "entities_global": [{"text": "inflammatory cytokine", "type": "ENTITY", "char_start": 96888, "char_end": 96909, "token_start": 27, "token_end": 28, "note": null}]}
+{"sentence_id": 581, "sentence_text": "CS at 50 - 200 microM reduced tumor necrosis factor ( TNF ) , interleukin - 1 ( IL - 1 ) , and IL - 6 activities in the culture supernatants from LPS - stimulated human blood monocytes without cytotoxicity .", "sentence_char_start_global": 96954, "sentence_char_end_global": 97161, "entities": [{"text": "tumor necrosis factor", "type": "ENTITY", "char_start": 30, "char_end": 51, "token_start": 7, "token_end": 9}, {"text": "TNF", "type": "ENTITY", "char_start": 54, "char_end": 57, "token_start": 11, "token_end": 11}, {"text": "interleukin - 1", "type": "ENTITY", "char_start": 62, "char_end": 77, "token_start": 14, "token_end": 16}, {"text": "IL - 1", "type": "ENTITY", "char_start": 80, "char_end": 86, "token_start": 18, "token_end": 20}, {"text": "IL - 6", "type": "ENTITY", "char_start": 95, "char_end": 101, "token_start": 24, "token_end": 26}], "entities_global": [{"text": "tumor necrosis factor", "type": "ENTITY", "char_start": 96984, "char_end": 97005, "token_start": 7, "token_end": 9, "note": null}, {"text": "TNF", "type": "ENTITY", "char_start": 97008, "char_end": 97011, "token_start": 11, "token_end": 11, "note": null}, {"text": "interleukin - 1", "type": "ENTITY", "char_start": 97016, "char_end": 97031, "token_start": 14, "token_end": 16, "note": null}, {"text": "IL - 1", "type": "ENTITY", "char_start": 97034, "char_end": 97040, "token_start": 18, "token_end": 20, "note": null}, {"text": "IL - 6", "type": "ENTITY", "char_start": 97049, "char_end": 97055, "token_start": 24, "token_end": 26, "note": null}]}
+{"sentence_id": 582, "sentence_text": "ELISA assay revealed that the production of TNF - alpha , IL - 1alpha , IL - 1beta , and IL - 6 was inhibited by CS .", "sentence_char_start_global": 97162, "sentence_char_end_global": 97279, "entities": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 44, "char_end": 55, "token_start": 7, "token_end": 9}, {"text": "IL - 1alpha", "type": "ENTITY", "char_start": 58, "char_end": 69, "token_start": 11, "token_end": 13}, {"text": "IL - 1beta", "type": "ENTITY", "char_start": 72, "char_end": 82, "token_start": 15, "token_end": 17}, {"text": "IL - 6", "type": "ENTITY", "char_start": 89, "char_end": 95, "token_start": 20, "token_end": 22}], "entities_global": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 97206, "char_end": 97217, "token_start": 7, "token_end": 9, "note": null}, {"text": "IL - 1alpha", "type": "ENTITY", "char_start": 97220, "char_end": 97231, "token_start": 11, "token_end": 13, "note": null}, {"text": "IL - 1beta", "type": "ENTITY", "char_start": 97234, "char_end": 97244, "token_start": 15, "token_end": 17, "note": null}, {"text": "IL - 6", "type": "ENTITY", "char_start": 97251, "char_end": 97257, "token_start": 20, "token_end": 22, "note": null}]}
+{"sentence_id": 583, "sentence_text": "Northern blot analysis showed that LPS - induced expression of these cytokine mRNA in monocytes was suppressed by CS .", "sentence_char_start_global": 97280, "sentence_char_end_global": 97398, "entities": [{"text": "cytokine mRNA", "type": "ENTITY", "char_start": 69, "char_end": 82, "token_start": 11, "token_end": 12}], "entities_global": [{"text": "cytokine mRNA", "type": "ENTITY", "char_start": 97349, "char_end": 97362, "token_start": 11, "token_end": 12, "note": null}]}
+{"sentence_id": 584, "sentence_text": "NF - kappaB activation was also inhibited by CS .", "sentence_char_start_global": 97399, "sentence_char_end_global": 97448, "entities": [], "entities_global": []}
+{"sentence_id": 585, "sentence_text": "These findings indicate that CS has a suppressive effect on proinflammatory cytokine production from monocytes , and this effect is based in part on the suppression of cytokine mRNA expression through inhibition of NF - kappaB activation .", "sentence_char_start_global": 97449, "sentence_char_end_global": 97688, "entities": [{"text": "cytokine mRNA", "type": "ENTITY", "char_start": 168, "char_end": 181, "token_start": 27, "token_end": 28}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 215, "char_end": 226, "token_start": 33, "token_end": 35}], "entities_global": [{"text": "cytokine mRNA", "type": "ENTITY", "char_start": 97617, "char_end": 97630, "token_start": 27, "token_end": 28, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 97664, "char_end": 97675, "token_start": 33, "token_end": 35, "note": null}]}
+{"sentence_id": 586, "sentence_text": "Elevated expression of differentiation inhibitory factor nm23 mRNA in monoblastic crisis of a patient with chronic myelogenous leukemia .", "sentence_char_start_global": 97689, "sentence_char_end_global": 97826, "entities": [{"text": "differentiation inhibitory factor nm23 mRNA", "type": "ENTITY", "char_start": 23, "char_end": 66, "token_start": 3, "token_end": 7}], "entities_global": [{"text": "differentiation inhibitory factor nm23 mRNA", "type": "ENTITY", "char_start": 97712, "char_end": 97755, "token_start": 3, "token_end": 7, "note": null}]}
+{"sentence_id": 587, "sentence_text": "Differentiation inhibitory factor nm23 gene has been found to be expressed in high quantities in acute myelogenous leukemia ( AML ) , especially in acute monocytic leukemia ( AML - M5 ) and is suggested as a new prognostic factor in AML - M5 .", "sentence_char_start_global": 97827, "sentence_char_end_global": 98070, "entities": [{"text": "Differentiation inhibitory factor", "type": "ENTITY", "char_start": 0, "char_end": 33, "token_start": 0, "token_end": 2}, {"text": "nm23 gene", "type": "ENTITY", "char_start": 34, "char_end": 43, "token_start": 3, "token_end": 4}], "entities_global": [{"text": "Differentiation inhibitory factor", "type": "ENTITY", "char_start": 97827, "char_end": 97860, "token_start": 0, "token_end": 2, "note": null}, {"text": "nm23 gene", "type": "ENTITY", "char_start": 97861, "char_end": 97870, "token_start": 3, "token_end": 4, "note": null}]}
+{"sentence_id": 588, "sentence_text": "We report an example of elevated expression of nm23 mRNA in a patient with chronic myelogenous leukemia ( CML ) who developed monoblastic crisis .", "sentence_char_start_global": 98071, "sentence_char_end_global": 98217, "entities": [{"text": "nm23 mRNA", "type": "ENTITY", "char_start": 47, "char_end": 56, "token_start": 8, "token_end": 9}], "entities_global": [{"text": "nm23 mRNA", "type": "ENTITY", "char_start": 98118, "char_end": 98127, "token_start": 8, "token_end": 9, "note": null}]}
+{"sentence_id": 589, "sentence_text": "Relative levels of nm23 - H1 and - H2 mRNA extracted from the patient ' s peripheral blood mononuclear cells and bone marrow mononuclear cells were measured by quantitative reverse transcriptase polymerase chain reaction .", "sentence_char_start_global": 98218, "sentence_char_end_global": 98440, "entities": [{"text": "nm23 - H1 and - H2 mRNA", "type": "ENTITY", "char_start": 19, "char_end": 42, "token_start": 3, "token_end": 9}], "entities_global": [{"text": "nm23 - H1 and - H2 mRNA", "type": "ENTITY", "char_start": 98237, "char_end": 98260, "token_start": 3, "token_end": 9, "note": null}]}
+{"sentence_id": 590, "sentence_text": "The level of nm23 - H1 mRNA in CML cells at the chronic phase was as high as that in bone marrow cells from healthy volunteers .", "sentence_char_start_global": 98441, "sentence_char_end_global": 98569, "entities": [{"text": "nm23 - H1 mRNA", "type": "ENTITY", "char_start": 13, "char_end": 27, "token_start": 3, "token_end": 6}], "entities_global": [{"text": "nm23 - H1 mRNA", "type": "ENTITY", "char_start": 98454, "char_end": 98468, "token_start": 3, "token_end": 6, "note": null}]}
+{"sentence_id": 591, "sentence_text": "The mRNA level of nm23 - H2 was slightly below the normal level .", "sentence_char_start_global": 98570, "sentence_char_end_global": 98635, "entities": [{"text": "nm23 - H2", "type": "ENTITY", "char_start": 18, "char_end": 27, "token_start": 4, "token_end": 6}], "entities_global": [{"text": "nm23 - H2", "type": "ENTITY", "char_start": 98588, "char_end": 98597, "token_start": 4, "token_end": 6, "note": null}]}
+{"sentence_id": 592, "sentence_text": "At blastic crisis , however , expression of both nm23 - H1 and - H2 mRNA was elevated to about three to nine times of that at the chronic phase .", "sentence_char_start_global": 98636, "sentence_char_end_global": 98781, "entities": [{"text": "nm23 - H1 and - H2 mRNA", "type": "ENTITY", "char_start": 49, "char_end": 72, "token_start": 9, "token_end": 15}], "entities_global": [{"text": "nm23 - H1 and - H2 mRNA", "type": "ENTITY", "char_start": 98685, "char_end": 98708, "token_start": 9, "token_end": 15, "note": null}]}
+{"sentence_id": 593, "sentence_text": "Proliferated blastic cells were positive for non - specific esterase , and the serum lysozyme level was elevated and diagnosed as monoblastic crisis .", "sentence_char_start_global": 98782, "sentence_char_end_global": 98932, "entities": [{"text": "non - specific esterase", "type": "ENTITY", "char_start": 45, "char_end": 68, "token_start": 6, "token_end": 9}], "entities_global": [{"text": "non - specific esterase", "type": "ENTITY", "char_start": 98827, "char_end": 98850, "token_start": 6, "token_end": 9, "note": null}]}
+{"sentence_id": 594, "sentence_text": "The patient received combined chemotherapy but response was partial .", "sentence_char_start_global": 98933, "sentence_char_end_global": 99002, "entities": [], "entities_global": []}
+{"sentence_id": 595, "sentence_text": "These findings are compatible with our previous report that nm23 gene is overexpressed in monocytic leukemia .", "sentence_char_start_global": 99003, "sentence_char_end_global": 99113, "entities": [{"text": "nm23 gene", "type": "ENTITY", "char_start": 60, "char_end": 69, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "nm23 gene", "type": "ENTITY", "char_start": 99063, "char_end": 99072, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 596, "sentence_text": "Increased transcription decreases the spontaneous mutation rate at the thymidine kinase locus in human cells .", "sentence_char_start_global": 99114, "sentence_char_end_global": 99224, "entities": [{"text": "thymidine kinase locus", "type": "ENTITY", "char_start": 71, "char_end": 93, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "thymidine kinase locus", "type": "ENTITY", "char_start": 99185, "char_end": 99207, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 597, "sentence_text": "Transcription increases DNA repair efficiency and modulates the distribution of certain types of DNA damage .", "sentence_char_start_global": 99225, "sentence_char_end_global": 99334, "entities": [], "entities_global": []}
+{"sentence_id": 598, "sentence_text": "Furthermore , increased transcription level stimulates spontaneous mutation rate in yeast .", "sentence_char_start_global": 99335, "sentence_char_end_global": 99426, "entities": [], "entities_global": []}
+{"sentence_id": 599, "sentence_text": "We explored whether transcription level affects spontaneous mutation rate in human cells .", "sentence_char_start_global": 99427, "sentence_char_end_global": 99517, "entities": [], "entities_global": []}
+{"sentence_id": 600, "sentence_text": "We first developed two thymidine kinase ( tk ) inducible human cell lines using the Gal4 - Estrogen receptor system .", "sentence_char_start_global": 99518, "sentence_char_end_global": 99635, "entities": [], "entities_global": []}
+{"sentence_id": 601, "sentence_text": "In our TK6i - G3 and G9 tk heterozygous cell lines , the active tk allele is linked to an inducible promoter element .", "sentence_char_start_global": 99636, "sentence_char_end_global": 99754, "entities": [{"text": "tk allele", "type": "ENTITY", "char_start": 64, "char_end": 73, "token_start": 14, "token_end": 15}, {"text": "promoter element", "type": "ENTITY", "char_start": 100, "char_end": 116, "token_start": 21, "token_end": 22}], "entities_global": [{"text": "tk allele", "type": "ENTITY", "char_start": 99700, "char_end": 99709, "token_start": 14, "token_end": 15, "note": null}, {"text": "promoter element", "type": "ENTITY", "char_start": 99736, "char_end": 99752, "token_start": 21, "token_end": 22, "note": null}]}
+{"sentence_id": 602, "sentence_text": "Tk mRNA is induced following treatment with estrogen .", "sentence_char_start_global": 99755, "sentence_char_end_global": 99809, "entities": [{"text": "Tk mRNA", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "Tk mRNA", "type": "ENTITY", "char_start": 99755, "char_end": 99762, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 603, "sentence_text": "Spontaneous mutation rate was significantly decreased in human cell lines after induction in contrast to the report in yeast .", "sentence_char_start_global": 99810, "sentence_char_end_global": 99936, "entities": [], "entities_global": []}
+{"sentence_id": 604, "sentence_text": "Thus , humans may have evolved different or additional mechanisms to deal with transcription related spontaneous mutagenesis .", "sentence_char_start_global": 99937, "sentence_char_end_global": 100063, "entities": [], "entities_global": []}
+{"sentence_id": 605, "sentence_text": "Copyright 1998 Elsevier Science B . V .", "sentence_char_start_global": 100064, "sentence_char_end_global": 100103, "entities": [], "entities_global": []}
+{"sentence_id": 606, "sentence_text": "All rights reserved .", "sentence_char_start_global": 100104, "sentence_char_end_global": 100125, "entities": [], "entities_global": []}
+{"sentence_id": 607, "sentence_text": "Mutation of BCL - 6 gene in normal B cells by the process of somatic hypermutation of Ig genes .", "sentence_char_start_global": 100126, "sentence_char_end_global": 100222, "entities": [{"text": "BCL - 6 gene", "type": "ENTITY", "char_start": 12, "char_end": 24, "token_start": 2, "token_end": 5}, {"text": "Ig genes", "type": "ENTITY", "char_start": 86, "char_end": 94, "token_start": 17, "token_end": 18}], "entities_global": [{"text": "BCL - 6 gene", "type": "ENTITY", "char_start": 100138, "char_end": 100150, "token_start": 2, "token_end": 5, "note": null}, {"text": "Ig genes", "type": "ENTITY", "char_start": 100212, "char_end": 100220, "token_start": 17, "token_end": 18, "note": null}]}
+{"sentence_id": 608, "sentence_text": "Immunoglobulin ( Ig ) genes are hypermutated in B lymphocytes that are the precursors to memory B cells .", "sentence_char_start_global": 100223, "sentence_char_end_global": 100328, "entities": [{"text": "Immunoglobulin ( Ig ) genes", "type": "ENTITY", "char_start": 0, "char_end": 27, "token_start": 0, "token_end": 4}], "entities_global": [{"text": "Immunoglobulin ( Ig ) genes", "type": "ENTITY", "char_start": 100223, "char_end": 100250, "token_start": 0, "token_end": 4, "note": null}]}
+{"sentence_id": 609, "sentence_text": "The mutations are linked to transcription initiation , but non - Ig promoters are permissible for the mutation process ; thus , other genes expressed in mutating B cells may also be subject to somatic hypermutation .", "sentence_char_start_global": 100329, "sentence_char_end_global": 100545, "entities": [{"text": "non - Ig promoters", "type": "ENTITY", "char_start": 59, "char_end": 77, "token_start": 9, "token_end": 12}], "entities_global": [{"text": "non - Ig promoters", "type": "ENTITY", "char_start": 100388, "char_end": 100406, "token_start": 9, "token_end": 12, "note": null}]}
+{"sentence_id": 610, "sentence_text": "Significant mutations were not observed in c - MYC , S14 , or alpha - fetoprotein ( AFP ) genes , but BCL - 6 was highly mutated in a large proportion of memory B cells of normal individuals .", "sentence_char_start_global": 100546, "sentence_char_end_global": 100738, "entities": [{"text": "c - MYC , S14 , or alpha - fetoprotein ( AFP ) genes", "type": "ENTITY", "char_start": 43, "char_end": 95, "token_start": 6, "token_end": 19}, {"text": "BCL - 6", "type": "ENTITY", "char_start": 102, "char_end": 109, "token_start": 22, "token_end": 24}], "entities_global": [{"text": "c - MYC , S14 , or alpha - fetoprotein ( AFP ) genes", "type": "ENTITY", "char_start": 100589, "char_end": 100641, "token_start": 6, "token_end": 19, "note": null}, {"text": "BCL - 6", "type": "ENTITY", "char_start": 100648, "char_end": 100655, "token_start": 22, "token_end": 24, "note": null}]}
+{"sentence_id": 611, "sentence_text": "The mutation pattern was similar to that of Ig genes .", "sentence_char_start_global": 100739, "sentence_char_end_global": 100793, "entities": [{"text": "Ig genes", "type": "ENTITY", "char_start": 44, "char_end": 52, "token_start": 8, "token_end": 9}], "entities_global": [{"text": "Ig genes", "type": "ENTITY", "char_start": 100783, "char_end": 100791, "token_start": 8, "token_end": 9, "note": null}]}
+{"sentence_id": 612, "sentence_text": "CD28 - mediated activation in CD45RA + and CD45RO + T cells : enhanced levels of reactive oxygen intermediates and c - Rel nuclear translocation in CD45RA + cells .", "sentence_char_start_global": 100794, "sentence_char_end_global": 100958, "entities": [], "entities_global": []}
+{"sentence_id": 613, "sentence_text": "We have analyzed the effect of complete T cell activation ( anti - CD3 plus anti - CD28 ) on the activation of NF - kappaB in CD45RA + ( naive ) and CD45RO + ( memory / effector ) T cells .", "sentence_char_start_global": 100959, "sentence_char_end_global": 101148, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 111, "char_end": 122, "token_start": 23, "token_end": 25}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 101070, "char_end": 101081, "token_start": 23, "token_end": 25, "note": null}]}
+{"sentence_id": 614, "sentence_text": "Long exposure ( 24 h ) induced stronger NF - kappaB DNA binding in CD45RA + cells than in CD45RO + cells .", "sentence_char_start_global": 101149, "sentence_char_end_global": 101255, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 40, "char_end": 51, "token_start": 8, "token_end": 10}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 101189, "char_end": 101200, "token_start": 8, "token_end": 10, "note": null}]}
+{"sentence_id": 615, "sentence_text": "Analysis of the nuclear c - Rel protein indicated that after anti - CD3 + anti - CD28 stimulation the level of c - Rel was higher in CD45RA + cells .", "sentence_char_start_global": 101256, "sentence_char_end_global": 101405, "entities": [{"text": "nuclear c - Rel protein", "type": "ENTITY", "char_start": 16, "char_end": 39, "token_start": 3, "token_end": 7}, {"text": "c - Rel", "type": "ENTITY", "char_start": 111, "char_end": 118, "token_start": 22, "token_end": 24}], "entities_global": [{"text": "nuclear c - Rel protein", "type": "ENTITY", "char_start": 101272, "char_end": 101295, "token_start": 3, "token_end": 7, "note": null}, {"text": "c - Rel", "type": "ENTITY", "char_start": 101367, "char_end": 101374, "token_start": 22, "token_end": 24, "note": null}]}
+{"sentence_id": 616, "sentence_text": "Analysis of the cytoplasmic inhibitor IkappaBalpha indicated that anti - CD3 + anti - CD28 stimulation induced a long - lasting degradation in CD45RA + cells but in CD45RO + cells the degradation process was more rapid .", "sentence_char_start_global": 101406, "sentence_char_end_global": 101626, "entities": [{"text": "cytoplasmic inhibitor", "type": "ENTITY", "char_start": 16, "char_end": 37, "token_start": 3, "token_end": 4}, {"text": "IkappaBalpha", "type": "ENTITY", "char_start": 38, "char_end": 50, "token_start": 5, "token_end": 5}], "entities_global": [{"text": "cytoplasmic inhibitor", "type": "ENTITY", "char_start": 101422, "char_end": 101443, "token_start": 3, "token_end": 4, "note": null}, {"text": "IkappaBalpha", "type": "ENTITY", "char_start": 101444, "char_end": 101456, "token_start": 5, "token_end": 5, "note": null}]}
+{"sentence_id": 617, "sentence_text": "Because the CD28 costimulus is known to induce the production of reactive oxygen intermediates ( ROIs ) , the intracellular ROI levels in CD45RA + and CD45RO + cells were compared by flow cytometry .", "sentence_char_start_global": 101627, "sentence_char_end_global": 101826, "entities": [{"text": "CD28", "type": "ENTITY", "char_start": 12, "char_end": 16, "token_start": 2, "token_end": 2}], "entities_global": [{"text": "CD28", "type": "ENTITY", "char_start": 101639, "char_end": 101643, "token_start": 2, "token_end": 2, "note": null}]}
+{"sentence_id": 618, "sentence_text": "ROIs were produced in both cell types , but more strongly in CD45RA + cells .", "sentence_char_start_global": 101827, "sentence_char_end_global": 101904, "entities": [], "entities_global": []}
+{"sentence_id": 619, "sentence_text": "The data presented in this study further emphasize the differences between CD45RA + and CD45RO + T lymphocytes in ROI - dependent signaling pathways .", "sentence_char_start_global": 101905, "sentence_char_end_global": 102055, "entities": [], "entities_global": []}
+{"sentence_id": 620, "sentence_text": "Non - Hodgkin ' s lymphoma involving bilateral breasts [ see comments ]", "sentence_char_start_global": 102056, "sentence_char_end_global": 102127, "entities": [], "entities_global": []}
+{"sentence_id": 621, "sentence_text": "We describe here two cases of diffuse large cell type non - Hodgkin ' s lymphoma affecting the bilateral breasts .", "sentence_char_start_global": 102128, "sentence_char_end_global": 102242, "entities": [], "entities_global": []}
+{"sentence_id": 622, "sentence_text": "The contralateral tumor in one case appeared 17 months after the first mastectomy , whereas the bilateral tumors occurred concurrently in the other patient who was pregnant and showed widespread dissemination at initial presentation .", "sentence_char_start_global": 102243, "sentence_char_end_global": 102477, "entities": [], "entities_global": []}
+{"sentence_id": 623, "sentence_text": "Lymphoma cells from both cases showed the mature B - cell immunophenotype and had rearrangements of the BCL6 gene .", "sentence_char_start_global": 102478, "sentence_char_end_global": 102593, "entities": [{"text": "BCL6 gene", "type": "ENTITY", "char_start": 104, "char_end": 113, "token_start": 17, "token_end": 18}], "entities_global": [{"text": "BCL6 gene", "type": "ENTITY", "char_start": 102582, "char_end": 102591, "token_start": 17, "token_end": 18, "note": null}]}
+{"sentence_id": 624, "sentence_text": "Both patients developed progressive disease despite chemo - radiotherapy and died of leukemic manifestations .", "sentence_char_start_global": 102594, "sentence_char_end_global": 102704, "entities": [], "entities_global": []}
+{"sentence_id": 625, "sentence_text": "There were no apparent pathological features of lymphomas of mucosa - associated lymphoid tissue origin", "sentence_char_start_global": 102705, "sentence_char_end_global": 102808, "entities": [], "entities_global": []}
+{"sentence_id": 626, "sentence_text": "Biochemical characterization of MIP - 1 alpha nuclear protein .", "sentence_char_start_global": 102809, "sentence_char_end_global": 102872, "entities": [{"text": "MIP - 1 alpha nuclear protein", "type": "ENTITY", "char_start": 32, "char_end": 61, "token_start": 3, "token_end": 8}], "entities_global": [{"text": "MIP - 1 alpha nuclear protein", "type": "ENTITY", "char_start": 102841, "char_end": 102870, "token_start": 3, "token_end": 8, "note": null}]}
+{"sentence_id": 627, "sentence_text": "A family of hematopoietic specific transcription factors , MIP - 1 alpha nuclear protein ( MNP ) family , has recently been identified .", "sentence_char_start_global": 102873, "sentence_char_end_global": 103009, "entities": [{"text": "hematopoietic specific transcription factors", "type": "ENTITY", "char_start": 12, "char_end": 56, "token_start": 3, "token_end": 6}, {"text": "MIP - 1 alpha nuclear protein ( MNP ) family", "type": "ENTITY", "char_start": 59, "char_end": 103, "token_start": 8, "token_end": 17}], "entities_global": [{"text": "hematopoietic specific transcription factors", "type": "ENTITY", "char_start": 102885, "char_end": 102929, "token_start": 3, "token_end": 6, "note": null}, {"text": "MIP - 1 alpha nuclear protein ( MNP ) family", "type": "ENTITY", "char_start": 102932, "char_end": 102976, "token_start": 8, "token_end": 17, "note": null}]}
+{"sentence_id": 628, "sentence_text": "They are intimately involved in regulating the transcription of the huMIP - 1 alpha gene in monocytes , T - cells , and transformed B - cells .", "sentence_char_start_global": 103010, "sentence_char_end_global": 103153, "entities": [{"text": "huMIP - 1 alpha gene", "type": "ENTITY", "char_start": 68, "char_end": 88, "token_start": 10, "token_end": 14}], "entities_global": [{"text": "huMIP - 1 alpha gene", "type": "ENTITY", "char_start": 103078, "char_end": 103098, "token_start": 10, "token_end": 14, "note": null}]}
+{"sentence_id": 629, "sentence_text": "One member of the family ( MNP - 1 ) is essential for promoter activity in monocytes and B - cells , while another ( MNP - 2 ) is required for full promotor activity in T - cells .", "sentence_char_start_global": 103154, "sentence_char_end_global": 103334, "entities": [{"text": "MNP - 1", "type": "ENTITY", "char_start": 27, "char_end": 34, "token_start": 6, "token_end": 8}, {"text": "MNP - 2", "type": "ENTITY", "char_start": 117, "char_end": 124, "token_start": 25, "token_end": 27}], "entities_global": [{"text": "MNP - 1", "type": "ENTITY", "char_start": 103181, "char_end": 103188, "token_start": 6, "token_end": 8, "note": null}, {"text": "MNP - 2", "type": "ENTITY", "char_start": 103271, "char_end": 103278, "token_start": 25, "token_end": 27, "note": null}]}
+{"sentence_id": 630, "sentence_text": "A third member of the family ( MNP - 3 ) is expressed in PMA induced HL60 cells and probably has a role in monocyte differentiation .", "sentence_char_start_global": 103335, "sentence_char_end_global": 103468, "entities": [{"text": "MNP - 3", "type": "ENTITY", "char_start": 31, "char_end": 38, "token_start": 7, "token_end": 9}], "entities_global": [{"text": "MNP - 3", "type": "ENTITY", "char_start": 103366, "char_end": 103373, "token_start": 7, "token_end": 9, "note": null}]}
+{"sentence_id": 631, "sentence_text": "In this communication we demonstrate by two techniques that MNP - 1 and MNP - 2 are distinct but related factors , and we present further evidence to show that MNP - 1 acts as a heterodimer .", "sentence_char_start_global": 103469, "sentence_char_end_global": 103660, "entities": [{"text": "MNP - 1", "type": "ENTITY", "char_start": 60, "char_end": 67, "token_start": 9, "token_end": 11}, {"text": "MNP - 2", "type": "ENTITY", "char_start": 72, "char_end": 79, "token_start": 13, "token_end": 15}, {"text": "MNP - 1", "type": "ENTITY", "char_start": 160, "char_end": 167, "token_start": 30, "token_end": 32}, {"text": "heterodimer", "type": "ENTITY", "char_start": 178, "char_end": 189, "token_start": 36, "token_end": 36}], "entities_global": [{"text": "MNP - 1", "type": "ENTITY", "char_start": 103529, "char_end": 103536, "token_start": 9, "token_end": 11, "note": null}, {"text": "MNP - 2", "type": "ENTITY", "char_start": 103541, "char_end": 103548, "token_start": 13, "token_end": 15, "note": null}, {"text": "MNP - 1", "type": "ENTITY", "char_start": 103629, "char_end": 103636, "token_start": 30, "token_end": 32, "note": null}, {"text": "heterodimer", "type": "ENTITY", "char_start": 103647, "char_end": 103658, "token_start": 36, "token_end": 36, "note": null}]}
+{"sentence_id": 632, "sentence_text": "Bcl - 3 expression and nuclear translocation are induced by granulocyte - macrophage colony - stimulating factor and erythropoietin in proliferating human erythroid precursors .", "sentence_char_start_global": 103661, "sentence_char_end_global": 103838, "entities": [{"text": "Bcl - 3", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 2}, {"text": "granulocyte - macrophage colony - stimulating factor", "type": "ENTITY", "char_start": 60, "char_end": 112, "token_start": 10, "token_end": 16}, {"text": "erythropoietin", "type": "ENTITY", "char_start": 117, "char_end": 131, "token_start": 18, "token_end": 18}], "entities_global": [{"text": "Bcl - 3", "type": "ENTITY", "char_start": 103661, "char_end": 103668, "token_start": 0, "token_end": 2, "note": null}, {"text": "granulocyte - macrophage colony - stimulating factor", "type": "ENTITY", "char_start": 103721, "char_end": 103773, "token_start": 10, "token_end": 16, "note": null}, {"text": "erythropoietin", "type": "ENTITY", "char_start": 103778, "char_end": 103792, "token_start": 18, "token_end": 18, "note": null}]}
+{"sentence_id": 633, "sentence_text": "Bcl - 3 is a proto - oncogene involved in the chromosomal translocation t ( 14 ; 19 ) found in some patients with chronic lymphocytic leukemia .", "sentence_char_start_global": 103839, "sentence_char_end_global": 103983, "entities": [{"text": "Bcl - 3", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 2}, {"text": "proto - oncogene", "type": "ENTITY", "char_start": 13, "char_end": 29, "token_start": 5, "token_end": 7}, {"text": "t ( 14 ; 19 )", "type": "ENTITY", "char_start": 72, "char_end": 85, "token_start": 13, "token_end": 18}], "entities_global": [{"text": "Bcl - 3", "type": "ENTITY", "char_start": 103839, "char_end": 103846, "token_start": 0, "token_end": 2, "note": null}, {"text": "proto - oncogene", "type": "ENTITY", "char_start": 103852, "char_end": 103868, "token_start": 5, "token_end": 7, "note": null}, {"text": "t ( 14 ; 19 )", "type": "ENTITY", "char_start": 103911, "char_end": 103924, "token_start": 13, "token_end": 18, "note": null}]}
+{"sentence_id": 634, "sentence_text": "It shares structural similarities with and is a member of the IkappaB family of proteins .", "sentence_char_start_global": 103984, "sentence_char_end_global": 104074, "entities": [{"text": "IkappaB family", "type": "ENTITY", "char_start": 62, "char_end": 76, "token_start": 11, "token_end": 12}], "entities_global": [{"text": "IkappaB family", "type": "ENTITY", "char_start": 104046, "char_end": 104060, "token_start": 11, "token_end": 12, "note": null}]}
+{"sentence_id": 635, "sentence_text": "In this report , involvement of Bcl - 3 in hematopoietic growth factor - stimulated erythroid proliferation and differentiation was examined .", "sentence_char_start_global": 104075, "sentence_char_end_global": 104217, "entities": [{"text": "Bcl - 3", "type": "ENTITY", "char_start": 32, "char_end": 39, "token_start": 6, "token_end": 8}], "entities_global": [{"text": "Bcl - 3", "type": "ENTITY", "char_start": 104107, "char_end": 104114, "token_start": 6, "token_end": 8, "note": null}]}
+{"sentence_id": 636, "sentence_text": "In TF - 1 cells , an erythroleukemia cell line , granulocyte - macrophage colony - stimulating factor ( GM - CSF ) and erythropoietin ( Epo ) greatly enhanced Bcl - 3 expression at both the protein and mRNA levels in association with stimulation of proliferation .", "sentence_char_start_global": 104218, "sentence_char_end_global": 104482, "entities": [{"text": "granulocyte - macrophage colony - stimulating factor", "type": "ENTITY", "char_start": 49, "char_end": 101, "token_start": 11, "token_end": 17}, {"text": "GM - CSF", "type": "ENTITY", "char_start": 104, "char_end": 112, "token_start": 19, "token_end": 21}, {"text": "erythropoietin", "type": "ENTITY", "char_start": 119, "char_end": 133, "token_start": 24, "token_end": 24}, {"text": "Epo", "type": "ENTITY", "char_start": 136, "char_end": 139, "token_start": 26, "token_end": 26}, {"text": "Bcl - 3", "type": "ENTITY", "char_start": 159, "char_end": 166, "token_start": 30, "token_end": 32}], "entities_global": [{"text": "granulocyte - macrophage colony - stimulating factor", "type": "ENTITY", "char_start": 104267, "char_end": 104319, "token_start": 11, "token_end": 17, "note": null}, {"text": "GM - CSF", "type": "ENTITY", "char_start": 104322, "char_end": 104330, "token_start": 19, "token_end": 21, "note": null}, {"text": "erythropoietin", "type": "ENTITY", "char_start": 104337, "char_end": 104351, "token_start": 24, "token_end": 24, "note": null}, {"text": "Epo", "type": "ENTITY", "char_start": 104354, "char_end": 104357, "token_start": 26, "token_end": 26, "note": null}, {"text": "Bcl - 3", "type": "ENTITY", "char_start": 104377, "char_end": 104384, "token_start": 30, "token_end": 32, "note": null}]}
+{"sentence_id": 637, "sentence_text": "Bcl - 3 protein was also highly expressed in early burst - forming unit - erythroid ( BFU - E ) - derived erythroid precursors ( day 7 ) and decreased during maturation ( days 10 and 14 ) , suggesting that Bcl - 3 is involved in normal erythroid proliferation .", "sentence_char_start_global": 104483, "sentence_char_end_global": 104744, "entities": [{"text": "Bcl - 3", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 2}, {"text": "Bcl - 3", "type": "ENTITY", "char_start": 206, "char_end": 213, "token_start": 42, "token_end": 44}], "entities_global": [{"text": "Bcl - 3", "type": "ENTITY", "char_start": 104483, "char_end": 104490, "token_start": 0, "token_end": 2, "note": null}, {"text": "Bcl - 3", "type": "ENTITY", "char_start": 104689, "char_end": 104696, "token_start": 42, "token_end": 44, "note": null}]}
+{"sentence_id": 638, "sentence_text": "In these hematopoietic cells , Bcl - 3 was hyperphosphorylated .", "sentence_char_start_global": 104745, "sentence_char_end_global": 104809, "entities": [{"text": "Bcl - 3", "type": "ENTITY", "char_start": 31, "char_end": 38, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "Bcl - 3", "type": "ENTITY", "char_start": 104776, "char_end": 104783, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 639, "sentence_text": "GM - CSF and Epo modulated the subcellular localization of Bcl - 3 .", "sentence_char_start_global": 104810, "sentence_char_end_global": 104878, "entities": [{"text": "GM - CSF", "type": "ENTITY", "char_start": 0, "char_end": 8, "token_start": 0, "token_end": 2}, {"text": "Epo", "type": "ENTITY", "char_start": 13, "char_end": 16, "token_start": 4, "token_end": 4}, {"text": "Bcl - 3", "type": "ENTITY", "char_start": 59, "char_end": 66, "token_start": 10, "token_end": 12}], "entities_global": [{"text": "GM - CSF", "type": "ENTITY", "char_start": 104810, "char_end": 104818, "token_start": 0, "token_end": 2, "note": null}, {"text": "Epo", "type": "ENTITY", "char_start": 104823, "char_end": 104826, "token_start": 4, "token_end": 4, "note": null}, {"text": "Bcl - 3", "type": "ENTITY", "char_start": 104869, "char_end": 104876, "token_start": 10, "token_end": 12, "note": null}]}
+{"sentence_id": 640, "sentence_text": "Upon stimulation of TF - 1 cells with GM - CSF or Epo , the nuclear translocation of Bcl - 3 was dramatically enhanced .", "sentence_char_start_global": 104879, "sentence_char_end_global": 104999, "entities": [{"text": "GM - CSF", "type": "ENTITY", "char_start": 38, "char_end": 46, "token_start": 8, "token_end": 10}, {"text": "Epo", "type": "ENTITY", "char_start": 50, "char_end": 53, "token_start": 12, "token_end": 12}, {"text": "Bcl - 3", "type": "ENTITY", "char_start": 85, "char_end": 92, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "GM - CSF", "type": "ENTITY", "char_start": 104917, "char_end": 104925, "token_start": 8, "token_end": 10, "note": null}, {"text": "Epo", "type": "ENTITY", "char_start": 104929, "char_end": 104932, "token_start": 12, "token_end": 12, "note": null}, {"text": "Bcl - 3", "type": "ENTITY", "char_start": 104964, "char_end": 104971, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 641, "sentence_text": "Overexpression of Bcl - 3 in TF - 1 cells by transient transfection along with the NF - kappaB factors p50 or p52 resulted in significant induction of an human immunodeficiency virus - type 1 ( HIV - 1 ) kappaB - TATA - luceriferase reporter plasmid , demonstrating that Bcl - 3 has a positive role in transactivation of kappaB - containing genes in erythroid cells .", "sentence_char_start_global": 105000, "sentence_char_end_global": 105367, "entities": [{"text": "Bcl - 3", "type": "ENTITY", "char_start": 18, "char_end": 25, "token_start": 2, "token_end": 4}, {"text": "NF - kappaB factors p50 or p52", "type": "ENTITY", "char_start": 83, "char_end": 113, "token_start": 16, "token_end": 22}, {"text": "human immunodeficiency virus - type 1 ( HIV - 1 ) kappaB - TATA - luceriferase reporter plasmid", "type": "ENTITY", "char_start": 154, "char_end": 249, "token_start": 29, "token_end": 46}, {"text": "Bcl - 3", "type": "ENTITY", "char_start": 271, "char_end": 278, "token_start": 50, "token_end": 52}, {"text": "kappaB - containing genes", "type": "ENTITY", "char_start": 321, "char_end": 346, "token_start": 60, "token_end": 63}], "entities_global": [{"text": "Bcl - 3", "type": "ENTITY", "char_start": 105018, "char_end": 105025, "token_start": 2, "token_end": 4, "note": null}, {"text": "NF - kappaB factors p50 or p52", "type": "ENTITY", "char_start": 105083, "char_end": 105113, "token_start": 16, "token_end": 22, "note": null}, {"text": "human immunodeficiency virus - type 1 ( HIV - 1 ) kappaB - TATA - luceriferase reporter plasmid", "type": "ENTITY", "char_start": 105154, "char_end": 105249, "token_start": 29, "token_end": 46, "note": null}, {"text": "Bcl - 3", "type": "ENTITY", "char_start": 105271, "char_end": 105278, "token_start": 50, "token_end": 52, "note": null}, {"text": "kappaB - containing genes", "type": "ENTITY", "char_start": 105321, "char_end": 105346, "token_start": 60, "token_end": 63, "note": null}]}
+{"sentence_id": 642, "sentence_text": "Stimulation with GM - CSF enhanced c - myb mRNA expression in these cells .", "sentence_char_start_global": 105368, "sentence_char_end_global": 105443, "entities": [{"text": "GM - CSF", "type": "ENTITY", "char_start": 17, "char_end": 25, "token_start": 2, "token_end": 4}, {"text": "c - myb mRNA", "type": "ENTITY", "char_start": 35, "char_end": 47, "token_start": 6, "token_end": 9}], "entities_global": [{"text": "GM - CSF", "type": "ENTITY", "char_start": 105385, "char_end": 105393, "token_start": 2, "token_end": 4, "note": null}, {"text": "c - myb mRNA", "type": "ENTITY", "char_start": 105403, "char_end": 105415, "token_start": 6, "token_end": 9, "note": null}]}
+{"sentence_id": 643, "sentence_text": "Bcl - 3 in nuclear extracts of TF - 1 cells bound to a kappaB enhancer in the c - myb promoter together with NF - kappaB2 / p52 and this binding activity was enhanced by GM - CSF stimulation .", "sentence_char_start_global": 105444, "sentence_char_end_global": 105636, "entities": [{"text": "Bcl - 3", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 2}, {"text": "kappaB enhancer", "type": "ENTITY", "char_start": 55, "char_end": 70, "token_start": 14, "token_end": 15}, {"text": "c - myb promoter", "type": "ENTITY", "char_start": 78, "char_end": 94, "token_start": 18, "token_end": 21}, {"text": "NF - kappaB2 / p52", "type": "ENTITY", "char_start": 109, "char_end": 127, "token_start": 24, "token_end": 28}, {"text": "GM - CSF", "type": "ENTITY", "char_start": 170, "char_end": 178, "token_start": 36, "token_end": 38}], "entities_global": [{"text": "Bcl - 3", "type": "ENTITY", "char_start": 105444, "char_end": 105451, "token_start": 0, "token_end": 2, "note": null}, {"text": "kappaB enhancer", "type": "ENTITY", "char_start": 105499, "char_end": 105514, "token_start": 14, "token_end": 15, "note": null}, {"text": "c - myb promoter", "type": "ENTITY", "char_start": 105522, "char_end": 105538, "token_start": 18, "token_end": 21, "note": null}, {"text": "NF - kappaB2 / p52", "type": "ENTITY", "char_start": 105553, "char_end": 105571, "token_start": 24, "token_end": 28, "note": null}, {"text": "GM - CSF", "type": "ENTITY", "char_start": 105614, "char_end": 105622, "token_start": 36, "token_end": 38, "note": null}]}
+{"sentence_id": 644, "sentence_text": "Furthermore , cotransfection of Bcl - 3 with p52 or p50 in TF - 1 cells resulted in significant activation of a c - myb kappaB - TATA - luceriferase reporter plasmid .", "sentence_char_start_global": 105637, "sentence_char_end_global": 105804, "entities": [{"text": "Bcl - 3", "type": "ENTITY", "char_start": 32, "char_end": 39, "token_start": 4, "token_end": 6}, {"text": "p52", "type": "ENTITY", "char_start": 45, "char_end": 48, "token_start": 8, "token_end": 8}, {"text": "p50", "type": "ENTITY", "char_start": 52, "char_end": 55, "token_start": 10, "token_end": 10}, {"text": "c - myb kappaB - TATA - luceriferase reporter plasmid", "type": "ENTITY", "char_start": 112, "char_end": 165, "token_start": 22, "token_end": 31}], "entities_global": [{"text": "Bcl - 3", "type": "ENTITY", "char_start": 105669, "char_end": 105676, "token_start": 4, "token_end": 6, "note": null}, {"text": "p52", "type": "ENTITY", "char_start": 105682, "char_end": 105685, "token_start": 8, "token_end": 8, "note": null}, {"text": "p50", "type": "ENTITY", "char_start": 105689, "char_end": 105692, "token_start": 10, "token_end": 10, "note": null}, {"text": "c - myb kappaB - TATA - luceriferase reporter plasmid", "type": "ENTITY", "char_start": 105749, "char_end": 105802, "token_start": 22, "token_end": 31, "note": null}]}
+{"sentence_id": 645, "sentence_text": "These findings suggest that Bcl - 3 may participate in the transcriptional regulation of certain kappaB - containing genes involved in hematopoiesis , including c - myb .", "sentence_char_start_global": 105805, "sentence_char_end_global": 105975, "entities": [{"text": "Bcl - 3", "type": "ENTITY", "char_start": 28, "char_end": 35, "token_start": 4, "token_end": 6}, {"text": "kappaB - containing genes", "type": "ENTITY", "char_start": 97, "char_end": 122, "token_start": 15, "token_end": 18}, {"text": "c - myb", "type": "ENTITY", "char_start": 161, "char_end": 168, "token_start": 24, "token_end": 26}], "entities_global": [{"text": "Bcl - 3", "type": "ENTITY", "char_start": 105833, "char_end": 105840, "token_start": 4, "token_end": 6, "note": null}, {"text": "kappaB - containing genes", "type": "ENTITY", "char_start": 105902, "char_end": 105927, "token_start": 15, "token_end": 18, "note": null}, {"text": "c - myb", "type": "ENTITY", "char_start": 105966, "char_end": 105973, "token_start": 24, "token_end": 26, "note": null}]}
+{"sentence_id": 646, "sentence_text": "Copyright 1998 by The American Society of Hematology .", "sentence_char_start_global": 105976, "sentence_char_end_global": 106030, "entities": [], "entities_global": []}
+{"sentence_id": 647, "sentence_text": "5 - Lipoxygenase compartmentalization in granulocytic cells is modulated by an internal bipartite nuclear localizing sequence and nuclear factor kappa B complex formation .", "sentence_char_start_global": 106031, "sentence_char_end_global": 106203, "entities": [{"text": "5 - Lipoxygenase", "type": "ENTITY", "char_start": 0, "char_end": 16, "token_start": 0, "token_end": 2}, {"text": "internal bipartite nuclear localizing sequence", "type": "ENTITY", "char_start": 79, "char_end": 125, "token_start": 11, "token_end": 15}, {"text": "nuclear factor kappa B complex", "type": "ENTITY", "char_start": 130, "char_end": 160, "token_start": 17, "token_end": 21}], "entities_global": [{"text": "5 - Lipoxygenase", "type": "ENTITY", "char_start": 106031, "char_end": 106047, "token_start": 0, "token_end": 2, "note": null}, {"text": "internal bipartite nuclear localizing sequence", "type": "ENTITY", "char_start": 106110, "char_end": 106156, "token_start": 11, "token_end": 15, "note": null}, {"text": "nuclear factor kappa B complex", "type": "ENTITY", "char_start": 106161, "char_end": 106191, "token_start": 17, "token_end": 21, "note": null}]}
+{"sentence_id": 648, "sentence_text": "A region of basic amino acids spanning residues 639 - 656 in the human 5 - lipoxygenase sequence resembles a consensus bipartite nuclear localizing sequence .", "sentence_char_start_global": 106204, "sentence_char_end_global": 106362, "entities": [{"text": "residues 639 - 656", "type": "ENTITY", "char_start": 39, "char_end": 57, "token_start": 7, "token_end": 10}, {"text": "human 5 - lipoxygenase sequence", "type": "ENTITY", "char_start": 65, "char_end": 96, "token_start": 13, "token_end": 17}, {"text": "consensus bipartite nuclear localizing sequence", "type": "ENTITY", "char_start": 109, "char_end": 156, "token_start": 20, "token_end": 24}], "entities_global": [{"text": "residues 639 - 656", "type": "ENTITY", "char_start": 106243, "char_end": 106261, "token_start": 7, "token_end": 10, "note": null}, {"text": "human 5 - lipoxygenase sequence", "type": "ENTITY", "char_start": 106269, "char_end": 106300, "token_start": 13, "token_end": 17, "note": null}, {"text": "consensus bipartite nuclear localizing sequence", "type": "ENTITY", "char_start": 106313, "char_end": 106360, "token_start": 20, "token_end": 24, "note": null}]}
+{"sentence_id": 649, "sentence_text": "A synthetic peptide consisting of the Kaposi fibroblast growth factor signal sequence fused to the 5 - lipoxygenase639 - 656 bipartite nuclear localizing sequence has a prominent inhibitory effect on 5 - lipoxygenase catalysis in granulocytic HL - 60 cells activated by calcium ionophor A23187 .", "sentence_char_start_global": 106363, "sentence_char_end_global": 106658, "entities": [{"text": "Kaposi fibroblast growth factor signal sequence", "type": "ENTITY", "char_start": 38, "char_end": 85, "token_start": 6, "token_end": 11}, {"text": "5 - lipoxygenase639 - 656 bipartite nuclear localizing sequence", "type": "ENTITY", "char_start": 99, "char_end": 162, "token_start": 15, "token_end": 23}, {"text": "5 - lipoxygenase", "type": "ENTITY", "char_start": 200, "char_end": 216, "token_start": 30, "token_end": 32}], "entities_global": [{"text": "Kaposi fibroblast growth factor signal sequence", "type": "ENTITY", "char_start": 106401, "char_end": 106448, "token_start": 6, "token_end": 11, "note": null}, {"text": "5 - lipoxygenase639 - 656 bipartite nuclear localizing sequence", "type": "ENTITY", "char_start": 106462, "char_end": 106525, "token_start": 15, "token_end": 23, "note": null}, {"text": "5 - lipoxygenase", "type": "ENTITY", "char_start": 106563, "char_end": 106579, "token_start": 30, "token_end": 32, "note": null}]}
+{"sentence_id": 650, "sentence_text": "Recombinant 5 - lipoxygenase was not affected by the peptide .", "sentence_char_start_global": 106659, "sentence_char_end_global": 106721, "entities": [{"text": "5 - lipoxygenase", "type": "ENTITY", "char_start": 12, "char_end": 28, "token_start": 1, "token_end": 3}], "entities_global": [{"text": "5 - lipoxygenase", "type": "ENTITY", "char_start": 106671, "char_end": 106687, "token_start": 1, "token_end": 3, "note": null}]}
+{"sentence_id": 651, "sentence_text": "The peptide also inhibited redistribution of 5 - lipoxygenase from the cytosol to the nuclear membrane of HL - 60 cells stimulated by A23187 .", "sentence_char_start_global": 106722, "sentence_char_end_global": 106864, "entities": [{"text": "5 - lipoxygenase", "type": "ENTITY", "char_start": 45, "char_end": 61, "token_start": 6, "token_end": 8}], "entities_global": [{"text": "5 - lipoxygenase", "type": "ENTITY", "char_start": 106767, "char_end": 106783, "token_start": 6, "token_end": 8, "note": null}]}
+{"sentence_id": 652, "sentence_text": "5 - Lipoxygenase protein was detected in nuclear factor kappaB ( NF - kappaB ) p65 subunit immunoprecipitate fractions prepared from HL - 60 cell lysates .", "sentence_char_start_global": 106865, "sentence_char_end_global": 107020, "entities": [{"text": "5 - Lipoxygenase protein", "type": "ENTITY", "char_start": 0, "char_end": 24, "token_start": 0, "token_end": 3}, {"text": "nuclear factor kappaB ( NF - kappaB ) p65 subunit", "type": "ENTITY", "char_start": 41, "char_end": 90, "token_start": 7, "token_end": 16}], "entities_global": [{"text": "5 - Lipoxygenase protein", "type": "ENTITY", "char_start": 106865, "char_end": 106889, "token_start": 0, "token_end": 3, "note": null}, {"text": "nuclear factor kappaB ( NF - kappaB ) p65 subunit", "type": "ENTITY", "char_start": 106906, "char_end": 106955, "token_start": 7, "token_end": 16, "note": null}]}
+{"sentence_id": 653, "sentence_text": "The amount of 5 - lipoxygenase protein coimmunoprecipitated by NF - kappaB antiserum was increased following A23187 stimulation .", "sentence_char_start_global": 107021, "sentence_char_end_global": 107150, "entities": [{"text": "5 - lipoxygenase protein", "type": "ENTITY", "char_start": 14, "char_end": 38, "token_start": 3, "token_end": 6}], "entities_global": [{"text": "5 - lipoxygenase protein", "type": "ENTITY", "char_start": 107035, "char_end": 107059, "token_start": 3, "token_end": 6, "note": null}]}
+{"sentence_id": 654, "sentence_text": "In cells treated with agents that block 5 - lipoxygenase translocation to the nucleus , 5 - lipoxygenase protein appearing in the NF - kappaB immunoprecipitate was diminished .", "sentence_char_start_global": 107151, "sentence_char_end_global": 107327, "entities": [{"text": "5 - lipoxygenase", "type": "ENTITY", "char_start": 40, "char_end": 56, "token_start": 7, "token_end": 9}, {"text": "5 - lipoxygenase", "type": "ENTITY", "char_start": 88, "char_end": 104, "token_start": 15, "token_end": 17}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 130, "char_end": 141, "token_start": 22, "token_end": 24}], "entities_global": [{"text": "5 - lipoxygenase", "type": "ENTITY", "char_start": 107191, "char_end": 107207, "token_start": 7, "token_end": 9, "note": null}, {"text": "5 - lipoxygenase", "type": "ENTITY", "char_start": 107239, "char_end": 107255, "token_start": 15, "token_end": 17, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 107281, "char_end": 107292, "token_start": 22, "token_end": 24, "note": null}]}
+{"sentence_id": 655, "sentence_text": "Our results implicate an internal bipartite nuclear localizing sequence as a regulatory domain that modulates 5 - lipoxygenase redistribution and catalysis in granulocytic cells .", "sentence_char_start_global": 107328, "sentence_char_end_global": 107507, "entities": [{"text": "internal bipartite nuclear localizing sequence", "type": "ENTITY", "char_start": 25, "char_end": 71, "token_start": 4, "token_end": 8}, {"text": "5 - lipoxygenase", "type": "ENTITY", "char_start": 110, "char_end": 126, "token_start": 15, "token_end": 17}], "entities_global": [{"text": "internal bipartite nuclear localizing sequence", "type": "ENTITY", "char_start": 107353, "char_end": 107399, "token_start": 4, "token_end": 8, "note": null}, {"text": "5 - lipoxygenase", "type": "ENTITY", "char_start": 107438, "char_end": 107454, "token_start": 15, "token_end": 17, "note": null}]}
+{"sentence_id": 656, "sentence_text": "Additionally , our results suggest that molecular determinants which govern 5 - lipoxygenase and NF - kappaB redistribution to the nucleus may be coordinately controlled in granulocytic cells .", "sentence_char_start_global": 107508, "sentence_char_end_global": 107701, "entities": [], "entities_global": []}
+{"sentence_id": 657, "sentence_text": "Copyright 1998 Academic Press .", "sentence_char_start_global": 107702, "sentence_char_end_global": 107733, "entities": [], "entities_global": []}
+{"sentence_id": 658, "sentence_text": "Inhibition of CD28 / CD3 - mediated costimulation of naive and memory human T lymphocytes by intracellular incorporation of polyclonal antibodies specific for the activator protein - 1 transcriptional complex .", "sentence_char_start_global": 107734, "sentence_char_end_global": 107944, "entities": [{"text": "polyclonal antibodies", "type": "ENTITY", "char_start": 124, "char_end": 145, "token_start": 19, "token_end": 20}, {"text": "activator protein - 1 transcriptional complex", "type": "ENTITY", "char_start": 163, "char_end": 208, "token_start": 24, "token_end": 29}], "entities_global": [{"text": "polyclonal antibodies", "type": "ENTITY", "char_start": 107858, "char_end": 107879, "token_start": 19, "token_end": 20, "note": null}, {"text": "activator protein - 1 transcriptional complex", "type": "ENTITY", "char_start": 107897, "char_end": 107942, "token_start": 24, "token_end": 29, "note": null}]}
+{"sentence_id": 659, "sentence_text": "A number of indirect methods have been utilized in demonstrating activator protein - 1 transcription factor function in IL - 2 promoter activity .", "sentence_char_start_global": 107945, "sentence_char_end_global": 108091, "entities": [{"text": "activator protein - 1", "type": "ENTITY", "char_start": 65, "char_end": 86, "token_start": 10, "token_end": 13}], "entities_global": [{"text": "activator protein - 1", "type": "ENTITY", "char_start": 108010, "char_end": 108031, "token_start": 10, "token_end": 13, "note": null}]}
+{"sentence_id": 660, "sentence_text": "However , there has been no direct demonstration that activator protein - 1 is involved in CD28 - dependent costimulation of IL - 2 gene transcription in freshly isolated naive and memory human T lymphocytes .", "sentence_char_start_global": 108092, "sentence_char_end_global": 108301, "entities": [{"text": "activator protein - 1", "type": "ENTITY", "char_start": 54, "char_end": 75, "token_start": 9, "token_end": 12}, {"text": "IL - 2 gene", "type": "ENTITY", "char_start": 125, "char_end": 136, "token_start": 21, "token_end": 24}], "entities_global": [{"text": "activator protein - 1", "type": "ENTITY", "char_start": 108146, "char_end": 108167, "token_start": 9, "token_end": 12, "note": null}, {"text": "IL - 2 gene", "type": "ENTITY", "char_start": 108217, "char_end": 108228, "token_start": 21, "token_end": 24, "note": null}]}
+{"sentence_id": 661, "sentence_text": "To address this issue , the method of scrape loading was applied to purified peripheral blood T lymphocytes .", "sentence_char_start_global": 108302, "sentence_char_end_global": 108411, "entities": [], "entities_global": []}
+{"sentence_id": 662, "sentence_text": "Since scrape loading relies on adherent cells , peripheral blood human T ( PB - T ) cells were immobilized on the nonspecific cell attachment factor poly - L - lysine .", "sentence_char_start_global": 108412, "sentence_char_end_global": 108580, "entities": [], "entities_global": []}
+{"sentence_id": 663, "sentence_text": "Cells scraped off poly - L - lysine in the presence of Ig FITC efficiently incorporated Ig , with relatively uniform fluorescence .", "sentence_char_start_global": 108581, "sentence_char_end_global": 108712, "entities": [{"text": "Ig FITC", "type": "ENTITY", "char_start": 55, "char_end": 62, "token_start": 12, "token_end": 13}], "entities_global": [{"text": "Ig FITC", "type": "ENTITY", "char_start": 108636, "char_end": 108643, "token_start": 12, "token_end": 13, "note": null}]}
+{"sentence_id": 664, "sentence_text": "T cells retained their physical parameters as measured by forward and side light scatter , and functional activity as measured by costimulation of proliferation and IL - 2 production after being scraped off this substrate .", "sentence_char_start_global": 108713, "sentence_char_end_global": 108936, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 165, "char_end": 171, "token_start": 25, "token_end": 27}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 108878, "char_end": 108884, "token_start": 25, "token_end": 27, "note": null}]}
+{"sentence_id": 665, "sentence_text": "CD28 / CD3 - costimulated T cells produced intracellular IL - 2 from all subsets measured ( CD4 + , CD4 - , CD45RO + , and CD45RO - ) .", "sentence_char_start_global": 108937, "sentence_char_end_global": 109072, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 57, "char_end": 63, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 108994, "char_end": 109000, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 666, "sentence_text": "IL - 2 production and intracellular accumulation in nonscraped PB - T cells activated with CD28 / CD3 coligation were skewed favoring CD45RO + and CD4 + subsets , as was IL - 2 production in scraped PB - T cells .", "sentence_char_start_global": 109073, "sentence_char_end_global": 109286, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 2}, {"text": "IL - 2", "type": "ENTITY", "char_start": 170, "char_end": 176, "token_start": 31, "token_end": 33}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 109073, "char_end": 109079, "token_start": 0, "token_end": 2, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 109243, "char_end": 109249, "token_start": 31, "token_end": 33, "note": null}]}
+{"sentence_id": 667, "sentence_text": "The intracellular incorporation of Abs specific for c - Fos and c - Jun family members by scrape loading inhibited the production and intracellular accumulation of IL - 2 within 6 h of costimulation with PMA / ionomycin , or costimulation by CD28 and CD3 ligation .", "sentence_char_start_global": 109287, "sentence_char_end_global": 109552, "entities": [{"text": "c - Fos and c - Jun family members", "type": "ENTITY", "char_start": 52, "char_end": 86, "token_start": 7, "token_end": 15}, {"text": "IL - 2", "type": "ENTITY", "char_start": 164, "char_end": 170, "token_start": 26, "token_end": 28}], "entities_global": [{"text": "c - Fos and c - Jun family members", "type": "ENTITY", "char_start": 109339, "char_end": 109373, "token_start": 7, "token_end": 15, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 109451, "char_end": 109457, "token_start": 26, "token_end": 28, "note": null}]}
+{"sentence_id": 668, "sentence_text": "Scrape loading thus provides an efficient mechanism for intracellular incorporation of macromolecules , and the first direct evidence that c - Fos and c - Jun are involved in transcription of the IL - 2 gene within its correct chromosomal context , in resting human T lymphocyte subpopulations .", "sentence_char_start_global": 109553, "sentence_char_end_global": 109848, "entities": [{"text": "c - Fos", "type": "ENTITY", "char_start": 139, "char_end": 146, "token_start": 19, "token_end": 21}, {"text": "c - Jun", "type": "ENTITY", "char_start": 151, "char_end": 158, "token_start": 23, "token_end": 25}, {"text": "IL - 2 gene", "type": "ENTITY", "char_start": 196, "char_end": 207, "token_start": 32, "token_end": 35}], "entities_global": [{"text": "c - Fos", "type": "ENTITY", "char_start": 109692, "char_end": 109699, "token_start": 19, "token_end": 21, "note": null}, {"text": "c - Jun", "type": "ENTITY", "char_start": 109704, "char_end": 109711, "token_start": 23, "token_end": 25, "note": null}, {"text": "IL - 2 gene", "type": "ENTITY", "char_start": 109749, "char_end": 109760, "token_start": 32, "token_end": 35, "note": null}]}
+{"sentence_id": 669, "sentence_text": "Differential expression of Nur77 family members in human T - lymphotropic virus type 1 - infected cells : transactivation of the TR3 / nur77 gene by Tax protein .", "sentence_char_start_global": 109849, "sentence_char_end_global": 110011, "entities": [{"text": "Nur77 family members", "type": "ENTITY", "char_start": 27, "char_end": 47, "token_start": 3, "token_end": 5}, {"text": "TR3 / nur77 gene", "type": "ENTITY", "char_start": 129, "char_end": 145, "token_start": 21, "token_end": 24}, {"text": "Tax protein", "type": "ENTITY", "char_start": 149, "char_end": 160, "token_start": 26, "token_end": 27}], "entities_global": [{"text": "Nur77 family members", "type": "ENTITY", "char_start": 109876, "char_end": 109896, "token_start": 3, "token_end": 5, "note": null}, {"text": "TR3 / nur77 gene", "type": "ENTITY", "char_start": 109978, "char_end": 109994, "token_start": 21, "token_end": 24, "note": null}, {"text": "Tax protein", "type": "ENTITY", "char_start": 109998, "char_end": 110009, "token_start": 26, "token_end": 27, "note": null}]}
+{"sentence_id": 670, "sentence_text": "We analyzed the differential expression and regulation of three members of the Nur77 transcription factor family by the human T - lymphotropic virus type 1 ( HTLV - 1 ) Tax protein .", "sentence_char_start_global": 110012, "sentence_char_end_global": 110194, "entities": [{"text": "Nur77 transcription factor family", "type": "ENTITY", "char_start": 79, "char_end": 112, "token_start": 12, "token_end": 15}, {"text": "Tax protein", "type": "ENTITY", "char_start": 169, "char_end": 180, "token_start": 30, "token_end": 31}], "entities_global": [{"text": "Nur77 transcription factor family", "type": "ENTITY", "char_start": 110091, "char_end": 110124, "token_start": 12, "token_end": 15, "note": null}, {"text": "Tax protein", "type": "ENTITY", "char_start": 110181, "char_end": 110192, "token_start": 30, "token_end": 31, "note": null}]}
+{"sentence_id": 671, "sentence_text": "We have demonstrated that in both HTLV - 1 - infected cells and Tax - expressing JPX - 9 cells , TR3 / nur77 is highly expressed , whereas neither NOR - 1 nor NOT expression is detectable .", "sentence_char_start_global": 110195, "sentence_char_end_global": 110384, "entities": [{"text": "TR3 / nur77", "type": "ENTITY", "char_start": 97, "char_end": 108, "token_start": 21, "token_end": 23}], "entities_global": [{"text": "TR3 / nur77", "type": "ENTITY", "char_start": 110292, "char_end": 110303, "token_start": 21, "token_end": 23, "note": null}]}
+{"sentence_id": 672, "sentence_text": "Transient transfection analysis further confirmed the Tax transactivation of the TR3 / nur77 promoter but not the NOR - 1 promoter in different cell types .", "sentence_char_start_global": 110385, "sentence_char_end_global": 110541, "entities": [{"text": "Tax", "type": "ENTITY", "char_start": 54, "char_end": 57, "token_start": 6, "token_end": 6}, {"text": "TR3 / nur77", "type": "ENTITY", "char_start": 81, "char_end": 92, "token_start": 10, "token_end": 12}, {"text": "NOR - 1 promoter", "type": "ENTITY", "char_start": 114, "char_end": 130, "token_start": 17, "token_end": 20}], "entities_global": [{"text": "Tax", "type": "ENTITY", "char_start": 110439, "char_end": 110442, "token_start": 6, "token_end": 6, "note": null}, {"text": "TR3 / nur77", "type": "ENTITY", "char_start": 110466, "char_end": 110477, "token_start": 10, "token_end": 12, "note": null}, {"text": "NOR - 1 promoter", "type": "ENTITY", "char_start": 110499, "char_end": 110515, "token_start": 17, "token_end": 20, "note": null}]}
+{"sentence_id": 673, "sentence_text": "Furthermore , expression of a luciferase reporter gene driven by the NGFI - B ( rat homolog of TR3 / Nur77 ) response element ( NBRE ) provided evidence that Tax - mediated transactivation resulted in the induction of a functional protein .", "sentence_char_start_global": 110542, "sentence_char_end_global": 110782, "entities": [{"text": "luciferase reporter gene", "type": "ENTITY", "char_start": 30, "char_end": 54, "token_start": 5, "token_end": 7}, {"text": "NGFI - B ( rat homolog of TR3 / Nur77 ) response element", "type": "ENTITY", "char_start": 69, "char_end": 125, "token_start": 11, "token_end": 23}, {"text": "NBRE", "type": "ENTITY", "char_start": 128, "char_end": 132, "token_start": 25, "token_end": 25}, {"text": "Tax", "type": "ENTITY", "char_start": 158, "char_end": 161, "token_start": 30, "token_end": 30}], "entities_global": [{"text": "luciferase reporter gene", "type": "ENTITY", "char_start": 110572, "char_end": 110596, "token_start": 5, "token_end": 7, "note": null}, {"text": "NGFI - B ( rat homolog of TR3 / Nur77 ) response element", "type": "ENTITY", "char_start": 110611, "char_end": 110667, "token_start": 11, "token_end": 23, "note": null}, {"text": "NBRE", "type": "ENTITY", "char_start": 110670, "char_end": 110674, "token_start": 25, "token_end": 25, "note": null}, {"text": "Tax", "type": "ENTITY", "char_start": 110700, "char_end": 110703, "token_start": 30, "token_end": 30, "note": null}]}
+{"sentence_id": 674, "sentence_text": "Cotransfection assays with the TR3 / nur77 promoter sequence or the NBRE binding motif together with a series of Tax mutants have shown that Tax - induced TR3 / nur77 expression is mediated by CREB / ATF - related transcription factors .", "sentence_char_start_global": 110783, "sentence_char_end_global": 111020, "entities": [{"text": "TR3 / nur77 promoter sequence", "type": "ENTITY", "char_start": 31, "char_end": 60, "token_start": 4, "token_end": 8}, {"text": "NBRE", "type": "ENTITY", "char_start": 68, "char_end": 72, "token_start": 11, "token_end": 11}, {"text": "Tax", "type": "ENTITY", "char_start": 113, "char_end": 116, "token_start": 19, "token_end": 19}, {"text": "Tax", "type": "ENTITY", "char_start": 141, "char_end": 144, "token_start": 24, "token_end": 24}, {"text": "TR3 / nur77", "type": "ENTITY", "char_start": 155, "char_end": 166, "token_start": 27, "token_end": 29}, {"text": "CREB / ATF - related transcription factors", "type": "ENTITY", "char_start": 193, "char_end": 235, "token_start": 34, "token_end": 40}], "entities_global": [{"text": "TR3 / nur77 promoter sequence", "type": "ENTITY", "char_start": 110814, "char_end": 110843, "token_start": 4, "token_end": 8, "note": null}, {"text": "NBRE", "type": "ENTITY", "char_start": 110851, "char_end": 110855, "token_start": 11, "token_end": 11, "note": null}, {"text": "Tax", "type": "ENTITY", "char_start": 110896, "char_end": 110899, "token_start": 19, "token_end": 19, "note": null}, {"text": "Tax", "type": "ENTITY", "char_start": 110924, "char_end": 110927, "token_start": 24, "token_end": 24, "note": null}, {"text": "TR3 / nur77", "type": "ENTITY", "char_start": 110938, "char_end": 110949, "token_start": 27, "token_end": 29, "note": null}, {"text": "CREB / ATF - related transcription factors", "type": "ENTITY", "char_start": 110976, "char_end": 111018, "token_start": 34, "token_end": 40, "note": null}]}
+{"sentence_id": 675, "sentence_text": "Negative regulation of the heat shock transcriptional response by HSBP1 .", "sentence_char_start_global": 111021, "sentence_char_end_global": 111094, "entities": [{"text": "HSBP1", "type": "ENTITY", "char_start": 66, "char_end": 71, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "HSBP1", "type": "ENTITY", "char_start": 111087, "char_end": 111092, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 676, "sentence_text": "In response to stress , heat shock factor 1 ( HSF1 ) acquires rapid DNA binding and transient transcriptional activity while undergoing conformational transition from an inert non - DNA - binding monomer to active functional trimers .", "sentence_char_start_global": 111095, "sentence_char_end_global": 111329, "entities": [{"text": "heat shock factor 1", "type": "ENTITY", "char_start": 24, "char_end": 43, "token_start": 5, "token_end": 8}, {"text": "HSF1", "type": "ENTITY", "char_start": 46, "char_end": 50, "token_start": 10, "token_end": 10}, {"text": "non - DNA - binding monomer", "type": "ENTITY", "char_start": 176, "char_end": 203, "token_start": 27, "token_end": 32}], "entities_global": [{"text": "heat shock factor 1", "type": "ENTITY", "char_start": 111119, "char_end": 111138, "token_start": 5, "token_end": 8, "note": null}, {"text": "HSF1", "type": "ENTITY", "char_start": 111141, "char_end": 111145, "token_start": 10, "token_end": 10, "note": null}, {"text": "non - DNA - binding monomer", "type": "ENTITY", "char_start": 111271, "char_end": 111298, "token_start": 27, "token_end": 32, "note": null}]}
+{"sentence_id": 677, "sentence_text": "Attenuation of the inducible transcriptional response occurs during heat shock or upon recovery at non - stress conditions and involves dissociation of the HSF1 trimer and loss of activity .", "sentence_char_start_global": 111330, "sentence_char_end_global": 111520, "entities": [{"text": "HSF1 trimer", "type": "ENTITY", "char_start": 156, "char_end": 167, "token_start": 23, "token_end": 24}], "entities_global": [{"text": "HSF1 trimer", "type": "ENTITY", "char_start": 111486, "char_end": 111497, "token_start": 23, "token_end": 24, "note": null}]}
+{"sentence_id": 678, "sentence_text": "We have used the hydrophobic repeats of the HSF1 trimerization domain in the yeast two - hybrid protein interaction assay to identify heat shock factor binding protein 1 ( HSBP1 ) , a novel , conserved , 76 - amino - acid protein that contains two extended arrays of hydrophobic repeats that interact with the HSF1 heptad repeats .", "sentence_char_start_global": 111521, "sentence_char_end_global": 111852, "entities": [{"text": "hydrophobic repeats", "type": "ENTITY", "char_start": 17, "char_end": 36, "token_start": 4, "token_end": 5}, {"text": "HSF1", "type": "ENTITY", "char_start": 44, "char_end": 48, "token_start": 8, "token_end": 8}, {"text": "heat shock factor binding protein 1", "type": "ENTITY", "char_start": 134, "char_end": 169, "token_start": 22, "token_end": 27}, {"text": "HSBP1", "type": "ENTITY", "char_start": 172, "char_end": 177, "token_start": 29, "token_end": 29}, {"text": "76 - amino - acid protein", "type": "ENTITY", "char_start": 204, "char_end": 229, "token_start": 37, "token_end": 42}, {"text": "hydrophobic repeats", "type": "ENTITY", "char_start": 267, "char_end": 286, "token_start": 49, "token_end": 50}, {"text": "HSF1 heptad repeats", "type": "ENTITY", "char_start": 310, "char_end": 329, "token_start": 55, "token_end": 57}], "entities_global": [{"text": "hydrophobic repeats", "type": "ENTITY", "char_start": 111538, "char_end": 111557, "token_start": 4, "token_end": 5, "note": null}, {"text": "HSF1", "type": "ENTITY", "char_start": 111565, "char_end": 111569, "token_start": 8, "token_end": 8, "note": null}, {"text": "heat shock factor binding protein 1", "type": "ENTITY", "char_start": 111655, "char_end": 111690, "token_start": 22, "token_end": 27, "note": null}, {"text": "HSBP1", "type": "ENTITY", "char_start": 111693, "char_end": 111698, "token_start": 29, "token_end": 29, "note": null}, {"text": "76 - amino - acid protein", "type": "ENTITY", "char_start": 111725, "char_end": 111750, "token_start": 37, "token_end": 42, "note": null}, {"text": "hydrophobic repeats", "type": "ENTITY", "char_start": 111788, "char_end": 111807, "token_start": 49, "token_end": 50, "note": null}, {"text": "HSF1 heptad repeats", "type": "ENTITY", "char_start": 111831, "char_end": 111850, "token_start": 55, "token_end": 57, "note": null}]}
+{"sentence_id": 679, "sentence_text": "HSBP1 is nuclear - localized and interacts in vivo with the active trimeric state of HSF1 that appears during heat shock .", "sentence_char_start_global": 111853, "sentence_char_end_global": 111975, "entities": [{"text": "HSBP1", "type": "ENTITY", "char_start": 0, "char_end": 5, "token_start": 0, "token_end": 0}, {"text": "HSF1", "type": "ENTITY", "char_start": 85, "char_end": 89, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "HSBP1", "type": "ENTITY", "char_start": 111853, "char_end": 111858, "token_start": 0, "token_end": 0, "note": null}, {"text": "HSF1", "type": "ENTITY", "char_start": 111938, "char_end": 111942, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 680, "sentence_text": "During attenuation of HSF1 to the inert monomer , HSBP1 associates with Hsp70 .", "sentence_char_start_global": 111976, "sentence_char_end_global": 112055, "entities": [{"text": "HSF1", "type": "ENTITY", "char_start": 22, "char_end": 26, "token_start": 3, "token_end": 3}, {"text": "HSBP1", "type": "ENTITY", "char_start": 50, "char_end": 55, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "HSF1", "type": "ENTITY", "char_start": 111998, "char_end": 112002, "token_start": 3, "token_end": 3, "note": null}, {"text": "HSBP1", "type": "ENTITY", "char_start": 112026, "char_end": 112031, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 681, "sentence_text": "HSBP1 negatively affects HSF1 DNA - binding activity , and overexpression of HSBP1 in mammalian cells represses the transactivation activity of HSF1 .", "sentence_char_start_global": 112056, "sentence_char_end_global": 112206, "entities": [{"text": "HSBP1", "type": "ENTITY", "char_start": 0, "char_end": 5, "token_start": 0, "token_end": 0}, {"text": "HSF1", "type": "ENTITY", "char_start": 25, "char_end": 29, "token_start": 3, "token_end": 3}, {"text": "HSBP1", "type": "ENTITY", "char_start": 77, "char_end": 82, "token_start": 12, "token_end": 12}, {"text": "HSF1", "type": "ENTITY", "char_start": 144, "char_end": 148, "token_start": 21, "token_end": 21}], "entities_global": [{"text": "HSBP1", "type": "ENTITY", "char_start": 112056, "char_end": 112061, "token_start": 0, "token_end": 0, "note": null}, {"text": "HSF1", "type": "ENTITY", "char_start": 112081, "char_end": 112085, "token_start": 3, "token_end": 3, "note": null}, {"text": "HSBP1", "type": "ENTITY", "char_start": 112133, "char_end": 112138, "token_start": 12, "token_end": 12, "note": null}, {"text": "HSF1", "type": "ENTITY", "char_start": 112200, "char_end": 112204, "token_start": 21, "token_end": 21, "note": null}]}
+{"sentence_id": 682, "sentence_text": "To establish a biological role for HSBP1 , the homologous Caenorhabditis elegans protein was overexpressed in body wall muscle cells and was shown to block activation of the heat shock response from a heat shock promoter - reporter construct .", "sentence_char_start_global": 112207, "sentence_char_end_global": 112450, "entities": [{"text": "HSBP1", "type": "ENTITY", "char_start": 35, "char_end": 40, "token_start": 6, "token_end": 6}, {"text": "Caenorhabditis elegans protein", "type": "ENTITY", "char_start": 58, "char_end": 88, "token_start": 10, "token_end": 12}, {"text": "heat shock promoter - reporter construct", "type": "ENTITY", "char_start": 201, "char_end": 241, "token_start": 33, "token_end": 38}], "entities_global": [{"text": "HSBP1", "type": "ENTITY", "char_start": 112242, "char_end": 112247, "token_start": 6, "token_end": 6, "note": null}, {"text": "Caenorhabditis elegans protein", "type": "ENTITY", "char_start": 112265, "char_end": 112295, "token_start": 10, "token_end": 12, "note": null}, {"text": "heat shock promoter - reporter construct", "type": "ENTITY", "char_start": 112408, "char_end": 112448, "token_start": 33, "token_end": 38, "note": null}]}
+{"sentence_id": 683, "sentence_text": "Alteration in the level of HSBP1 expression in C . elegans has severe effects on survival of the animals after thermal and chemical stress , consistent with a role for HSBP1 as a negative regulator of the heat shock response .", "sentence_char_start_global": 112451, "sentence_char_end_global": 112677, "entities": [{"text": "HSBP1", "type": "ENTITY", "char_start": 27, "char_end": 32, "token_start": 5, "token_end": 5}, {"text": "HSBP1", "type": "ENTITY", "char_start": 168, "char_end": 173, "token_start": 30, "token_end": 30}], "entities_global": [{"text": "HSBP1", "type": "ENTITY", "char_start": 112478, "char_end": 112483, "token_start": 5, "token_end": 5, "note": null}, {"text": "HSBP1", "type": "ENTITY", "char_start": 112619, "char_end": 112624, "token_start": 30, "token_end": 30, "note": null}]}
+{"sentence_id": 684, "sentence_text": "Long - range transcriptional regulation of cytokine gene expression .", "sentence_char_start_global": 112678, "sentence_char_end_global": 112747, "entities": [], "entities_global": []}
+{"sentence_id": 685, "sentence_text": "Most studies on the control of cytokine gene expression have involved the functional analysis of proximal promoters .", "sentence_char_start_global": 112748, "sentence_char_end_global": 112865, "entities": [{"text": "proximal promoters", "type": "ENTITY", "char_start": 97, "char_end": 115, "token_start": 15, "token_end": 16}], "entities_global": [{"text": "proximal promoters", "type": "ENTITY", "char_start": 112845, "char_end": 112863, "token_start": 15, "token_end": 16, "note": null}]}
+{"sentence_id": 686, "sentence_text": "Recent work has identified distal elements that mediate long - range cytokine gene regulation and has implicated chromatin reorganization in regulation of cytokine gene loci .", "sentence_char_start_global": 112866, "sentence_char_end_global": 113041, "entities": [{"text": "distal elements", "type": "ENTITY", "char_start": 27, "char_end": 42, "token_start": 4, "token_end": 5}, {"text": "cytokine gene loci", "type": "ENTITY", "char_start": 155, "char_end": 173, "token_start": 22, "token_end": 24}], "entities_global": [{"text": "distal elements", "type": "ENTITY", "char_start": 112893, "char_end": 112908, "token_start": 4, "token_end": 5, "note": null}, {"text": "cytokine gene loci", "type": "ENTITY", "char_start": 113021, "char_end": 113039, "token_start": 22, "token_end": 24, "note": null}]}
+{"sentence_id": 687, "sentence_text": "These studies have begun to elucidate the basis for cell - specificity and high - level expression of cytokine genes .", "sentence_char_start_global": 113042, "sentence_char_end_global": 113160, "entities": [{"text": "cytokine genes", "type": "ENTITY", "char_start": 102, "char_end": 116, "token_start": 18, "token_end": 19}], "entities_global": [{"text": "cytokine genes", "type": "ENTITY", "char_start": 113144, "char_end": 113158, "token_start": 18, "token_end": 19, "note": null}]}
+{"sentence_id": 688, "sentence_text": "A signaling complex of Ca2 + - calmodulin - dependent protein kinase IV and protein phosphatase 2A [ see comments ]", "sentence_char_start_global": 113161, "sentence_char_end_global": 113276, "entities": [{"text": "Ca2 + - calmodulin - dependent protein kinase IV", "type": "ENTITY", "char_start": 23, "char_end": 71, "token_start": 4, "token_end": 12}, {"text": "protein phosphatase 2A", "type": "ENTITY", "char_start": 76, "char_end": 98, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "Ca2 + - calmodulin - dependent protein kinase IV", "type": "ENTITY", "char_start": 113184, "char_end": 113232, "token_start": 4, "token_end": 12, "note": null}, {"text": "protein phosphatase 2A", "type": "ENTITY", "char_start": 113237, "char_end": 113259, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 689, "sentence_text": "Stimulation of T lymphocytes results in a rapid increase in intracellular calcium concentration ( [ Ca2 + ] i ) that parallels the activation of Ca2 + - calmodulin - dependent protein kinase IV ( CaMKIV ) , a nuclear enzyme that can phosphorylate and activate the cyclic adenosine monophosphate ( cAMP ) response element - binding protein ( CREB ) .", "sentence_char_start_global": 113277, "sentence_char_end_global": 113626, "entities": [{"text": "Ca2 + - calmodulin - dependent protein kinase IV", "type": "ENTITY", "char_start": 145, "char_end": 193, "token_start": 25, "token_end": 33}, {"text": "CaMKIV", "type": "ENTITY", "char_start": 196, "char_end": 202, "token_start": 35, "token_end": 35}, {"text": "nuclear enzyme", "type": "ENTITY", "char_start": 209, "char_end": 223, "token_start": 39, "token_end": 40}, {"text": "cyclic adenosine monophosphate ( cAMP ) response element - binding protein", "type": "ENTITY", "char_start": 264, "char_end": 338, "token_start": 47, "token_end": 57}, {"text": "CREB", "type": "ENTITY", "char_start": 341, "char_end": 345, "token_start": 59, "token_end": 59}], "entities_global": [{"text": "Ca2 + - calmodulin - dependent protein kinase IV", "type": "ENTITY", "char_start": 113422, "char_end": 113470, "token_start": 25, "token_end": 33, "note": null}, {"text": "CaMKIV", "type": "ENTITY", "char_start": 113473, "char_end": 113479, "token_start": 35, "token_end": 35, "note": null}, {"text": "nuclear enzyme", "type": "ENTITY", "char_start": 113486, "char_end": 113500, "token_start": 39, "token_end": 40, "note": null}, {"text": "cyclic adenosine monophosphate ( cAMP ) response element - binding protein", "type": "ENTITY", "char_start": 113541, "char_end": 113615, "token_start": 47, "token_end": 57, "note": null}, {"text": "CREB", "type": "ENTITY", "char_start": 113618, "char_end": 113622, "token_start": 59, "token_end": 59, "note": null}]}
+{"sentence_id": 690, "sentence_text": "However , inactivation of CaMKIV occurs despite the sustained increase in [ Ca2 + ] i that is required for T cell activation .", "sentence_char_start_global": 113627, "sentence_char_end_global": 113753, "entities": [{"text": "CaMKIV", "type": "ENTITY", "char_start": 26, "char_end": 32, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "CaMKIV", "type": "ENTITY", "char_start": 113653, "char_end": 113659, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 691, "sentence_text": "A stable and stoichiometric complex of CaMKIV with protein serine - threonine phosphatase 2A ( PP2A ) was identified in which PP2A dephosphorylates CaMKIV and functions as a negative regulator of CaMKIV signaling .", "sentence_char_start_global": 113754, "sentence_char_end_global": 113968, "entities": [{"text": "CaMKIV", "type": "ENTITY", "char_start": 39, "char_end": 45, "token_start": 6, "token_end": 6}, {"text": "protein serine - threonine phosphatase 2A", "type": "ENTITY", "char_start": 51, "char_end": 92, "token_start": 8, "token_end": 13}, {"text": "PP2A", "type": "ENTITY", "char_start": 95, "char_end": 99, "token_start": 15, "token_end": 15}, {"text": "PP2A", "type": "ENTITY", "char_start": 126, "char_end": 130, "token_start": 21, "token_end": 21}, {"text": "CaMKIV", "type": "ENTITY", "char_start": 148, "char_end": 154, "token_start": 23, "token_end": 23}, {"text": "CaMKIV", "type": "ENTITY", "char_start": 196, "char_end": 202, "token_start": 31, "token_end": 31}], "entities_global": [{"text": "CaMKIV", "type": "ENTITY", "char_start": 113793, "char_end": 113799, "token_start": 6, "token_end": 6, "note": null}, {"text": "protein serine - threonine phosphatase 2A", "type": "ENTITY", "char_start": 113805, "char_end": 113846, "token_start": 8, "token_end": 13, "note": null}, {"text": "PP2A", "type": "ENTITY", "char_start": 113849, "char_end": 113853, "token_start": 15, "token_end": 15, "note": null}, {"text": "PP2A", "type": "ENTITY", "char_start": 113880, "char_end": 113884, "token_start": 21, "token_end": 21, "note": null}, {"text": "CaMKIV", "type": "ENTITY", "char_start": 113902, "char_end": 113908, "token_start": 23, "token_end": 23, "note": null}, {"text": "CaMKIV", "type": "ENTITY", "char_start": 113950, "char_end": 113956, "token_start": 31, "token_end": 31, "note": null}]}
+{"sentence_id": 692, "sentence_text": "In Jurkat T cells , inhibition of PP2A activity by small t antigen enhanced activation of CREB - mediated transcription by CaMKIV .", "sentence_char_start_global": 113969, "sentence_char_end_global": 114100, "entities": [{"text": "PP2A", "type": "ENTITY", "char_start": 34, "char_end": 38, "token_start": 7, "token_end": 7}, {"text": "CREB", "type": "ENTITY", "char_start": 90, "char_end": 94, "token_start": 16, "token_end": 16}, {"text": "CaMKIV", "type": "ENTITY", "char_start": 123, "char_end": 129, "token_start": 21, "token_end": 21}], "entities_global": [{"text": "PP2A", "type": "ENTITY", "char_start": 114003, "char_end": 114007, "token_start": 7, "token_end": 7, "note": null}, {"text": "CREB", "type": "ENTITY", "char_start": 114059, "char_end": 114063, "token_start": 16, "token_end": 16, "note": null}, {"text": "CaMKIV", "type": "ENTITY", "char_start": 114092, "char_end": 114098, "token_start": 21, "token_end": 21, "note": null}]}
+{"sentence_id": 693, "sentence_text": "These findings reveal an intracellular signaling mechanism whereby a protein serine - threonine kinase ( CaMKIV ) is regulated by a tightly associated protein serine - threonine phosphatase ( PP2A ) .", "sentence_char_start_global": 114101, "sentence_char_end_global": 114301, "entities": [{"text": "protein serine - threonine kinase", "type": "ENTITY", "char_start": 69, "char_end": 102, "token_start": 9, "token_end": 13}, {"text": "CaMKIV", "type": "ENTITY", "char_start": 105, "char_end": 111, "token_start": 15, "token_end": 15}, {"text": "protein serine - threonine phosphatase", "type": "ENTITY", "char_start": 151, "char_end": 189, "token_start": 23, "token_end": 27}, {"text": "PP2A", "type": "ENTITY", "char_start": 192, "char_end": 196, "token_start": 29, "token_end": 29}], "entities_global": [{"text": "protein serine - threonine kinase", "type": "ENTITY", "char_start": 114170, "char_end": 114203, "token_start": 9, "token_end": 13, "note": null}, {"text": "CaMKIV", "type": "ENTITY", "char_start": 114206, "char_end": 114212, "token_start": 15, "token_end": 15, "note": null}, {"text": "protein serine - threonine phosphatase", "type": "ENTITY", "char_start": 114252, "char_end": 114290, "token_start": 23, "token_end": 27, "note": null}, {"text": "PP2A", "type": "ENTITY", "char_start": 114293, "char_end": 114297, "token_start": 29, "token_end": 29, "note": null}]}
+{"sentence_id": 694, "sentence_text": "Hypoxia down - regulates MCP - 1 expression : implications for macrophage distribution in tumors .", "sentence_char_start_global": 114302, "sentence_char_end_global": 114400, "entities": [{"text": "MCP - 1", "type": "ENTITY", "char_start": 25, "char_end": 32, "token_start": 4, "token_end": 6}], "entities_global": [{"text": "MCP - 1", "type": "ENTITY", "char_start": 114327, "char_end": 114334, "token_start": 4, "token_end": 6, "note": null}]}
+{"sentence_id": 695, "sentence_text": "Monocyte chemoattractant protein 1 ( MCP - 1 ) is likely to contribute to the macrophage infiltrate in human ovarian carcinomas .", "sentence_char_start_global": 114401, "sentence_char_end_global": 114530, "entities": [{"text": "Monocyte chemoattractant protein 1", "type": "ENTITY", "char_start": 0, "char_end": 34, "token_start": 0, "token_end": 3}, {"text": "MCP - 1", "type": "ENTITY", "char_start": 37, "char_end": 44, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "Monocyte chemoattractant protein 1", "type": "ENTITY", "char_start": 114401, "char_end": 114435, "token_start": 0, "token_end": 3, "note": null}, {"text": "MCP - 1", "type": "ENTITY", "char_start": 114438, "char_end": 114445, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 696, "sentence_text": "Although MCP - 1 is predominantly expressed by the tumor parenchyma , macrophages accumulate at highest density in necrotic regions , which are associated with low oxygen tensions .", "sentence_char_start_global": 114531, "sentence_char_end_global": 114712, "entities": [{"text": "MCP - 1", "type": "ENTITY", "char_start": 9, "char_end": 16, "token_start": 1, "token_end": 3}], "entities_global": [{"text": "MCP - 1", "type": "ENTITY", "char_start": 114540, "char_end": 114547, "token_start": 1, "token_end": 3, "note": null}]}
+{"sentence_id": 697, "sentence_text": "Tumor necrosis factor alpha ( TNF - alpha ) can stimulate MCP - 1 production and is also present within ovarian carcinomas .", "sentence_char_start_global": 114713, "sentence_char_end_global": 114837, "entities": [{"text": "Tumor necrosis factor alpha", "type": "ENTITY", "char_start": 0, "char_end": 27, "token_start": 0, "token_end": 3}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 30, "char_end": 41, "token_start": 5, "token_end": 7}, {"text": "MCP - 1", "type": "ENTITY", "char_start": 58, "char_end": 65, "token_start": 11, "token_end": 13}], "entities_global": [{"text": "Tumor necrosis factor alpha", "type": "ENTITY", "char_start": 114713, "char_end": 114740, "token_start": 0, "token_end": 3, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 114743, "char_end": 114754, "token_start": 5, "token_end": 7, "note": null}, {"text": "MCP - 1", "type": "ENTITY", "char_start": 114771, "char_end": 114778, "token_start": 11, "token_end": 13, "note": null}]}
+{"sentence_id": 698, "sentence_text": "We have investigated the effect of hypoxia both on MCP - 1 expression in ovarian cancer cell lines and monocyte migration .", "sentence_char_start_global": 114838, "sentence_char_end_global": 114961, "entities": [{"text": "MCP - 1", "type": "ENTITY", "char_start": 51, "char_end": 58, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "MCP - 1", "type": "ENTITY", "char_start": 114889, "char_end": 114896, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 699, "sentence_text": "Hypoxia down - regulated TNF - alpha - induced MCP - 1 mRNA and protein production by ovarian cancer cells .", "sentence_char_start_global": 114962, "sentence_char_end_global": 115070, "entities": [{"text": "TNF - alpha - induced MCP - 1 mRNA", "type": "ENTITY", "char_start": 25, "char_end": 59, "token_start": 4, "token_end": 12}], "entities_global": [{"text": "TNF - alpha - induced MCP - 1 mRNA", "type": "ENTITY", "char_start": 114987, "char_end": 115021, "token_start": 4, "token_end": 12, "note": null}]}
+{"sentence_id": 700, "sentence_text": "The effect was mimicked by cobalt chloride and desferrioxamine , consistent with a specific oxygen - sensing mechanism .", "sentence_char_start_global": 115071, "sentence_char_end_global": 115191, "entities": [], "entities_global": []}
+{"sentence_id": 701, "sentence_text": "Unlike antioxidants , hypoxia did not inhibit nuclear factor KB mobilization .", "sentence_char_start_global": 115192, "sentence_char_end_global": 115270, "entities": [], "entities_global": []}
+{"sentence_id": 702, "sentence_text": "Monocyte migration in response to MCP - 1 was also diminished under hypoxic conditions .", "sentence_char_start_global": 115271, "sentence_char_end_global": 115359, "entities": [{"text": "MCP - 1", "type": "ENTITY", "char_start": 34, "char_end": 41, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "MCP - 1", "type": "ENTITY", "char_start": 115305, "char_end": 115312, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 703, "sentence_text": "Down - regulation of MCP - 1 expression and the inhibition of monocyte migration are independent effects of hypoxia that may contribute to the distribution of macrophages within ovarian tumors .", "sentence_char_start_global": 115360, "sentence_char_end_global": 115554, "entities": [{"text": "MCP - 1", "type": "ENTITY", "char_start": 21, "char_end": 28, "token_start": 4, "token_end": 6}], "entities_global": [{"text": "MCP - 1", "type": "ENTITY", "char_start": 115381, "char_end": 115388, "token_start": 4, "token_end": 6, "note": null}]}
+{"sentence_id": 704, "sentence_text": "Activation of nuclear factor kappa B inflammatory bowel disease [ see comments ]", "sentence_char_start_global": 115555, "sentence_char_end_global": 115635, "entities": [{"text": "nuclear factor kappa B", "type": "ENTITY", "char_start": 14, "char_end": 36, "token_start": 2, "token_end": 5}], "entities_global": [{"text": "nuclear factor kappa B", "type": "ENTITY", "char_start": 115569, "char_end": 115591, "token_start": 2, "token_end": 5, "note": null}]}
+{"sentence_id": 705, "sentence_text": "BACKGROUND : Expression of pro - inflammatory cytokines is increased in the intestinal lamina propria of patients with inflammatory bowel disease ( IBD ) .", "sentence_char_start_global": 115636, "sentence_char_end_global": 115791, "entities": [{"text": "pro - inflammatory cytokines", "type": "ENTITY", "char_start": 27, "char_end": 55, "token_start": 4, "token_end": 7}], "entities_global": [{"text": "pro - inflammatory cytokines", "type": "ENTITY", "char_start": 115663, "char_end": 115691, "token_start": 4, "token_end": 7, "note": null}]}
+{"sentence_id": 706, "sentence_text": "Nuclear factor kappa B ( NF kappa B ) controls transcription of inflammation genes .", "sentence_char_start_global": 115792, "sentence_char_end_global": 115876, "entities": [{"text": "Nuclear factor kappa B", "type": "ENTITY", "char_start": 0, "char_end": 22, "token_start": 0, "token_end": 3}, {"text": "NF kappa B", "type": "ENTITY", "char_start": 25, "char_end": 35, "token_start": 5, "token_end": 7}, {"text": "inflammation genes", "type": "ENTITY", "char_start": 64, "char_end": 82, "token_start": 12, "token_end": 13}], "entities_global": [{"text": "Nuclear factor kappa B", "type": "ENTITY", "char_start": 115792, "char_end": 115814, "token_start": 0, "token_end": 3, "note": null}, {"text": "NF kappa B", "type": "ENTITY", "char_start": 115817, "char_end": 115827, "token_start": 5, "token_end": 7, "note": null}, {"text": "inflammation genes", "type": "ENTITY", "char_start": 115856, "char_end": 115874, "token_start": 12, "token_end": 13, "note": null}]}
+{"sentence_id": 707, "sentence_text": "On activation , NF kappa B is rapidly released from its cytoplasmic inhibitor ( I kappa B ) , transmigrates into the nucleus , and binds to DNA response elements in gene promoter regions .", "sentence_char_start_global": 115877, "sentence_char_end_global": 116065, "entities": [{"text": "NF kappa B", "type": "ENTITY", "char_start": 16, "char_end": 26, "token_start": 3, "token_end": 5}, {"text": "cytoplasmic inhibitor", "type": "ENTITY", "char_start": 56, "char_end": 77, "token_start": 11, "token_end": 12}, {"text": "I kappa B", "type": "ENTITY", "char_start": 80, "char_end": 89, "token_start": 14, "token_end": 16}, {"text": "DNA response elements", "type": "ENTITY", "char_start": 140, "char_end": 161, "token_start": 27, "token_end": 29}], "entities_global": [{"text": "NF kappa B", "type": "ENTITY", "char_start": 115893, "char_end": 115903, "token_start": 3, "token_end": 5, "note": null}, {"text": "cytoplasmic inhibitor", "type": "ENTITY", "char_start": 115933, "char_end": 115954, "token_start": 11, "token_end": 12, "note": null}, {"text": "I kappa B", "type": "ENTITY", "char_start": 115957, "char_end": 115966, "token_start": 14, "token_end": 16, "note": null}, {"text": "DNA response elements", "type": "ENTITY", "char_start": 116017, "char_end": 116038, "token_start": 27, "token_end": 29, "note": null}]}
+{"sentence_id": 708, "sentence_text": "AIMS : To investigate whether increased activation of NF kappa B is important in IBD and may be down - regulated by anti - inflammatory treatment .", "sentence_char_start_global": 116066, "sentence_char_end_global": 116213, "entities": [{"text": "NF kappa B", "type": "ENTITY", "char_start": 54, "char_end": 64, "token_start": 8, "token_end": 10}], "entities_global": [{"text": "NF kappa B", "type": "ENTITY", "char_start": 116120, "char_end": 116130, "token_start": 8, "token_end": 10, "note": null}]}
+{"sentence_id": 709, "sentence_text": "METHODS : Activation of NF kappa B was determined by western blot assessment and electrophoretic mobility shift assay in nuclear extracts of colonic biopsy samples as well as lamina propria mononuclear cells .", "sentence_char_start_global": 116214, "sentence_char_end_global": 116423, "entities": [{"text": "NF kappa B", "type": "ENTITY", "char_start": 24, "char_end": 34, "token_start": 4, "token_end": 6}], "entities_global": [{"text": "NF kappa B", "type": "ENTITY", "char_start": 116238, "char_end": 116248, "token_start": 4, "token_end": 6, "note": null}]}
+{"sentence_id": 710, "sentence_text": "RESULTS : Nuclear levels of NF kappa B p65 are increased in lamina propria biopsy specimens from patients with Crohn ' s disease in comparison with patients with ulcerative colitis and controls .", "sentence_char_start_global": 116424, "sentence_char_end_global": 116619, "entities": [{"text": "NF kappa B", "type": "ENTITY", "char_start": 28, "char_end": 38, "token_start": 5, "token_end": 7}, {"text": "p65", "type": "ENTITY", "char_start": 39, "char_end": 42, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "NF kappa B", "type": "ENTITY", "char_start": 116452, "char_end": 116462, "token_start": 5, "token_end": 7, "note": null}, {"text": "p65", "type": "ENTITY", "char_start": 116463, "char_end": 116466, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 711, "sentence_text": "Increased activation of NF kappa B was detected in lamina propria mononuclear cells from patients with active IBD .", "sentence_char_start_global": 116620, "sentence_char_end_global": 116735, "entities": [{"text": "NF kappa B", "type": "ENTITY", "char_start": 24, "char_end": 34, "token_start": 3, "token_end": 5}], "entities_global": [{"text": "NF kappa B", "type": "ENTITY", "char_start": 116644, "char_end": 116654, "token_start": 3, "token_end": 5, "note": null}]}
+{"sentence_id": 712, "sentence_text": "Corticosteroids strongly inhibit intestinal NF kappa B activation in IBD in vivo and in vitro by stabilising the cytosolic inhibitor I kappa B alpha against activation induced degradation .", "sentence_char_start_global": 116736, "sentence_char_end_global": 116925, "entities": [{"text": "NF kappa B", "type": "ENTITY", "char_start": 44, "char_end": 54, "token_start": 4, "token_end": 6}, {"text": "cytosolic inhibitor", "type": "ENTITY", "char_start": 113, "char_end": 132, "token_start": 18, "token_end": 19}, {"text": "I kappa B", "type": "ENTITY", "char_start": 133, "char_end": 142, "token_start": 20, "token_end": 22}], "entities_global": [{"text": "NF kappa B", "type": "ENTITY", "char_start": 116780, "char_end": 116790, "token_start": 4, "token_end": 6, "note": null}, {"text": "cytosolic inhibitor", "type": "ENTITY", "char_start": 116849, "char_end": 116868, "token_start": 18, "token_end": 19, "note": null}, {"text": "I kappa B", "type": "ENTITY", "char_start": 116869, "char_end": 116878, "token_start": 20, "token_end": 22, "note": null}]}
+{"sentence_id": 713, "sentence_text": "CONCLUSIONS : In both IBDs , but particularly Crohn ' s disease , increased activation of NF kappa B may be involved in the regulation of the inflammatory response .", "sentence_char_start_global": 116926, "sentence_char_end_global": 117091, "entities": [{"text": "NF kappa B", "type": "ENTITY", "char_start": 90, "char_end": 100, "token_start": 16, "token_end": 18}], "entities_global": [{"text": "NF kappa B", "type": "ENTITY", "char_start": 117016, "char_end": 117026, "token_start": 16, "token_end": 18, "note": null}]}
+{"sentence_id": 714, "sentence_text": "Inhibition of NF kappa B activation may represent a mechanism by which steroids exert an anti - inflammatory effect in IBD", "sentence_char_start_global": 117092, "sentence_char_end_global": 117214, "entities": [{"text": "NF kappa B", "type": "ENTITY", "char_start": 14, "char_end": 24, "token_start": 2, "token_end": 4}], "entities_global": [{"text": "NF kappa B", "type": "ENTITY", "char_start": 117106, "char_end": 117116, "token_start": 2, "token_end": 4, "note": null}]}
+{"sentence_id": 715, "sentence_text": "Insufficient glycemic control increases nuclear factor - kappa B binding activity in peripheral blood mononuclear cells isolated from patients with type 1 diabetes .", "sentence_char_start_global": 117215, "sentence_char_end_global": 117380, "entities": [{"text": "nuclear factor - kappa B", "type": "ENTITY", "char_start": 40, "char_end": 64, "token_start": 4, "token_end": 8}], "entities_global": [{"text": "nuclear factor - kappa B", "type": "ENTITY", "char_start": 117255, "char_end": 117279, "token_start": 4, "token_end": 8, "note": null}]}
+{"sentence_id": 716, "sentence_text": "OBJECTIVE : The redox - sensitive transcription factor nuclear factor - kappa B ( NF - kappa B ) is believed to contribute to late diabetic complications .", "sentence_char_start_global": 117381, "sentence_char_end_global": 117536, "entities": [{"text": "redox - sensitive transcription factor nuclear factor - kappa B", "type": "ENTITY", "char_start": 16, "char_end": 79, "token_start": 3, "token_end": 12}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 82, "char_end": 94, "token_start": 14, "token_end": 17}], "entities_global": [{"text": "redox - sensitive transcription factor nuclear factor - kappa B", "type": "ENTITY", "char_start": 117397, "char_end": 117460, "token_start": 3, "token_end": 12, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 117463, "char_end": 117475, "token_start": 14, "token_end": 17, "note": null}]}
+{"sentence_id": 717, "sentence_text": "It is unknown whether NF - kappa B is influenced by glycemic control .", "sentence_char_start_global": 117537, "sentence_char_end_global": 117607, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 22, "char_end": 34, "token_start": 4, "token_end": 7}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 117559, "char_end": 117571, "token_start": 4, "token_end": 7, "note": null}]}
+{"sentence_id": 718, "sentence_text": "RESEARCH DESIGN AND METHODS : To determine whether NF - kappa B is activated in patients with insufficient glycemic control ( HbA1c > 10 % ) , we developed a tissue culture - independent electrophoretic mobility shift assay ( EMSA ) - based semiquantitative detection system that allowed us to determine NF - kappa B activation in ex vivo - isolated peripheral blood mononuclear cells ( PBMCs ) .", "sentence_char_start_global": 117608, "sentence_char_end_global": 118004, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 51, "char_end": 63, "token_start": 8, "token_end": 11}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 304, "char_end": 316, "token_start": 51, "token_end": 54}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 117659, "char_end": 117671, "token_start": 8, "token_end": 11, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 117912, "char_end": 117924, "token_start": 51, "token_end": 54, "note": null}]}
+{"sentence_id": 719, "sentence_text": "We included 43 patients with type 1 diabetes in this cross - sectional study .", "sentence_char_start_global": 118005, "sentence_char_end_global": 118083, "entities": [], "entities_global": []}
+{"sentence_id": 720, "sentence_text": "10 of those received the antioxidant thioctic acid ( 600 mg / day p . o . ) for 2 weeks .", "sentence_char_start_global": 118084, "sentence_char_end_global": 118173, "entities": [], "entities_global": []}
+{"sentence_id": 721, "sentence_text": "RESULTS : Monocytes of patients with HbA1c levels > 10 % demonstrated significantly higher NF - kappa B binding activity in an EMSA and a stronger NF - kappa B staining in immunohistochemistry than monocytes of patients with HbA1c levels of 6 - 8 % .", "sentence_char_start_global": 118174, "sentence_char_end_global": 118424, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 91, "char_end": 103, "token_start": 14, "token_end": 17}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 147, "char_end": 159, "token_start": 26, "token_end": 29}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 118265, "char_end": 118277, "token_start": 14, "token_end": 17, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 118321, "char_end": 118333, "token_start": 26, "token_end": 29, "note": null}]}
+{"sentence_id": 722, "sentence_text": "The increase in NF - kappa B activation correlated with an increase in plasmatic markers of lipid peroxidation .", "sentence_char_start_global": 118425, "sentence_char_end_global": 118537, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 16, "char_end": 28, "token_start": 3, "token_end": 6}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 118441, "char_end": 118453, "token_start": 3, "token_end": 6, "note": null}]}
+{"sentence_id": 723, "sentence_text": "Treatment with the antioxidant thioctic acid decreased NF - kappa B binding activity .", "sentence_char_start_global": 118538, "sentence_char_end_global": 118624, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 55, "char_end": 67, "token_start": 7, "token_end": 10}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 118593, "char_end": 118605, "token_start": 7, "token_end": 10, "note": null}]}
+{"sentence_id": 724, "sentence_text": "CONCLUSIONS : Hyperglycemia induces activation of the transcription factor NF - kappa B in ex vivo - isolated PBMCs of patients with type 1 diabetes .", "sentence_char_start_global": 118625, "sentence_char_end_global": 118775, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 75, "char_end": 87, "token_start": 9, "token_end": 12}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 118700, "char_end": 118712, "token_start": 9, "token_end": 12, "note": null}]}
+{"sentence_id": 725, "sentence_text": "NF - kappa B activation is at least partially dependent on oxidative stress , since the antioxidant thioctic acid significantly lowered the extent of NF - kappa B binding activity .", "sentence_char_start_global": 118776, "sentence_char_end_global": 118957, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 0, "char_end": 12, "token_start": 0, "token_end": 3}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 150, "char_end": 162, "token_start": 24, "token_end": 27}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 118776, "char_end": 118788, "token_start": 0, "token_end": 3, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 118926, "char_end": 118938, "token_start": 24, "token_end": 27, "note": null}]}
+{"sentence_id": 726, "sentence_text": "Synergistic activation of MAP kinase ( ERK1 / 2 ) by erythropoietin and stem cell factor is essential for expanded erythropoiesis .", "sentence_char_start_global": 118958, "sentence_char_end_global": 119089, "entities": [{"text": "MAP kinase", "type": "ENTITY", "char_start": 26, "char_end": 36, "token_start": 3, "token_end": 4}, {"text": "ERK1 / 2", "type": "ENTITY", "char_start": 39, "char_end": 47, "token_start": 6, "token_end": 8}, {"text": "erythropoietin", "type": "ENTITY", "char_start": 53, "char_end": 67, "token_start": 11, "token_end": 11}, {"text": "stem cell factor", "type": "ENTITY", "char_start": 72, "char_end": 88, "token_start": 13, "token_end": 15}], "entities_global": [{"text": "MAP kinase", "type": "ENTITY", "char_start": 118984, "char_end": 118994, "token_start": 3, "token_end": 4, "note": null}, {"text": "ERK1 / 2", "type": "ENTITY", "char_start": 118997, "char_end": 119005, "token_start": 6, "token_end": 8, "note": null}, {"text": "erythropoietin", "type": "ENTITY", "char_start": 119011, "char_end": 119025, "token_start": 11, "token_end": 11, "note": null}, {"text": "stem cell factor", "type": "ENTITY", "char_start": 119030, "char_end": 119046, "token_start": 13, "token_end": 15, "note": null}]}
+{"sentence_id": 727, "sentence_text": "Stem cell factor ( SCF ) and erythropoietin ( EPO ) work synergistically to support erythropoiesis , but the mechanism for this synergism is unknown .", "sentence_char_start_global": 119090, "sentence_char_end_global": 119240, "entities": [{"text": "Stem cell factor", "type": "ENTITY", "char_start": 0, "char_end": 16, "token_start": 0, "token_end": 2}, {"text": "SCF", "type": "ENTITY", "char_start": 19, "char_end": 22, "token_start": 4, "token_end": 4}, {"text": "erythropoietin", "type": "ENTITY", "char_start": 29, "char_end": 43, "token_start": 7, "token_end": 7}, {"text": "EPO", "type": "ENTITY", "char_start": 46, "char_end": 49, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "Stem cell factor", "type": "ENTITY", "char_start": 119090, "char_end": 119106, "token_start": 0, "token_end": 2, "note": null}, {"text": "SCF", "type": "ENTITY", "char_start": 119109, "char_end": 119112, "token_start": 4, "token_end": 4, "note": null}, {"text": "erythropoietin", "type": "ENTITY", "char_start": 119119, "char_end": 119133, "token_start": 7, "token_end": 7, "note": null}, {"text": "EPO", "type": "ENTITY", "char_start": 119136, "char_end": 119139, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 728, "sentence_text": "By using purified human erythroid colony - forming cells ( ECFC ) , we have found that SCF and EPO synergistically activate MAP kinase ( MAPK , ERK1 / 2 ) , which correlates with the cell growth and thus may be responsible for the synergistic effects .", "sentence_char_start_global": 119241, "sentence_char_end_global": 119493, "entities": [{"text": "SCF", "type": "ENTITY", "char_start": 87, "char_end": 90, "token_start": 17, "token_end": 17}, {"text": "EPO", "type": "ENTITY", "char_start": 95, "char_end": 98, "token_start": 19, "token_end": 19}, {"text": "MAP kinase", "type": "ENTITY", "char_start": 124, "char_end": 134, "token_start": 22, "token_end": 23}, {"text": "MAPK", "type": "ENTITY", "char_start": 137, "char_end": 141, "token_start": 25, "token_end": 25}, {"text": "ERK1 / 2", "type": "ENTITY", "char_start": 144, "char_end": 152, "token_start": 27, "token_end": 29}], "entities_global": [{"text": "SCF", "type": "ENTITY", "char_start": 119328, "char_end": 119331, "token_start": 17, "token_end": 17, "note": null}, {"text": "EPO", "type": "ENTITY", "char_start": 119336, "char_end": 119339, "token_start": 19, "token_end": 19, "note": null}, {"text": "MAP kinase", "type": "ENTITY", "char_start": 119365, "char_end": 119375, "token_start": 22, "token_end": 23, "note": null}, {"text": "MAPK", "type": "ENTITY", "char_start": 119378, "char_end": 119382, "token_start": 25, "token_end": 25, "note": null}, {"text": "ERK1 / 2", "type": "ENTITY", "char_start": 119385, "char_end": 119393, "token_start": 27, "token_end": 29, "note": null}]}
+{"sentence_id": 729, "sentence_text": "Treatment of the cells with PD98059 and wortmannin , inhibitors of MEK and PI - 3 kinase , respectively , inhibited the synergistic activation of MAPK and also the cell growth , further supporting this conclusion .", "sentence_char_start_global": 119494, "sentence_char_end_global": 119708, "entities": [{"text": "MEK", "type": "ENTITY", "char_start": 67, "char_end": 70, "token_start": 11, "token_end": 11}, {"text": "PI - 3 kinase", "type": "ENTITY", "char_start": 75, "char_end": 88, "token_start": 13, "token_end": 16}, {"text": "MAPK", "type": "ENTITY", "char_start": 146, "char_end": 150, "token_start": 25, "token_end": 25}], "entities_global": [{"text": "MEK", "type": "ENTITY", "char_start": 119561, "char_end": 119564, "token_start": 11, "token_end": 11, "note": null}, {"text": "PI - 3 kinase", "type": "ENTITY", "char_start": 119569, "char_end": 119582, "token_start": 13, "token_end": 16, "note": null}, {"text": "MAPK", "type": "ENTITY", "char_start": 119640, "char_end": 119644, "token_start": 25, "token_end": 25, "note": null}]}
+{"sentence_id": 730, "sentence_text": "Wortmannin only inhibits MAPK activation induced by EPO but not that by SCF , suggesting that SCF and EPO may activate MAPK through different pathways , which would facilitate synergy .", "sentence_char_start_global": 119709, "sentence_char_end_global": 119894, "entities": [{"text": "MAPK", "type": "ENTITY", "char_start": 25, "char_end": 29, "token_start": 3, "token_end": 3}, {"text": "EPO", "type": "ENTITY", "char_start": 52, "char_end": 55, "token_start": 7, "token_end": 7}, {"text": "SCF", "type": "ENTITY", "char_start": 72, "char_end": 75, "token_start": 12, "token_end": 12}, {"text": "SCF", "type": "ENTITY", "char_start": 94, "char_end": 97, "token_start": 16, "token_end": 16}, {"text": "EPO", "type": "ENTITY", "char_start": 102, "char_end": 105, "token_start": 18, "token_end": 18}, {"text": "MAPK", "type": "ENTITY", "char_start": 119, "char_end": 123, "token_start": 21, "token_end": 21}], "entities_global": [{"text": "MAPK", "type": "ENTITY", "char_start": 119734, "char_end": 119738, "token_start": 3, "token_end": 3, "note": null}, {"text": "EPO", "type": "ENTITY", "char_start": 119761, "char_end": 119764, "token_start": 7, "token_end": 7, "note": null}, {"text": "SCF", "type": "ENTITY", "char_start": 119781, "char_end": 119784, "token_start": 12, "token_end": 12, "note": null}, {"text": "SCF", "type": "ENTITY", "char_start": 119803, "char_end": 119806, "token_start": 16, "token_end": 16, "note": null}, {"text": "EPO", "type": "ENTITY", "char_start": 119811, "char_end": 119814, "token_start": 18, "token_end": 18, "note": null}, {"text": "MAPK", "type": "ENTITY", "char_start": 119828, "char_end": 119832, "token_start": 21, "token_end": 21, "note": null}]}
+{"sentence_id": 731, "sentence_text": "Furthermore , EPO , but not SCF , led to activation of STAT5 , whereas SCF and wortmannin had no effect on the EPO - induced STAT5 activation , suggesting that STAT5 is not involved in the synergistic action of SCF and EPO .", "sentence_char_start_global": 119895, "sentence_char_end_global": 120119, "entities": [{"text": "EPO", "type": "ENTITY", "char_start": 14, "char_end": 17, "token_start": 2, "token_end": 2}, {"text": "SCF", "type": "ENTITY", "char_start": 28, "char_end": 31, "token_start": 6, "token_end": 6}, {"text": "STAT5", "type": "ENTITY", "char_start": 55, "char_end": 60, "token_start": 12, "token_end": 12}, {"text": "SCF", "type": "ENTITY", "char_start": 71, "char_end": 74, "token_start": 15, "token_end": 15}, {"text": "EPO", "type": "ENTITY", "char_start": 111, "char_end": 114, "token_start": 23, "token_end": 23}, {"text": "STAT5", "type": "ENTITY", "char_start": 125, "char_end": 130, "token_start": 26, "token_end": 26}, {"text": "STAT5", "type": "ENTITY", "char_start": 160, "char_end": 165, "token_start": 31, "token_end": 31}, {"text": "SCF", "type": "ENTITY", "char_start": 211, "char_end": 214, "token_start": 40, "token_end": 40}, {"text": "EPO", "type": "ENTITY", "char_start": 219, "char_end": 222, "token_start": 42, "token_end": 42}], "entities_global": [{"text": "EPO", "type": "ENTITY", "char_start": 119909, "char_end": 119912, "token_start": 2, "token_end": 2, "note": null}, {"text": "SCF", "type": "ENTITY", "char_start": 119923, "char_end": 119926, "token_start": 6, "token_end": 6, "note": null}, {"text": "STAT5", "type": "ENTITY", "char_start": 119950, "char_end": 119955, "token_start": 12, "token_end": 12, "note": null}, {"text": "SCF", "type": "ENTITY", "char_start": 119966, "char_end": 119969, "token_start": 15, "token_end": 15, "note": null}, {"text": "EPO", "type": "ENTITY", "char_start": 120006, "char_end": 120009, "token_start": 23, "token_end": 23, "note": null}, {"text": "STAT5", "type": "ENTITY", "char_start": 120020, "char_end": 120025, "token_start": 26, "token_end": 26, "note": null}, {"text": "STAT5", "type": "ENTITY", "char_start": 120055, "char_end": 120060, "token_start": 31, "token_end": 31, "note": null}, {"text": "SCF", "type": "ENTITY", "char_start": 120106, "char_end": 120109, "token_start": 40, "token_end": 40, "note": null}, {"text": "EPO", "type": "ENTITY", "char_start": 120114, "char_end": 120117, "token_start": 42, "token_end": 42, "note": null}]}
+{"sentence_id": 732, "sentence_text": "Together , the data suggest that synergistic activation of MAPK by SCF and EPO is essential for expanded erythropoiesis .", "sentence_char_start_global": 120120, "sentence_char_end_global": 120241, "entities": [{"text": "MAPK", "type": "ENTITY", "char_start": 59, "char_end": 63, "token_start": 9, "token_end": 9}, {"text": "SCF", "type": "ENTITY", "char_start": 67, "char_end": 70, "token_start": 11, "token_end": 11}, {"text": "EPO", "type": "ENTITY", "char_start": 75, "char_end": 78, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "MAPK", "type": "ENTITY", "char_start": 120179, "char_end": 120183, "token_start": 9, "token_end": 9, "note": null}, {"text": "SCF", "type": "ENTITY", "char_start": 120187, "char_end": 120190, "token_start": 11, "token_end": 11, "note": null}, {"text": "EPO", "type": "ENTITY", "char_start": 120195, "char_end": 120198, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 733, "sentence_text": "Copyright 1998 by The American Society of Hematology .", "sentence_char_start_global": 120242, "sentence_char_end_global": 120296, "entities": [], "entities_global": []}
+{"sentence_id": 734, "sentence_text": "The molecular and phenotypic profile of primary central nervous system lymphoma identifies distinct categories of the disease and is consistent with histogenetic derivation from germinal center - related B cells .", "sentence_char_start_global": 120297, "sentence_char_end_global": 120510, "entities": [], "entities_global": []}
+{"sentence_id": 735, "sentence_text": "Primary central nervous system lymphoma ( PCNSL ) is a major cause of morbidity and mortality among human immunodeficiency virus ( HIV ) - infected individuals .", "sentence_char_start_global": 120511, "sentence_char_end_global": 120672, "entities": [], "entities_global": []}
+{"sentence_id": 736, "sentence_text": "The precise histogenetic derivation and the molecular pathogenesis of PCNSL is poorly understood .", "sentence_char_start_global": 120673, "sentence_char_end_global": 120771, "entities": [], "entities_global": []}
+{"sentence_id": 737, "sentence_text": "In an attempt to clarify the histogenesis and pathogenesis of these lymphomas , 49 PCNSL ( 26 acquired immunodeficiency syndrome [ AIDS ] - related and 23 AIDS - unrelated ) were analyzed for multiple biologic markers , which are known to bear histogenetic and pathogenetic significance for mature B - cell neoplasms .", "sentence_char_start_global": 120772, "sentence_char_end_global": 121090, "entities": [], "entities_global": []}
+{"sentence_id": 738, "sentence_text": "PCNSL associated frequently ( 50 . 0 % ) with mutations of BCL - 6 5 ' noncoding regions , which are regarded as a marker of B - cell transition through the germinal center ( GC ) .", "sentence_char_start_global": 121091, "sentence_char_end_global": 121272, "entities": [{"text": "BCL - 6 5 ' noncoding regions", "type": "ENTITY", "char_start": 59, "char_end": 88, "token_start": 12, "token_end": 18}], "entities_global": [{"text": "BCL - 6 5 ' noncoding regions", "type": "ENTITY", "char_start": 121150, "char_end": 121179, "token_start": 12, "token_end": 18, "note": null}]}
+{"sentence_id": 739, "sentence_text": "Expression of BCL - 6 protein , which is restricted to GC B cells throughout physiologic B - cell maturation , was detected in 100 % AIDS - unrelated PCNSL and in 56 . 2 % AIDS - related cases .", "sentence_char_start_global": 121273, "sentence_char_end_global": 121467, "entities": [{"text": "BCL - 6 protein", "type": "ENTITY", "char_start": 14, "char_end": 29, "token_start": 2, "token_end": 5}], "entities_global": [{"text": "BCL - 6 protein", "type": "ENTITY", "char_start": 121287, "char_end": 121302, "token_start": 2, "token_end": 5, "note": null}]}
+{"sentence_id": 740, "sentence_text": "Notably , among AIDS - related PCNSL , expression of BCL - 6 was mutually exclusive with expression of Epstein - Barr virus ( EBV ) - encoded latent membrane protein ( LMP ) - 1 and , with few exceptions , also of BCL - 2 .", "sentence_char_start_global": 121468, "sentence_char_end_global": 121691, "entities": [{"text": "BCL - 6", "type": "ENTITY", "char_start": 53, "char_end": 60, "token_start": 10, "token_end": 12}, {"text": "Epstein - Barr virus ( EBV ) - encoded latent membrane protein ( LMP ) - 1", "type": "ENTITY", "char_start": 103, "char_end": 177, "token_start": 19, "token_end": 35}, {"text": "BCL - 2", "type": "ENTITY", "char_start": 214, "char_end": 221, "token_start": 44, "token_end": 46}], "entities_global": [{"text": "BCL - 6", "type": "ENTITY", "char_start": 121521, "char_end": 121528, "token_start": 10, "token_end": 12, "note": null}, {"text": "Epstein - Barr virus ( EBV ) - encoded latent membrane protein ( LMP ) - 1", "type": "ENTITY", "char_start": 121571, "char_end": 121645, "token_start": 19, "token_end": 35, "note": null}, {"text": "BCL - 2", "type": "ENTITY", "char_start": 121682, "char_end": 121689, "token_start": 44, "token_end": 46, "note": null}]}
+{"sentence_id": 741, "sentence_text": "All but one PCNSL expressed hMSH2 , which among mature B cells selectively stains GC B cells .", "sentence_char_start_global": 121692, "sentence_char_end_global": 121786, "entities": [], "entities_global": []}
+{"sentence_id": 742, "sentence_text": "These data suggest that PCNSL may be frequently related to GC B cells and may be segregated into two major biologic categories based on the expression pattern of BCL - 6 , LMP - 1 , and BCL - 2 .", "sentence_char_start_global": 121787, "sentence_char_end_global": 121982, "entities": [{"text": "BCL - 6", "type": "ENTITY", "char_start": 162, "char_end": 169, "token_start": 28, "token_end": 30}, {"text": "LMP - 1", "type": "ENTITY", "char_start": 172, "char_end": 179, "token_start": 32, "token_end": 34}, {"text": "BCL - 2", "type": "ENTITY", "char_start": 186, "char_end": 193, "token_start": 37, "token_end": 39}], "entities_global": [{"text": "BCL - 6", "type": "ENTITY", "char_start": 121949, "char_end": 121956, "token_start": 28, "token_end": 30, "note": null}, {"text": "LMP - 1", "type": "ENTITY", "char_start": 121959, "char_end": 121966, "token_start": 32, "token_end": 34, "note": null}, {"text": "BCL - 2", "type": "ENTITY", "char_start": 121973, "char_end": 121980, "token_start": 37, "token_end": 39, "note": null}]}
+{"sentence_id": 743, "sentence_text": "BCL - 6 ( + ) / LMP - 1 ( - ) / BCL - 2 ( - ) PCNSL occur both in the presence and in the absence of HIV infection and consistently display a large noncleaved cell morphology .", "sentence_char_start_global": 121983, "sentence_char_end_global": 122159, "entities": [{"text": "BCL - 6", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 2}, {"text": "LMP - 1", "type": "ENTITY", "char_start": 16, "char_end": 23, "token_start": 7, "token_end": 9}, {"text": "BCL - 2", "type": "ENTITY", "char_start": 32, "char_end": 39, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "BCL - 6", "type": "ENTITY", "char_start": 121983, "char_end": 121990, "token_start": 0, "token_end": 2, "note": null}, {"text": "LMP - 1", "type": "ENTITY", "char_start": 121999, "char_end": 122006, "token_start": 7, "token_end": 9, "note": null}, {"text": "BCL - 2", "type": "ENTITY", "char_start": 122015, "char_end": 122022, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 744, "sentence_text": "Conversely , BCL - 6 ( - ) / LMP - 1 ( + ) / BCL - 2 ( + ) PCNSL are restricted to HIV - infected hosts and are represented by lymphomas with immunoblastic features .", "sentence_char_start_global": 122160, "sentence_char_end_global": 122326, "entities": [{"text": "BCL - 6", "type": "ENTITY", "char_start": 13, "char_end": 20, "token_start": 2, "token_end": 4}, {"text": "LMP - 1", "type": "ENTITY", "char_start": 29, "char_end": 36, "token_start": 9, "token_end": 11}, {"text": "BCL - 2", "type": "ENTITY", "char_start": 45, "char_end": 52, "token_start": 16, "token_end": 18}], "entities_global": [{"text": "BCL - 6", "type": "ENTITY", "char_start": 122173, "char_end": 122180, "token_start": 2, "token_end": 4, "note": null}, {"text": "LMP - 1", "type": "ENTITY", "char_start": 122189, "char_end": 122196, "token_start": 9, "token_end": 11, "note": null}, {"text": "BCL - 2", "type": "ENTITY", "char_start": 122205, "char_end": 122212, "token_start": 16, "token_end": 18, "note": null}]}
+{"sentence_id": 745, "sentence_text": "These data are relevant for the pathogenesis and histogenesis of PCNSL and may be helpful to segregate distinct biologic and prognostic categories of these lymphomas .", "sentence_char_start_global": 122327, "sentence_char_end_global": 122494, "entities": [], "entities_global": []}
+{"sentence_id": 746, "sentence_text": "Copyright 1998 by The American Society of Hematology .", "sentence_char_start_global": 122495, "sentence_char_end_global": 122549, "entities": [], "entities_global": []}
+{"sentence_id": 747, "sentence_text": "Antioxidant regulation of phorbol ester - induced adhesion of human Jurkat T - cells to endothelial cells .", "sentence_char_start_global": 122550, "sentence_char_end_global": 122657, "entities": [], "entities_global": []}
+{"sentence_id": 748, "sentence_text": "Regulation of adhesion molecule expression and function by reactive oxygen species via specific redox sensitive mechanisms have been reported .", "sentence_char_start_global": 122658, "sentence_char_end_global": 122801, "entities": [], "entities_global": []}
+{"sentence_id": 749, "sentence_text": "The effects of clinically safe antioxidants in the regulation of adhesion molecule expression in human endothelial cells ( ECV ) , and adherence of human Jurkat T cells to ECV cells were investigated .", "sentence_char_start_global": 122802, "sentence_char_end_global": 123003, "entities": [], "entities_global": []}
+{"sentence_id": 750, "sentence_text": "The thiol antioxidant , alpha - lipoate , at clinically relevant doses down - regulated phorbol 12 - myristate 13 - acetate ( PMA ) - induced adhesion molecule expression and cell - cell adhesion .", "sentence_char_start_global": 123004, "sentence_char_end_global": 123201, "entities": [], "entities_global": []}
+{"sentence_id": 751, "sentence_text": "Inhibition of PMA - induced ICAM - 1 and VCAM - 1 expression as well as PMA - induced adhesion of Jurkat T - cells to ECV cells by alpha - lipoate was dose dependent ( 50 - 250 microM ) .", "sentence_char_start_global": 123202, "sentence_char_end_global": 123389, "entities": [], "entities_global": []}
+{"sentence_id": 752, "sentence_text": "The effect was significant for ICAM - 1 ( p < . 01 ) and VCAM - 1 ( p < . 01 ) expression in cells pretreated with 100 microM alpha - lipoate compared to PMA - activated untreated cells .", "sentence_char_start_global": 123390, "sentence_char_end_global": 123577, "entities": [{"text": "ICAM - 1", "type": "ENTITY", "char_start": 31, "char_end": 39, "token_start": 5, "token_end": 7}, {"text": "VCAM - 1", "type": "ENTITY", "char_start": 57, "char_end": 65, "token_start": 15, "token_end": 17}], "entities_global": [{"text": "ICAM - 1", "type": "ENTITY", "char_start": 123421, "char_end": 123429, "token_start": 5, "token_end": 7, "note": null}, {"text": "VCAM - 1", "type": "ENTITY", "char_start": 123447, "char_end": 123455, "token_start": 15, "token_end": 17, "note": null}]}
+{"sentence_id": 753, "sentence_text": "Inhibition of PMA - induced adhesion molecule expression and cell - cell adhesion was more pronounced when a combination of antioxidants , alpha - lipoate and alpha - tocopherol , were used compared to the use of either of these antioxidant alone .", "sentence_char_start_global": 123578, "sentence_char_end_global": 123826, "entities": [], "entities_global": []}
+{"sentence_id": 754, "sentence_text": "The regulation of adhesion molecule expression and function by low concentration of antioxidants investigated does not appear to be NF - kappaB regulated or transcription dependent because no change in the mRNA response was observed .", "sentence_char_start_global": 123827, "sentence_char_end_global": 124061, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 132, "char_end": 143, "token_start": 19, "token_end": 21}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 123959, "char_end": 123970, "token_start": 19, "token_end": 21, "note": null}]}
+{"sentence_id": 755, "sentence_text": "Protein kinase C ( PKC ) has been suggested to regulate PMA - induced adhesion molecule expression by post - transcriptional stabilization of adhesion molecule mRNA .", "sentence_char_start_global": 124062, "sentence_char_end_global": 124228, "entities": [{"text": "Protein kinase C", "type": "ENTITY", "char_start": 0, "char_end": 16, "token_start": 0, "token_end": 2}, {"text": "PKC", "type": "ENTITY", "char_start": 19, "char_end": 22, "token_start": 4, "token_end": 4}, {"text": "adhesion molecule mRNA", "type": "ENTITY", "char_start": 142, "char_end": 164, "token_start": 23, "token_end": 25}], "entities_global": [{"text": "Protein kinase C", "type": "ENTITY", "char_start": 124062, "char_end": 124078, "token_start": 0, "token_end": 2, "note": null}, {"text": "PKC", "type": "ENTITY", "char_start": 124081, "char_end": 124084, "token_start": 4, "token_end": 4, "note": null}, {"text": "adhesion molecule mRNA", "type": "ENTITY", "char_start": 124204, "char_end": 124226, "token_start": 23, "token_end": 25, "note": null}]}
+{"sentence_id": 756, "sentence_text": "Alpha - lipoate pretreatment did not influence the response of PKC activity to PMA .", "sentence_char_start_global": 124229, "sentence_char_end_global": 124313, "entities": [{"text": "PKC", "type": "ENTITY", "char_start": 63, "char_end": 66, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "PKC", "type": "ENTITY", "char_start": 124292, "char_end": 124295, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 757, "sentence_text": "Oxidants are known to be involved in the regulation of cell adhesion processes .", "sentence_char_start_global": 124314, "sentence_char_end_global": 124394, "entities": [], "entities_global": []}
+{"sentence_id": 758, "sentence_text": "Treatment of ECV cells with PMA induced generation of intracellular oxidants .", "sentence_char_start_global": 124395, "sentence_char_end_global": 124473, "entities": [], "entities_global": []}
+{"sentence_id": 759, "sentence_text": "Alpha - lipoate ( 100 or 250 microM ) treatment decreased PMA - induced generation of intracellular oxidants .", "sentence_char_start_global": 124474, "sentence_char_end_global": 124584, "entities": [], "entities_global": []}
+{"sentence_id": 760, "sentence_text": "The inhibitory effect of low concentration of alpha - lipaote alone or in combination with alpha - tocopherol on agonist - induced adhesion processes observed in this study may be of potential therapeutic value .", "sentence_char_start_global": 124585, "sentence_char_end_global": 124797, "entities": [], "entities_global": []}
+{"sentence_id": 761, "sentence_text": "Binding of human immunodeficiency virus type 1 to CD4 and CXCR4 receptors differentially regulates expression of inflammatory genes and activates the MEK / ERK signaling pathway .", "sentence_char_start_global": 124798, "sentence_char_end_global": 124977, "entities": [{"text": "CD4 and CXCR4 receptors", "type": "ENTITY", "char_start": 50, "char_end": 73, "token_start": 8, "token_end": 11}, {"text": "inflammatory genes", "type": "ENTITY", "char_start": 113, "char_end": 131, "token_start": 16, "token_end": 17}, {"text": "MEK", "type": "ENTITY", "char_start": 150, "char_end": 153, "token_start": 21, "token_end": 21}], "entities_global": [{"text": "CD4 and CXCR4 receptors", "type": "ENTITY", "char_start": 124848, "char_end": 124871, "token_start": 8, "token_end": 11, "note": null}, {"text": "inflammatory genes", "type": "ENTITY", "char_start": 124911, "char_end": 124929, "token_start": 16, "token_end": 17, "note": null}, {"text": "MEK", "type": "ENTITY", "char_start": 124948, "char_end": 124951, "token_start": 21, "token_end": 21, "note": null}]}
+{"sentence_id": 762, "sentence_text": "We have previously shown that binding of human immunodeficiency virus type 1 ( HIV - 1 ) virions to CD4 receptors stimulates association of Lck with Raf - 1 and results in the activation of Raf - 1 kinase in a Ras - independent manner .", "sentence_char_start_global": 124978, "sentence_char_end_global": 125214, "entities": [{"text": "CD4 receptors", "type": "ENTITY", "char_start": 100, "char_end": 113, "token_start": 19, "token_end": 20}, {"text": "Lck", "type": "ENTITY", "char_start": 140, "char_end": 143, "token_start": 24, "token_end": 24}, {"text": "Raf - 1", "type": "ENTITY", "char_start": 149, "char_end": 156, "token_start": 26, "token_end": 28}, {"text": "Raf - 1", "type": "ENTITY", "char_start": 190, "char_end": 197, "token_start": 35, "token_end": 37}], "entities_global": [{"text": "CD4 receptors", "type": "ENTITY", "char_start": 125078, "char_end": 125091, "token_start": 19, "token_end": 20, "note": null}, {"text": "Lck", "type": "ENTITY", "char_start": 125118, "char_end": 125121, "token_start": 24, "token_end": 24, "note": null}, {"text": "Raf - 1", "type": "ENTITY", "char_start": 125127, "char_end": 125134, "token_start": 26, "token_end": 28, "note": null}, {"text": "Raf - 1", "type": "ENTITY", "char_start": 125168, "char_end": 125175, "token_start": 35, "token_end": 37, "note": null}]}
+{"sentence_id": 763, "sentence_text": "In the present study , we demonstrate that HIV - 1 envelope glycoproteins of both T - cell - tropic and macrophagetropic strains rapidly activate the ERK / mitogen - activated protein ( MAP ) kinase pathway and the binding of nuclear transcription factors ( AP - 1 , NF - kappaB , and C / EBP ) and stimulate expression of cytokine and chemokine genes .", "sentence_char_start_global": 125215, "sentence_char_end_global": 125568, "entities": [{"text": "HIV - 1 envelope glycoproteins", "type": "ENTITY", "char_start": 43, "char_end": 73, "token_start": 8, "token_end": 12}, {"text": "nuclear transcription factors", "type": "ENTITY", "char_start": 226, "char_end": 255, "token_start": 41, "token_end": 43}, {"text": "AP - 1", "type": "ENTITY", "char_start": 258, "char_end": 264, "token_start": 45, "token_end": 47}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 267, "char_end": 278, "token_start": 49, "token_end": 51}, {"text": "C / EBP", "type": "ENTITY", "char_start": 285, "char_end": 292, "token_start": 54, "token_end": 56}, {"text": "cytokine and chemokine genes", "type": "ENTITY", "char_start": 323, "char_end": 351, "token_start": 62, "token_end": 65}], "entities_global": [{"text": "HIV - 1 envelope glycoproteins", "type": "ENTITY", "char_start": 125258, "char_end": 125288, "token_start": 8, "token_end": 12, "note": null}, {"text": "nuclear transcription factors", "type": "ENTITY", "char_start": 125441, "char_end": 125470, "token_start": 41, "token_end": 43, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 125473, "char_end": 125479, "token_start": 45, "token_end": 47, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 125482, "char_end": 125493, "token_start": 49, "token_end": 51, "note": null}, {"text": "C / EBP", "type": "ENTITY", "char_start": 125500, "char_end": 125507, "token_start": 54, "token_end": 56, "note": null}, {"text": "cytokine and chemokine genes", "type": "ENTITY", "char_start": 125538, "char_end": 125566, "token_start": 62, "token_end": 65, "note": null}]}
+{"sentence_id": 764, "sentence_text": "The activation of this signaling pathway requires functional CD4 receptors and is independent of binding to CXCR4 .", "sentence_char_start_global": 125569, "sentence_char_end_global": 125684, "entities": [{"text": "CD4 receptors", "type": "ENTITY", "char_start": 61, "char_end": 74, "token_start": 8, "token_end": 9}, {"text": "CXCR4", "type": "ENTITY", "char_start": 108, "char_end": 113, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "CD4 receptors", "type": "ENTITY", "char_start": 125630, "char_end": 125643, "token_start": 8, "token_end": 9, "note": null}, {"text": "CXCR4", "type": "ENTITY", "char_start": 125677, "char_end": 125682, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 765, "sentence_text": "Binding of the natural ligand stromal cell - derived factor 1 ( SDF - 1 ) to CXCR4 , which inhibits entry of T - cell - tropic HIV - 1 , activates also the ERK / MAP kinase pathway .", "sentence_char_start_global": 125685, "sentence_char_end_global": 125867, "entities": [{"text": "stromal cell - derived factor 1", "type": "ENTITY", "char_start": 30, "char_end": 61, "token_start": 5, "token_end": 10}, {"text": "SDF - 1", "type": "ENTITY", "char_start": 64, "char_end": 71, "token_start": 12, "token_end": 14}, {"text": "CXCR4", "type": "ENTITY", "char_start": 77, "char_end": 82, "token_start": 17, "token_end": 17}, {"text": "MAP kinase", "type": "ENTITY", "char_start": 162, "char_end": 172, "token_start": 37, "token_end": 38}], "entities_global": [{"text": "stromal cell - derived factor 1", "type": "ENTITY", "char_start": 125715, "char_end": 125746, "token_start": 5, "token_end": 10, "note": null}, {"text": "SDF - 1", "type": "ENTITY", "char_start": 125749, "char_end": 125756, "token_start": 12, "token_end": 14, "note": null}, {"text": "CXCR4", "type": "ENTITY", "char_start": 125762, "char_end": 125767, "token_start": 17, "token_end": 17, "note": null}, {"text": "MAP kinase", "type": "ENTITY", "char_start": 125847, "char_end": 125857, "token_start": 37, "token_end": 38, "note": null}]}
+{"sentence_id": 766, "sentence_text": "However , SDF - 1 did not affect the CD4 - mediated expression of cytokine and chemokine genes .", "sentence_char_start_global": 125868, "sentence_char_end_global": 125964, "entities": [{"text": "SDF - 1", "type": "ENTITY", "char_start": 10, "char_end": 17, "token_start": 2, "token_end": 4}, {"text": "cytokine and chemokine genes", "type": "ENTITY", "char_start": 66, "char_end": 94, "token_start": 14, "token_end": 17}], "entities_global": [{"text": "SDF - 1", "type": "ENTITY", "char_start": 125878, "char_end": 125885, "token_start": 2, "token_end": 4, "note": null}, {"text": "cytokine and chemokine genes", "type": "ENTITY", "char_start": 125934, "char_end": 125962, "token_start": 14, "token_end": 17, "note": null}]}
+{"sentence_id": 767, "sentence_text": "These results provide firm molecular evidence that binding of HIV - 1 envelope glycoproteins to CD4 receptor initiates a signaling pathway ( s ) independent of the binding to the chemokine receptor that leads to the aberrant expression of inflammatory genes and may contribute significantly to HIV - 1 replication as well as to deregulation of the immune system .", "sentence_char_start_global": 125965, "sentence_char_end_global": 126328, "entities": [{"text": "HIV - 1 envelope glycoproteins", "type": "ENTITY", "char_start": 62, "char_end": 92, "token_start": 9, "token_end": 13}, {"text": "CD4 receptor", "type": "ENTITY", "char_start": 96, "char_end": 108, "token_start": 15, "token_end": 16}, {"text": "chemokine receptor", "type": "ENTITY", "char_start": 179, "char_end": 197, "token_start": 30, "token_end": 31}, {"text": "inflammatory genes", "type": "ENTITY", "char_start": 239, "char_end": 257, "token_start": 39, "token_end": 40}], "entities_global": [{"text": "HIV - 1 envelope glycoproteins", "type": "ENTITY", "char_start": 126027, "char_end": 126057, "token_start": 9, "token_end": 13, "note": null}, {"text": "CD4 receptor", "type": "ENTITY", "char_start": 126061, "char_end": 126073, "token_start": 15, "token_end": 16, "note": null}, {"text": "chemokine receptor", "type": "ENTITY", "char_start": 126144, "char_end": 126162, "token_start": 30, "token_end": 31, "note": null}, {"text": "inflammatory genes", "type": "ENTITY", "char_start": 126204, "char_end": 126222, "token_start": 39, "token_end": 40, "note": null}]}
+{"sentence_id": 768, "sentence_text": "Antigen receptor signaling induces MAP kinase - mediated phosphorylation and degradation of the BCL - 6 transcription factor .", "sentence_char_start_global": 126329, "sentence_char_end_global": 126455, "entities": [{"text": "BCL - 6", "type": "ENTITY", "char_start": 96, "char_end": 103, "token_start": 13, "token_end": 15}, {"text": "transcription factor", "type": "ENTITY", "char_start": 104, "char_end": 124, "token_start": 16, "token_end": 17}], "entities_global": [{"text": "BCL - 6", "type": "ENTITY", "char_start": 126425, "char_end": 126432, "token_start": 13, "token_end": 15, "note": null}, {"text": "transcription factor", "type": "ENTITY", "char_start": 126433, "char_end": 126453, "token_start": 16, "token_end": 17, "note": null}]}
+{"sentence_id": 769, "sentence_text": "The bcl - 6 proto - oncogene encodes a POZ / zinc finger transcriptional repressor expressed in germinal center ( GC ) B and T cells and required for GC formation and antibody affinity maturation .", "sentence_char_start_global": 126456, "sentence_char_end_global": 126653, "entities": [{"text": "bcl - 6 proto - oncogene", "type": "ENTITY", "char_start": 4, "char_end": 28, "token_start": 1, "token_end": 6}, {"text": "POZ / zinc finger transcriptional repressor", "type": "ENTITY", "char_start": 39, "char_end": 82, "token_start": 9, "token_end": 14}], "entities_global": [{"text": "bcl - 6 proto - oncogene", "type": "ENTITY", "char_start": 126460, "char_end": 126484, "token_start": 1, "token_end": 6, "note": null}, {"text": "POZ / zinc finger transcriptional repressor", "type": "ENTITY", "char_start": 126495, "char_end": 126538, "token_start": 9, "token_end": 14, "note": null}]}
+{"sentence_id": 770, "sentence_text": "Deregulation of bcl - 6 expression by chromosomal rearrangements and point mutations of the bcl - 6 promoter region are implicated in the pathogenesis of B - cell lymphoma .", "sentence_char_start_global": 126654, "sentence_char_end_global": 126827, "entities": [{"text": "bcl - 6", "type": "ENTITY", "char_start": 16, "char_end": 23, "token_start": 2, "token_end": 4}, {"text": "bcl - 6 promoter region", "type": "ENTITY", "char_start": 92, "char_end": 115, "token_start": 14, "token_end": 18}], "entities_global": [{"text": "bcl - 6", "type": "ENTITY", "char_start": 126670, "char_end": 126677, "token_start": 2, "token_end": 4, "note": null}, {"text": "bcl - 6 promoter region", "type": "ENTITY", "char_start": 126746, "char_end": 126769, "token_start": 14, "token_end": 18, "note": null}]}
+{"sentence_id": 771, "sentence_text": "The signals regulating bcl - 6 expression are not known .", "sentence_char_start_global": 126828, "sentence_char_end_global": 126885, "entities": [{"text": "bcl - 6", "type": "ENTITY", "char_start": 23, "char_end": 30, "token_start": 3, "token_end": 5}], "entities_global": [{"text": "bcl - 6", "type": "ENTITY", "char_start": 126851, "char_end": 126858, "token_start": 3, "token_end": 5, "note": null}]}
+{"sentence_id": 772, "sentence_text": "Here we show that antigen receptor activation leads to BCL - 6 phosphorylation by mitogen - activated protein kinase ( MAPK ) .", "sentence_char_start_global": 126886, "sentence_char_end_global": 127013, "entities": [{"text": "BCL - 6", "type": "ENTITY", "char_start": 55, "char_end": 62, "token_start": 9, "token_end": 11}, {"text": "mitogen - activated protein kinase", "type": "ENTITY", "char_start": 82, "char_end": 116, "token_start": 14, "token_end": 18}, {"text": "MAPK", "type": "ENTITY", "char_start": 119, "char_end": 123, "token_start": 20, "token_end": 20}], "entities_global": [{"text": "BCL - 6", "type": "ENTITY", "char_start": 126941, "char_end": 126948, "token_start": 9, "token_end": 11, "note": null}, {"text": "mitogen - activated protein kinase", "type": "ENTITY", "char_start": 126968, "char_end": 127002, "token_start": 14, "token_end": 18, "note": null}, {"text": "MAPK", "type": "ENTITY", "char_start": 127005, "char_end": 127009, "token_start": 20, "token_end": 20, "note": null}]}
+{"sentence_id": 773, "sentence_text": "Phosphorylation , in turn , targets BCL - 6 for rapid degradation by the ubiquitin / proteasome pathway .", "sentence_char_start_global": 127014, "sentence_char_end_global": 127119, "entities": [{"text": "BCL - 6", "type": "ENTITY", "char_start": 36, "char_end": 43, "token_start": 6, "token_end": 8}, {"text": "ubiquitin", "type": "ENTITY", "char_start": 73, "char_end": 82, "token_start": 14, "token_end": 14}, {"text": "proteasome", "type": "ENTITY", "char_start": 85, "char_end": 95, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "BCL - 6", "type": "ENTITY", "char_start": 127050, "char_end": 127057, "token_start": 6, "token_end": 8, "note": null}, {"text": "ubiquitin", "type": "ENTITY", "char_start": 127087, "char_end": 127096, "token_start": 14, "token_end": 14, "note": null}, {"text": "proteasome", "type": "ENTITY", "char_start": 127099, "char_end": 127109, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 774, "sentence_text": "These findings indicate that BCL - 6 expression is directly controlled by the antigen receptor via MAPK activation .", "sentence_char_start_global": 127120, "sentence_char_end_global": 127236, "entities": [{"text": "BCL - 6", "type": "ENTITY", "char_start": 29, "char_end": 36, "token_start": 4, "token_end": 6}, {"text": "MAPK", "type": "ENTITY", "char_start": 99, "char_end": 103, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "BCL - 6", "type": "ENTITY", "char_start": 127149, "char_end": 127156, "token_start": 4, "token_end": 6, "note": null}, {"text": "MAPK", "type": "ENTITY", "char_start": 127219, "char_end": 127223, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 775, "sentence_text": "This signaling pathway may be crucial for the control of B - cell differentiation and antibody response and has implications for the regulation of other POZ / zinc finger transcription factors in other tissues .", "sentence_char_start_global": 127237, "sentence_char_end_global": 127448, "entities": [{"text": "POZ / zinc finger transcription factors", "type": "ENTITY", "char_start": 153, "char_end": 192, "token_start": 25, "token_end": 30}], "entities_global": [{"text": "POZ / zinc finger transcription factors", "type": "ENTITY", "char_start": 127390, "char_end": 127429, "token_start": 25, "token_end": 30, "note": null}]}
+{"sentence_id": 776, "sentence_text": "Glucocorticoid receptors are differentially expressed in the cells and tissues of the immune system .", "sentence_char_start_global": 127449, "sentence_char_end_global": 127550, "entities": [{"text": "Glucocorticoid receptors", "type": "ENTITY", "char_start": 0, "char_end": 24, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "Glucocorticoid receptors", "type": "ENTITY", "char_start": 127449, "char_end": 127473, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 777, "sentence_text": "Cytosolic glucocorticoid receptor ( GR ) binding studies on immune tissues demonstrate that the thymus exhibits three to four times higher levels of GR protein than the spleen .", "sentence_char_start_global": 127551, "sentence_char_end_global": 127728, "entities": [{"text": "Cytosolic glucocorticoid receptor", "type": "ENTITY", "char_start": 0, "char_end": 33, "token_start": 0, "token_end": 2}, {"text": "GR", "type": "ENTITY", "char_start": 36, "char_end": 38, "token_start": 4, "token_end": 4}, {"text": "GR protein", "type": "ENTITY", "char_start": 149, "char_end": 159, "token_start": 23, "token_end": 24}], "entities_global": [{"text": "Cytosolic glucocorticoid receptor", "type": "ENTITY", "char_start": 127551, "char_end": 127584, "token_start": 0, "token_end": 2, "note": null}, {"text": "GR", "type": "ENTITY", "char_start": 127587, "char_end": 127589, "token_start": 4, "token_end": 4, "note": null}, {"text": "GR protein", "type": "ENTITY", "char_start": 127700, "char_end": 127710, "token_start": 23, "token_end": 24, "note": null}]}
+{"sentence_id": 778, "sentence_text": "High levels of GR are consistent with the exquisite sensitivity of the thymus to glucocorticoid exposure .", "sentence_char_start_global": 127729, "sentence_char_end_global": 127835, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 15, "char_end": 17, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 127744, "char_end": 127746, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 779, "sentence_text": "Nevertheless , whole cell binding studies reveal similar levels of GR in immature thymic T lymphocytes and more mature , splenic T lymphocytes .", "sentence_char_start_global": 127836, "sentence_char_end_global": 127980, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 67, "char_end": 69, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 127903, "char_end": 127905, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 780, "sentence_text": "Moreover , whole cell binding techniques indicate that neutrophils ( which represent roughly 30 % of splenic leukocytes ) exhibit higher GR than both T and B lymphocytes , further contradicting results from cytosolic binding studies .", "sentence_char_start_global": 127981, "sentence_char_end_global": 128215, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 137, "char_end": 139, "token_start": 21, "token_end": 21}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 128118, "char_end": 128120, "token_start": 21, "token_end": 21, "note": null}]}
+{"sentence_id": 781, "sentence_text": "To address these inconsistencies , GR protein was assessed in immune cells and tissues using cytosolic radioligand binding .", "sentence_char_start_global": 128216, "sentence_char_end_global": 128340, "entities": [{"text": "GR protein", "type": "ENTITY", "char_start": 35, "char_end": 45, "token_start": 5, "token_end": 6}], "entities_global": [{"text": "GR protein", "type": "ENTITY", "char_start": 128251, "char_end": 128261, "token_start": 5, "token_end": 6, "note": null}]}
+{"sentence_id": 782, "sentence_text": "Western blot analysis , and immunocytochemistry .", "sentence_char_start_global": 128341, "sentence_char_end_global": 128390, "entities": [], "entities_global": []}
+{"sentence_id": 783, "sentence_text": "Consistent with previous cytosolic receptor binding studies on immune tissue homogenates , thymic T cells were found to have higher levels of GR than T cells isolated from the spleen .", "sentence_char_start_global": 128391, "sentence_char_end_global": 128575, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 142, "char_end": 144, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 128533, "char_end": 128535, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 784, "sentence_text": "In addition , neutrophils were found to have fewer GR than lymphocytes and monocytes .", "sentence_char_start_global": 128576, "sentence_char_end_global": 128662, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 51, "char_end": 53, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 128627, "char_end": 128629, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 785, "sentence_text": "These results indicate a meaningful relationship between receptor expression and known sensitivity to glucocorticoids .", "sentence_char_start_global": 128663, "sentence_char_end_global": 128782, "entities": [], "entities_global": []}
+{"sentence_id": 786, "sentence_text": "Functional replacement of the mouse E2A gene with a human HEB cDNA .", "sentence_char_start_global": 128783, "sentence_char_end_global": 128851, "entities": [{"text": "mouse E2A gene", "type": "ENTITY", "char_start": 30, "char_end": 44, "token_start": 4, "token_end": 6}, {"text": "human HEB cDNA", "type": "ENTITY", "char_start": 52, "char_end": 66, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "mouse E2A gene", "type": "ENTITY", "char_start": 128813, "char_end": 128827, "token_start": 4, "token_end": 6, "note": null}, {"text": "human HEB cDNA", "type": "ENTITY", "char_start": 128835, "char_end": 128849, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 787, "sentence_text": "The mammalian E2A , HEB , and E2 - 2 genes encode a unique class of basic helix - loop - helix ( bHLH ) transcription factors that are evolutionarily conserved and essential for embryonic and postnatal development .", "sentence_char_start_global": 128852, "sentence_char_end_global": 129067, "entities": [{"text": "mammalian E2A , HEB , and E2 - 2 genes", "type": "ENTITY", "char_start": 4, "char_end": 42, "token_start": 1, "token_end": 10}, {"text": "basic helix - loop - helix ( bHLH ) transcription factors", "type": "ENTITY", "char_start": 68, "char_end": 125, "token_start": 16, "token_end": 26}], "entities_global": [{"text": "mammalian E2A , HEB , and E2 - 2 genes", "type": "ENTITY", "char_start": 128856, "char_end": 128894, "token_start": 1, "token_end": 10, "note": null}, {"text": "basic helix - loop - helix ( bHLH ) transcription factors", "type": "ENTITY", "char_start": 128920, "char_end": 128977, "token_start": 16, "token_end": 26, "note": null}]}
+{"sentence_id": 788, "sentence_text": "While the structural and functional similarities among the gene products are well demonstrated , it is not clear why deletion of E2A , but not HEB or E2 - 2 , leads to a complete arrest in B - lymphocyte development .", "sentence_char_start_global": 129068, "sentence_char_end_global": 129285, "entities": [{"text": "gene products", "type": "ENTITY", "char_start": 59, "char_end": 72, "token_start": 8, "token_end": 9}, {"text": "E2A", "type": "ENTITY", "char_start": 129, "char_end": 132, "token_start": 21, "token_end": 21}, {"text": "HEB", "type": "ENTITY", "char_start": 143, "char_end": 146, "token_start": 25, "token_end": 25}, {"text": "E2 - 2", "type": "ENTITY", "char_start": 150, "char_end": 156, "token_start": 27, "token_end": 29}], "entities_global": [{"text": "gene products", "type": "ENTITY", "char_start": 129127, "char_end": 129140, "token_start": 8, "token_end": 9, "note": null}, {"text": "E2A", "type": "ENTITY", "char_start": 129197, "char_end": 129200, "token_start": 21, "token_end": 21, "note": null}, {"text": "HEB", "type": "ENTITY", "char_start": 129211, "char_end": 129214, "token_start": 25, "token_end": 25, "note": null}, {"text": "E2 - 2", "type": "ENTITY", "char_start": 129218, "char_end": 129224, "token_start": 27, "token_end": 29, "note": null}]}
+{"sentence_id": 789, "sentence_text": "To understand the molecular basis of the functional specificity between E2A and HEB / E2 - 2 in mammalian development , we generated and tested a panel of E2A knockin mutations including subtle mutations in the E12 and E47 exons and substitution of both E12 and E47 exons with a human HEB cDNA .", "sentence_char_start_global": 129286, "sentence_char_end_global": 129581, "entities": [{"text": "E2A", "type": "ENTITY", "char_start": 72, "char_end": 75, "token_start": 10, "token_end": 10}, {"text": "HEB", "type": "ENTITY", "char_start": 80, "char_end": 83, "token_start": 12, "token_end": 12}, {"text": "E2 - 2", "type": "ENTITY", "char_start": 86, "char_end": 92, "token_start": 14, "token_end": 16}, {"text": "E2A", "type": "ENTITY", "char_start": 155, "char_end": 158, "token_start": 28, "token_end": 28}, {"text": "E12 and E47 exons", "type": "ENTITY", "char_start": 211, "char_end": 228, "token_start": 36, "token_end": 39}, {"text": "E12 and E47 exons", "type": "ENTITY", "char_start": 254, "char_end": 271, "token_start": 44, "token_end": 47}, {"text": "human HEB cDNA", "type": "ENTITY", "char_start": 279, "char_end": 293, "token_start": 50, "token_end": 52}], "entities_global": [{"text": "E2A", "type": "ENTITY", "char_start": 129358, "char_end": 129361, "token_start": 10, "token_end": 10, "note": null}, {"text": "HEB", "type": "ENTITY", "char_start": 129366, "char_end": 129369, "token_start": 12, "token_end": 12, "note": null}, {"text": "E2 - 2", "type": "ENTITY", "char_start": 129372, "char_end": 129378, "token_start": 14, "token_end": 16, "note": null}, {"text": "E2A", "type": "ENTITY", "char_start": 129441, "char_end": 129444, "token_start": 28, "token_end": 28, "note": null}, {"text": "E12 and E47 exons", "type": "ENTITY", "char_start": 129497, "char_end": 129514, "token_start": 36, "token_end": 39, "note": null}, {"text": "E12 and E47 exons", "type": "ENTITY", "char_start": 129540, "char_end": 129557, "token_start": 44, "token_end": 47, "note": null}, {"text": "human HEB cDNA", "type": "ENTITY", "char_start": 129565, "char_end": 129579, "token_start": 50, "token_end": 52, "note": null}]}
+{"sentence_id": 790, "sentence_text": "We find that the alternatively spliced E12 and E47 bHLH proteins of the E2A gene play similar and additive roles in supporting B lymphopoiesis .", "sentence_char_start_global": 129582, "sentence_char_end_global": 129726, "entities": [{"text": "E12 and E47 bHLH proteins", "type": "ENTITY", "char_start": 39, "char_end": 64, "token_start": 6, "token_end": 10}, {"text": "E2A gene", "type": "ENTITY", "char_start": 72, "char_end": 80, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "E12 and E47 bHLH proteins", "type": "ENTITY", "char_start": 129621, "char_end": 129646, "token_start": 6, "token_end": 10, "note": null}, {"text": "E2A gene", "type": "ENTITY", "char_start": 129654, "char_end": 129662, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 791, "sentence_text": "Further , we find that HEB driven by the endogenous E2A promoter can functionally replace E2A in supporting B - cell commitment and differentiation toward completion .", "sentence_char_start_global": 129727, "sentence_char_end_global": 129894, "entities": [{"text": "HEB", "type": "ENTITY", "char_start": 23, "char_end": 26, "token_start": 5, "token_end": 5}, {"text": "endogenous E2A promoter", "type": "ENTITY", "char_start": 41, "char_end": 64, "token_start": 9, "token_end": 11}, {"text": "E2A", "type": "ENTITY", "char_start": 90, "char_end": 93, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "HEB", "type": "ENTITY", "char_start": 129750, "char_end": 129753, "token_start": 5, "token_end": 5, "note": null}, {"text": "endogenous E2A promoter", "type": "ENTITY", "char_start": 129768, "char_end": 129791, "token_start": 9, "token_end": 11, "note": null}, {"text": "E2A", "type": "ENTITY", "char_start": 129817, "char_end": 129820, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 792, "sentence_text": "Finally , the postnatal lethality associated with E2A disruption is fully rescued by the addition of HEB .", "sentence_char_start_global": 129895, "sentence_char_end_global": 130001, "entities": [{"text": "E2A", "type": "ENTITY", "char_start": 50, "char_end": 53, "token_start": 7, "token_end": 7}, {"text": "HEB", "type": "ENTITY", "char_start": 101, "char_end": 104, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "E2A", "type": "ENTITY", "char_start": 129945, "char_end": 129948, "token_start": 7, "token_end": 7, "note": null}, {"text": "HEB", "type": "ENTITY", "char_start": 129996, "char_end": 129999, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 793, "sentence_text": "This study suggests that the functional divergence among E12 , E47 , and HEB in different cell types is partially defined by the context of gene expression .", "sentence_char_start_global": 130002, "sentence_char_end_global": 130159, "entities": [{"text": "E12", "type": "ENTITY", "char_start": 57, "char_end": 60, "token_start": 8, "token_end": 8}, {"text": "E47", "type": "ENTITY", "char_start": 63, "char_end": 66, "token_start": 10, "token_end": 10}, {"text": "HEB", "type": "ENTITY", "char_start": 73, "char_end": 76, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "E12", "type": "ENTITY", "char_start": 130059, "char_end": 130062, "token_start": 8, "token_end": 8, "note": null}, {"text": "E47", "type": "ENTITY", "char_start": 130065, "char_end": 130068, "token_start": 10, "token_end": 10, "note": null}, {"text": "HEB", "type": "ENTITY", "char_start": 130075, "char_end": 130078, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 794, "sentence_text": "Biased dependency of CD80 versus CD86 in the induction of transcription factors regulating the human IL - 2 promoter .", "sentence_char_start_global": 130160, "sentence_char_end_global": 130278, "entities": [{"text": "CD80", "type": "ENTITY", "char_start": 21, "char_end": 25, "token_start": 3, "token_end": 3}, {"text": "CD86", "type": "ENTITY", "char_start": 33, "char_end": 37, "token_start": 5, "token_end": 5}, {"text": "transcription factors", "type": "ENTITY", "char_start": 58, "char_end": 79, "token_start": 10, "token_end": 11}, {"text": "human IL - 2 promoter", "type": "ENTITY", "char_start": 95, "char_end": 116, "token_start": 14, "token_end": 18}], "entities_global": [{"text": "CD80", "type": "ENTITY", "char_start": 130181, "char_end": 130185, "token_start": 3, "token_end": 3, "note": null}, {"text": "CD86", "type": "ENTITY", "char_start": 130193, "char_end": 130197, "token_start": 5, "token_end": 5, "note": null}, {"text": "transcription factors", "type": "ENTITY", "char_start": 130218, "char_end": 130239, "token_start": 10, "token_end": 11, "note": null}, {"text": "human IL - 2 promoter", "type": "ENTITY", "char_start": 130255, "char_end": 130276, "token_start": 14, "token_end": 18, "note": null}]}
+{"sentence_id": 795, "sentence_text": "In addition to the signals obtained by ligation of the TCR , T cells need additional , co - stimulatory signals to be activated .", "sentence_char_start_global": 130279, "sentence_char_end_global": 130408, "entities": [], "entities_global": []}
+{"sentence_id": 796, "sentence_text": "One such co - stimulatory signal is delivered when CD28 on T cells binds to CD80 or CD86 on antigen - presenting cells ( APC ) .", "sentence_char_start_global": 130409, "sentence_char_end_global": 130537, "entities": [{"text": "CD28", "type": "ENTITY", "char_start": 51, "char_end": 55, "token_start": 9, "token_end": 9}, {"text": "CD80", "type": "ENTITY", "char_start": 76, "char_end": 80, "token_start": 15, "token_end": 15}, {"text": "CD86", "type": "ENTITY", "char_start": 84, "char_end": 88, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "CD28", "type": "ENTITY", "char_start": 130460, "char_end": 130464, "token_start": 9, "token_end": 9, "note": null}, {"text": "CD80", "type": "ENTITY", "char_start": 130485, "char_end": 130489, "token_start": 15, "token_end": 15, "note": null}, {"text": "CD86", "type": "ENTITY", "char_start": 130493, "char_end": 130497, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 797, "sentence_text": "In the present study , we analyzed the ability of CD80 and CD86 to co - stimulate human T cells activated by superantigen .", "sentence_char_start_global": 130538, "sentence_char_end_global": 130661, "entities": [{"text": "CD80", "type": "ENTITY", "char_start": 50, "char_end": 54, "token_start": 10, "token_end": 10}, {"text": "CD86", "type": "ENTITY", "char_start": 59, "char_end": 63, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "CD80", "type": "ENTITY", "char_start": 130588, "char_end": 130592, "token_start": 10, "token_end": 10, "note": null}, {"text": "CD86", "type": "ENTITY", "char_start": 130597, "char_end": 130601, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 798, "sentence_text": "Using the Raji B cell lymphoma , which express similar levels of CD80 and CD86 , it was found that T cell proliferation was mainly co - stimulated by CD80 .", "sentence_char_start_global": 130662, "sentence_char_end_global": 130818, "entities": [{"text": "CD80", "type": "ENTITY", "char_start": 65, "char_end": 69, "token_start": 12, "token_end": 12}, {"text": "CD86", "type": "ENTITY", "char_start": 74, "char_end": 78, "token_start": 14, "token_end": 14}, {"text": "CD80", "type": "ENTITY", "char_start": 150, "char_end": 154, "token_start": 29, "token_end": 29}], "entities_global": [{"text": "CD80", "type": "ENTITY", "char_start": 130727, "char_end": 130731, "token_start": 12, "token_end": 12, "note": null}, {"text": "CD86", "type": "ENTITY", "char_start": 130736, "char_end": 130740, "token_start": 14, "token_end": 14, "note": null}, {"text": "CD80", "type": "ENTITY", "char_start": 130812, "char_end": 130816, "token_start": 29, "token_end": 29, "note": null}]}
+{"sentence_id": 799, "sentence_text": "To further characterize the consequences of this biased co - stimulatory dependency , we employed a well - defined system of transfected CHO cells expressing human MHC class II together with CD80 , CD86 or CD80 and CD86 .", "sentence_char_start_global": 130819, "sentence_char_end_global": 131040, "entities": [{"text": "human MHC class II", "type": "ENTITY", "char_start": 158, "char_end": 176, "token_start": 25, "token_end": 28}, {"text": "CD80", "type": "ENTITY", "char_start": 191, "char_end": 195, "token_start": 31, "token_end": 31}, {"text": "CD86", "type": "ENTITY", "char_start": 198, "char_end": 202, "token_start": 33, "token_end": 33}, {"text": "CD80", "type": "ENTITY", "char_start": 206, "char_end": 210, "token_start": 35, "token_end": 35}, {"text": "CD86", "type": "ENTITY", "char_start": 215, "char_end": 219, "token_start": 37, "token_end": 37}], "entities_global": [{"text": "human MHC class II", "type": "ENTITY", "char_start": 130977, "char_end": 130995, "token_start": 25, "token_end": 28, "note": null}, {"text": "CD80", "type": "ENTITY", "char_start": 131010, "char_end": 131014, "token_start": 31, "token_end": 31, "note": null}, {"text": "CD86", "type": "ENTITY", "char_start": 131017, "char_end": 131021, "token_start": 33, "token_end": 33, "note": null}, {"text": "CD80", "type": "ENTITY", "char_start": 131025, "char_end": 131029, "token_start": 35, "token_end": 35, "note": null}, {"text": "CD86", "type": "ENTITY", "char_start": 131034, "char_end": 131038, "token_start": 37, "token_end": 37, "note": null}]}
+{"sentence_id": 800, "sentence_text": "Proliferation of freshly prepared CD4 + T cells required the presence of either CD80 or CD86 .", "sentence_char_start_global": 131041, "sentence_char_end_global": 131135, "entities": [{"text": "CD80", "type": "ENTITY", "char_start": 80, "char_end": 84, "token_start": 13, "token_end": 13}, {"text": "CD86", "type": "ENTITY", "char_start": 88, "char_end": 92, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "CD80", "type": "ENTITY", "char_start": 131121, "char_end": 131125, "token_start": 13, "token_end": 13, "note": null}, {"text": "CD86", "type": "ENTITY", "char_start": 131129, "char_end": 131133, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 801, "sentence_text": "However , IL - 2 production reached only suboptimal levels in the presence of CD86 but optimal levels with CD80 .", "sentence_char_start_global": 131136, "sentence_char_end_global": 131249, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 10, "char_end": 16, "token_start": 2, "token_end": 4}, {"text": "CD86", "type": "ENTITY", "char_start": 78, "char_end": 82, "token_start": 14, "token_end": 14}, {"text": "CD80", "type": "ENTITY", "char_start": 107, "char_end": 111, "token_start": 19, "token_end": 19}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 131146, "char_end": 131152, "token_start": 2, "token_end": 4, "note": null}, {"text": "CD86", "type": "ENTITY", "char_start": 131214, "char_end": 131218, "token_start": 14, "token_end": 14, "note": null}, {"text": "CD80", "type": "ENTITY", "char_start": 131243, "char_end": 131247, "token_start": 19, "token_end": 19, "note": null}]}
+{"sentence_id": 802, "sentence_text": "To analyze IL - 2 transcriptional activity in CD80 and CD86 co - stimulated T cells we used Jurkat T cells transfected with luciferase reporter gene constructs .", "sentence_char_start_global": 131250, "sentence_char_end_global": 131411, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 11, "char_end": 17, "token_start": 2, "token_end": 4}, {"text": "CD80", "type": "ENTITY", "char_start": 46, "char_end": 50, "token_start": 8, "token_end": 8}, {"text": "CD86", "type": "ENTITY", "char_start": 55, "char_end": 59, "token_start": 10, "token_end": 10}, {"text": "luciferase reporter gene constructs", "type": "ENTITY", "char_start": 124, "char_end": 159, "token_start": 23, "token_end": 26}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 131261, "char_end": 131267, "token_start": 2, "token_end": 4, "note": null}, {"text": "CD80", "type": "ENTITY", "char_start": 131296, "char_end": 131300, "token_start": 8, "token_end": 8, "note": null}, {"text": "CD86", "type": "ENTITY", "char_start": 131305, "char_end": 131309, "token_start": 10, "token_end": 10, "note": null}, {"text": "luciferase reporter gene constructs", "type": "ENTITY", "char_start": 131374, "char_end": 131409, "token_start": 23, "token_end": 26, "note": null}]}
+{"sentence_id": 803, "sentence_text": "CD80 induced higher levels of IL - 2 promoter - enhancer activity compared to CD86 .", "sentence_char_start_global": 131412, "sentence_char_end_global": 131496, "entities": [{"text": "CD80", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 30, "char_end": 45, "token_start": 5, "token_end": 8}, {"text": "CD86", "type": "ENTITY", "char_start": 78, "char_end": 82, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "CD80", "type": "ENTITY", "char_start": 131412, "char_end": 131416, "token_start": 0, "token_end": 0, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 131442, "char_end": 131457, "token_start": 5, "token_end": 8, "note": null}, {"text": "CD86", "type": "ENTITY", "char_start": 131490, "char_end": 131494, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 804, "sentence_text": "Furthermore , the activity of transcription factors regulating the IL - 2 promoter - enhancer region including activation protein - 1 , CD28 response element and nuclear factor kappaB were 4 - 8 times higher after CD80 compared to CD86 ligation .", "sentence_char_start_global": 131497, "sentence_char_end_global": 131743, "entities": [{"text": "transcription factors", "type": "ENTITY", "char_start": 30, "char_end": 51, "token_start": 5, "token_end": 6}, {"text": "IL - 2 promoter - enhancer region", "type": "ENTITY", "char_start": 67, "char_end": 100, "token_start": 9, "token_end": 15}, {"text": "activation protein - 1", "type": "ENTITY", "char_start": 111, "char_end": 133, "token_start": 17, "token_end": 20}, {"text": "CD28 response element", "type": "ENTITY", "char_start": 136, "char_end": 157, "token_start": 22, "token_end": 24}, {"text": "nuclear factor kappaB", "type": "ENTITY", "char_start": 162, "char_end": 183, "token_start": 26, "token_end": 28}, {"text": "CD80", "type": "ENTITY", "char_start": 214, "char_end": 218, "token_start": 36, "token_end": 36}, {"text": "CD86", "type": "ENTITY", "char_start": 231, "char_end": 235, "token_start": 39, "token_end": 39}], "entities_global": [{"text": "transcription factors", "type": "ENTITY", "char_start": 131527, "char_end": 131548, "token_start": 5, "token_end": 6, "note": null}, {"text": "IL - 2 promoter - enhancer region", "type": "ENTITY", "char_start": 131564, "char_end": 131597, "token_start": 9, "token_end": 15, "note": null}, {"text": "activation protein - 1", "type": "ENTITY", "char_start": 131608, "char_end": 131630, "token_start": 17, "token_end": 20, "note": null}, {"text": "CD28 response element", "type": "ENTITY", "char_start": 131633, "char_end": 131654, "token_start": 22, "token_end": 24, "note": null}, {"text": "nuclear factor kappaB", "type": "ENTITY", "char_start": 131659, "char_end": 131680, "token_start": 26, "token_end": 28, "note": null}, {"text": "CD80", "type": "ENTITY", "char_start": 131711, "char_end": 131715, "token_start": 36, "token_end": 36, "note": null}, {"text": "CD86", "type": "ENTITY", "char_start": 131728, "char_end": 131732, "token_start": 39, "token_end": 39, "note": null}]}
+{"sentence_id": 805, "sentence_text": "Our results suggest that the eventual appearance of CD80 on recently activated CD86 + APC is important for the superinduction of IL - 2 production and to support vigorous T cell proliferation .", "sentence_char_start_global": 131744, "sentence_char_end_global": 131937, "entities": [{"text": "CD80", "type": "ENTITY", "char_start": 52, "char_end": 56, "token_start": 8, "token_end": 8}, {"text": "IL - 2", "type": "ENTITY", "char_start": 129, "char_end": 135, "token_start": 21, "token_end": 23}], "entities_global": [{"text": "CD80", "type": "ENTITY", "char_start": 131796, "char_end": 131800, "token_start": 8, "token_end": 8, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 131873, "char_end": 131879, "token_start": 21, "token_end": 23, "note": null}]}
+{"sentence_id": 806, "sentence_text": "Duplication of the DR3 gene on human chromosome 1p36 and its deletion in human neuroblastoma .", "sentence_char_start_global": 131938, "sentence_char_end_global": 132032, "entities": [{"text": "DR3 gene", "type": "ENTITY", "char_start": 19, "char_end": 27, "token_start": 3, "token_end": 4}, {"text": "human chromosome 1p36", "type": "ENTITY", "char_start": 31, "char_end": 52, "token_start": 6, "token_end": 8}], "entities_global": [{"text": "DR3 gene", "type": "ENTITY", "char_start": 131957, "char_end": 131965, "token_start": 3, "token_end": 4, "note": null}, {"text": "human chromosome 1p36", "type": "ENTITY", "char_start": 131969, "char_end": 131990, "token_start": 6, "token_end": 8, "note": null}]}
+{"sentence_id": 807, "sentence_text": "The human DR3 gene , whose product is also known as Wsl - 1 / APO - 3 / TRAMP / LARD , encodes a tumor necrosis factor - related receptor that is expressed primarily on the surface of thymocytes and lymphocytes .", "sentence_char_start_global": 132033, "sentence_char_end_global": 132245, "entities": [{"text": "human DR3 gene", "type": "ENTITY", "char_start": 4, "char_end": 18, "token_start": 1, "token_end": 3}, {"text": "Wsl - 1 / APO - 3 / TRAMP / LARD", "type": "ENTITY", "char_start": 52, "char_end": 84, "token_start": 11, "token_end": 21}, {"text": "tumor necrosis factor - related receptor", "type": "ENTITY", "char_start": 97, "char_end": 137, "token_start": 25, "token_end": 30}], "entities_global": [{"text": "human DR3 gene", "type": "ENTITY", "char_start": 132037, "char_end": 132051, "token_start": 1, "token_end": 3, "note": null}, {"text": "Wsl - 1 / APO - 3 / TRAMP / LARD", "type": "ENTITY", "char_start": 132085, "char_end": 132117, "token_start": 11, "token_end": 21, "note": null}, {"text": "tumor necrosis factor - related receptor", "type": "ENTITY", "char_start": 132130, "char_end": 132170, "token_start": 25, "token_end": 30, "note": null}]}
+{"sentence_id": 808, "sentence_text": "DR3 is capable of inducing both NF - kappa B activation and apoptosis when overexpressed in mammalian cells , although its ligand has not yet been identified .", "sentence_char_start_global": 132246, "sentence_char_end_global": 132405, "entities": [{"text": "DR3", "type": "ENTITY", "char_start": 0, "char_end": 3, "token_start": 0, "token_end": 0}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 32, "char_end": 44, "token_start": 6, "token_end": 9}], "entities_global": [{"text": "DR3", "type": "ENTITY", "char_start": 132246, "char_end": 132249, "token_start": 0, "token_end": 0, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 132278, "char_end": 132290, "token_start": 6, "token_end": 9, "note": null}]}
+{"sentence_id": 809, "sentence_text": "We report here that the DR3 gene locus is tandemly duplicated on human chromosome band 1p36 . 2 - p36 . 3 and that these genes are hemizygously deleted and / or translocated to another chromosome in neuroblastoma ( NB ) cell lines with amplified MYCN .", "sentence_char_start_global": 132406, "sentence_char_end_global": 132658, "entities": [{"text": "DR3 gene locus", "type": "ENTITY", "char_start": 24, "char_end": 38, "token_start": 5, "token_end": 7}, {"text": "human chromosome band 1p36 . 2 - p36 . 3", "type": "ENTITY", "char_start": 65, "char_end": 105, "token_start": 12, "token_end": 21}], "entities_global": [{"text": "DR3 gene locus", "type": "ENTITY", "char_start": 132430, "char_end": 132444, "token_start": 5, "token_end": 7, "note": null}, {"text": "human chromosome band 1p36 . 2 - p36 . 3", "type": "ENTITY", "char_start": 132471, "char_end": 132511, "token_start": 12, "token_end": 21, "note": null}]}
+{"sentence_id": 810, "sentence_text": "Duplication of at least a portion of the DR3 gene , including the extracellular and transmembrane regions but not the cytoplasmic domain , was demonstrated by both fluorescence in situ hybridization and genomic Southern blotting .", "sentence_char_start_global": 132659, "sentence_char_end_global": 132889, "entities": [{"text": "DR3 gene", "type": "ENTITY", "char_start": 41, "char_end": 49, "token_start": 8, "token_end": 9}, {"text": "extracellular and transmembrane regions", "type": "ENTITY", "char_start": 66, "char_end": 105, "token_start": 13, "token_end": 16}, {"text": "cytoplasmic domain", "type": "ENTITY", "char_start": 118, "char_end": 136, "token_start": 20, "token_end": 21}], "entities_global": [{"text": "DR3 gene", "type": "ENTITY", "char_start": 132700, "char_end": 132708, "token_start": 8, "token_end": 9, "note": null}, {"text": "extracellular and transmembrane regions", "type": "ENTITY", "char_start": 132725, "char_end": 132764, "token_start": 13, "token_end": 16, "note": null}, {"text": "cytoplasmic domain", "type": "ENTITY", "char_start": 132777, "char_end": 132795, "token_start": 20, "token_end": 21, "note": null}]}
+{"sentence_id": 811, "sentence_text": "In most NB cell lines , both the DR3 and the DR3L sequences are simultaneously deleted and / or translocated to another chromosome .", "sentence_char_start_global": 132890, "sentence_char_end_global": 133022, "entities": [{"text": "DR3 and the DR3L sequences", "type": "ENTITY", "char_start": 33, "char_end": 59, "token_start": 8, "token_end": 12}, {"text": "chromosome", "type": "ENTITY", "char_start": 120, "char_end": 130, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "DR3 and the DR3L sequences", "type": "ENTITY", "char_start": 132923, "char_end": 132949, "token_start": 8, "token_end": 12, "note": null}, {"text": "chromosome", "type": "ENTITY", "char_start": 133010, "char_end": 133020, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 812, "sentence_text": "Finally , DR3 / Wsl - 1 protein expression is quite variable among these NB cell lines , with very low or undetectable levels in 7 of 17 NB cell lines", "sentence_char_start_global": 133023, "sentence_char_end_global": 133173, "entities": [{"text": "DR3 / Wsl - 1 protein", "type": "ENTITY", "char_start": 10, "char_end": 31, "token_start": 2, "token_end": 7}], "entities_global": [{"text": "DR3 / Wsl - 1 protein", "type": "ENTITY", "char_start": 133033, "char_end": 133054, "token_start": 2, "token_end": 7, "note": null}]}
+{"sentence_id": 813, "sentence_text": "Differential protection of normal and malignant human myeloid progenitors ( CFU - GM ) from Ara - C toxicity using cycloheximide .", "sentence_char_start_global": 133174, "sentence_char_end_global": 133304, "entities": [], "entities_global": []}
+{"sentence_id": 814, "sentence_text": "Cycloheximide , a reversible protein synthesis inhibitor , is thought to block DNA replication in normal cells by preventing synthesis of a labile protein .", "sentence_char_start_global": 133305, "sentence_char_end_global": 133461, "entities": [{"text": "labile protein", "type": "ENTITY", "char_start": 140, "char_end": 154, "token_start": 22, "token_end": 23}], "entities_global": [{"text": "labile protein", "type": "ENTITY", "char_start": 133445, "char_end": 133459, "token_start": 22, "token_end": 23, "note": null}]}
+{"sentence_id": 815, "sentence_text": "In animal systems , cycloheximide protects normal cells from cytotoxic S - phase specific agents , such as cytosine arabinoside ( Ara - C ) .", "sentence_char_start_global": 133462, "sentence_char_end_global": 133603, "entities": [], "entities_global": []}
+{"sentence_id": 816, "sentence_text": "Malignant cells appear not to be susceptible to cycloheximide - induced cycle arrest and , subsequently , may not be protected from Ara - C cytotoxicity .", "sentence_char_start_global": 133604, "sentence_char_end_global": 133758, "entities": [], "entities_global": []}
+{"sentence_id": 817, "sentence_text": "The effect of cycloheximide on granulocyte / macrophage progenitors ( CFU - GM ) after in vitro Ara - C exposure was examined using normal human bone marrow , malignant progenitors from patients with chronic myelogenous leukemia ( CML ) , and clonogenic cells from the human acute nonlymphocytic leukemia cell lines HL - 60 and KG - 1 .", "sentence_char_start_global": 133759, "sentence_char_end_global": 134095, "entities": [], "entities_global": []}
+{"sentence_id": 818, "sentence_text": "Mononuclear or clonogenic cells were incubated for one hour with cycloheximide , followed by the addition , for three or 17 hours , of Ara - C before being plated in a methylcellulose culture system .", "sentence_char_start_global": 134096, "sentence_char_end_global": 134296, "entities": [], "entities_global": []}
+{"sentence_id": 819, "sentence_text": "CFU - GM survival was significantly increase if normal cells were treated with cycloheximide before Ara - C exposure .", "sentence_char_start_global": 134297, "sentence_char_end_global": 134415, "entities": [], "entities_global": []}
+{"sentence_id": 820, "sentence_text": "Similar cycloheximide pretreatment of CML progenitors and clonogenic HL - 60 and KG - 1 cells failed to protect CFU - GM from Ara - C - induced cytotoxicity .", "sentence_char_start_global": 134416, "sentence_char_end_global": 134574, "entities": [], "entities_global": []}
+{"sentence_id": 821, "sentence_text": "Primary cortisol resistance accompanied by a reduction in glucocorticoid receptors in two members of the same family .", "sentence_char_start_global": 134575, "sentence_char_end_global": 134693, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 58, "char_end": 82, "token_start": 8, "token_end": 9}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 134633, "char_end": 134657, "token_start": 8, "token_end": 9, "note": null}]}
+{"sentence_id": 822, "sentence_text": "This report describes studies of a man suspected of having primary cortisol resistance .", "sentence_char_start_global": 134694, "sentence_char_end_global": 134782, "entities": [], "entities_global": []}
+{"sentence_id": 823, "sentence_text": "This conclusion is based on his high plasma cortisol levels and high 24 - h urinary 17 - hydroxycorticosteroi and cortisol excretion , plus the fact that he had no manifestations of Cushing ' s syndrome .", "sentence_char_start_global": 134783, "sentence_char_end_global": 134987, "entities": [], "entities_global": []}
+{"sentence_id": 824, "sentence_text": "Among family members tested , his mother also had hypercortisolemia .", "sentence_char_start_global": 134988, "sentence_char_end_global": 135057, "entities": [], "entities_global": []}
+{"sentence_id": 825, "sentence_text": "Both mother and son had high levels of unbound plasma cortisol , but their plasma ACTH concentrations were within the normal range .", "sentence_char_start_global": 135058, "sentence_char_end_global": 135190, "entities": [], "entities_global": []}
+{"sentence_id": 826, "sentence_text": "Both were partially resistant to dexamethasone adrenal suppression , and both had mild hypertension without hypokalemia .", "sentence_char_start_global": 135191, "sentence_char_end_global": 135312, "entities": [], "entities_global": []}
+{"sentence_id": 827, "sentence_text": "To study this apparent end - organ resistance to cortisol , we examined the glucocorticoid receptors in peripheral mononuclear cells .", "sentence_char_start_global": 135313, "sentence_char_end_global": 135447, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 76, "char_end": 100, "token_start": 14, "token_end": 15}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 135389, "char_end": 135413, "token_start": 14, "token_end": 15, "note": null}]}
+{"sentence_id": 828, "sentence_text": "Using whole cell assays , glucocorticoid receptors in both patients were found to have reduced total binding capacity .", "sentence_char_start_global": 135448, "sentence_char_end_global": 135567, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 26, "char_end": 50, "token_start": 5, "token_end": 6}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 135474, "char_end": 135498, "token_start": 5, "token_end": 6, "note": null}]}
+{"sentence_id": 829, "sentence_text": "We conclude that these two patients , members of the same family , have primary cortisol resistance accompanied by a reduced number of glucocorticoid receptors .", "sentence_char_start_global": 135568, "sentence_char_end_global": 135729, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 135, "char_end": 159, "token_start": 23, "token_end": 24}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 135703, "char_end": 135727, "token_start": 23, "token_end": 24, "note": null}]}
+{"sentence_id": 830, "sentence_text": "[ Glucocorticoid receptors and response to polychemotherapy in acute lymphatic leukemia ]", "sentence_char_start_global": 135730, "sentence_char_end_global": 135819, "entities": [{"text": "Glucocorticoid receptors", "type": "ENTITY", "char_start": 2, "char_end": 26, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "Glucocorticoid receptors", "type": "ENTITY", "char_start": 135732, "char_end": 135756, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 831, "sentence_text": "Glucocorticoid receptor ( GR ) levels were quantified in leukemic blasts from peripheral blood of 86 patients with acute lymphoblastic leukemia .", "sentence_char_start_global": 135820, "sentence_char_end_global": 135965, "entities": [{"text": "Glucocorticoid receptor", "type": "ENTITY", "char_start": 0, "char_end": 23, "token_start": 0, "token_end": 1}, {"text": "GR", "type": "ENTITY", "char_start": 26, "char_end": 28, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "Glucocorticoid receptor", "type": "ENTITY", "char_start": 135820, "char_end": 135843, "token_start": 0, "token_end": 1, "note": null}, {"text": "GR", "type": "ENTITY", "char_start": 135846, "char_end": 135848, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 832, "sentence_text": "The subsequent achievement of complete remission after combination chemotherapy was correlated with high receptor levels .", "sentence_char_start_global": 135966, "sentence_char_end_global": 136088, "entities": [], "entities_global": []}
+{"sentence_id": 833, "sentence_text": "Forty - seven of 50 patients with leukemic cells containing more than 6 , 000 receptor sites and 22 of 36 patients with cells containing less than 6 , 000 receptor sites achieved remission .", "sentence_char_start_global": 136089, "sentence_char_end_global": 136279, "entities": [], "entities_global": []}
+{"sentence_id": 834, "sentence_text": "The study of glucocorticoid receptors in leukemic cells may predict response to combination chemotherapy in patients with acute lymphoblastic leukemia .", "sentence_char_start_global": 136280, "sentence_char_end_global": 136432, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 13, "char_end": 37, "token_start": 3, "token_end": 4}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 136293, "char_end": 136317, "token_start": 3, "token_end": 4, "note": null}]}
+{"sentence_id": 835, "sentence_text": "Specific uptake of 1 , 25 - dihydroxycholecalcif by human chronic myeloid leukemia cells .", "sentence_char_start_global": 136433, "sentence_char_end_global": 136523, "entities": [], "entities_global": []}
+{"sentence_id": 836, "sentence_text": "We have examined mononuclear cell preparations from patients with chronic myeloid leukemia [ CML ] for binding of and response to 1 , 25 - dihydroxycholecalcif [ 1 , 25 - ( OH ) 2D3 ] .", "sentence_char_start_global": 136524, "sentence_char_end_global": 136709, "entities": [], "entities_global": []}
+{"sentence_id": 837, "sentence_text": "Whole cells specifically took up [ 3H ] - 1 , 25 - ( OH ) 2D3 with high affinity ( Kd 3 . 6 X 10 ( - 11 ) M ) and low capacity .", "sentence_char_start_global": 136710, "sentence_char_end_global": 136838, "entities": [], "entities_global": []}
+{"sentence_id": 838, "sentence_text": "Subcellular fractionation of labeled cells showed that binding was restricted to cytosols and nuclei .", "sentence_char_start_global": 136839, "sentence_char_end_global": 136941, "entities": [], "entities_global": []}
+{"sentence_id": 839, "sentence_text": "Sucrose gradient centrifugation of cells preincubated with [ 3H ] - 1 , 25 - ( OH ) 2D3 revealed a single 3 . 6S peak which was totally displaced with 100 - fold excess nonradioactive hormone .", "sentence_char_start_global": 136942, "sentence_char_end_global": 137135, "entities": [], "entities_global": []}
+{"sentence_id": 840, "sentence_text": "However , we were unable to demonstrate specific binding of 1 , 25 - ( OH ) 2D3 by postlabeling standard cytosol preparations .", "sentence_char_start_global": 137136, "sentence_char_end_global": 137263, "entities": [], "entities_global": []}
+{"sentence_id": 841, "sentence_text": "In addition , cytosols prepared from a mixture of CML cells and 1 , 25 - ( OH ) 2D3 receptor - positive T47D ( human breast cancer ) cells had less than 10 % of the binding measured in T47D cytosol alone .", "sentence_char_start_global": 137264, "sentence_char_end_global": 137469, "entities": [], "entities_global": []}
+{"sentence_id": 842, "sentence_text": "However , the levels of binding in T47D cytosols were not reduced if the receptors were occupied with [ 3H ] - 1 , 25 - ( OH ) 2D3 prior to the addition of the CML cytosols .", "sentence_char_start_global": 137470, "sentence_char_end_global": 137644, "entities": [], "entities_global": []}
+{"sentence_id": 843, "sentence_text": "Thus , CML cells appear to contain both the receptor for 1 , 25 - ( OH ) 2D3 and an unknown substance which prevents its detection following the preparation of cytosol .", "sentence_char_start_global": 137645, "sentence_char_end_global": 137814, "entities": [], "entities_global": []}
+{"sentence_id": 844, "sentence_text": "Cells from patients with CML in the chronic phase specifically bound more 1 , 25 - ( OH ) 2D3 [ 18 . 0 + / - 3 . 2 ( S . E . ) fmol / 10 ( 7 ) cells ] than did those in acute myeloid transformation [ 7 . 2 + / - 1 . 5 ] or than did cells from patients with acute myeloid leukemia [ 2 . 6 + / - 0 . 8 ] .", "sentence_char_start_global": 137815, "sentence_char_end_global": 138118, "entities": [], "entities_global": []}
+{"sentence_id": 845, "sentence_text": "Only cells from the first group of patients responded to the addition of 1 , 25 - ( OH ) 2D3 by differentiating along the monocyte - macrophage pathway .", "sentence_char_start_global": 138119, "sentence_char_end_global": 138272, "entities": [], "entities_global": []}
+{"sentence_id": 846, "sentence_text": "We conclude that the differentiation - induction effect of 1 , 25 - ( OH ) 2D3 is likely to depend on adequate levels of receptor and that intact cells rather than cytosol preparations should be studied before cells of a particular tissue are designated as receptor negative .", "sentence_char_start_global": 138273, "sentence_char_end_global": 138549, "entities": [], "entities_global": []}
+{"sentence_id": 847, "sentence_text": "Effect of cell cycle position on dexamethasone binding by mouse and human lymphoid cell lines : correlation between an increase in dexamethasone binding during S phase and dexamethasone sensitivity .", "sentence_char_start_global": 138550, "sentence_char_end_global": 138749, "entities": [], "entities_global": []}
+{"sentence_id": 848, "sentence_text": "We determined the effect of cell cycle position on the amount of dexamethasone that was specifically bound by mouse and human lymphoid cell lines .", "sentence_char_start_global": 138750, "sentence_char_end_global": 138897, "entities": [], "entities_global": []}
+{"sentence_id": 849, "sentence_text": "Cell lines that were either sensitive or resistant to growth inhibition by dexamethasone were compared .", "sentence_char_start_global": 138898, "sentence_char_end_global": 139002, "entities": [], "entities_global": []}
+{"sentence_id": 850, "sentence_text": "Exponentially growing cells were separated by centrifugal elutriation into fractions that corresponded to different positions in the cell cycle .", "sentence_char_start_global": 139003, "sentence_char_end_global": 139148, "entities": [], "entities_global": []}
+{"sentence_id": 851, "sentence_text": "The cell cycle phase distribution of each fraction was estimated by flow cytometry and autoradiography .", "sentence_char_start_global": 139149, "sentence_char_end_global": 139253, "entities": [], "entities_global": []}
+{"sentence_id": 852, "sentence_text": "The amount of dexamethasone bound per cell in each fraction was measured by a whole cell binding assay .", "sentence_char_start_global": 139254, "sentence_char_end_global": 139358, "entities": [], "entities_global": []}
+{"sentence_id": 853, "sentence_text": "In three dexamethasone - sensitive cell lines ( two mouse and one human ) , we found that the amount of dexamethasone bound per cell increased 2 - 4 - fold between G1 phase and S phase , and then decreased during G2 / M phase .", "sentence_char_start_global": 139359, "sentence_char_end_global": 139586, "entities": [], "entities_global": []}
+{"sentence_id": 854, "sentence_text": "Results were the same when the amount of dexamethasone bound per milligram of cell protein was measured .", "sentence_char_start_global": 139587, "sentence_char_end_global": 139692, "entities": [{"text": "cell protein", "type": "ENTITY", "char_start": 78, "char_end": 90, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "cell protein", "type": "ENTITY", "char_start": 139665, "char_end": 139677, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 855, "sentence_text": "Binding affinity was the same during G1 phase and S phase , but the proportion of bound dexamethasone that translocated to the nucleus was greater during S phase .", "sentence_char_start_global": 139693, "sentence_char_end_global": 139856, "entities": [], "entities_global": []}
+{"sentence_id": 856, "sentence_text": "In contrast , we found that the amount of dexamethasone bound per cell by three dexamethasone - resistant cell lines ( two mouse and one human ) did not increase during S phase .", "sentence_char_start_global": 139857, "sentence_char_end_global": 140035, "entities": [], "entities_global": []}
+{"sentence_id": 857, "sentence_text": "Our results indicate that cell cycle changes in dexamethasone binding are not simply related to changes in cell protein or cell volume during the cell cycle .", "sentence_char_start_global": 140036, "sentence_char_end_global": 140194, "entities": [{"text": "cell protein", "type": "ENTITY", "char_start": 107, "char_end": 119, "token_start": 17, "token_end": 18}], "entities_global": [{"text": "cell protein", "type": "ENTITY", "char_start": 140143, "char_end": 140155, "token_start": 17, "token_end": 18, "note": null}]}
+{"sentence_id": 858, "sentence_text": "An increase in dexamethasone binding during S phase may be required for dexamethasone to inhibit cell growth , and a failure of dexamethasone binding to increase during S phase might represent a new mechanism of dexamethasone resistance in lymphoid cells .", "sentence_char_start_global": 140195, "sentence_char_end_global": 140451, "entities": [], "entities_global": []}
+{"sentence_id": 859, "sentence_text": "Presence and steroid inducibility of glutamine synthetase in human leukemic cells .", "sentence_char_start_global": 140452, "sentence_char_end_global": 140535, "entities": [{"text": "glutamine synthetase", "type": "ENTITY", "char_start": 37, "char_end": 57, "token_start": 5, "token_end": 6}], "entities_global": [{"text": "glutamine synthetase", "type": "ENTITY", "char_start": 140489, "char_end": 140509, "token_start": 5, "token_end": 6, "note": null}]}
+{"sentence_id": 860, "sentence_text": "Glutamine synthetase ( EC 6 . 3 . 1 . 2 ; GS ) is present in lymphoblasts from patients with acute lymphoblastic leukemia ( ALL ) as well as in normal peripheral blood lymphocytes .", "sentence_char_start_global": 140536, "sentence_char_end_global": 140717, "entities": [{"text": "Glutamine synthetase", "type": "ENTITY", "char_start": 0, "char_end": 20, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "Glutamine synthetase", "type": "ENTITY", "char_start": 140536, "char_end": 140556, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 861, "sentence_text": "In 16 out of 20 ALL patients studied exposure of the cells to physiological concentrations of dexamethasone in vitro increased enzyme activity above the control levels .", "sentence_char_start_global": 140718, "sentence_char_end_global": 140887, "entities": [{"text": "enzyme", "type": "ENTITY", "char_start": 127, "char_end": 133, "token_start": 20, "token_end": 20}], "entities_global": [{"text": "enzyme", "type": "ENTITY", "char_start": 140845, "char_end": 140851, "token_start": 20, "token_end": 20, "note": null}]}
+{"sentence_id": 862, "sentence_text": "The increase was specific for glucocorticoid receptor ligands .", "sentence_char_start_global": 140888, "sentence_char_end_global": 140951, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 30, "char_end": 53, "token_start": 5, "token_end": 6}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 140918, "char_end": 140941, "token_start": 5, "token_end": 6, "note": null}]}
+{"sentence_id": 863, "sentence_text": "A direct correlation was found between the magnitude of glucocorticoid - mediated increase of GS activity and the cellular levels of specific glucocorticoid receptors assayed in the same cell specimen .", "sentence_char_start_global": 140952, "sentence_char_end_global": 141154, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 142, "char_end": 166, "token_start": 22, "token_end": 23}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 141094, "char_end": 141118, "token_start": 22, "token_end": 23, "note": null}]}
+{"sentence_id": 864, "sentence_text": "Moreover , the basal levels of the enzyme measured in cells prior to exposure to dexamethasone correlated negatively with receptor density .", "sentence_char_start_global": 141155, "sentence_char_end_global": 141295, "entities": [{"text": "enzyme", "type": "ENTITY", "char_start": 35, "char_end": 41, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "enzyme", "type": "ENTITY", "char_start": 141190, "char_end": 141196, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 865, "sentence_text": "It is suggested that the presence of steroid - inducible GS in ALL cells may prove to be a marker for functional receptor sites .", "sentence_char_start_global": 141296, "sentence_char_end_global": 141425, "entities": [{"text": "steroid - inducible GS", "type": "ENTITY", "char_start": 37, "char_end": 59, "token_start": 7, "token_end": 10}, {"text": "functional receptor sites", "type": "ENTITY", "char_start": 102, "char_end": 127, "token_start": 21, "token_end": 23}], "entities_global": [{"text": "steroid - inducible GS", "type": "ENTITY", "char_start": 141333, "char_end": 141355, "token_start": 7, "token_end": 10, "note": null}, {"text": "functional receptor sites", "type": "ENTITY", "char_start": 141398, "char_end": 141423, "token_start": 21, "token_end": 23, "note": null}]}
+{"sentence_id": 866, "sentence_text": "Binding of progestins to the glucocorticoid receptor .", "sentence_char_start_global": 141426, "sentence_char_end_global": 141480, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 29, "char_end": 52, "token_start": 5, "token_end": 6}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 141455, "char_end": 141478, "token_start": 5, "token_end": 6, "note": null}]}
+{"sentence_id": 867, "sentence_text": "Correlation to their glucocorticoid - like effects on in vitro functions of human mononuclear leukocytes .", "sentence_char_start_global": 141481, "sentence_char_end_global": 141587, "entities": [], "entities_global": []}
+{"sentence_id": 868, "sentence_text": "A number of physiological and synthetic progestins were tested for their ability to compete with [ 3H ] dexamethasone for the binding to the glucocorticoid receptor of human mononuclear leukocytes and their ability to elicit glucocorticoid - like effects on the same cells .", "sentence_char_start_global": 141588, "sentence_char_end_global": 141862, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 141, "char_end": 164, "token_start": 24, "token_end": 25}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 141729, "char_end": 141752, "token_start": 24, "token_end": 25, "note": null}]}
+{"sentence_id": 869, "sentence_text": "As compared to the reference compound dexamethasone ( relative receptor binding affinity defined as 100 % ) , two potent synthetic progestins with a pregnane - type structure , megestrol acetate and medroxyprogesterone acetate , were found to display a considerable binding affinity towards the receptor ( 46 and 42 % , respectively ) .", "sentence_char_start_global": 141863, "sentence_char_end_global": 142199, "entities": [], "entities_global": []}
+{"sentence_id": 870, "sentence_text": "The relative binding affinity of the naturally occurring ligand , cortisol , to the receptor was clearly lower ( 25 % ) .", "sentence_char_start_global": 142200, "sentence_char_end_global": 142321, "entities": [], "entities_global": []}
+{"sentence_id": 871, "sentence_text": "The effective binding of medroxyprogesterone acetate to the glucocorticoid receptor was confirmed by direct binding studies utilizing a tritiated derivative of this steroid .", "sentence_char_start_global": 142322, "sentence_char_end_global": 142496, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 60, "char_end": 83, "token_start": 8, "token_end": 9}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 142382, "char_end": 142405, "token_start": 8, "token_end": 9, "note": null}]}
+{"sentence_id": 872, "sentence_text": "No evidence for the existence of a specific progesterone receptor in human mononuclear leukocytes was obtained as judged by the results of competition experiments where a progesterone receptor - specific ligand [ 3H ] Org 2058 was used .", "sentence_char_start_global": 142497, "sentence_char_end_global": 142734, "entities": [{"text": "progesterone receptor", "type": "ENTITY", "char_start": 44, "char_end": 65, "token_start": 8, "token_end": 9}], "entities_global": [{"text": "progesterone receptor", "type": "ENTITY", "char_start": 142541, "char_end": 142562, "token_start": 8, "token_end": 9, "note": null}]}
+{"sentence_id": 873, "sentence_text": "Medroxyprogesterone acetate and megestrol acetate also induced glucocorticoid - like effects on the lymphocyte functions .", "sentence_char_start_global": 142735, "sentence_char_end_global": 142857, "entities": [], "entities_global": []}
+{"sentence_id": 874, "sentence_text": "These included inhibition of the proliferative responses to the T - cell mitogens concanavalin A and phytohaemagglutinin and an enhanced accumulation of immunoglobulin secreting cells in pokeweed mitogen - stimulated cultures .", "sentence_char_start_global": 142858, "sentence_char_end_global": 143085, "entities": [{"text": "T - cell mitogens", "type": "ENTITY", "char_start": 64, "char_end": 81, "token_start": 9, "token_end": 12}, {"text": "concanavalin A", "type": "ENTITY", "char_start": 82, "char_end": 96, "token_start": 13, "token_end": 14}, {"text": "phytohaemagglutinin", "type": "ENTITY", "char_start": 101, "char_end": 120, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "T - cell mitogens", "type": "ENTITY", "char_start": 142922, "char_end": 142939, "token_start": 9, "token_end": 12, "note": null}, {"text": "concanavalin A", "type": "ENTITY", "char_start": 142940, "char_end": 142954, "token_start": 13, "token_end": 14, "note": null}, {"text": "phytohaemagglutinin", "type": "ENTITY", "char_start": 142959, "char_end": 142978, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 875, "sentence_text": "The progestin effect appears to be mediated through a radiosensitive ( suppressor ) subpopulation of T lymphocytes .", "sentence_char_start_global": 143086, "sentence_char_end_global": 143202, "entities": [], "entities_global": []}
+{"sentence_id": 876, "sentence_text": "In contrast , the synthetic progestins related structurally to 19 - nortestosterone , norethisterone and d - norgestrel , were virtually devoid of binding affinity towards the glucocorticoid receptor nor did they measurably influence the in vitro lymphocyte functions .", "sentence_char_start_global": 143203, "sentence_char_end_global": 143472, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 176, "char_end": 199, "token_start": 27, "token_end": 28}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 143379, "char_end": 143402, "token_start": 27, "token_end": 28, "note": null}]}
+{"sentence_id": 877, "sentence_text": "These studies demonstrate that certain progestins in common clinical use probably possess inherent glucocorticoid activity and suggest that side effects attributable to this character ( e . g . suppression of the pituitary - adrenal axis ) might be expected when these compounds are used in pharmacological doses .", "sentence_char_start_global": 143473, "sentence_char_end_global": 143787, "entities": [], "entities_global": []}
+{"sentence_id": 878, "sentence_text": "Metabolic and ultrastructural aspects of the in vitro lysis of chronic lymphocytic leukemia cells by glucocorticoids .", "sentence_char_start_global": 143788, "sentence_char_end_global": 143906, "entities": [], "entities_global": []}
+{"sentence_id": 879, "sentence_text": "Human chronic lymphocytic leukemia ( CLL ) cells like prothymocytes and immunoactivated T - lymphocytes are readily lysed in vitro by pharmacological concentrations of glucocorticoids such as cortisol , whereas peripheral blood lymphocytes and thymocytes are unaffected by the hormone .", "sentence_char_start_global": 143907, "sentence_char_end_global": 144193, "entities": [{"text": "hormone", "type": "ENTITY", "char_start": 277, "char_end": 284, "token_start": 39, "token_end": 39}], "entities_global": [{"text": "hormone", "type": "ENTITY", "char_start": 144184, "char_end": 144191, "token_start": 39, "token_end": 39, "note": null}]}
+{"sentence_id": 880, "sentence_text": "In this study , metabolic and ultrastructural aspects of the cortisol - induced killing process of CLL cells are recorded .", "sentence_char_start_global": 144194, "sentence_char_end_global": 144317, "entities": [], "entities_global": []}
+{"sentence_id": 881, "sentence_text": "In vitro lysis was found to be temperature dependent and was detected only after 6 to 8 hr incubation with cortisol by means of the trypan blue exclusion test .", "sentence_char_start_global": 144318, "sentence_char_end_global": 144478, "entities": [], "entities_global": []}
+{"sentence_id": 882, "sentence_text": "However , 30 min of incubation with cortisol at either 37 degrees or 4 degrees followed by the removal of the hormone was still sufficient to induce the lytic process .", "sentence_char_start_global": 144479, "sentence_char_end_global": 144647, "entities": [{"text": "hormone", "type": "ENTITY", "char_start": 110, "char_end": 117, "token_start": 21, "token_end": 21}], "entities_global": [{"text": "hormone", "type": "ENTITY", "char_start": 144589, "char_end": 144596, "token_start": 21, "token_end": 21, "note": null}]}
+{"sentence_id": 883, "sentence_text": "Ultrastructural studies demonstrated sequential changes in the cytoplasm , including swelling of mitochondria and cytoplasmic decompartmentalizati , followed by loss of surface microvilli with the appearance of ` ` holes ' ' in the cell membrane , and subsequent condensation of nuclear chromatin .", "sentence_char_start_global": 144648, "sentence_char_end_global": 144946, "entities": [{"text": "nuclear chromatin", "type": "ENTITY", "char_start": 279, "char_end": 296, "token_start": 41, "token_end": 42}], "entities_global": [{"text": "nuclear chromatin", "type": "ENTITY", "char_start": 144927, "char_end": 144944, "token_start": 41, "token_end": 42, "note": null}]}
+{"sentence_id": 884, "sentence_text": "The large holes in the membrane appearing after 6 hr of incubation with the hormone may be the cause for the penetration of the viable stain into the dead cells , as seen by light microscopy .", "sentence_char_start_global": 144947, "sentence_char_end_global": 145139, "entities": [{"text": "hormone", "type": "ENTITY", "char_start": 76, "char_end": 83, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "hormone", "type": "ENTITY", "char_start": 145023, "char_end": 145030, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 885, "sentence_text": "Addition of metabolic inhibitors including actinomycin D , puromycin , and cycloheximide following administration of cortisol resulted in inhibition of the cell lysis .", "sentence_char_start_global": 145140, "sentence_char_end_global": 145308, "entities": [], "entities_global": []}
+{"sentence_id": 886, "sentence_text": "An excess of an antagonist such as cortexolone was found to inhibit the cortisol - induced cytolysis of the CLL cells .", "sentence_char_start_global": 145309, "sentence_char_end_global": 145428, "entities": [], "entities_global": []}
+{"sentence_id": 887, "sentence_text": "It is suggested that the glucocorticoid - induced lysis of human CLL cells is similar to the phenomenon observed in rat or murine lymphocytes and is mediated by interaction of the steroid molecule with the cytoplasmic receptor .", "sentence_char_start_global": 145429, "sentence_char_end_global": 145657, "entities": [{"text": "cytoplasmic receptor", "type": "ENTITY", "char_start": 206, "char_end": 226, "token_start": 35, "token_end": 36}], "entities_global": [{"text": "cytoplasmic receptor", "type": "ENTITY", "char_start": 145635, "char_end": 145655, "token_start": 35, "token_end": 36, "note": null}]}
+{"sentence_id": 888, "sentence_text": "The resulting complex appears to activate specific gene ( s ) the products of which eventually cause cytolysis .", "sentence_char_start_global": 145658, "sentence_char_end_global": 145770, "entities": [{"text": "gene", "type": "ENTITY", "char_start": 51, "char_end": 55, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "gene", "type": "ENTITY", "char_start": 145709, "char_end": 145713, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 889, "sentence_text": "Glucocorticoid receptors in lymphoid tumors .", "sentence_char_start_global": 145771, "sentence_char_end_global": 145816, "entities": [{"text": "Glucocorticoid receptors", "type": "ENTITY", "char_start": 0, "char_end": 24, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "Glucocorticoid receptors", "type": "ENTITY", "char_start": 145771, "char_end": 145795, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 890, "sentence_text": "There is a range of levels of glucocorticoid receptor numbers seen in the various subclasses of acute lymphatic leukemia ( ALL ) .", "sentence_char_start_global": 145817, "sentence_char_end_global": 145947, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 30, "char_end": 53, "token_start": 7, "token_end": 8}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 145847, "char_end": 145870, "token_start": 7, "token_end": 8, "note": null}]}
+{"sentence_id": 891, "sentence_text": "This variability can not be explained by the known correlation between active cell proliferation and an increase in the number of receptors , since the tumors with the highest growth fraction ( i . e . , Burkitt ' s lymphoma and T - cell leukemia ) tend to have lower average receptor numbers than do tumors with lower growth fractions such as common ALL .", "sentence_char_start_global": 145948, "sentence_char_end_global": 146304, "entities": [], "entities_global": []}
+{"sentence_id": 892, "sentence_text": "All clinical specimens from patients with lymphatic leukemia have some measurable level of glucocorticoid receptors ; therefore , the resistance seen in vivo can not be explained by the lack of receptors .", "sentence_char_start_global": 146305, "sentence_char_end_global": 146510, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 91, "char_end": 115, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 146396, "char_end": 146420, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 893, "sentence_text": "However , there has been a positive correlation , in our hands , with receptor level and prognosis .", "sentence_char_start_global": 146511, "sentence_char_end_global": 146611, "entities": [], "entities_global": []}
+{"sentence_id": 894, "sentence_text": "On the basis of in vitro models , it is proposed that perhaps the high receptor cell lines ( i . e . , common ALL of childhood ) have relative stability of their genetic material making glucocorticoid - resistant mutations less likely to occur in patients with these cells than in low - receptor cell lines ( i . e . , T - cell leukemia ) .", "sentence_char_start_global": 146612, "sentence_char_end_global": 146952, "entities": [], "entities_global": []}
+{"sentence_id": 895, "sentence_text": "This greater genetic variability in the low - receptor lines could account for the earlier emergence of clinical glucocorticoid resistance in these patients .", "sentence_char_start_global": 146953, "sentence_char_end_global": 147111, "entities": [], "entities_global": []}
+{"sentence_id": 896, "sentence_text": "[ Tumor histology and steroid receptors in breast carcinoma ]", "sentence_char_start_global": 147112, "sentence_char_end_global": 147173, "entities": [{"text": "steroid receptors", "type": "ENTITY", "char_start": 22, "char_end": 39, "token_start": 4, "token_end": 5}], "entities_global": [{"text": "steroid receptors", "type": "ENTITY", "char_start": 147134, "char_end": 147151, "token_start": 4, "token_end": 5, "note": null}]}
+{"sentence_id": 897, "sentence_text": "In Specimens of 115 patients with breast cancer 4 tumorparameters ( tumorsize , tumorboder , nucleargrade , lymphocytic stromal reaction ) 3 features of regional lymphnodes ( sinushistiocytosis , T - cellreaction , lymphnode metastases ) and estrogen and progesteron receptors were determined .", "sentence_char_start_global": 147174, "sentence_char_end_global": 147468, "entities": [{"text": "estrogen and progesteron receptors", "type": "ENTITY", "char_start": 242, "char_end": 276, "token_start": 37, "token_end": 40}], "entities_global": [{"text": "estrogen and progesteron receptors", "type": "ENTITY", "char_start": 147416, "char_end": 147450, "token_start": 37, "token_end": 40, "note": null}]}
+{"sentence_id": 898, "sentence_text": "A strong sinushistiocytosis and T - cellreaction could be verified mainly in metastases in free lymphnodes .", "sentence_char_start_global": 147469, "sentence_char_end_global": 147577, "entities": [], "entities_global": []}
+{"sentence_id": 899, "sentence_text": "The steroid receptor content does not correlate with histological parameters", "sentence_char_start_global": 147578, "sentence_char_end_global": 147654, "entities": [{"text": "steroid receptor", "type": "ENTITY", "char_start": 4, "char_end": 20, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "steroid receptor", "type": "ENTITY", "char_start": 147582, "char_end": 147598, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 900, "sentence_text": "Aldosterone - receptor deficiency in pseudohypoaldosteron .", "sentence_char_start_global": 147655, "sentence_char_end_global": 147714, "entities": [{"text": "Aldosterone - receptor", "type": "ENTITY", "char_start": 0, "char_end": 22, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "Aldosterone - receptor", "type": "ENTITY", "char_start": 147655, "char_end": 147677, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 901, "sentence_text": "Pseudohypoaldosteron , a syndrome characterized by salt wasting and failure to thrive , usually presents in infancy as high urinary levels of sodium despite hyponatremia , hyperkalemia , hyperreninemia , and elevated aldosterone levels .", "sentence_char_start_global": 147715, "sentence_char_end_global": 147952, "entities": [], "entities_global": []}
+{"sentence_id": 902, "sentence_text": "We have investigated this syndrome for the possibility of abnormal Type I or ` ` mineralocorticoid - like ' ' receptors , which have intrinsic steroid specificity indistinguishable from that of renal mineralocorticoid receptors and are found in many tissues and cells , including mononuclear leukocytes .", "sentence_char_start_global": 147953, "sentence_char_end_global": 148257, "entities": [{"text": "abnormal Type I", "type": "ENTITY", "char_start": 58, "char_end": 73, "token_start": 9, "token_end": 11}, {"text": "` ` mineralocorticoid - like ' ' receptors", "type": "ENTITY", "char_start": 77, "char_end": 119, "token_start": 13, "token_end": 20}, {"text": "renal mineralocorticoid receptors", "type": "ENTITY", "char_start": 194, "char_end": 227, "token_start": 31, "token_end": 33}], "entities_global": [{"text": "abnormal Type I", "type": "ENTITY", "char_start": 148011, "char_end": 148026, "token_start": 9, "token_end": 11, "note": null}, {"text": "` ` mineralocorticoid - like ' ' receptors", "type": "ENTITY", "char_start": 148030, "char_end": 148072, "token_start": 13, "token_end": 20, "note": null}, {"text": "renal mineralocorticoid receptors", "type": "ENTITY", "char_start": 148147, "char_end": 148180, "token_start": 31, "token_end": 33, "note": null}]}
+{"sentence_id": 903, "sentence_text": "We have studied three patients with pseudohypoaldosteron : the 28 - year - old index case in Melbourne ( Patient 1 ) and two siblings in Munich , eight and two years of age ( Patients 2 and 3 ) ; clinically , Patient 3 had a less severe case than his sister .", "sentence_char_start_global": 148258, "sentence_char_end_global": 148517, "entities": [], "entities_global": []}
+{"sentence_id": 904, "sentence_text": "Percoll - separated control monocytes bound [ 3H ] aldosterone with high affinity ( Kd approximately 3 nM ) and limited capacity ( 150 to 600 sites per cell ) .", "sentence_char_start_global": 148518, "sentence_char_end_global": 148678, "entities": [], "entities_global": []}
+{"sentence_id": 905, "sentence_text": "On repeated examination , no [ 3H ] aldosterone binding was found in monocytes from Patients 1 and 2 ; in Patient 3 , the levels were 62 sites per cell , more than 2 S . D . below those of the control .", "sentence_char_start_global": 148679, "sentence_char_end_global": 148881, "entities": [], "entities_global": []}
+{"sentence_id": 906, "sentence_text": "Levels in the parents of the Munich patients ( first cousins ) were normal .", "sentence_char_start_global": 148882, "sentence_char_end_global": 148958, "entities": [], "entities_global": []}
+{"sentence_id": 907, "sentence_text": "It appears that pseudohypoaldosteron is caused by a Type I receptor defect , that the defect may be complete or partial , that transmission may be autosomal recessive , and that the study of patients with pseudohypoaldosteron may indicate physiologic roles for Type I receptors in nonepithelial tissues .", "sentence_char_start_global": 148959, "sentence_char_end_global": 149263, "entities": [{"text": "Type I receptors", "type": "ENTITY", "char_start": 261, "char_end": 277, "token_start": 42, "token_end": 44}], "entities_global": [{"text": "Type I receptors", "type": "ENTITY", "char_start": 149220, "char_end": 149236, "token_start": 42, "token_end": 44, "note": null}]}
+{"sentence_id": 908, "sentence_text": "Glucocorticoid inhibition of urokinase - like plasminogen activators in cultured human lymphoblasts .", "sentence_char_start_global": 149264, "sentence_char_end_global": 149365, "entities": [{"text": "urokinase - like plasminogen activators", "type": "ENTITY", "char_start": 29, "char_end": 68, "token_start": 3, "token_end": 7}], "entities_global": [{"text": "urokinase - like plasminogen activators", "type": "ENTITY", "char_start": 149293, "char_end": 149332, "token_start": 3, "token_end": 7, "note": null}]}
+{"sentence_id": 909, "sentence_text": "Two human lymphoblast cell lines , LICR - LON - HMy2 ( HMy2 cells ) and GM4672A cells , are moderately growth inhibited by dexamethasone ( 1 , 4 - pregnadien - 9 - fluoro - 16 alpha - methyl - 11 beta , 17 alpha , 21 - triol - 3 , 20 - dione ) ( Dex ) .", "sentence_char_start_global": 149366, "sentence_char_end_global": 149619, "entities": [], "entities_global": []}
+{"sentence_id": 910, "sentence_text": "Both cell types secrete a urokinase ( UK ) - like plasminogen activator ( PA ) .", "sentence_char_start_global": 149620, "sentence_char_end_global": 149700, "entities": [{"text": "urokinase ( UK ) - like plasminogen activator", "type": "ENTITY", "char_start": 26, "char_end": 71, "token_start": 5, "token_end": 12}, {"text": "PA", "type": "ENTITY", "char_start": 74, "char_end": 76, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "urokinase ( UK ) - like plasminogen activator", "type": "ENTITY", "char_start": 149646, "char_end": 149691, "token_start": 5, "token_end": 12, "note": null}, {"text": "PA", "type": "ENTITY", "char_start": 149694, "char_end": 149696, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 911, "sentence_text": "Treatment of both HMy2 and GM4672A cells with Dex for 1 - 4 days inhibits extracellular PA activity in a concentration - dependent manner , being half - maximal at approximately 1 X 10 ( - 9 ) M .", "sentence_char_start_global": 149701, "sentence_char_end_global": 149897, "entities": [{"text": "PA", "type": "ENTITY", "char_start": 88, "char_end": 90, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "PA", "type": "ENTITY", "char_start": 149789, "char_end": 149791, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 912, "sentence_text": "Inhibition of PA in both cell types is specific for active glucocorticoids , and this specificity parallels the ability of various steroids to bind to glucocorticoid receptors .", "sentence_char_start_global": 149898, "sentence_char_end_global": 150075, "entities": [{"text": "PA", "type": "ENTITY", "char_start": 14, "char_end": 16, "token_start": 2, "token_end": 2}, {"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 151, "char_end": 175, "token_start": 25, "token_end": 26}], "entities_global": [{"text": "PA", "type": "ENTITY", "char_start": 149912, "char_end": 149914, "token_start": 2, "token_end": 2, "note": null}, {"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 150049, "char_end": 150073, "token_start": 25, "token_end": 26, "note": null}]}
+{"sentence_id": 913, "sentence_text": "HMy2 cell PA is fully suppressible by Dex , whereas up to one third of the activator expressed by GM4672A cells is resistant to glucocorticoid inhibition .", "sentence_char_start_global": 150076, "sentence_char_end_global": 150231, "entities": [{"text": "PA", "type": "ENTITY", "char_start": 10, "char_end": 12, "token_start": 2, "token_end": 2}], "entities_global": [{"text": "PA", "type": "ENTITY", "char_start": 150086, "char_end": 150088, "token_start": 2, "token_end": 2, "note": null}]}
+{"sentence_id": 914, "sentence_text": "Mixing experiments using a UK standard and conditioned media from Dex - treated cells suggest an absence of glucocorticoid - inducible inhibitors to UK or plasmin in both cell types .", "sentence_char_start_global": 150232, "sentence_char_end_global": 150415, "entities": [{"text": "glucocorticoid - inducible inhibitors", "type": "ENTITY", "char_start": 108, "char_end": 145, "token_start": 18, "token_end": 21}, {"text": "UK", "type": "ENTITY", "char_start": 149, "char_end": 151, "token_start": 23, "token_end": 23}, {"text": "plasmin", "type": "ENTITY", "char_start": 155, "char_end": 162, "token_start": 25, "token_end": 25}], "entities_global": [{"text": "glucocorticoid - inducible inhibitors", "type": "ENTITY", "char_start": 150340, "char_end": 150377, "token_start": 18, "token_end": 21, "note": null}, {"text": "UK", "type": "ENTITY", "char_start": 150381, "char_end": 150383, "token_start": 23, "token_end": 23, "note": null}, {"text": "plasmin", "type": "ENTITY", "char_start": 150387, "char_end": 150394, "token_start": 25, "token_end": 25, "note": null}]}
+{"sentence_id": 915, "sentence_text": "However , conditioned media from Dex - treated GM4672A cells inhibits a portion of the homologous cellular activator in conditioned media from control GM4672A cells .", "sentence_char_start_global": 150416, "sentence_char_end_global": 150582, "entities": [], "entities_global": []}
+{"sentence_id": 916, "sentence_text": "Thus , low levels of glucocorticoid - inducible inhibitors may contribute to , but can not fully account for , Dex inhibition of GM4672A PA activity .", "sentence_char_start_global": 150583, "sentence_char_end_global": 150733, "entities": [{"text": "glucocorticoid - inducible inhibitors", "type": "ENTITY", "char_start": 21, "char_end": 58, "token_start": 5, "token_end": 8}, {"text": "GM4672A PA", "type": "ENTITY", "char_start": 129, "char_end": 139, "token_start": 23, "token_end": 24}], "entities_global": [{"text": "glucocorticoid - inducible inhibitors", "type": "ENTITY", "char_start": 150604, "char_end": 150641, "token_start": 5, "token_end": 8, "note": null}, {"text": "GM4672A PA", "type": "ENTITY", "char_start": 150712, "char_end": 150722, "token_start": 23, "token_end": 24, "note": null}]}
+{"sentence_id": 917, "sentence_text": "Glucocorticoid - inducible inhibitors in HMy2 cells are either totally absent or are present at undetectable levels .", "sentence_char_start_global": 150734, "sentence_char_end_global": 150851, "entities": [{"text": "Glucocorticoid - inducible inhibitors", "type": "ENTITY", "char_start": 0, "char_end": 37, "token_start": 0, "token_end": 3}], "entities_global": [{"text": "Glucocorticoid - inducible inhibitors", "type": "ENTITY", "char_start": 150734, "char_end": 150771, "token_start": 0, "token_end": 3, "note": null}]}
+{"sentence_id": 918, "sentence_text": "Thus , regulation of UK - like PAs in HMy2 and GM4672A cells differs with respect to the extent to which glucocorticoids inhibit constitutively expressed activator levels , as well as the possible contribution of glucocorticoid - inducible inhibitors to the regulatory process in GM4672A cells .", "sentence_char_start_global": 150852, "sentence_char_end_global": 151147, "entities": [{"text": "UK - like PAs", "type": "ENTITY", "char_start": 21, "char_end": 34, "token_start": 4, "token_end": 7}, {"text": "constitutively expressed activator", "type": "ENTITY", "char_start": 129, "char_end": 163, "token_start": 23, "token_end": 25}, {"text": "glucocorticoid - inducible inhibitors", "type": "ENTITY", "char_start": 213, "char_end": 250, "token_start": 35, "token_end": 38}], "entities_global": [{"text": "UK - like PAs", "type": "ENTITY", "char_start": 150873, "char_end": 150886, "token_start": 4, "token_end": 7, "note": null}, {"text": "constitutively expressed activator", "type": "ENTITY", "char_start": 150981, "char_end": 151015, "token_start": 23, "token_end": 25, "note": null}, {"text": "glucocorticoid - inducible inhibitors", "type": "ENTITY", "char_start": 151065, "char_end": 151102, "token_start": 35, "token_end": 38, "note": null}]}
+{"sentence_id": 919, "sentence_text": "Characterization of aldosterone binding sites in circulating human mononuclear leukocytes .", "sentence_char_start_global": 151148, "sentence_char_end_global": 151239, "entities": [], "entities_global": []}
+{"sentence_id": 920, "sentence_text": "Aldosterone binding sites in human mononuclear leukocytes were characterized after separation of cells from blood by a Percoll gradient .", "sentence_char_start_global": 151240, "sentence_char_end_global": 151377, "entities": [], "entities_global": []}
+{"sentence_id": 921, "sentence_text": "After washing and resuspension in RPMI - 1640 medium , cells were incubated at 37 degrees C for 1 h with different concentrations of [ 3H ] aldosterone plus a 100 - fold concentration of RU - 26988 ( 11 alpha , 17 alpha - dihydroxy - 17 beta - propynylandrost - 1 , 4 , 6 - trien - 3 - one ) , with or without an excess of unlabeled aldosterone .", "sentence_char_start_global": 151378, "sentence_char_end_global": 151724, "entities": [], "entities_global": []}
+{"sentence_id": 922, "sentence_text": "Aldosterone binds to a single class of receptors with an affinity of 2 . 7 + / - 0 . 5 nM ( means + / - SD , n = 14 ) and a capacity of 290 + / - 108 sites / cell ( n = 14 ) .", "sentence_char_start_global": 151725, "sentence_char_end_global": 151900, "entities": [], "entities_global": []}
+{"sentence_id": 923, "sentence_text": "The specificity data show a hierarchy of affinity of desoxycorticosterone = corticosterone = aldosterone greater than hydrocortisone greater than dexamethasone .", "sentence_char_start_global": 151901, "sentence_char_end_global": 152062, "entities": [], "entities_global": []}
+{"sentence_id": 924, "sentence_text": "The results indicate that mononuclear leukocytes could be useful for studying the physiological significance of these mineralocorticoid receptors and their regulation in humans .", "sentence_char_start_global": 152063, "sentence_char_end_global": 152241, "entities": [{"text": "mineralocorticoid receptors", "type": "ENTITY", "char_start": 118, "char_end": 145, "token_start": 16, "token_end": 17}], "entities_global": [{"text": "mineralocorticoid receptors", "type": "ENTITY", "char_start": 152181, "char_end": 152208, "token_start": 16, "token_end": 17, "note": null}]}
+{"sentence_id": 925, "sentence_text": "Mineralocorticoid and glucocorticoid receptors in circulating mononuclear leukocytes of patients with primary hyperaldosteronism .", "sentence_char_start_global": 152242, "sentence_char_end_global": 152372, "entities": [{"text": "Mineralocorticoid and glucocorticoid receptors", "type": "ENTITY", "char_start": 0, "char_end": 46, "token_start": 0, "token_end": 3}], "entities_global": [{"text": "Mineralocorticoid and glucocorticoid receptors", "type": "ENTITY", "char_start": 152242, "char_end": 152288, "token_start": 0, "token_end": 3, "note": null}]}
+{"sentence_id": 926, "sentence_text": "Mineralocorticoid and glucocorticoid receptors were measured in circulating mononuclear leukocytes in 5 patients affected by Conn ' s syndrome ( 3 cases of bilateral adrenal hyperplasia and 2 cases of adenoma plus unilateral hyperplasia ) .", "sentence_char_start_global": 152373, "sentence_char_end_global": 152613, "entities": [{"text": "Mineralocorticoid and glucocorticoid receptors", "type": "ENTITY", "char_start": 0, "char_end": 46, "token_start": 0, "token_end": 3}], "entities_global": [{"text": "Mineralocorticoid and glucocorticoid receptors", "type": "ENTITY", "char_start": 152373, "char_end": 152419, "token_start": 0, "token_end": 3, "note": null}]}
+{"sentence_id": 927, "sentence_text": "The number of the binding sites per cell resulted significantly lower ( 189 + / - 114 , mean + / - SD ) , as compared with the normal controls ( 298 + / - 105 ) .", "sentence_char_start_global": 152614, "sentence_char_end_global": 152776, "entities": [], "entities_global": []}
+{"sentence_id": 928, "sentence_text": "The affinity of aldosterone for the receptor was found to be not different than that of healthy control subjects .", "sentence_char_start_global": 152777, "sentence_char_end_global": 152891, "entities": [], "entities_global": []}
+{"sentence_id": 929, "sentence_text": "The capacity and the affinity of dexamethasone for glucocorticoid receptors ranged in the normal values .", "sentence_char_start_global": 152892, "sentence_char_end_global": 152997, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 51, "char_end": 75, "token_start": 8, "token_end": 9}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 152943, "char_end": 152967, "token_start": 8, "token_end": 9, "note": null}]}
+{"sentence_id": 930, "sentence_text": "These data suggest a possible down - regulation of mineralocorticoid receptors in humans .", "sentence_char_start_global": 152998, "sentence_char_end_global": 153088, "entities": [{"text": "mineralocorticoid receptors", "type": "ENTITY", "char_start": 51, "char_end": 78, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "mineralocorticoid receptors", "type": "ENTITY", "char_start": 153049, "char_end": 153076, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 931, "sentence_text": "Short - term and long - term effects of estrogen on lymphoid tissues and lymphoid cells with some remarks on the significance for carcinogenesis .", "sentence_char_start_global": 153089, "sentence_char_end_global": 153235, "entities": [], "entities_global": []}
+{"sentence_id": 932, "sentence_text": "Estrogens have long been thought to play a role in regulating the immune system .", "sentence_char_start_global": 153236, "sentence_char_end_global": 153317, "entities": [], "entities_global": []}
+{"sentence_id": 933, "sentence_text": "The difference in some types of immune responses between males and females is well - known , as is the pronounced thymic involution induced by exogenous estrogens .", "sentence_char_start_global": 153318, "sentence_char_end_global": 153482, "entities": [], "entities_global": []}
+{"sentence_id": 934, "sentence_text": "Estrogens stimulate some aspects of macrophage activity and , depending on dose and mitogen , inhibit or stimulate lymphocyte proliferative response in vitro .", "sentence_char_start_global": 153483, "sentence_char_end_global": 153642, "entities": [{"text": "mitogen", "type": "ENTITY", "char_start": 84, "char_end": 91, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "mitogen", "type": "ENTITY", "char_start": 153567, "char_end": 153574, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 935, "sentence_text": "Another example is the estrogen effect on the delayed type hypersensitivity response .", "sentence_char_start_global": 153643, "sentence_char_end_global": 153729, "entities": [], "entities_global": []}
+{"sentence_id": 936, "sentence_text": "A broad review is given of such estrogen effects on lymphoid tissue and immune response .", "sentence_char_start_global": 153730, "sentence_char_end_global": 153819, "entities": [], "entities_global": []}
+{"sentence_id": 937, "sentence_text": "Most of the studies published so far are phenomenological .", "sentence_char_start_global": 153820, "sentence_char_end_global": 153879, "entities": [], "entities_global": []}
+{"sentence_id": 938, "sentence_text": "However , the recent description of estrogen receptors in the thymus and in some lymphocyte subpopulations , as well as a deeper understanding of regulating factors in the immune system , open the possibility of a more detailed understanding of the estrogen mechanism of interference .", "sentence_char_start_global": 153880, "sentence_char_end_global": 154165, "entities": [{"text": "estrogen receptors", "type": "ENTITY", "char_start": 36, "char_end": 54, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "estrogen receptors", "type": "ENTITY", "char_start": 153916, "char_end": 153934, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 939, "sentence_text": "Estrogen effects in adults are reversible .", "sentence_char_start_global": 154166, "sentence_char_end_global": 154209, "entities": [], "entities_global": []}
+{"sentence_id": 940, "sentence_text": "After treating neonatal mice with the synthetic estrogen diethylstilbestrol ( DES ) , disturbances are induced in lymphocyte populations and lymphocyte functions which are permanent and irreversible .", "sentence_char_start_global": 154210, "sentence_char_end_global": 154410, "entities": [], "entities_global": []}
+{"sentence_id": 941, "sentence_text": "Lymphocytes from adult , neonatally DES - treated female mice have a reduced mitogen response to ConA and LPS ( T and B cell mitogen ) and the delayed type hypersensitivity response is depressed .", "sentence_char_start_global": 154411, "sentence_char_end_global": 154607, "entities": [{"text": "ConA", "type": "ENTITY", "char_start": 97, "char_end": 101, "token_start": 16, "token_end": 16}, {"text": "LPS", "type": "ENTITY", "char_start": 106, "char_end": 109, "token_start": 18, "token_end": 18}, {"text": "T and B cell mitogen", "type": "ENTITY", "char_start": 112, "char_end": 132, "token_start": 20, "token_end": 24}], "entities_global": [{"text": "ConA", "type": "ENTITY", "char_start": 154508, "char_end": 154512, "token_start": 16, "token_end": 16, "note": null}, {"text": "LPS", "type": "ENTITY", "char_start": 154517, "char_end": 154520, "token_start": 18, "token_end": 18, "note": null}, {"text": "T and B cell mitogen", "type": "ENTITY", "char_start": 154523, "char_end": 154543, "token_start": 20, "token_end": 24, "note": null}]}
+{"sentence_id": 942, "sentence_text": "A detailed analysis demonstrated a decreased T helper cell population .", "sentence_char_start_global": 154608, "sentence_char_end_global": 154679, "entities": [], "entities_global": []}
+{"sentence_id": 943, "sentence_text": "The activity of Natural Killer cells is permanently reduced and this functional impairment is related to a decreased number of these cells , in turn determined at the bone marrow level .", "sentence_char_start_global": 154680, "sentence_char_end_global": 154866, "entities": [], "entities_global": []}
+{"sentence_id": 944, "sentence_text": "The same animals have an increased sensitivity to chemical carcinogens ( methylcholanthrene ) and they spontaneously develop epithelial changes in the uterine cervix which morphologically are similar to adenocarcinoma .", "sentence_char_start_global": 154867, "sentence_char_end_global": 155086, "entities": [], "entities_global": []}
+{"sentence_id": 945, "sentence_text": "The association between estrogen - associated malignancy and estrogen effects in lymphocyte functions deserves further study .", "sentence_char_start_global": 155087, "sentence_char_end_global": 155213, "entities": [], "entities_global": []}
+{"sentence_id": 946, "sentence_text": "Drugs affecting the hormonal receptors of normal and leukaemic peripheral leucocytes .", "sentence_char_start_global": 155214, "sentence_char_end_global": 155300, "entities": [], "entities_global": []}
+{"sentence_id": 947, "sentence_text": "The authors investigated the behaviour of steroid hormone uptake in leukaemic cells ( CML , CLL , AML , ALL ) , in basal conditions and after incubation with drugs which modify the cellular concentration of cAMP , PGE and PGF .", "sentence_char_start_global": 155301, "sentence_char_end_global": 155528, "entities": [], "entities_global": []}
+{"sentence_id": 948, "sentence_text": "The results demonstrated the presence in leukaemic cells of an alteration in the incorporation of steroid hormones .", "sentence_char_start_global": 155529, "sentence_char_end_global": 155645, "entities": [], "entities_global": []}
+{"sentence_id": 949, "sentence_text": "This alteration was scarcely modified by incubation with theophylline , which increases cellular concentration of cAMP .", "sentence_char_start_global": 155646, "sentence_char_end_global": 155766, "entities": [{"text": "theophylline", "type": "ENTITY", "char_start": 57, "char_end": 69, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "theophylline", "type": "ENTITY", "char_start": 155703, "char_end": 155715, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 950, "sentence_text": "On the other hand , it was moderately counteracted by thioproline and was evidently inhibited by flurbiprofen , which also reduced cellular concentrations of prostaglandins , particularly PGE2 , with the exception of PGF2 which showed a poor response .", "sentence_char_start_global": 155767, "sentence_char_end_global": 156019, "entities": [], "entities_global": []}
+{"sentence_id": 951, "sentence_text": "Differences were observed in the behavior of hormonal uptake of CML , in contrast to that of AML , CLL and ALL peripheral leucocytes .", "sentence_char_start_global": 156020, "sentence_char_end_global": 156154, "entities": [], "entities_global": []}
+{"sentence_id": 952, "sentence_text": "Human breast cancer and impaired NK cell function .", "sentence_char_start_global": 156155, "sentence_char_end_global": 156206, "entities": [], "entities_global": []}
+{"sentence_id": 953, "sentence_text": "Recent advances in tumor immunology have led to the discovery of a new lymphoid cell with unique antitumor activity .", "sentence_char_start_global": 156207, "sentence_char_end_global": 156324, "entities": [], "entities_global": []}
+{"sentence_id": 954, "sentence_text": "Natural killer ( NK ) cells form an antitumor surveillance system and appear to be vital in preventing tumor growth and metastasis in animal models .", "sentence_char_start_global": 156325, "sentence_char_end_global": 156474, "entities": [], "entities_global": []}
+{"sentence_id": 955, "sentence_text": "We studied NK activity in patients with benign and malignant breast disease , using a chromium - 51 release microtiter cytotoxicity assay with K562 cells as targets .", "sentence_char_start_global": 156475, "sentence_char_end_global": 156641, "entities": [], "entities_global": []}
+{"sentence_id": 956, "sentence_text": "Compared with benign controls , patients with malignancies had significantly depressed NK - mediated lysis ( P less than 0 . 01 ) .", "sentence_char_start_global": 156642, "sentence_char_end_global": 156773, "entities": [], "entities_global": []}
+{"sentence_id": 957, "sentence_text": "Furthermore , lysis in those with advanced disease ( stages II , III , and IV ) was significantly less than in those with limited disease ( stage I ) ( P less than 0 . 01 ) .", "sentence_char_start_global": 156774, "sentence_char_end_global": 156948, "entities": [], "entities_global": []}
+{"sentence_id": 958, "sentence_text": "NK activity was not correlated to estrogen or progesterone receptor states .", "sentence_char_start_global": 156949, "sentence_char_end_global": 157025, "entities": [], "entities_global": []}
+{"sentence_id": 959, "sentence_text": "Positive correlation of a depressed natural killer activity with the extent of tumor spread supports the concept of an NK cell immune surveillance system in breast cancer and emphasizes its importance in this malignancy .", "sentence_char_start_global": 157026, "sentence_char_end_global": 157247, "entities": [], "entities_global": []}
+{"sentence_id": 960, "sentence_text": "Immunosuppressive effect of serum progesterone during pregnancy depends on the progesterone binding capacity of the lymphocytes .", "sentence_char_start_global": 157248, "sentence_char_end_global": 157377, "entities": [], "entities_global": []}
+{"sentence_id": 961, "sentence_text": "Cytotoxic activity and progesterone binding capacity of the lymphocytes , together with serum progesterone concentrations , were determined in women with normal pregnancy or with a clinical diagnosis of threatened abortion or threatened premature labour .", "sentence_char_start_global": 157378, "sentence_char_end_global": 157633, "entities": [], "entities_global": []}
+{"sentence_id": 962, "sentence_text": "The lymphocytes of women with threatened abortion or threatened premature labour showed significantly higher cytotoxic activity ( P less than 0 . 001 ) and significantly lower progesterone binding capacity ( P less than 0 . 001 ) than did lymphocytes obtained from the healthy pregnant women .", "sentence_char_start_global": 157634, "sentence_char_end_global": 157927, "entities": [], "entities_global": []}
+{"sentence_id": 963, "sentence_text": "Significant inverse correlation was found between progesterone binding capacity and cytotoxic activity of the lymphocytes ( P less than 0 . 001 ) , but the progesterone concentration of the pregnancy serum appeared to have no influence on the other two parameters .", "sentence_char_start_global": 157928, "sentence_char_end_global": 158193, "entities": [], "entities_global": []}
+{"sentence_id": 964, "sentence_text": "The findings indicate that intact progesterone binding capacity of the lymphocytes is an essential factor for the manifestation of the blocking effect exerted by pregnancy serum on lymphocyte cytotoxicity in vitro .", "sentence_char_start_global": 158194, "sentence_char_end_global": 158409, "entities": [], "entities_global": []}
+{"sentence_id": 965, "sentence_text": "Serum sex steroid and peptide hormone concentrations , and endometrial estrogen and progestin receptor levels during administration of human leukocyte interferon .", "sentence_char_start_global": 158410, "sentence_char_end_global": 158573, "entities": [{"text": "human leukocyte interferon", "type": "ENTITY", "char_start": 135, "char_end": 161, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "human leukocyte interferon", "type": "ENTITY", "char_start": 158545, "char_end": 158571, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 966, "sentence_text": "Five normally cycling healthy women were given daily subcutaneous injections of human leukocyte interferon ( 3 X 10 ( 6 ) units / day ) from the 3rd through 23rd day of the menstrual cycle , and serum steroid and peptide hormone concentrations monitored at 3 - day intervals during the treatment and the preceding control cycle .", "sentence_char_start_global": 158574, "sentence_char_end_global": 158903, "entities": [{"text": "human leukocyte interferon", "type": "ENTITY", "char_start": 80, "char_end": 106, "token_start": 11, "token_end": 13}], "entities_global": [{"text": "human leukocyte interferon", "type": "ENTITY", "char_start": 158654, "char_end": 158680, "token_start": 11, "token_end": 13, "note": null}]}
+{"sentence_id": 967, "sentence_text": "Concentrations of cytosol and nuclear estrogen receptors ( ERC and ERN , respectively ) and progestin receptors ( PRC and PRN ) were also measured from endometrial biopsies taken on the 24th day of the control and treatment cycle .", "sentence_char_start_global": 158904, "sentence_char_end_global": 159135, "entities": [{"text": "cytosol and nuclear estrogen receptors", "type": "ENTITY", "char_start": 18, "char_end": 56, "token_start": 2, "token_end": 6}, {"text": "ERC", "type": "ENTITY", "char_start": 59, "char_end": 62, "token_start": 8, "token_end": 8}, {"text": "ERN", "type": "ENTITY", "char_start": 67, "char_end": 70, "token_start": 10, "token_end": 10}, {"text": "progestin receptors", "type": "ENTITY", "char_start": 92, "char_end": 111, "token_start": 15, "token_end": 16}, {"text": "PRC", "type": "ENTITY", "char_start": 114, "char_end": 117, "token_start": 18, "token_end": 18}, {"text": "PRN", "type": "ENTITY", "char_start": 122, "char_end": 125, "token_start": 20, "token_end": 20}], "entities_global": [{"text": "cytosol and nuclear estrogen receptors", "type": "ENTITY", "char_start": 158922, "char_end": 158960, "token_start": 2, "token_end": 6, "note": null}, {"text": "ERC", "type": "ENTITY", "char_start": 158963, "char_end": 158966, "token_start": 8, "token_end": 8, "note": null}, {"text": "ERN", "type": "ENTITY", "char_start": 158971, "char_end": 158974, "token_start": 10, "token_end": 10, "note": null}, {"text": "progestin receptors", "type": "ENTITY", "char_start": 158996, "char_end": 159015, "token_start": 15, "token_end": 16, "note": null}, {"text": "PRC", "type": "ENTITY", "char_start": 159018, "char_end": 159021, "token_start": 18, "token_end": 18, "note": null}, {"text": "PRN", "type": "ENTITY", "char_start": 159026, "char_end": 159029, "token_start": 20, "token_end": 20, "note": null}]}
+{"sentence_id": 968, "sentence_text": "In addition , an extensive monitoring of clinical chemical and hematological tests from the blood samples were performed .", "sentence_char_start_global": 159136, "sentence_char_end_global": 159258, "entities": [], "entities_global": []}
+{"sentence_id": 969, "sentence_text": "Serum estradiol and progesterone concentrations were significantly decreased during the treatment cycle , suggesting that interferon interacts in vivo with the function of both FSH and LH .", "sentence_char_start_global": 159259, "sentence_char_end_global": 159448, "entities": [{"text": "interferon", "type": "ENTITY", "char_start": 122, "char_end": 132, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "interferon", "type": "ENTITY", "char_start": 159381, "char_end": 159391, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 970, "sentence_text": "No significant changes were observed in the serum peptide hormone concentrations measured ( FSH , LH , prolactin , insulin , growth hormone and TSH ) ; neither were the levels of endometrial ERC , ERN , PRC and PRN affected by interferon administration .", "sentence_char_start_global": 159449, "sentence_char_end_global": 159703, "entities": [{"text": "endometrial ERC , ERN , PRC and PRN", "type": "ENTITY", "char_start": 179, "char_end": 214, "token_start": 32, "token_end": 39}, {"text": "interferon", "type": "ENTITY", "char_start": 227, "char_end": 237, "token_start": 42, "token_end": 42}], "entities_global": [{"text": "endometrial ERC , ERN , PRC and PRN", "type": "ENTITY", "char_start": 159628, "char_end": 159663, "token_start": 32, "token_end": 39, "note": null}, {"text": "interferon", "type": "ENTITY", "char_start": 159676, "char_end": 159686, "token_start": 42, "token_end": 42, "note": null}]}
+{"sentence_id": 971, "sentence_text": "As expected , interferon administration resulted in decreased leukocyte counts .", "sentence_char_start_global": 159704, "sentence_char_end_global": 159784, "entities": [{"text": "interferon", "type": "ENTITY", "char_start": 14, "char_end": 24, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "interferon", "type": "ENTITY", "char_start": 159718, "char_end": 159728, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 972, "sentence_text": "Moreover , an increasing tendency in the activities of serum alkaline phosphatase and gamma - glutamyltransferase during the interferon therapy shows that interferon may slightly interfere with the liver function .", "sentence_char_start_global": 159785, "sentence_char_end_global": 159999, "entities": [{"text": "serum alkaline phosphatase", "type": "ENTITY", "char_start": 55, "char_end": 81, "token_start": 9, "token_end": 11}, {"text": "gamma - glutamyltransferase", "type": "ENTITY", "char_start": 86, "char_end": 113, "token_start": 13, "token_end": 15}, {"text": "interferon", "type": "ENTITY", "char_start": 125, "char_end": 135, "token_start": 18, "token_end": 18}, {"text": "interferon", "type": "ENTITY", "char_start": 155, "char_end": 165, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "serum alkaline phosphatase", "type": "ENTITY", "char_start": 159840, "char_end": 159866, "token_start": 9, "token_end": 11, "note": null}, {"text": "gamma - glutamyltransferase", "type": "ENTITY", "char_start": 159871, "char_end": 159898, "token_start": 13, "token_end": 15, "note": null}, {"text": "interferon", "type": "ENTITY", "char_start": 159910, "char_end": 159920, "token_start": 18, "token_end": 18, "note": null}, {"text": "interferon", "type": "ENTITY", "char_start": 159940, "char_end": 159950, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 973, "sentence_text": "These results suggest that one of the mechanisms by which interferon treatment may affect the growth of hormone - dependent neoplasms could be the interaction with production and / or function of circulating hormonal compounds .", "sentence_char_start_global": 160000, "sentence_char_end_global": 160228, "entities": [{"text": "interferon", "type": "ENTITY", "char_start": 58, "char_end": 68, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "interferon", "type": "ENTITY", "char_start": 160058, "char_end": 160068, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 974, "sentence_text": "[ Glucocorticoid receptor level in the blood leukocytes in different acute diseases ]", "sentence_char_start_global": 160229, "sentence_char_end_global": 160314, "entities": [{"text": "Glucocorticoid receptor", "type": "ENTITY", "char_start": 2, "char_end": 25, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "Glucocorticoid receptor", "type": "ENTITY", "char_start": 160231, "char_end": 160254, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 975, "sentence_text": "Content of glucocorticoid receptors in cytosol of blood leukocytes , concentration of cortisol and amount of leukocytes in blood were studied in 20 patients with acute impairments within the second day of the disease .", "sentence_char_start_global": 160315, "sentence_char_end_global": 160533, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 11, "char_end": 35, "token_start": 2, "token_end": 3}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 160326, "char_end": 160350, "token_start": 2, "token_end": 3, "note": null}]}
+{"sentence_id": 976, "sentence_text": "Content of receptors in cytosol of blood leukocytes was studied using 3H - triamcinolone acetonide .", "sentence_char_start_global": 160534, "sentence_char_end_global": 160634, "entities": [], "entities_global": []}
+{"sentence_id": 977, "sentence_text": "Distinct increase in amount of the leukocyte glucocorticoid receptors was found in patients with poisoning by dichlorethane and hypnotic drugs under conditions of acute myocardial infarction .", "sentence_char_start_global": 160635, "sentence_char_end_global": 160827, "entities": [{"text": "leukocyte glucocorticoid receptors", "type": "ENTITY", "char_start": 35, "char_end": 69, "token_start": 6, "token_end": 8}], "entities_global": [{"text": "leukocyte glucocorticoid receptors", "type": "ENTITY", "char_start": 160670, "char_end": 160704, "token_start": 6, "token_end": 8, "note": null}]}
+{"sentence_id": 978, "sentence_text": "In acute pancreatitis content of the leukocyte receptors was not altered as compared with controls .", "sentence_char_start_global": 160828, "sentence_char_end_global": 160928, "entities": [{"text": "leukocyte receptors", "type": "ENTITY", "char_start": 37, "char_end": 56, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "leukocyte receptors", "type": "ENTITY", "char_start": 160865, "char_end": 160884, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 979, "sentence_text": "Concentration of endogenous cortisol was increased in blood of all the patients , except of the cases of acetate intoxication .", "sentence_char_start_global": 160929, "sentence_char_end_global": 161056, "entities": [], "entities_global": []}
+{"sentence_id": 980, "sentence_text": "Reverse correlation was observed between concentration of cortisol in blood and content of glucocorticoid receptors in leukocytes .", "sentence_char_start_global": 161057, "sentence_char_end_global": 161188, "entities": [], "entities_global": []}
+{"sentence_id": 981, "sentence_text": "But in the patients with acute pancreatitis the decrease in content of leukocyte glucocorticoid receptors was not observed although there was an increase in cortisol concentration in blood .", "sentence_char_start_global": 161189, "sentence_char_end_global": 161379, "entities": [{"text": "leukocyte glucocorticoid receptors", "type": "ENTITY", "char_start": 71, "char_end": 105, "token_start": 12, "token_end": 14}], "entities_global": [{"text": "leukocyte glucocorticoid receptors", "type": "ENTITY", "char_start": 161260, "char_end": 161294, "token_start": 12, "token_end": 14, "note": null}]}
+{"sentence_id": 982, "sentence_text": "The role of glucocorticoid receptors in immunological processes under conditions of purulent complications and possibility to regulate the metabolism in leukocytes", "sentence_char_start_global": 161380, "sentence_char_end_global": 161543, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 12, "char_end": 36, "token_start": 3, "token_end": 4}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 161392, "char_end": 161416, "token_start": 3, "token_end": 4, "note": null}]}
+{"sentence_id": 983, "sentence_text": "Therapeutic concentrations of glucocorticoids suppress the antimicrobial activity of human macrophages without impairing their responsiveness to gamma interferon .", "sentence_char_start_global": 161544, "sentence_char_end_global": 161707, "entities": [{"text": "gamma interferon", "type": "ENTITY", "char_start": 145, "char_end": 161, "token_start": 16, "token_end": 17}], "entities_global": [{"text": "gamma interferon", "type": "ENTITY", "char_start": 161689, "char_end": 161705, "token_start": 16, "token_end": 17, "note": null}]}
+{"sentence_id": 984, "sentence_text": "By exposing human blood - derived macrophages and alveolar macrophages in vitro to dexamethasone , we showed in these studies that glucocorticoids markedly suppress the antimicrobial activity of macrophages but not macrophage activation by lymphokines .", "sentence_char_start_global": 161708, "sentence_char_end_global": 161961, "entities": [], "entities_global": []}
+{"sentence_id": 985, "sentence_text": "As little as 2 . 5 X 10 ( - 8 ) mol / liter of dexamethasone prevented macrophages from inhibiting germination of Aspergillus spores or from eliminating ingested bacteria such as Listeria , Nocardia , or Salmonella .", "sentence_char_start_global": 161962, "sentence_char_end_global": 162178, "entities": [], "entities_global": []}
+{"sentence_id": 986, "sentence_text": "Damage to macrophage function was inhibited by progesterone and appeared to be receptor - mediated .", "sentence_char_start_global": 162179, "sentence_char_end_global": 162279, "entities": [], "entities_global": []}
+{"sentence_id": 987, "sentence_text": "In accordance with in vivo observations , dexamethasone required 24 - 36 h to suppress antimicrobial activity .", "sentence_char_start_global": 162280, "sentence_char_end_global": 162391, "entities": [], "entities_global": []}
+{"sentence_id": 988, "sentence_text": "While glucocorticoids interfered with base - line activity of macrophages , dexamethasone concentrations comparable to drug levels in patients had no effect on macrophage activation .", "sentence_char_start_global": 162392, "sentence_char_end_global": 162575, "entities": [], "entities_global": []}
+{"sentence_id": 989, "sentence_text": "Proliferating lymphocytes and gamma - interferon thus increased the antimicrobial activity of phagocytes exposed to glucocorticoids over that of control cells .", "sentence_char_start_global": 162576, "sentence_char_end_global": 162736, "entities": [{"text": "gamma - interferon", "type": "ENTITY", "char_start": 30, "char_end": 48, "token_start": 3, "token_end": 5}], "entities_global": [{"text": "gamma - interferon", "type": "ENTITY", "char_start": 162606, "char_end": 162624, "token_start": 3, "token_end": 5, "note": null}]}
+{"sentence_id": 990, "sentence_text": "Macrophage activation and correction of the dexamethasone effect by gamma - interferon , however , was dependent on the pathogen .", "sentence_char_start_global": 162737, "sentence_char_end_global": 162867, "entities": [{"text": "gamma - interferon", "type": "ENTITY", "char_start": 68, "char_end": 86, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "gamma - interferon", "type": "ENTITY", "char_start": 162805, "char_end": 162823, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 991, "sentence_text": "The lymphokine enhanced the antimicrobial activity of dexamethasone - treated macrophages against Listeria and Salmonella but not against Aspergillus or Nocardia .", "sentence_char_start_global": 162868, "sentence_char_end_global": 163031, "entities": [{"text": "lymphokine", "type": "ENTITY", "char_start": 4, "char_end": 14, "token_start": 1, "token_end": 1}], "entities_global": [{"text": "lymphokine", "type": "ENTITY", "char_start": 162872, "char_end": 162882, "token_start": 1, "token_end": 1, "note": null}]}
+{"sentence_id": 992, "sentence_text": "Dexamethasone - induced damage to the antimicrobial activity of human macrophages in vitro parallels observations that glucocorticoids render laboratory animals susceptible to listeriosis and aspergillosis by damaging resident macrophages .", "sentence_char_start_global": 163032, "sentence_char_end_global": 163272, "entities": [], "entities_global": []}
+{"sentence_id": 993, "sentence_text": "Suppression of macrophage antimicrobial activity should thus be considered when treating patients with glucocorticoids ; its prevention by gamma - interferon might be beneficial for some but not all pathogens .", "sentence_char_start_global": 163273, "sentence_char_end_global": 163483, "entities": [{"text": "gamma - interferon", "type": "ENTITY", "char_start": 139, "char_end": 157, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "gamma - interferon", "type": "ENTITY", "char_start": 163412, "char_end": 163430, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 994, "sentence_text": "Interleukin 2 receptor ( Tac antigen ) expression in HTLV - I - associated adult T - cell leukemia .", "sentence_char_start_global": 163484, "sentence_char_end_global": 163584, "entities": [{"text": "Interleukin 2 receptor", "type": "ENTITY", "char_start": 0, "char_end": 22, "token_start": 0, "token_end": 2}, {"text": "Tac antigen", "type": "ENTITY", "char_start": 25, "char_end": 36, "token_start": 4, "token_end": 5}], "entities_global": [{"text": "Interleukin 2 receptor", "type": "ENTITY", "char_start": 163484, "char_end": 163506, "token_start": 0, "token_end": 2, "note": null}, {"text": "Tac antigen", "type": "ENTITY", "char_start": 163509, "char_end": 163520, "token_start": 4, "token_end": 5, "note": null}]}
+{"sentence_id": 995, "sentence_text": "Interleukin - 2 ( IL - 2 ) is a lymphokine synthesized by some T - cells following activation .", "sentence_char_start_global": 163585, "sentence_char_end_global": 163680, "entities": [{"text": "Interleukin - 2", "type": "ENTITY", "char_start": 0, "char_end": 15, "token_start": 0, "token_end": 2}, {"text": "IL - 2", "type": "ENTITY", "char_start": 18, "char_end": 24, "token_start": 4, "token_end": 6}, {"text": "lymphokine", "type": "ENTITY", "char_start": 32, "char_end": 42, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "Interleukin - 2", "type": "ENTITY", "char_start": 163585, "char_end": 163600, "token_start": 0, "token_end": 2, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 163603, "char_end": 163609, "token_start": 4, "token_end": 6, "note": null}, {"text": "lymphokine", "type": "ENTITY", "char_start": 163617, "char_end": 163627, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 996, "sentence_text": "Resting T - cells do not express IL - 2 receptors , but receptors are rapidly expressed on T - cells following interaction of antigens , mitogens , or monoclonal antibodies with the antigen - specific T - cell receptor complex .", "sentence_char_start_global": 163681, "sentence_char_end_global": 163909, "entities": [{"text": "IL - 2 receptors", "type": "ENTITY", "char_start": 33, "char_end": 49, "token_start": 7, "token_end": 10}, {"text": "monoclonal antibodies", "type": "ENTITY", "char_start": 151, "char_end": 172, "token_start": 29, "token_end": 30}, {"text": "antigen - specific T - cell receptor complex", "type": "ENTITY", "char_start": 182, "char_end": 226, "token_start": 33, "token_end": 40}], "entities_global": [{"text": "IL - 2 receptors", "type": "ENTITY", "char_start": 163714, "char_end": 163730, "token_start": 7, "token_end": 10, "note": null}, {"text": "monoclonal antibodies", "type": "ENTITY", "char_start": 163832, "char_end": 163853, "token_start": 29, "token_end": 30, "note": null}, {"text": "antigen - specific T - cell receptor complex", "type": "ENTITY", "char_start": 163863, "char_end": 163907, "token_start": 33, "token_end": 40, "note": null}]}
+{"sentence_id": 997, "sentence_text": "Using anti - Tac , a monoclonal antibody that recognizes the IL - 2 receptor , the receptor has been purified and shown to be a Mr 33 , 000 peptide that is posttranslationally glycosylated to a Mr 55 , 000 mature form .", "sentence_char_start_global": 163910, "sentence_char_end_global": 164129, "entities": [{"text": "anti - Tac", "type": "ENTITY", "char_start": 6, "char_end": 16, "token_start": 1, "token_end": 3}, {"text": "monoclonal antibody", "type": "ENTITY", "char_start": 21, "char_end": 40, "token_start": 6, "token_end": 7}, {"text": "IL - 2 receptor", "type": "ENTITY", "char_start": 61, "char_end": 76, "token_start": 11, "token_end": 14}], "entities_global": [{"text": "anti - Tac", "type": "ENTITY", "char_start": 163916, "char_end": 163926, "token_start": 1, "token_end": 3, "note": null}, {"text": "monoclonal antibody", "type": "ENTITY", "char_start": 163931, "char_end": 163950, "token_start": 6, "token_end": 7, "note": null}, {"text": "IL - 2 receptor", "type": "ENTITY", "char_start": 163971, "char_end": 163986, "token_start": 11, "token_end": 14, "note": null}]}
+{"sentence_id": 998, "sentence_text": "Normal resting T - cells and most leukemic T - cell populations do not express IL - 2 receptors ; however , the leukemic cells of the 11 patients examined who had human T - cell lymphotropic virus - associated adult T - cell leukemia expressed the Tac antigen .", "sentence_char_start_global": 164130, "sentence_char_end_global": 164391, "entities": [{"text": "IL - 2 receptors", "type": "ENTITY", "char_start": 79, "char_end": 95, "token_start": 15, "token_end": 18}, {"text": "Tac antigen", "type": "ENTITY", "char_start": 248, "char_end": 259, "token_start": 47, "token_end": 48}], "entities_global": [{"text": "IL - 2 receptors", "type": "ENTITY", "char_start": 164209, "char_end": 164225, "token_start": 15, "token_end": 18, "note": null}, {"text": "Tac antigen", "type": "ENTITY", "char_start": 164378, "char_end": 164389, "token_start": 47, "token_end": 48, "note": null}]}
+{"sentence_id": 999, "sentence_text": "In human T - cell lymphotropic virus - I infected cells , the Mr 42 , 000 long open reading frame protein encoded in part by the pX region of this virus may act as a transacting transcriptional activator that induces IL - 2 receptor gene transcription , thus providing an explanation for the constant association of IL - 2 receptor expression with adult T - cell lymphotropic virus - I infection of lymphoid cells .", "sentence_char_start_global": 164392, "sentence_char_end_global": 164807, "entities": [{"text": "open reading frame protein", "type": "ENTITY", "char_start": 79, "char_end": 105, "token_start": 18, "token_end": 21}, {"text": "pX region", "type": "ENTITY", "char_start": 129, "char_end": 138, "token_start": 27, "token_end": 28}, {"text": "transacting transcriptional activator", "type": "ENTITY", "char_start": 166, "char_end": 203, "token_start": 36, "token_end": 38}, {"text": "IL - 2 receptor gene", "type": "ENTITY", "char_start": 217, "char_end": 237, "token_start": 41, "token_end": 45}, {"text": "IL - 2 receptor", "type": "ENTITY", "char_start": 316, "char_end": 331, "token_start": 57, "token_end": 60}], "entities_global": [{"text": "open reading frame protein", "type": "ENTITY", "char_start": 164471, "char_end": 164497, "token_start": 18, "token_end": 21, "note": null}, {"text": "pX region", "type": "ENTITY", "char_start": 164521, "char_end": 164530, "token_start": 27, "token_end": 28, "note": null}, {"text": "transacting transcriptional activator", "type": "ENTITY", "char_start": 164558, "char_end": 164595, "token_start": 36, "token_end": 38, "note": null}, {"text": "IL - 2 receptor gene", "type": "ENTITY", "char_start": 164609, "char_end": 164629, "token_start": 41, "token_end": 45, "note": null}, {"text": "IL - 2 receptor", "type": "ENTITY", "char_start": 164708, "char_end": 164723, "token_start": 57, "token_end": 60, "note": null}]}
+{"sentence_id": 1000, "sentence_text": "The constant expression of large numbers of IL - 2 receptors which may be aberrant may play a role in the uncontrolled growth of adult T - cell leukemia cells .", "sentence_char_start_global": 164808, "sentence_char_end_global": 164968, "entities": [{"text": "IL - 2 receptors", "type": "ENTITY", "char_start": 44, "char_end": 60, "token_start": 7, "token_end": 10}], "entities_global": [{"text": "IL - 2 receptors", "type": "ENTITY", "char_start": 164852, "char_end": 164868, "token_start": 7, "token_end": 10, "note": null}]}
+{"sentence_id": 1001, "sentence_text": "Two patients with Tac - positive adult T - cell leukemia have been treated with the anti - Tac .", "sentence_char_start_global": 164969, "sentence_char_end_global": 165065, "entities": [{"text": "anti - Tac", "type": "ENTITY", "char_start": 84, "char_end": 94, "token_start": 16, "token_end": 18}], "entities_global": [{"text": "anti - Tac", "type": "ENTITY", "char_start": 165053, "char_end": 165063, "token_start": 16, "token_end": 18, "note": null}]}
+{"sentence_id": 1002, "sentence_text": "One of the patients had 6 - and 3 - mo remissions of his leukemia following two courses of therapy with this monoclonal antibody directed toward this growth factor receptor .", "sentence_char_start_global": 165066, "sentence_char_end_global": 165240, "entities": [{"text": "monoclonal antibody", "type": "ENTITY", "char_start": 109, "char_end": 128, "token_start": 22, "token_end": 23}, {"text": "growth factor receptor", "type": "ENTITY", "char_start": 150, "char_end": 172, "token_start": 27, "token_end": 29}], "entities_global": [{"text": "monoclonal antibody", "type": "ENTITY", "char_start": 165175, "char_end": 165194, "token_start": 22, "token_end": 23, "note": null}, {"text": "growth factor receptor", "type": "ENTITY", "char_start": 165216, "char_end": 165238, "token_start": 27, "token_end": 29, "note": null}]}
+{"sentence_id": 1003, "sentence_text": "Lymphocyte glucocorticoid receptor binding in depressed patients with hypercortisolemia .", "sentence_char_start_global": 165241, "sentence_char_end_global": 165330, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 11, "char_end": 34, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 165252, "char_end": 165275, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 1004, "sentence_text": "Despite elevated levels of serum and urinary cortisol , patients with depressive illness manifest none of the clinical stigmata of glucocorticoid excess .", "sentence_char_start_global": 165331, "sentence_char_end_global": 165485, "entities": [], "entities_global": []}
+{"sentence_id": 1005, "sentence_text": "This hypercortisolemia in the absence of clinical effects suggests a state of hormone resistance and could be mediated by alterations in the glucocorticoid receptor .", "sentence_char_start_global": 165486, "sentence_char_end_global": 165652, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 141, "char_end": 164, "token_start": 22, "token_end": 23}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 165627, "char_end": 165650, "token_start": 22, "token_end": 23, "note": null}]}
+{"sentence_id": 1006, "sentence_text": "Earlier studies have shown that small doses of glucocorticoids cause a decrease in glucocorticoid receptor binding in normal human lymphocytes .", "sentence_char_start_global": 165653, "sentence_char_end_global": 165797, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 83, "char_end": 106, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 165736, "char_end": 165759, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 1007, "sentence_text": "White cells from depressed patients with significant hypercortisolemia would be expected to show a similar change in receptor concentration if peripheral tissues are adequately exposed to and sensitive to the hormone .", "sentence_char_start_global": 165798, "sentence_char_end_global": 166016, "entities": [], "entities_global": []}
+{"sentence_id": 1008, "sentence_text": "In this study we compared the binding of [ 3H ] dexamethasone to lymphocytes from normal subjects and depressed patients with hypercortisolemia .", "sentence_char_start_global": 166017, "sentence_char_end_global": 166162, "entities": [], "entities_global": []}
+{"sentence_id": 1009, "sentence_text": "Lymphocytes from normal subjects had a mean receptor concentration of 10 . 2 + / - 0 . 66 fm / 10 ( 6 ) cells ( S . E . M . ) and a dissociation constant of 4 . 8 + / - 0 . 47 nM .", "sentence_char_start_global": 166163, "sentence_char_end_global": 166343, "entities": [], "entities_global": []}
+{"sentence_id": 1010, "sentence_text": "Lymphocytes from depressed patients with abnormal 0800 h serum cortisol after dexamethasone had a mean receptor concentration of 8 . 8 + / - 0 . 75 fm / 10 ( 6 ) cells , which was not significantly different from that in lymphocytes from normal subjects or from depressed subjects with normal post - dexamethasone cortisol levels ( 9 . 4 + / - 0 . 95 fm / 10 ( 6 ) cells ) .", "sentence_char_start_global": 166344, "sentence_char_end_global": 166718, "entities": [], "entities_global": []}
+{"sentence_id": 1011, "sentence_text": "Lymphocytes from depressed patients with elevated urinary free cortisol excretion ( UFC ) also had normal receptor concentration and binding affinity for dexamethasone .", "sentence_char_start_global": 166719, "sentence_char_end_global": 166888, "entities": [], "entities_global": []}
+{"sentence_id": 1012, "sentence_text": "The lack of a change in lymphocyte glucocorticoid receptor concentration in the presence of cortisol excess suggests the possibility that hypercortisolemia in depressive illness represents a state of peripheral glucocorticoid resistance .", "sentence_char_start_global": 166889, "sentence_char_end_global": 167127, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 35, "char_end": 58, "token_start": 7, "token_end": 8}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 166924, "char_end": 166947, "token_start": 7, "token_end": 8, "note": null}]}
+{"sentence_id": 1013, "sentence_text": "Structure and regulation of the glucocorticoid hormone receptor .", "sentence_char_start_global": 167128, "sentence_char_end_global": 167193, "entities": [{"text": "glucocorticoid hormone receptor", "type": "ENTITY", "char_start": 32, "char_end": 63, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "glucocorticoid hormone receptor", "type": "ENTITY", "char_start": 167160, "char_end": 167191, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 1014, "sentence_text": "The glucocorticoid receptor is an intracellular protein which possesses three distinct domains , one that binds agonist and antagonist steroids , one that binds DNA , and one that binds anti - receptor antibodies and is required for glucocorticoid modulation of gene expression .", "sentence_char_start_global": 167194, "sentence_char_end_global": 167473, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 4, "char_end": 27, "token_start": 1, "token_end": 2}, {"text": "intracellular protein", "type": "ENTITY", "char_start": 34, "char_end": 55, "token_start": 5, "token_end": 6}, {"text": "anti - receptor antibodies", "type": "ENTITY", "char_start": 186, "char_end": 212, "token_start": 30, "token_end": 33}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 167198, "char_end": 167221, "token_start": 1, "token_end": 2, "note": null}, {"text": "intracellular protein", "type": "ENTITY", "char_start": 167228, "char_end": 167249, "token_start": 5, "token_end": 6, "note": null}, {"text": "anti - receptor antibodies", "type": "ENTITY", "char_start": 167380, "char_end": 167406, "token_start": 30, "token_end": 33, "note": null}]}
+{"sentence_id": 1015, "sentence_text": "In intact cells , receptor number , affinity and activity can change in response to factors that bind to the receptor , or that act indirectly through ill - defined mechanisms which may include resumption or arrest of cell cycling and variations in intracellular calcium ion concentrations .", "sentence_char_start_global": 167474, "sentence_char_end_global": 167765, "entities": [], "entities_global": []}
+{"sentence_id": 1016, "sentence_text": "Some of these factors appear to exert their effect by controlling critical receptor properties such as ATP - dependent phosphorylation , integrity of thiol groups , and exposure of key amino acid residues .", "sentence_char_start_global": 167766, "sentence_char_end_global": 167972, "entities": [{"text": "thiol groups", "type": "ENTITY", "char_start": 150, "char_end": 162, "token_start": 23, "token_end": 24}, {"text": "key amino acid residues", "type": "ENTITY", "char_start": 181, "char_end": 204, "token_start": 29, "token_end": 32}], "entities_global": [{"text": "thiol groups", "type": "ENTITY", "char_start": 167916, "char_end": 167928, "token_start": 23, "token_end": 24, "note": null}, {"text": "key amino acid residues", "type": "ENTITY", "char_start": 167947, "char_end": 167970, "token_start": 29, "token_end": 32, "note": null}]}
+{"sentence_id": 1017, "sentence_text": "Glucocorticoid agonists promote the ' transformation ' of the receptor into the DNA - binding state , which is competent for modulating gene expression .", "sentence_char_start_global": 167973, "sentence_char_end_global": 168126, "entities": [], "entities_global": []}
+{"sentence_id": 1018, "sentence_text": "Glucocorticoid antagonists are steroids that interact with the receptor but either fail to produce a stable complex or produce a stable but inefficient complex .", "sentence_char_start_global": 168127, "sentence_char_end_global": 168288, "entities": [{"text": "stable complex", "type": "ENTITY", "char_start": 101, "char_end": 115, "token_start": 15, "token_end": 16}, {"text": "stable but inefficient complex", "type": "ENTITY", "char_start": 129, "char_end": 159, "token_start": 20, "token_end": 23}], "entities_global": [{"text": "stable complex", "type": "ENTITY", "char_start": 168228, "char_end": 168242, "token_start": 15, "token_end": 16, "note": null}, {"text": "stable but inefficient complex", "type": "ENTITY", "char_start": 168256, "char_end": 168286, "token_start": 20, "token_end": 23, "note": null}]}
+{"sentence_id": 1019, "sentence_text": "Although substituent groups that confer agonist or antagonist activity to the steroid have been identified , the molecular determinants of this difference at the receptor level remain unknown .", "sentence_char_start_global": 168289, "sentence_char_end_global": 168482, "entities": [], "entities_global": []}
+{"sentence_id": 1020, "sentence_text": "Most in vitro and in vivo data on receptor regulation can be accommodated by postulating the existence of an intracellular cycle that involves five states of the receptor .", "sentence_char_start_global": 168483, "sentence_char_end_global": 168655, "entities": [], "entities_global": []}
+{"sentence_id": 1021, "sentence_text": "The active free receptor is phosphorylated , reduced , and presumably oligomeric ( state A ) .", "sentence_char_start_global": 168656, "sentence_char_end_global": 168750, "entities": [], "entities_global": []}
+{"sentence_id": 1022, "sentence_text": "Following binding of an agonist ( state B ) , it can become transformed by dissociation into its subunits and dephosphorylation ( state C ) .", "sentence_char_start_global": 168751, "sentence_char_end_global": 168892, "entities": [], "entities_global": []}
+{"sentence_id": 1023, "sentence_text": "The transformed receptor then interacts with chromatin ( state D ) .", "sentence_char_start_global": 168893, "sentence_char_end_global": 168961, "entities": [{"text": "transformed receptor", "type": "ENTITY", "char_start": 4, "char_end": 24, "token_start": 1, "token_end": 2}, {"text": "chromatin", "type": "ENTITY", "char_start": 45, "char_end": 54, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "transformed receptor", "type": "ENTITY", "char_start": 168897, "char_end": 168917, "token_start": 1, "token_end": 2, "note": null}, {"text": "chromatin", "type": "ENTITY", "char_start": 168938, "char_end": 168947, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 1024, "sentence_text": "Dissociation of the steroid and oxidation of receptor thiol group ( s ) lead to the inactive receptor form ( state E ) .", "sentence_char_start_global": 168962, "sentence_char_end_global": 169082, "entities": [{"text": "receptor thiol group", "type": "ENTITY", "char_start": 45, "char_end": 65, "token_start": 7, "token_end": 9}], "entities_global": [{"text": "receptor thiol group", "type": "ENTITY", "char_start": 169007, "char_end": 169027, "token_start": 7, "token_end": 9, "note": null}]}
+{"sentence_id": 1025, "sentence_text": "Reduction and rephosphorylation of the receptor enable it to bind steroids again so that the cycle is closed .", "sentence_char_start_global": 169083, "sentence_char_end_global": 169193, "entities": [], "entities_global": []}
+{"sentence_id": 1026, "sentence_text": "Thermodynamics of steroid binding to the human glucocorticoid receptor .", "sentence_char_start_global": 169194, "sentence_char_end_global": 169266, "entities": [{"text": "human glucocorticoid receptor", "type": "ENTITY", "char_start": 41, "char_end": 70, "token_start": 6, "token_end": 8}], "entities_global": [{"text": "human glucocorticoid receptor", "type": "ENTITY", "char_start": 169235, "char_end": 169264, "token_start": 6, "token_end": 8, "note": null}]}
+{"sentence_id": 1027, "sentence_text": "The thermodynamics of the interaction of glucocorticoids with their receptor were studied in cytosol from human lymphoblastoid cells .", "sentence_char_start_global": 169267, "sentence_char_end_global": 169401, "entities": [], "entities_global": []}
+{"sentence_id": 1028, "sentence_text": "The rate and affinity constants of dexamethasone and cortisol between 0 degree and 25 degrees C were calculated by curve - fitting from time - course and equilibrium kinetics .", "sentence_char_start_global": 169402, "sentence_char_end_global": 169578, "entities": [], "entities_global": []}
+{"sentence_id": 1029, "sentence_text": "The data were consistent with a simple reversible bimolecular interaction .", "sentence_char_start_global": 169579, "sentence_char_end_global": 169654, "entities": [], "entities_global": []}
+{"sentence_id": 1030, "sentence_text": "Arrhenius and Va n ' t Hoff plots were curvilinear for both steroids .", "sentence_char_start_global": 169655, "sentence_char_end_global": 169725, "entities": [], "entities_global": []}
+{"sentence_id": 1031, "sentence_text": "At equilibrium , the solution for the equation delta G = delta H - T X delta S ( eqn . 1 ) was ( in kJ X mol - 1 ) - 47 = 36 - 83 ( dexamethasone ) and - 42 = - 9 - 33 ( cortisol ) at 0 degree C .", "sentence_char_start_global": 169726, "sentence_char_end_global": 169922, "entities": [], "entities_global": []}
+{"sentence_id": 1032, "sentence_text": "Enthalpy and entropy changes decreased quasi - linearly with temperature such that , at 25 degrees C , the respective values were - 50 = - 75 + 25 and - 43 = - 48 + 5 .", "sentence_char_start_global": 169923, "sentence_char_end_global": 170091, "entities": [], "entities_global": []}
+{"sentence_id": 1033, "sentence_text": "Thus , for both steroids , the interaction was entropy - driven at low temperature and became entirely enthalpy - driven at 20 degrees C .", "sentence_char_start_global": 170092, "sentence_char_end_global": 170230, "entities": [], "entities_global": []}
+{"sentence_id": 1034, "sentence_text": "Thermodynamic values for the transition state were calculated from the rate constants .", "sentence_char_start_global": 170231, "sentence_char_end_global": 170318, "entities": [], "entities_global": []}
+{"sentence_id": 1035, "sentence_text": "For the forward reaction , eqn . ( 1 ) gave 45 = 84 - 39 ( dexamethasone ) and 46 = 60 - 14 ( cortisol ) at 0 degree C , and 44 = 24 + 20 ( dexamethasone ) and 46 = 28 + 18 ( cortisol ) at 25 degrees C .", "sentence_char_start_global": 170319, "sentence_char_end_global": 170522, "entities": [], "entities_global": []}
+{"sentence_id": 1036, "sentence_text": "These data fit quite well with a two - step model [ Ross & Subramanian ( 1981 ) Biochemistry 20 , 3096 - 3102 ] proposed for ligand - protein interactions , which involves a partial immobilization of the reacting species governed by hydrophobic forces , followed by stabilization of the complex by short - range interactions .", "sentence_char_start_global": 170523, "sentence_char_end_global": 170849, "entities": [], "entities_global": []}
+{"sentence_id": 1037, "sentence_text": "On the basis of this model , an analysis of the transition - state thermodynamics led to the conclusion that no more than half of the steroid molecular area is engaged in the binding process .", "sentence_char_start_global": 170850, "sentence_char_end_global": 171042, "entities": [], "entities_global": []}
+{"sentence_id": 1038, "sentence_text": "Cell cycle - related changes in number of T - lymphocyte receptors for glucocorticoids and insulin .", "sentence_char_start_global": 171043, "sentence_char_end_global": 171143, "entities": [{"text": "T - lymphocyte receptors", "type": "ENTITY", "char_start": 42, "char_end": 66, "token_start": 8, "token_end": 11}], "entities_global": [{"text": "T - lymphocyte receptors", "type": "ENTITY", "char_start": 171085, "char_end": 171109, "token_start": 8, "token_end": 11, "note": null}]}
+{"sentence_id": 1039, "sentence_text": "Enriched human peripheral T - lymphocytes were stimulated with PHA and examined for variations in insulin and glucocorticoid ( dexamethasone ) receptor numbers during the early phases of the cell cycle .", "sentence_char_start_global": 171144, "sentence_char_end_global": 171347, "entities": [], "entities_global": []}
+{"sentence_id": 1040, "sentence_text": "Cells in G0 , G1a and G1b phases , where the G1a - G1b transition is an Interleukin 2 dependent event , were quantitated by flow cytometry .", "sentence_char_start_global": 171348, "sentence_char_end_global": 171488, "entities": [{"text": "Interleukin 2", "type": "ENTITY", "char_start": 72, "char_end": 85, "token_start": 17, "token_end": 18}], "entities_global": [{"text": "Interleukin 2", "type": "ENTITY", "char_start": 171420, "char_end": 171433, "token_start": 17, "token_end": 18, "note": null}]}
+{"sentence_id": 1041, "sentence_text": "Few but significant numbers of glucocorticoid receptors ( 2700 / cell ) and no insulin receptors ( - 1 / cell ) were found in the resting ( G0 ) phase .", "sentence_char_start_global": 171489, "sentence_char_end_global": 171641, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 31, "char_end": 55, "token_start": 5, "token_end": 6}, {"text": "insulin receptors", "type": "ENTITY", "char_start": 79, "char_end": 96, "token_start": 14, "token_end": 15}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 171520, "char_end": 171544, "token_start": 5, "token_end": 6, "note": null}, {"text": "insulin receptors", "type": "ENTITY", "char_start": 171568, "char_end": 171585, "token_start": 14, "token_end": 15, "note": null}]}
+{"sentence_id": 1042, "sentence_text": "As cells entered the G1a phase the specific binding of dexamethasone increased and of insulin took place .", "sentence_char_start_global": 171642, "sentence_char_end_global": 171748, "entities": [], "entities_global": []}
+{"sentence_id": 1043, "sentence_text": "Although the specific binding further increased as T - cells entered the G1b phase ( as measured at 44 h of incubation and using hydroxyurea - treated cells ) , the major changes in the specific binding of dexamethasone took place during the period 16 - 20 h after stimulation .", "sentence_char_start_global": 171749, "sentence_char_end_global": 172027, "entities": [], "entities_global": []}
+{"sentence_id": 1044, "sentence_text": "Based on these findings , it is concluded that both receptor types ( cell membrane and cytoplasmic receptors ) are being formed and increased at G1 phase prior to cell proliferation , indicating the importance of G1 phase in immunoregulation .", "sentence_char_start_global": 172028, "sentence_char_end_global": 172271, "entities": [{"text": "cell membrane and cytoplasmic receptors", "type": "ENTITY", "char_start": 69, "char_end": 108, "token_start": 13, "token_end": 17}], "entities_global": [{"text": "cell membrane and cytoplasmic receptors", "type": "ENTITY", "char_start": 172097, "char_end": 172136, "token_start": 13, "token_end": 17, "note": null}]}
+{"sentence_id": 1045, "sentence_text": "Glucocorticoid receptors and cortico - sensitivity in a human clonal monocytic cell line , CM - SM .", "sentence_char_start_global": 172272, "sentence_char_end_global": 172372, "entities": [{"text": "Glucocorticoid receptors", "type": "ENTITY", "char_start": 0, "char_end": 24, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "Glucocorticoid receptors", "type": "ENTITY", "char_start": 172272, "char_end": 172296, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 1046, "sentence_text": "CM - SM is a clonal line of human precursor mononuclear phagocytes inducible to macrophage differentiation in response to the tumor promoter phorbol ester 12 - O - tetradecanoyl - phorbol - 13 - acetate ( TPA ) .", "sentence_char_start_global": 172373, "sentence_char_end_global": 172585, "entities": [], "entities_global": []}
+{"sentence_id": 1047, "sentence_text": "Untreated CM - SM cells contain single class , high - affinity ( KD = 4 . 0 X 10 ( - 9 ) M ) glucocorticoid - specific receptor sites ( approximately 60 , 000 per cell ) , as measured by a whole cell assay , at 37 degrees C , using [ 3H ] triamcinolone acetonide ( TA ) .", "sentence_char_start_global": 172586, "sentence_char_end_global": 172857, "entities": [], "entities_global": []}
+{"sentence_id": 1048, "sentence_text": "Exposure of CM - SM to dexamethasone ( DEX ) produced a progressive , dose - and time - related series of changes in CM - SM cell growth , saturation density , morphology , and functional properties , with half - maximal effects at about 10 ( - 9 ) M for DEX .", "sentence_char_start_global": 172858, "sentence_char_end_global": 173118, "entities": [], "entities_global": []}
+{"sentence_id": 1049, "sentence_text": "TA - receptor sites rapidly decreased ( about 70 % ) after DEX treatment , without any apparent change in steroid specificity and affinity .", "sentence_char_start_global": 173119, "sentence_char_end_global": 173259, "entities": [], "entities_global": []}
+{"sentence_id": 1050, "sentence_text": "After 5 days in culture with a saturating concentration ( 3 . 6 X 10 ( - 8 ) M ) of hormone , the cells reached a saturation density of about 9 . 0 X 10 ( 6 ) viable cells / ml ( about 4 . 0 X 10 ( 6 ) viable cells / ml in the controls ) , while the modal volume of the resulting cell population was approximately 60 % , as compared to the volume of untreated cells .", "sentence_char_start_global": 173260, "sentence_char_end_global": 173627, "entities": [], "entities_global": []}
+{"sentence_id": 1051, "sentence_text": "DEX - treated cells appeared less differentiated than controls , as assessed by combined morphologic , antigenic , and cytoenzymatic analyses .", "sentence_char_start_global": 173628, "sentence_char_end_global": 173771, "entities": [], "entities_global": []}
+{"sentence_id": 1052, "sentence_text": "DEX almost completely inhibited TPA activation of the following macrophage functions : adherency to the culture plate , expression of lysosomal enzymes , Fc and C3 receptors , and stimulation of phagocytosis .", "sentence_char_start_global": 173772, "sentence_char_end_global": 173981, "entities": [{"text": "lysosomal enzymes", "type": "ENTITY", "char_start": 134, "char_end": 151, "token_start": 20, "token_end": 21}, {"text": "Fc and C3 receptors", "type": "ENTITY", "char_start": 154, "char_end": 173, "token_start": 23, "token_end": 26}], "entities_global": [{"text": "lysosomal enzymes", "type": "ENTITY", "char_start": 173906, "char_end": 173923, "token_start": 20, "token_end": 21, "note": null}, {"text": "Fc and C3 receptors", "type": "ENTITY", "char_start": 173926, "char_end": 173945, "token_start": 23, "token_end": 26, "note": null}]}
+{"sentence_id": 1053, "sentence_text": "After removal of DEX , the cells , within a few passages , returned to a state apparently identical to the untreated controls and could be induced to macrophage differentiation in response to TPA .", "sentence_char_start_global": 173982, "sentence_char_end_global": 174179, "entities": [], "entities_global": []}
+{"sentence_id": 1054, "sentence_text": "Acute lymphoblastic leukemia in children : current status , controversies , and future perspective .", "sentence_char_start_global": 174180, "sentence_char_end_global": 174280, "entities": [], "entities_global": []}
+{"sentence_id": 1055, "sentence_text": "Disease - free survival ( DFS ) in childhood ALL is 60 % , and survival in good , average , and poor prognostic groups defined by initial WBC and age is 90 , 60 , and 45 % , respectively .", "sentence_char_start_global": 174281, "sentence_char_end_global": 174469, "entities": [], "entities_global": []}
+{"sentence_id": 1056, "sentence_text": "Additional immunological , morphological , biochemical , cytokinetic , and cytogenetic factors have been identified , illustrating the heterogeneity of ALL and its derivation from malignant clones at various stages of differentiation and with varying rates of proliferation .", "sentence_char_start_global": 174470, "sentence_char_end_global": 174745, "entities": [], "entities_global": []}
+{"sentence_id": 1057, "sentence_text": "Of biologic importance , these factors may refine further the characteristic features of clinically - determined prognostic groups .", "sentence_char_start_global": 174746, "sentence_char_end_global": 174878, "entities": [], "entities_global": []}
+{"sentence_id": 1058, "sentence_text": "Multivariate analysis of large prospective trials with homogeneous therapy will be required to determine the independent prognostic importance of these factors .", "sentence_char_start_global": 174879, "sentence_char_end_global": 175040, "entities": [], "entities_global": []}
+{"sentence_id": 1059, "sentence_text": "Current treatment strategies in ALL include ( 1 ) tailoring therapy and its intensity to prognostic groups ; ( 2 ) multiple - drug combinations in induction ; ( 3 ) early use of intrathecal ( IT ) methotrexate ( MTX ) ; ( 4 ) CNS prophylaxis with IT MTX alone in good prognosis patients and combined cranial radiation ( CXRT ) , 1800 rads plus IT MTX , in average and poor prognosis patients .", "sentence_char_start_global": 175041, "sentence_char_end_global": 175434, "entities": [], "entities_global": []}
+{"sentence_id": 1060, "sentence_text": "Current studies show a CNS relapse rate of 5 % in all prognostic groups .", "sentence_char_start_global": 175435, "sentence_char_end_global": 175508, "entities": [], "entities_global": []}
+{"sentence_id": 1061, "sentence_text": "Late neuropsychological defects caused by cranial XRT and IT MTX have prompted programs designed to reduce the potential late toxicity of CNS prophylaxis .", "sentence_char_start_global": 175509, "sentence_char_end_global": 175664, "entities": [], "entities_global": []}
+{"sentence_id": 1062, "sentence_text": "More pronounced in younger children , these abnormalities include decreased IQ , visual - motor incoordination , poor performance in mathematics , and memory dysfunction .", "sentence_char_start_global": 175665, "sentence_char_end_global": 175836, "entities": [], "entities_global": []}
+{"sentence_id": 1063, "sentence_text": "Until 1980 , more intensive induction , consolidation , and maintenance therapy had failed to prolong DFS in children with a poor prognosis .", "sentence_char_start_global": 175837, "sentence_char_end_global": 175978, "entities": [], "entities_global": []}
+{"sentence_id": 1064, "sentence_text": "In West Germany ( Berlin - Frankfurt - Muenster protocol ) a 70 to 75 % DFS is seen in all patients regardless of initial WBC , suggesting that effective therapy will override prognostic factors .", "sentence_char_start_global": 175979, "sentence_char_end_global": 176175, "entities": [], "entities_global": []}
+{"sentence_id": 1065, "sentence_text": "Ultra - high - dose MTX , without cranial radiation , is also showing promise in poor prognosis patients .", "sentence_char_start_global": 176176, "sentence_char_end_global": 176282, "entities": [], "entities_global": []}
+{"sentence_id": 1066, "sentence_text": "Other issues include the optimal duration of therapy , the role of testicular biopsies , and prophylactic testicular radiation .", "sentence_char_start_global": 176283, "sentence_char_end_global": 176411, "entities": [], "entities_global": []}
+{"sentence_id": 1067, "sentence_text": "Recent studies suggest that prognostic factors lose their significance after 2 years of continuous complete remission and that 2 years of maintenance therapy is adequate .", "sentence_char_start_global": 176412, "sentence_char_end_global": 176583, "entities": [], "entities_global": []}
+{"sentence_id": 1068, "sentence_text": "Bilateral open - wedge testicular biopsies have identified occult testicular disease in 8 to 10 % of males .", "sentence_char_start_global": 176584, "sentence_char_end_global": 176692, "entities": [], "entities_global": []}
+{"sentence_id": 1069, "sentence_text": "A unified approach to children with leukemia / lymphoma , a group with a particularly poor prognosis , utilizing NHL - type therapy may be more effective than conventional ALL therapy .", "sentence_char_start_global": 176693, "sentence_char_end_global": 176878, "entities": [], "entities_global": []}
+{"sentence_id": 1070, "sentence_text": "( ABSTRACT TRUNCATED AT 400 WORDS )", "sentence_char_start_global": 176879, "sentence_char_end_global": 176914, "entities": [], "entities_global": []}
+{"sentence_id": 1071, "sentence_text": "Glucocorticoid receptor and in vitro sensitivity to steroid hormones in human lymphoproliferative diseases and myeloid leukemia .", "sentence_char_start_global": 176915, "sentence_char_end_global": 177044, "entities": [{"text": "Glucocorticoid receptor", "type": "ENTITY", "char_start": 0, "char_end": 23, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "Glucocorticoid receptor", "type": "ENTITY", "char_start": 176915, "char_end": 176938, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 1072, "sentence_text": "The glucocorticoid receptor ( GR ) quantitation by a whole - cell assay and / or cytosol technique and the in vitro sensitivity to steroids have been assessed in peripheral blood cells from normal donors and patients with chronic lymphatic leukemia ( CLL ) , acute lymphoblastic leukemia ( ALL ) , lymphosarcoma cell leukemia ( LSCL ) , acute nonlymphatic leukemia ( ANLL ) , and chronic myeloid leukemia ( CML ) .", "sentence_char_start_global": 177045, "sentence_char_end_global": 177459, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 4, "char_end": 27, "token_start": 1, "token_end": 2}, {"text": "GR", "type": "ENTITY", "char_start": 30, "char_end": 32, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 177049, "char_end": 177072, "token_start": 1, "token_end": 2, "note": null}, {"text": "GR", "type": "ENTITY", "char_start": 177075, "char_end": 177077, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 1073, "sentence_text": "Within the lymphoproliferative diseases , ALL cells exhibited the highest GR concentration ( regardless of the method used ) and the highest in vitro inhibition of spontaneous [ 3H ] thymidine ( [ 3H ] TdR ) uptake by glucocorticoids .", "sentence_char_start_global": 177460, "sentence_char_end_global": 177695, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 74, "char_end": 76, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 177534, "char_end": 177536, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 1074, "sentence_text": "A significant relationship between GR concentration ( whole - cell assay ) and in vitro sensitivity to dexamethasone was also found .", "sentence_char_start_global": 177696, "sentence_char_end_global": 177829, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 35, "char_end": 37, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 177731, "char_end": 177733, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 1075, "sentence_text": "On the contrary , CLL cells presented the highest sensitivity to glucocorticoids in PHA - stimulated cell cultures .", "sentence_char_start_global": 177830, "sentence_char_end_global": 177946, "entities": [], "entities_global": []}
+{"sentence_id": 1076, "sentence_text": "Cells from the only two ALL patients who did not undergo a remission after glucocorticoid - inclusive chemotherapy had both the lowest in vitro sensitivity to dexamethasone and the lowest GR concentration with whole - cell assay .", "sentence_char_start_global": 177947, "sentence_char_end_global": 178177, "entities": [], "entities_global": []}
+{"sentence_id": 1077, "sentence_text": "Concerning myeloid leukemia , ANLL patients had GR concentrations slightly higher than those found in the ALL group but exhibited the lowest degree of inhibition of spontaneous [ 3H ] TdR uptake by dexamethasone ( stimulatory effects occurred in some cases ) .", "sentence_char_start_global": 178178, "sentence_char_end_global": 178438, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 48, "char_end": 50, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 178226, "char_end": 178228, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 1078, "sentence_text": "CML cells exhibited an inhibition degree by in vitro glucocorticoids significantly higher than that of ANLL cells but not different from that of lymphoproliferative diseases .", "sentence_char_start_global": 178439, "sentence_char_end_global": 178614, "entities": [], "entities_global": []}
+{"sentence_id": 1079, "sentence_text": "No clear relationship among GR pattern , in vitro cell sensitivity to glucocorticoids , and clinicohematologic parameters was observed in myeloid leukemia - bearing patients .", "sentence_char_start_global": 178615, "sentence_char_end_global": 178790, "entities": [], "entities_global": []}
+{"sentence_id": 1080, "sentence_text": "Glucocorticoid receptors and in vitro corticosensitivity of peanut - positive and peanut - negative human thymocyte subpopulations .", "sentence_char_start_global": 178791, "sentence_char_end_global": 178923, "entities": [{"text": "Glucocorticoid receptors", "type": "ENTITY", "char_start": 0, "char_end": 24, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "Glucocorticoid receptors", "type": "ENTITY", "char_start": 178791, "char_end": 178815, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 1081, "sentence_text": "In 6 human thymus glands , the immature subset of thymocytes was separated from the more mature one , by differential peanut lectin agglutination .", "sentence_char_start_global": 178924, "sentence_char_end_global": 179071, "entities": [], "entities_global": []}
+{"sentence_id": 1082, "sentence_text": "These 2 cell subpopulations were analyzed for glucocorticoid receptor content by using a whole cell assay , with ( 3H ) - triamcinolone acetonide as tracer .", "sentence_char_start_global": 179072, "sentence_char_end_global": 179229, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 46, "char_end": 69, "token_start": 7, "token_end": 8}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 179118, "char_end": 179141, "token_start": 7, "token_end": 8, "note": null}]}
+{"sentence_id": 1083, "sentence_text": "The unagglutinated thymocytes ( peanut negative ) contained about 2 times more receptor sites per cell than agglutinated ( peanut positive ) ones ( 7650 + / - 1550 S . D . verus 3195 + / - 896 S . D . ) .", "sentence_char_start_global": 179230, "sentence_char_end_global": 179434, "entities": [], "entities_global": []}
+{"sentence_id": 1084, "sentence_text": "The affinity for steroid was similar in both cell subsets , as was the stereospecificity for glucocorticoids , the time - course of steroid - receptor association , and cytoplasmic to nuclear translocation .", "sentence_char_start_global": 179435, "sentence_char_end_global": 179642, "entities": [], "entities_global": []}
+{"sentence_id": 1085, "sentence_text": "Despite the greater number of glucocorticoid receptor sites , the peanut - negative thymocyte subpopulation did not differ from the peanut - positive one in its sensitivity to the inhibitory effects of triamcinolone acetonide , as determined by measurements of the incorporation of radiolabeled precursors of protein and DNA .", "sentence_char_start_global": 179643, "sentence_char_end_global": 179969, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 30, "char_end": 53, "token_start": 5, "token_end": 6}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 179673, "char_end": 179696, "token_start": 5, "token_end": 6, "note": null}]}
+{"sentence_id": 1086, "sentence_text": "Moreover , the peanut - negative subset appeared more resistant in vitro to the steroid - induced cell lysis as compared to the peanut - positive one .", "sentence_char_start_global": 179970, "sentence_char_end_global": 180121, "entities": [], "entities_global": []}
+{"sentence_id": 1087, "sentence_text": "Thus , our data suggest that glucocorticoid receptor density and corticosensitivity are not directly correlated and that the number of glucocorticoid receptor sites may be dependent on the degree of immunologic maturation", "sentence_char_start_global": 180122, "sentence_char_end_global": 180343, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 135, "char_end": 158, "token_start": 20, "token_end": 21}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 180257, "char_end": 180280, "token_start": 20, "token_end": 21, "note": null}]}
+{"sentence_id": 1088, "sentence_text": "Defective binding and function of 1 , 25 - dihydroxyvitamin D3 receptors in peripheral mononuclear cells of patients with end - organ resistance to 1 , 25 - dihydroxyvitamin D .", "sentence_char_start_global": 180344, "sentence_char_end_global": 180521, "entities": [{"text": "1 , 25 - dihydroxyvitamin D3 receptors", "type": "ENTITY", "char_start": 34, "char_end": 72, "token_start": 5, "token_end": 11}], "entities_global": [{"text": "1 , 25 - dihydroxyvitamin D3 receptors", "type": "ENTITY", "char_start": 180378, "char_end": 180416, "token_start": 5, "token_end": 11, "note": null}]}
+{"sentence_id": 1089, "sentence_text": "Lectin - induced DNA synthesis by peripheral mononuclear cells from 17 normal donors was inhibited ( 40 - 60 % ) by 1 , 25 - dihydroxyvitamin D3 ( 1 , 25 [ OH ] 2D3 ) at physiological concentrations ( 10 ( - 10 ) - 10 ( - 9 ) M ) .", "sentence_char_start_global": 180522, "sentence_char_end_global": 180753, "entities": [], "entities_global": []}
+{"sentence_id": 1090, "sentence_text": "The lymphocytes acquire specific receptors for 1 , 25 ( OH ) 2D3 upon activation by the lectins .", "sentence_char_start_global": 180754, "sentence_char_end_global": 180851, "entities": [{"text": "lectins", "type": "ENTITY", "char_start": 88, "char_end": 95, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "lectins", "type": "ENTITY", "char_start": 180842, "char_end": 180849, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 1091, "sentence_text": "This process precedes the inhibitory effect of 1 , 25 ( OH ) 2D3 .", "sentence_char_start_global": 180852, "sentence_char_end_global": 180918, "entities": [], "entities_global": []}
+{"sentence_id": 1092, "sentence_text": "We studied lymphocytes from six patients from four different kindreds with the syndrome of hereditary end - organ resistance to 1 , 25 ( OH ) 2D ( the so - called vitamin D - dependent rickets type II ) .", "sentence_char_start_global": 180919, "sentence_char_end_global": 181123, "entities": [], "entities_global": []}
+{"sentence_id": 1093, "sentence_text": "In five patients ( three kindreds ) peripheral blood mononuclear cells did not acquire receptors for 1 , 25 ( OH ) 2D3 upon phytohemagglutinin - induced activation .", "sentence_char_start_global": 181124, "sentence_char_end_global": 181289, "entities": [], "entities_global": []}
+{"sentence_id": 1094, "sentence_text": "Moreover , in contrast to normal lymphocytes , the mitogenic stimulation of these patients ' lymphocytes by phytohemagglutinin and concanavalin A was not inhibited by 1 , 25 ( OH ) 2D3 .", "sentence_char_start_global": 181290, "sentence_char_end_global": 181476, "entities": [{"text": "phytohemagglutinin", "type": "ENTITY", "char_start": 108, "char_end": 126, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "phytohemagglutinin", "type": "ENTITY", "char_start": 181398, "char_end": 181416, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 1095, "sentence_text": "Activated lymphocytes of the sixth patient from a fourth kindred exhibited normal binding of [ 3H ] 1 , 25 ( OH ) 2D3 but the hormone failed to inhibit the mitogenic stimulation .", "sentence_char_start_global": 181477, "sentence_char_end_global": 181656, "entities": [], "entities_global": []}
+{"sentence_id": 1096, "sentence_text": "A similar pattern of the vitamin D effector system was previously observed in fibroblasts cultured from skin biopsies of the same group of patients .", "sentence_char_start_global": 181657, "sentence_char_end_global": 181806, "entities": [], "entities_global": []}
+{"sentence_id": 1097, "sentence_text": "The conclusions from these findings are : ( a ) the inhibition of mitogenic stimulation by 1 , 25 ( OH ) 2D3 is mediated by specific functional receptors to the hormone ; and ( b ) the receptors for 1 , 25 ( OH ) 2D3 in mononuclear cells are probably controlled genetically by the same mechanisms as the effector system in well - characterized target organs of the hormone , such as intestine and kidney .", "sentence_char_start_global": 181807, "sentence_char_end_global": 182212, "entities": [{"text": "specific functional receptors", "type": "ENTITY", "char_start": 124, "char_end": 153, "token_start": 26, "token_end": 28}], "entities_global": [{"text": "specific functional receptors", "type": "ENTITY", "char_start": 181931, "char_end": 181960, "token_start": 26, "token_end": 28, "note": null}]}
+{"sentence_id": 1098, "sentence_text": "Glucocorticoid receptors of mononuclear leukocytes from myasthenia gravis patients .", "sentence_char_start_global": 182213, "sentence_char_end_global": 182297, "entities": [{"text": "Glucocorticoid receptors", "type": "ENTITY", "char_start": 0, "char_end": 24, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "Glucocorticoid receptors", "type": "ENTITY", "char_start": 182213, "char_end": 182237, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 1099, "sentence_text": "The present study was performed to analyse glucocorticoid receptor ( GR ) binding in peripheral blood mononuclear leukocytes ( MNL ) from 39 myasthenia gravis ( MG ) patients ( unoperated patients ( n = 13 ) , thymectomized patients ( n = 14 ) and patients receiving glucocorticoids : thymectomized ( n = 11 ) and unoperated ( n = 6 ] .", "sentence_char_start_global": 182298, "sentence_char_end_global": 182634, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 43, "char_end": 66, "token_start": 7, "token_end": 8}, {"text": "GR", "type": "ENTITY", "char_start": 69, "char_end": 71, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 182341, "char_end": 182364, "token_start": 7, "token_end": 8, "note": null}, {"text": "GR", "type": "ENTITY", "char_start": 182367, "char_end": 182369, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 1100, "sentence_text": "A whole cell binding assay with 3 ( H ) dexamethasone was used .", "sentence_char_start_global": 182635, "sentence_char_end_global": 182699, "entities": [], "entities_global": []}
+{"sentence_id": 1101, "sentence_text": "GR mean values were significantly higher in the MNL of MG patients ( thymectomized or not ) not receiving glucocorticoid than in the MNL of healthy donors .", "sentence_char_start_global": 182700, "sentence_char_end_global": 182856, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 0, "char_end": 2, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 182700, "char_end": 182702, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 1102, "sentence_text": "Affinity was within the normal range .", "sentence_char_start_global": 182857, "sentence_char_end_global": 182895, "entities": [], "entities_global": []}
+{"sentence_id": 1103, "sentence_text": "Sex , age or clinical forms of illness did not influence the results .", "sentence_char_start_global": 182896, "sentence_char_end_global": 182966, "entities": [], "entities_global": []}
+{"sentence_id": 1104, "sentence_text": "In patients receiving prednisone ( Pd ) the GR values were significantly lower than in MG patients without Pd therapy , independent of Pd dose or time of administration .", "sentence_char_start_global": 182967, "sentence_char_end_global": 183137, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 44, "char_end": 46, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 183011, "char_end": 183013, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 1105, "sentence_text": "No differences in receptor binding between normal subjects and MG patients receiving Pd have been found .", "sentence_char_start_global": 183138, "sentence_char_end_global": 183243, "entities": [], "entities_global": []}
+{"sentence_id": 1106, "sentence_text": "Immunological interference of high dose corticosteroids .", "sentence_char_start_global": 183244, "sentence_char_end_global": 183301, "entities": [], "entities_global": []}
+{"sentence_id": 1107, "sentence_text": "High - dose corticosteroids ( HDC ) will influence cellular as well as humoral participants of the immune response .", "sentence_char_start_global": 183302, "sentence_char_end_global": 183418, "entities": [], "entities_global": []}
+{"sentence_id": 1108, "sentence_text": "The lymphoid tissue will decrease in size and weight after prolonged treatment with HDC .", "sentence_char_start_global": 183419, "sentence_char_end_global": 183508, "entities": [], "entities_global": []}
+{"sentence_id": 1109, "sentence_text": "Lymphocyte functions will be impaired .", "sentence_char_start_global": 183509, "sentence_char_end_global": 183548, "entities": [], "entities_global": []}
+{"sentence_id": 1110, "sentence_text": "Reduced synthesis of B - as well as T - lymphocytes will be seen .", "sentence_char_start_global": 183549, "sentence_char_end_global": 183615, "entities": [], "entities_global": []}
+{"sentence_id": 1111, "sentence_text": "The inhibitory effect on B - cell function can be observed both as decreased serum levels of immunoglobulins and as impaired binding of antibodies and complement to the cellular surface .", "sentence_char_start_global": 183616, "sentence_char_end_global": 183803, "entities": [{"text": "immunoglobulins", "type": "ENTITY", "char_start": 93, "char_end": 108, "token_start": 17, "token_end": 17}, {"text": "antibodies", "type": "ENTITY", "char_start": 136, "char_end": 146, "token_start": 23, "token_end": 23}], "entities_global": [{"text": "immunoglobulins", "type": "ENTITY", "char_start": 183709, "char_end": 183724, "token_start": 17, "token_end": 17, "note": null}, {"text": "antibodies", "type": "ENTITY", "char_start": 183752, "char_end": 183762, "token_start": 23, "token_end": 23, "note": null}]}
+{"sentence_id": 1112, "sentence_text": "Reduced T - cell function indicated by impaired stimulation by PHA and porkweed as well as by impaired lymphokinin effects on leukocyte migration inhibition has been reported .", "sentence_char_start_global": 183804, "sentence_char_end_global": 183980, "entities": [{"text": "PHA", "type": "ENTITY", "char_start": 63, "char_end": 66, "token_start": 10, "token_end": 10}, {"text": "porkweed", "type": "ENTITY", "char_start": 71, "char_end": 79, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "PHA", "type": "ENTITY", "char_start": 183867, "char_end": 183870, "token_start": 10, "token_end": 10, "note": null}, {"text": "porkweed", "type": "ENTITY", "char_start": 183875, "char_end": 183883, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 1113, "sentence_text": "Reduced lymphocyte adherence to antigen and suppressed lymphocyte reaction have also been observed .", "sentence_char_start_global": 183981, "sentence_char_end_global": 184081, "entities": [], "entities_global": []}
+{"sentence_id": 1114, "sentence_text": "Humoral factors involved in chemotaxis , opsonisation , phagocytosis , vascular permeability leading to leakage of fluid and cells and factors involved in lysis of antigens are impaired .", "sentence_char_start_global": 184082, "sentence_char_end_global": 184269, "entities": [], "entities_global": []}
+{"sentence_id": 1115, "sentence_text": "This can be explained partly by the observed reduced complement activation via the alternative as well as the classical pathway in association with HDC therapy .", "sentence_char_start_global": 184270, "sentence_char_end_global": 184431, "entities": [], "entities_global": []}
+{"sentence_id": 1116, "sentence_text": "Acute processes with increased vascular permeability and accumulation of leukocytes as impairing factors could be influenced beneficially by HDC therapy .", "sentence_char_start_global": 184432, "sentence_char_end_global": 184586, "entities": [], "entities_global": []}
+{"sentence_id": 1117, "sentence_text": "This positive effect can be seen in treatment of septic shock or rejection of a transplant .", "sentence_char_start_global": 184587, "sentence_char_end_global": 184679, "entities": [], "entities_global": []}
+{"sentence_id": 1118, "sentence_text": "However , if sepsis or rejection is not rapidly reversed , complications such as multisystem organ failure and bacteremia are prone to appear .", "sentence_char_start_global": 184680, "sentence_char_end_global": 184823, "entities": [], "entities_global": []}
+{"sentence_id": 1119, "sentence_text": "Identification of human leukemic glucocorticoid receptors using affinity labeling and anti - human glucocorticoid receptor antibodies .", "sentence_char_start_global": 184824, "sentence_char_end_global": 184959, "entities": [{"text": "human leukemic glucocorticoid receptors", "type": "ENTITY", "char_start": 18, "char_end": 57, "token_start": 2, "token_end": 5}, {"text": "anti - human glucocorticoid receptor antibodies", "type": "ENTITY", "char_start": 86, "char_end": 133, "token_start": 10, "token_end": 15}], "entities_global": [{"text": "human leukemic glucocorticoid receptors", "type": "ENTITY", "char_start": 184842, "char_end": 184881, "token_start": 2, "token_end": 5, "note": null}, {"text": "anti - human glucocorticoid receptor antibodies", "type": "ENTITY", "char_start": 184910, "char_end": 184957, "token_start": 10, "token_end": 15, "note": null}]}
+{"sentence_id": 1120, "sentence_text": "Antisera raised against human lymphoid glucocorticoid receptors were used in combination with the glucocorticoid receptor affinity label [ 3H ] dexamethasone 21 - mesylate [ ( 3H ] DM ) to identify the glucocorticoid receptors of the human B - lymphoblastoid cell line IM - 9 and the human T - cell leukemic cell line CEM - C7 .", "sentence_char_start_global": 184960, "sentence_char_end_global": 185288, "entities": [{"text": "human lymphoid glucocorticoid receptors", "type": "ENTITY", "char_start": 24, "char_end": 63, "token_start": 3, "token_end": 6}, {"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 202, "char_end": 226, "token_start": 33, "token_end": 34}], "entities_global": [{"text": "human lymphoid glucocorticoid receptors", "type": "ENTITY", "char_start": 184984, "char_end": 185023, "token_start": 3, "token_end": 6, "note": null}, {"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 185162, "char_end": 185186, "token_start": 33, "token_end": 34, "note": null}]}
+{"sentence_id": 1121, "sentence_text": "Antisera were obtained following immunization of New Zealand White rabbits with [ 3H ] triamcinolone acetonide [ ( 3H ] TA ) - glucocorticoid receptor complexes partially purified by two - stage DNA - cellulose chromatography .", "sentence_char_start_global": 185289, "sentence_char_end_global": 185516, "entities": [{"text": "[ 3H ] triamcinolone acetonide [ ( 3H ] TA ) - glucocorticoid receptor complexes", "type": "ENTITY", "char_start": 80, "char_end": 160, "token_start": 11, "token_end": 25}], "entities_global": [{"text": "[ 3H ] triamcinolone acetonide [ ( 3H ] TA ) - glucocorticoid receptor complexes", "type": "ENTITY", "char_start": 185369, "char_end": 185449, "token_start": 11, "token_end": 25, "note": null}]}
+{"sentence_id": 1122, "sentence_text": "The presence of anti - human glucocorticoid receptor antibodies was verified by : ( a ) adsorption of [ 3H ] TA - receptor - antibody complexes to Protein A ; ( b ) a shift to higher apparent molecular weight in the elution position from Sephacryl S300 of [ 3H ] TA - receptor complexes incubated with immune serum ; and ( c ) the ability of immune serum to displace [ 3H ] TA - receptor complexes on sucrose gradients .", "sentence_char_start_global": 185517, "sentence_char_end_global": 185937, "entities": [{"text": "anti - human glucocorticoid receptor antibodies", "type": "ENTITY", "char_start": 16, "char_end": 63, "token_start": 3, "token_end": 8}, {"text": "[ 3H ] TA - receptor - antibody complexes", "type": "ENTITY", "char_start": 102, "char_end": 143, "token_start": 18, "token_end": 26}, {"text": "Protein A", "type": "ENTITY", "char_start": 147, "char_end": 156, "token_start": 28, "token_end": 29}, {"text": "[ 3H ] TA - receptor complexes", "type": "ENTITY", "char_start": 256, "char_end": 286, "token_start": 49, "token_end": 55}, {"text": "[ 3H ] TA - receptor complexes", "type": "ENTITY", "char_start": 367, "char_end": 397, "token_start": 72, "token_end": 78}], "entities_global": [{"text": "anti - human glucocorticoid receptor antibodies", "type": "ENTITY", "char_start": 185533, "char_end": 185580, "token_start": 3, "token_end": 8, "note": null}, {"text": "[ 3H ] TA - receptor - antibody complexes", "type": "ENTITY", "char_start": 185619, "char_end": 185660, "token_start": 18, "token_end": 26, "note": null}, {"text": "Protein A", "type": "ENTITY", "char_start": 185664, "char_end": 185673, "token_start": 28, "token_end": 29, "note": null}, {"text": "[ 3H ] TA - receptor complexes", "type": "ENTITY", "char_start": 185773, "char_end": 185803, "token_start": 49, "token_end": 55, "note": null}, {"text": "[ 3H ] TA - receptor complexes", "type": "ENTITY", "char_start": 185884, "char_end": 185914, "token_start": 72, "token_end": 78, "note": null}]}
+{"sentence_id": 1123, "sentence_text": "These antibodies also recognized rat liver and murine S49 cell glucocorticoid receptors .", "sentence_char_start_global": 185938, "sentence_char_end_global": 186027, "entities": [{"text": "antibodies", "type": "ENTITY", "char_start": 6, "char_end": 16, "token_start": 1, "token_end": 1}, {"text": "murine S49 cell glucocorticoid receptors", "type": "ENTITY", "char_start": 47, "char_end": 87, "token_start": 7, "token_end": 11}], "entities_global": [{"text": "antibodies", "type": "ENTITY", "char_start": 185944, "char_end": 185954, "token_start": 1, "token_end": 1, "note": null}, {"text": "murine S49 cell glucocorticoid receptors", "type": "ENTITY", "char_start": 185985, "char_end": 186025, "token_start": 7, "token_end": 11, "note": null}]}
+{"sentence_id": 1124, "sentence_text": "Sodium dodecyl sulfate - polyacrylamide gel electrophoresis of [ 3H ] DM - labeled IM - 9 cytosol identified a major competable band with a molecular weight of approximately 90 , 000 , three minor competable components with molecular weights of approximately 78 , 000 , approximately 51 , 000 , and approximately 38 , 500 , and at least 21 other noncompetable components .", "sentence_char_start_global": 186028, "sentence_char_end_global": 186400, "entities": [], "entities_global": []}
+{"sentence_id": 1125, "sentence_text": "Following immunoprecipitation of [ 3H ] DM - labeled cytosol with immune serum , only the Mr 90 , 000 and 78 , 000 components were seen .", "sentence_char_start_global": 186401, "sentence_char_end_global": 186538, "entities": [], "entities_global": []}
+{"sentence_id": 1126, "sentence_text": "Sodium dodecyl sulfate - polyacrylamide gel electrophoresis of [ 3H ] DM - labeled CEM - C7 cytosol revealed a larger number of [ 3H ] DM - labeled components .", "sentence_char_start_global": 186539, "sentence_char_end_global": 186699, "entities": [], "entities_global": []}
+{"sentence_id": 1127, "sentence_text": "However , after immunoprecipitation of [ 3H ] DM - labeled CEM - C7 cytosol , a predominant competable component with a molecular weight of 90 , 000 was easily identified .", "sentence_char_start_global": 186700, "sentence_char_end_global": 186872, "entities": [], "entities_global": []}
+{"sentence_id": 1128, "sentence_text": "This component was markedly diminished when cytosols from the glucocorticoid receptor - deficient cell line ICR - 27 were used .", "sentence_char_start_global": 186873, "sentence_char_end_global": 187001, "entities": [], "entities_global": []}
+{"sentence_id": 1129, "sentence_text": "Thus , the combination of affinity labeling and anti - human glucocorticoid receptor antibodies is capable of providing direct physical identification of human lymphoid glucocorticoid receptors .", "sentence_char_start_global": 187002, "sentence_char_end_global": 187197, "entities": [{"text": "anti - human glucocorticoid receptor antibodies", "type": "ENTITY", "char_start": 48, "char_end": 95, "token_start": 8, "token_end": 13}, {"text": "human lymphoid glucocorticoid receptors", "type": "ENTITY", "char_start": 154, "char_end": 193, "token_start": 22, "token_end": 25}], "entities_global": [{"text": "anti - human glucocorticoid receptor antibodies", "type": "ENTITY", "char_start": 187050, "char_end": 187097, "token_start": 8, "token_end": 13, "note": null}, {"text": "human lymphoid glucocorticoid receptors", "type": "ENTITY", "char_start": 187156, "char_end": 187195, "token_start": 22, "token_end": 25, "note": null}]}
+{"sentence_id": 1130, "sentence_text": "Effect of thymosin on glucocorticoid receptor activity and glucocorticoid sensitivity of human thymocytes .", "sentence_char_start_global": 187198, "sentence_char_end_global": 187305, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 22, "char_end": 45, "token_start": 4, "token_end": 5}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 187220, "char_end": 187243, "token_start": 4, "token_end": 5, "note": null}]}
+{"sentence_id": 1131, "sentence_text": "Incubation with thymosin fraction 5 , ( TMS F5 at 300 micrograms / ml ) a partially purified thymic factor , reduced the steroid binding activity of human infant thymocytes from 9 . 6 + / - 2 . 1 fmole / ml to 5 . 0 + / - 2 . 0 fmole / ml .", "sentence_char_start_global": 187306, "sentence_char_end_global": 187546, "entities": [], "entities_global": []}
+{"sentence_id": 1132, "sentence_text": "The glucocorticoid receptor activity in normal infant thymocytes was found to be 2 , 146 + / - 726 ( s . d . ) sites per cell with dissociation constant of 1 . 4 + / - 0 . 6 X 10 ( - 8 ) M .", "sentence_char_start_global": 187547, "sentence_char_end_global": 187737, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 4, "char_end": 27, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 187551, "char_end": 187574, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 1133, "sentence_text": "TMS F5 also increased the resistance of human thymocytes to the cytolytic effect of dexamethasone ( 2 . 5 X 10 ( - 8 ) M ) to 168 . 6 + / - 30 . 2 % of control ( P less than 0 . 01 ) .", "sentence_char_start_global": 187738, "sentence_char_end_global": 187922, "entities": [], "entities_global": []}
+{"sentence_id": 1134, "sentence_text": "In animals , medullary and peripheral blood T cells are more resistant to glucocorticoids than immature thymic T cells .", "sentence_char_start_global": 187923, "sentence_char_end_global": 188043, "entities": [], "entities_global": []}
+{"sentence_id": 1135, "sentence_text": "The results show that thymosin can induce changes consistent with differentiation in human thymocytes .", "sentence_char_start_global": 188044, "sentence_char_end_global": 188147, "entities": [], "entities_global": []}
+{"sentence_id": 1136, "sentence_text": "These in vitro results are consistent with a physiological role of thymosin in intrathymic T cell maturation in man .", "sentence_char_start_global": 188148, "sentence_char_end_global": 188265, "entities": [], "entities_global": []}
+{"sentence_id": 1137, "sentence_text": "Incubation of a human malignant thymus derived T cell line ( MOLT 3 ) with TMS F5 also resulted in a significant reduction of the number of steroid binding sites to 44 . 2 + / - 15 . 3 % of control ( P less than 0 . 05 ) , but TMS F5 did not significantly reduce the glucocorticoid sensitivity of MOLT 3 cells .", "sentence_char_start_global": 188266, "sentence_char_end_global": 188577, "entities": [], "entities_global": []}
+{"sentence_id": 1138, "sentence_text": "Specific high - affinity receptors for 1 , 25 - dihydroxyvitamin D3 in human peripheral blood mononuclear cells : presence in monocytes and induction in T lymphocytes following activation .", "sentence_char_start_global": 188578, "sentence_char_end_global": 188767, "entities": [{"text": "Specific high - affinity receptors", "type": "ENTITY", "char_start": 0, "char_end": 34, "token_start": 0, "token_end": 4}], "entities_global": [{"text": "Specific high - affinity receptors", "type": "ENTITY", "char_start": 188578, "char_end": 188612, "token_start": 0, "token_end": 4, "note": null}]}
+{"sentence_id": 1139, "sentence_text": "Human peripheral blood monocytes have high affinity binding sites for 1 , 25 - ( OH ) 2D3 ( Kd 0 . 14 nM , sedimentation coefficient 3 . 7S ) .", "sentence_char_start_global": 188768, "sentence_char_end_global": 188911, "entities": [], "entities_global": []}
+{"sentence_id": 1140, "sentence_text": "Resting human peripheral blood T lymphocytes , however , do not have a demonstrable 1 , 25 - ( OH ) 2D3 receptor .", "sentence_char_start_global": 188912, "sentence_char_end_global": 189026, "entities": [{"text": "1 , 25 - ( OH ) 2D3 receptor", "type": "ENTITY", "char_start": 84, "char_end": 112, "token_start": 14, "token_end": 22}], "entities_global": [{"text": "1 , 25 - ( OH ) 2D3 receptor", "type": "ENTITY", "char_start": 188996, "char_end": 189024, "token_start": 14, "token_end": 22, "note": null}]}
+{"sentence_id": 1141, "sentence_text": "After activation with phytohemagglutinin the T cells exhibit the receptor within 24 h , and this expression is blocked by cycloheximide .", "sentence_char_start_global": 189027, "sentence_char_end_global": 189164, "entities": [{"text": "phytohemagglutinin", "type": "ENTITY", "char_start": 22, "char_end": 40, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "phytohemagglutinin", "type": "ENTITY", "char_start": 189049, "char_end": 189067, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 1142, "sentence_text": "The receptor in activated T lymphocytes has a sedimentation coefficient of 3 . 7S and a high affinity ( Kd 0 . 10 nM ) for the ligand .", "sentence_char_start_global": 189165, "sentence_char_end_global": 189300, "entities": [], "entities_global": []}
+{"sentence_id": 1143, "sentence_text": "Effects of chronic glucocorticoid excess in man on insulin binding to circulating cells : differences between endogenous and exogenous hypercorticism .", "sentence_char_start_global": 189301, "sentence_char_end_global": 189452, "entities": [], "entities_global": []}
+{"sentence_id": 1144, "sentence_text": "We measured [ 125I ] insulin binding to circulating monocytes or erythrocytes from 16 patients with chronic glucocorticoid excess , 9 chronically treated with prednisone and 7 with adrenocortical hyperfunction .", "sentence_char_start_global": 189453, "sentence_char_end_global": 189664, "entities": [], "entities_global": []}
+{"sentence_id": 1145, "sentence_text": "With monocytes , [ 125I ] insulin binding was iincreased in all patients .", "sentence_char_start_global": 189665, "sentence_char_end_global": 189739, "entities": [], "entities_global": []}
+{"sentence_id": 1146, "sentence_text": "Analysis of binding data indicated that increased binding in patients treated with prednisone was due to an ncrease in receptor concentration , whereas in patients with adrenocortical hyperfunction , it was due to an increase in receptor affinity .", "sentence_char_start_global": 189740, "sentence_char_end_global": 189988, "entities": [], "entities_global": []}
+{"sentence_id": 1147, "sentence_text": "With erythrocytes from patients with adrenocortical hyperfunction there was an increase in receptor affinity and a decrease in receptor concentration , so that the binding of [ 125I ] insulin was normal .", "sentence_char_start_global": 189989, "sentence_char_end_global": 190193, "entities": [], "entities_global": []}
+{"sentence_id": 1148, "sentence_text": "The disparity of results between endogenous and exogenous hypercorticism , between the two cell types , and between the present studies and previous studies suggest that the effects of glucocorticoid excess on the insulin receptor are extremely complex and wide - ranging and that in this condition , extrapolations in humans from data with circulating cells to liver and muscle may not be appropriate .", "sentence_char_start_global": 190194, "sentence_char_end_global": 190597, "entities": [{"text": "insulin receptor", "type": "ENTITY", "char_start": 214, "char_end": 230, "token_start": 33, "token_end": 34}], "entities_global": [{"text": "insulin receptor", "type": "ENTITY", "char_start": 190408, "char_end": 190424, "token_start": 33, "token_end": 34, "note": null}]}
+{"sentence_id": 1149, "sentence_text": "Reduced level of cellular glucocorticoid receptors in patients with anorexia nervosa .", "sentence_char_start_global": 190598, "sentence_char_end_global": 190684, "entities": [{"text": "cellular glucocorticoid receptors", "type": "ENTITY", "char_start": 17, "char_end": 50, "token_start": 3, "token_end": 5}], "entities_global": [{"text": "cellular glucocorticoid receptors", "type": "ENTITY", "char_start": 190615, "char_end": 190648, "token_start": 3, "token_end": 5, "note": null}]}
+{"sentence_id": 1150, "sentence_text": "Specific glucocorticoid receptors were measured in circulating mononuclear leukocytes from 12 patients with anorexia nervosa and 21 healthy control subjects .", "sentence_char_start_global": 190685, "sentence_char_end_global": 190843, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 9, "char_end": 33, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 190694, "char_end": 190718, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 1151, "sentence_text": "Cells from patients were found to contain a significantly ( p less than 0 . 01 ) lower level of glucocorticoid receptor ( 3830 + / - 210 sites / cell , mean + / - SE ) than those from controls ( 4930 + / - 250 sites / cell ) .", "sentence_char_start_global": 190844, "sentence_char_end_global": 191070, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 96, "char_end": 119, "token_start": 20, "token_end": 21}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 190940, "char_end": 190963, "token_start": 20, "token_end": 21, "note": null}]}
+{"sentence_id": 1152, "sentence_text": "A partial glucocorticoid receptor defect may well explain the abnormal cortisol metabolism and glucocorticoid resistance commonly found in patients with anorexia nervosa .", "sentence_char_start_global": 191071, "sentence_char_end_global": 191242, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 10, "char_end": 33, "token_start": 2, "token_end": 3}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 191081, "char_end": 191104, "token_start": 2, "token_end": 3, "note": null}]}
+{"sentence_id": 1153, "sentence_text": "Regulation of the glucocorticoid receptor in human lymphocytes .", "sentence_char_start_global": 191243, "sentence_char_end_global": 191307, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 18, "char_end": 41, "token_start": 3, "token_end": 4}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 191261, "char_end": 191284, "token_start": 3, "token_end": 4, "note": null}]}
+{"sentence_id": 1154, "sentence_text": "The presence of a glucocorticoid receptor in human lymphocytes is well established , but factors affecting its regulation have not been described .", "sentence_char_start_global": 191308, "sentence_char_end_global": 191455, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 18, "char_end": 41, "token_start": 4, "token_end": 5}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 191326, "char_end": 191349, "token_start": 4, "token_end": 5, "note": null}]}
+{"sentence_id": 1155, "sentence_text": "Using a competitive binding whole cell assay , we have examined the binding of [ 3H ] - dexamethasone at 24 and 37 degrees C in untreated normal subjects and in healthy subjects taking various glucocorticoid preparations .", "sentence_char_start_global": 191456, "sentence_char_end_global": 191678, "entities": [], "entities_global": []}
+{"sentence_id": 1156, "sentence_text": "At 24 degrees C normal human lymphocytes had 6000 binding sites / cell and a dissociation constant of 4 x 10 ( - 9 ) M .", "sentence_char_start_global": 191679, "sentence_char_end_global": 191799, "entities": [], "entities_global": []}
+{"sentence_id": 1157, "sentence_text": "The administration of 1 mg of dexamethasone , 5 mg of prednisone , and 37 . 5 mg of cortisone acetate resulted in a 30 % decrease in binding sites after 1 week with no change in binding affinity .", "sentence_char_start_global": 191800, "sentence_char_end_global": 191996, "entities": [], "entities_global": []}
+{"sentence_id": 1158, "sentence_text": "No changes in the number of binding sites was noted before 1 week and the diminished number persisted for 1 week after discontinuation of glucocorticoid treatment .", "sentence_char_start_global": 191997, "sentence_char_end_global": 192161, "entities": [], "entities_global": []}
+{"sentence_id": 1159, "sentence_text": "Lymphocytes from hospitalized patients taking 40 - 60 mg of dexamethasone daily demonstrated the same change in number of binding sites that was seen in normal subjects taking 1 mg of dexamethasone .", "sentence_char_start_global": 192162, "sentence_char_end_global": 192361, "entities": [], "entities_global": []}
+{"sentence_id": 1160, "sentence_text": "When binding assays were carried out at physiologic temperature there was the same decrease in number of binding sites after dexamethasone administration , and in addition , there was a two - fold increase in binding affinity .", "sentence_char_start_global": 192362, "sentence_char_end_global": 192589, "entities": [], "entities_global": []}
+{"sentence_id": 1161, "sentence_text": "Glucocorticoid administration results in a time - dependent decrease in the number of lymphocyte glucocorticoid binding sites that is independent of the type of glucocorticoid administered .", "sentence_char_start_global": 192590, "sentence_char_end_global": 192780, "entities": [], "entities_global": []}
+{"sentence_id": 1162, "sentence_text": "This is the first in vivo demonstration that glucocorticoids modulate their own receptors in man .", "sentence_char_start_global": 192781, "sentence_char_end_global": 192879, "entities": [], "entities_global": []}
+{"sentence_id": 1163, "sentence_text": "Immunoglobulin localization in benign and malignant lesions of the human mammary gland .", "sentence_char_start_global": 192880, "sentence_char_end_global": 192968, "entities": [], "entities_global": []}
+{"sentence_id": 1164, "sentence_text": "Using direct imunofluorescence , lesions from 266 human breast specimens were studied for the presence of IgA , IgM , or IgG localization .", "sentence_char_start_global": 192969, "sentence_char_end_global": 193108, "entities": [], "entities_global": []}
+{"sentence_id": 1165, "sentence_text": "The lesions included benign elements from 66 subcutaneous mastectomy specimens in which the absence of simultaneous breast malignancy was documented , primary breast carcinomas from 153 mastectomy specimens , and 47 biopsies containing metastatic breast cancer .", "sentence_char_start_global": 193109, "sentence_char_end_global": 193371, "entities": [], "entities_global": []}
+{"sentence_id": 1166, "sentence_text": "A statistically significant association of IgA and IgM with benign lesions was contrasted to the association of IgG with malignant lesions .", "sentence_char_start_global": 193372, "sentence_char_end_global": 193512, "entities": [{"text": "IgA", "type": "ENTITY", "char_start": 43, "char_end": 46, "token_start": 5, "token_end": 5}, {"text": "IgM", "type": "ENTITY", "char_start": 51, "char_end": 54, "token_start": 7, "token_end": 7}, {"text": "IgG", "type": "ENTITY", "char_start": 112, "char_end": 115, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "IgA", "type": "ENTITY", "char_start": 193415, "char_end": 193418, "token_start": 5, "token_end": 5, "note": null}, {"text": "IgM", "type": "ENTITY", "char_start": 193423, "char_end": 193426, "token_start": 7, "token_end": 7, "note": null}, {"text": "IgG", "type": "ENTITY", "char_start": 193484, "char_end": 193487, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 1167, "sentence_text": "In both primary and metastatic lesions , IgG localization was associated with estrogen - receptor - poor primary cancers as compared with estrogen - receptor - rich primary cancers .", "sentence_char_start_global": 193513, "sentence_char_end_global": 193695, "entities": [{"text": "IgG", "type": "ENTITY", "char_start": 41, "char_end": 44, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "IgG", "type": "ENTITY", "char_start": 193554, "char_end": 193557, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 1168, "sentence_text": "Among primary breast cancer patients , IgG localization in the tumor correlated with relative lymphopenia .", "sentence_char_start_global": 193696, "sentence_char_end_global": 193803, "entities": [{"text": "IgG", "type": "ENTITY", "char_start": 39, "char_end": 42, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "IgG", "type": "ENTITY", "char_start": 193735, "char_end": 193738, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 1169, "sentence_text": "A shorter disease - free interval was noted in association with IgG localization among the metastatic breast lesions .", "sentence_char_start_global": 193804, "sentence_char_end_global": 193922, "entities": [{"text": "IgG", "type": "ENTITY", "char_start": 64, "char_end": 67, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "IgG", "type": "ENTITY", "char_start": 193868, "char_end": 193871, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 1170, "sentence_text": "No statistically significant association between stage of disease and immunoglobulin presence was demonstrable .", "sentence_char_start_global": 193923, "sentence_char_end_global": 194035, "entities": [], "entities_global": []}
+{"sentence_id": 1171, "sentence_text": "Moderate - to - severe intraductal epithelial hyperplasias were more often associated with immunoglobulin G localization that were other benign lesions", "sentence_char_start_global": 194036, "sentence_char_end_global": 194187, "entities": [{"text": "immunoglobulin G", "type": "ENTITY", "char_start": 91, "char_end": 107, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "immunoglobulin G", "type": "ENTITY", "char_start": 194127, "char_end": 194143, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 1172, "sentence_text": "Correlation of steroid receptors with histologic differentiation in mammary carcinoma .", "sentence_char_start_global": 194188, "sentence_char_end_global": 194275, "entities": [{"text": "steroid receptors", "type": "ENTITY", "char_start": 15, "char_end": 32, "token_start": 2, "token_end": 3}], "entities_global": [{"text": "steroid receptors", "type": "ENTITY", "char_start": 194203, "char_end": 194220, "token_start": 2, "token_end": 3, "note": null}]}
+{"sentence_id": 1173, "sentence_text": "A Singapore experience .", "sentence_char_start_global": 194276, "sentence_char_end_global": 194300, "entities": [], "entities_global": []}
+{"sentence_id": 1174, "sentence_text": "Cancer of the breast is the most common tumor in females in Singapore , with the rate of 20 . 7 per 100 , 000 per year ( 1977 estimate ) , which is predicted to increase to 29 . 8 per 100 , 000 women per year by 1995 .", "sentence_char_start_global": 194301, "sentence_char_end_global": 194519, "entities": [], "entities_global": []}
+{"sentence_id": 1175, "sentence_text": "A detailed histopathologic review of 50 primary breast cancer tumors analyzed for estrogen receptor ( ER ) level was carried out and a variety of morphologic features correlated with ER results to identify any factors that will improve the management and prognosis for breast cancer .", "sentence_char_start_global": 194520, "sentence_char_end_global": 194804, "entities": [{"text": "estrogen receptor", "type": "ENTITY", "char_start": 82, "char_end": 99, "token_start": 12, "token_end": 13}, {"text": "ER", "type": "ENTITY", "char_start": 102, "char_end": 104, "token_start": 15, "token_end": 15}, {"text": "ER", "type": "ENTITY", "char_start": 183, "char_end": 185, "token_start": 29, "token_end": 29}], "entities_global": [{"text": "estrogen receptor", "type": "ENTITY", "char_start": 194602, "char_end": 194619, "token_start": 12, "token_end": 13, "note": null}, {"text": "ER", "type": "ENTITY", "char_start": 194622, "char_end": 194624, "token_start": 15, "token_end": 15, "note": null}, {"text": "ER", "type": "ENTITY", "char_start": 194703, "char_end": 194705, "token_start": 29, "token_end": 29, "note": null}]}
+{"sentence_id": 1176, "sentence_text": "Cytosol was incubated with 3H - estradiol in the presence and absence of cold diethylstilbestrol , and bound and free hormone were separated by Dextran - coated charcoal method .", "sentence_char_start_global": 194805, "sentence_char_end_global": 194983, "entities": [], "entities_global": []}
+{"sentence_id": 1177, "sentence_text": "Tumors binding more than 5 fmol / mg cytosol protein were classified as ER - positive .", "sentence_char_start_global": 194984, "sentence_char_end_global": 195071, "entities": [{"text": "cytosol protein", "type": "ENTITY", "char_start": 37, "char_end": 52, "token_start": 8, "token_end": 9}, {"text": "ER", "type": "ENTITY", "char_start": 72, "char_end": 74, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "cytosol protein", "type": "ENTITY", "char_start": 195021, "char_end": 195036, "token_start": 8, "token_end": 9, "note": null}, {"text": "ER", "type": "ENTITY", "char_start": 195056, "char_end": 195058, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 1178, "sentence_text": "Progesterone receptor ( PR ) level was analyzed in some specimens with the use of a similar method .", "sentence_char_start_global": 195072, "sentence_char_end_global": 195172, "entities": [{"text": "Progesterone receptor", "type": "ENTITY", "char_start": 0, "char_end": 21, "token_start": 0, "token_end": 1}, {"text": "PR", "type": "ENTITY", "char_start": 24, "char_end": 26, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "Progesterone receptor", "type": "ENTITY", "char_start": 195072, "char_end": 195093, "token_start": 0, "token_end": 1, "note": null}, {"text": "PR", "type": "ENTITY", "char_start": 195096, "char_end": 195098, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 1179, "sentence_text": "Most of the patients were Chinese ( 90 % ) .", "sentence_char_start_global": 195173, "sentence_char_end_global": 195217, "entities": [], "entities_global": []}
+{"sentence_id": 1180, "sentence_text": "Three patients were Malays , one was Indian , and one was European in this series .", "sentence_char_start_global": 195218, "sentence_char_end_global": 195301, "entities": [], "entities_global": []}
+{"sentence_id": 1181, "sentence_text": "Results indicated that there was strong correlation between ER level , age , and histologic grade of the tumors .", "sentence_char_start_global": 195302, "sentence_char_end_global": 195415, "entities": [{"text": "ER", "type": "ENTITY", "char_start": 60, "char_end": 62, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "ER", "type": "ENTITY", "char_start": 195362, "char_end": 195364, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 1182, "sentence_text": "No correlation existed between absence or presence of lymph node metastases and ER .", "sentence_char_start_global": 195416, "sentence_char_end_global": 195500, "entities": [{"text": "ER", "type": "ENTITY", "char_start": 80, "char_end": 82, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "ER", "type": "ENTITY", "char_start": 195496, "char_end": 195498, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 1183, "sentence_text": "Although there was a trend for ER - positive tumors to have a low - grade lymphocytic infiltration , the difference was not statistically significant .", "sentence_char_start_global": 195501, "sentence_char_end_global": 195652, "entities": [{"text": "ER", "type": "ENTITY", "char_start": 31, "char_end": 33, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "ER", "type": "ENTITY", "char_start": 195532, "char_end": 195534, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 1184, "sentence_text": "Mononuclear cells infiltrating human mammary carcinomas : immunohistochemical analysis with monoclonal antibodies .", "sentence_char_start_global": 195653, "sentence_char_end_global": 195768, "entities": [{"text": "monoclonal antibodies", "type": "ENTITY", "char_start": 92, "char_end": 113, "token_start": 10, "token_end": 11}], "entities_global": [{"text": "monoclonal antibodies", "type": "ENTITY", "char_start": 195745, "char_end": 195766, "token_start": 10, "token_end": 11, "note": null}]}
+{"sentence_id": 1185, "sentence_text": "Breast carcinomas were examined by the immunoperoxidase technique using antisera specific for lymphocyte subsets , monocytes , NK cells and major histocompatibility antigens ( HLA - A , - B , - C ; Ia - like ) .", "sentence_char_start_global": 195769, "sentence_char_end_global": 195980, "entities": [{"text": "major histocompatibility antigens", "type": "ENTITY", "char_start": 140, "char_end": 173, "token_start": 20, "token_end": 22}, {"text": "HLA - A", "type": "ENTITY", "char_start": 176, "char_end": 183, "token_start": 24, "token_end": 26}, {"text": "- B", "type": "ENTITY", "char_start": 186, "char_end": 189, "token_start": 28, "token_end": 29}, {"text": "Ia - like", "type": "ENTITY", "char_start": 198, "char_end": 207, "token_start": 34, "token_end": 36}], "entities_global": [{"text": "major histocompatibility antigens", "type": "ENTITY", "char_start": 195909, "char_end": 195942, "token_start": 20, "token_end": 22, "note": null}, {"text": "HLA - A", "type": "ENTITY", "char_start": 195945, "char_end": 195952, "token_start": 24, "token_end": 26, "note": null}, {"text": "- B", "type": "ENTITY", "char_start": 195955, "char_end": 195958, "token_start": 28, "token_end": 29, "note": null}, {"text": "Ia - like", "type": "ENTITY", "char_start": 195967, "char_end": 195976, "token_start": 34, "token_end": 36, "note": null}]}
+{"sentence_id": 1186, "sentence_text": "Sixty - four per cent of the patients had a moderate or strong mononuclear cell infiltration , 77 % of the patients without mononuclear cell infiltration had receptors for estrogens as compared to 51 % of the patients with infiltration .", "sentence_char_start_global": 195981, "sentence_char_end_global": 196218, "entities": [], "entities_global": []}
+{"sentence_id": 1187, "sentence_text": "The majority of the infiltrating mononuclear cells were T cells ; generally the OKT8 cells were predominant .", "sentence_char_start_global": 196219, "sentence_char_end_global": 196328, "entities": [], "entities_global": []}
+{"sentence_id": 1188, "sentence_text": "The Leu 3A / OKT8 cell ratio was not related to histological type , tumor size , age of the patient or presence of metastases .", "sentence_char_start_global": 196329, "sentence_char_end_global": 196456, "entities": [], "entities_global": []}
+{"sentence_id": 1189, "sentence_text": "Some of the T cells had the Ia antigen and were thus probably activated .", "sentence_char_start_global": 196457, "sentence_char_end_global": 196530, "entities": [{"text": "Ia antigen", "type": "ENTITY", "char_start": 28, "char_end": 38, "token_start": 7, "token_end": 8}], "entities_global": [{"text": "Ia antigen", "type": "ENTITY", "char_start": 196485, "char_end": 196495, "token_start": 7, "token_end": 8, "note": null}]}
+{"sentence_id": 1190, "sentence_text": "The B cells were either absent or less numerous than the T cells .", "sentence_char_start_global": 196531, "sentence_char_end_global": 196597, "entities": [], "entities_global": []}
+{"sentence_id": 1191, "sentence_text": "There was no relation between their distribution and the various parameters studied .", "sentence_char_start_global": 196598, "sentence_char_end_global": 196683, "entities": [], "entities_global": []}
+{"sentence_id": 1192, "sentence_text": "A few monocytes were heterogeneous according to their markers ( OKM I and acid phosphatase ) .", "sentence_char_start_global": 196684, "sentence_char_end_global": 196778, "entities": [{"text": "OKM I", "type": "ENTITY", "char_start": 64, "char_end": 69, "token_start": 10, "token_end": 11}], "entities_global": [{"text": "OKM I", "type": "ENTITY", "char_start": 196748, "char_end": 196753, "token_start": 10, "token_end": 11, "note": null}]}
+{"sentence_id": 1193, "sentence_text": "In 6 cases only there was a strong infiltration of mononuclear cells positive for acid phosphatase .", "sentence_char_start_global": 196779, "sentence_char_end_global": 196879, "entities": [{"text": "acid phosphatase", "type": "ENTITY", "char_start": 82, "char_end": 98, "token_start": 14, "token_end": 15}], "entities_global": [{"text": "acid phosphatase", "type": "ENTITY", "char_start": 196861, "char_end": 196877, "token_start": 14, "token_end": 15, "note": null}]}
+{"sentence_id": 1194, "sentence_text": "The number of the natural killer cells was also low .", "sentence_char_start_global": 196880, "sentence_char_end_global": 196933, "entities": [], "entities_global": []}
+{"sentence_id": 1195, "sentence_text": "Only a few mononuclear infiltrating cells had receptors for transferrin .", "sentence_char_start_global": 196934, "sentence_char_end_global": 197007, "entities": [], "entities_global": []}
+{"sentence_id": 1196, "sentence_text": "There was a positive correlation between the inflammatory infiltration and the presence of HLA class - I antigens on tumor cell s .", "sentence_char_start_global": 197008, "sentence_char_end_global": 197139, "entities": [{"text": "HLA class - I antigens", "type": "ENTITY", "char_start": 91, "char_end": 113, "token_start": 13, "token_end": 17}], "entities_global": [{"text": "HLA class - I antigens", "type": "ENTITY", "char_start": 197099, "char_end": 197121, "token_start": 13, "token_end": 17, "note": null}]}
+{"sentence_id": 1197, "sentence_text": "Some of the antisera specific for lymphocyte subsets also stained the breast carcinoma cells .", "sentence_char_start_global": 197140, "sentence_char_end_global": 197234, "entities": [], "entities_global": []}
+{"sentence_id": 1198, "sentence_text": "The great variations in the subsets of mononuclear cells in breast carcinomas may correspond to various systems of defense against neoplasm .", "sentence_char_start_global": 197235, "sentence_char_end_global": 197376, "entities": [], "entities_global": []}
+{"sentence_id": 1199, "sentence_text": "A case of male pseudohermaphroditis with normal androgen receptor binding and 47 , XYY karyotype .", "sentence_char_start_global": 197377, "sentence_char_end_global": 197475, "entities": [{"text": "androgen receptor", "type": "ENTITY", "char_start": 48, "char_end": 65, "token_start": 7, "token_end": 8}], "entities_global": [{"text": "androgen receptor", "type": "ENTITY", "char_start": 197425, "char_end": 197442, "token_start": 7, "token_end": 8, "note": null}]}
+{"sentence_id": 1200, "sentence_text": "A case of male pseudohermaphroditis with 47 , XYY karyotype in blood and cutaneous fibroblasts is described .", "sentence_char_start_global": 197476, "sentence_char_end_global": 197585, "entities": [], "entities_global": []}
+{"sentence_id": 1201, "sentence_text": "The plasma testosterone response to HCG stimulation was slightly below the normal range on two occasions suggesting a deficit of gonadal function .", "sentence_char_start_global": 197586, "sentence_char_end_global": 197733, "entities": [], "entities_global": []}
+{"sentence_id": 1202, "sentence_text": "A study of the receptors for dihydrotestosterone in fibroblasts of genital and nongenital skin showed a normal concentration of receptors in genital skin ; 5 - alpha - reductase activity in fibroblasts of the genital skin was low , but the plasma relationship testosterone / dihydrotestosterone under HCG stimulation was normal .", "sentence_char_start_global": 197734, "sentence_char_end_global": 198063, "entities": [{"text": "5 - alpha - reductase", "type": "ENTITY", "char_start": 156, "char_end": 177, "token_start": 24, "token_end": 28}], "entities_global": [{"text": "5 - alpha - reductase", "type": "ENTITY", "char_start": 197890, "char_end": 197911, "token_start": 24, "token_end": 28, "note": null}]}
+{"sentence_id": 1203, "sentence_text": "The diagnostic possibility of a complete testicular feminization syndrome with normal receptors for dihydrotestosterone is commented on .", "sentence_char_start_global": 198064, "sentence_char_end_global": 198201, "entities": [], "entities_global": []}
+{"sentence_id": 1204, "sentence_text": "1 , 25 - Dihydroxyvitamin D3 inhibits antigen - induced T cell activation .", "sentence_char_start_global": 198202, "sentence_char_end_global": 198277, "entities": [], "entities_global": []}
+{"sentence_id": 1205, "sentence_text": "The proliferative response of murine spleen and thymus cells to antigen but not to lectin was inhibited by the active metabolite of vitamin D3 , 1 , 25 - ( OH ) 2D3 .", "sentence_char_start_global": 198278, "sentence_char_end_global": 198444, "entities": [{"text": "antigen", "type": "ENTITY", "char_start": 64, "char_end": 71, "token_start": 10, "token_end": 10}, {"text": "lectin", "type": "ENTITY", "char_start": 83, "char_end": 89, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "antigen", "type": "ENTITY", "char_start": 198342, "char_end": 198349, "token_start": 10, "token_end": 10, "note": null}, {"text": "lectin", "type": "ENTITY", "char_start": 198361, "char_end": 198367, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 1206, "sentence_text": "To directly examine the effect of 1 , 25 - ( OH ) 2D3 on T cell activation in the absence of other complicating interactions , we utilized a panel of cloned Ia - restricted T cell hybridomas that secrete IL 2 on activation by cloned Ia - bearing stimulator cells ( TA3 ) or when stimulated by mitogen .", "sentence_char_start_global": 198445, "sentence_char_end_global": 198747, "entities": [{"text": "IL 2", "type": "ENTITY", "char_start": 204, "char_end": 208, "token_start": 40, "token_end": 41}], "entities_global": [{"text": "IL 2", "type": "ENTITY", "char_start": 198649, "char_end": 198653, "token_start": 40, "token_end": 41, "note": null}]}
+{"sentence_id": 1207, "sentence_text": "Physiologic concentrations of 1 , 25 - ( OH ) 2D3 ( 0 . 01 to 0 . 1 nm ) inhibited the antigen - induced secretion of IL 2 by several of these T cell hybridomas .", "sentence_char_start_global": 198748, "sentence_char_end_global": 198910, "entities": [], "entities_global": []}
+{"sentence_id": 1208, "sentence_text": "This inhibition was dependent on the concentration of the free hormone and could be overcome by increasing the number of Ia - bearing stimulator cells used .", "sentence_char_start_global": 198911, "sentence_char_end_global": 199068, "entities": [], "entities_global": []}
+{"sentence_id": 1209, "sentence_text": "Pretreatment of the T hybridoma but not the TA3 stimulator cell with 1 , 25 - ( OH ) 2D3 resulted in inhibition of activation .", "sentence_char_start_global": 199069, "sentence_char_end_global": 199196, "entities": [], "entities_global": []}
+{"sentence_id": 1210, "sentence_text": "These results are consistent with the finding that specific 1 , 25 - ( OH ) 2D3 receptors are present on the T cell hybridomas but are lacking in TA3 cells .", "sentence_char_start_global": 199197, "sentence_char_end_global": 199354, "entities": [{"text": "1 , 25 - ( OH ) 2D3 receptors", "type": "ENTITY", "char_start": 60, "char_end": 89, "token_start": 9, "token_end": 17}], "entities_global": [{"text": "1 , 25 - ( OH ) 2D3 receptors", "type": "ENTITY", "char_start": 199257, "char_end": 199286, "token_start": 9, "token_end": 17, "note": null}]}
+{"sentence_id": 1211, "sentence_text": "1 , 25 - ( OH ) 2D3 failed , however , to inhibit the activation of the T cell hybridomas by lectin or by an anti - Thy - 1 antibody .", "sentence_char_start_global": 199355, "sentence_char_end_global": 199489, "entities": [{"text": "lectin", "type": "ENTITY", "char_start": 93, "char_end": 99, "token_start": 22, "token_end": 22}, {"text": "anti - Thy - 1 antibody", "type": "ENTITY", "char_start": 109, "char_end": 132, "token_start": 26, "token_end": 31}], "entities_global": [{"text": "lectin", "type": "ENTITY", "char_start": 199448, "char_end": 199454, "token_start": 22, "token_end": 22, "note": null}, {"text": "anti - Thy - 1 antibody", "type": "ENTITY", "char_start": 199464, "char_end": 199487, "token_start": 26, "token_end": 31, "note": null}]}
+{"sentence_id": 1212, "sentence_text": "These findings suggest that 1 , 25 - ( OH ) 2D3 may be interfering with early events of antigen - induced T cell activation , perhaps by hindering T cell recognition of the relevant antigen on stimulator cell surfaces .", "sentence_char_start_global": 199490, "sentence_char_end_global": 199709, "entities": [], "entities_global": []}
+{"sentence_id": 1213, "sentence_text": "This system should prove useful in studying the molecular mechanisms by which 1 , 25 - ( OH ) 2D3 acts to inhibit T cell activation and subsequent IL 2 production .", "sentence_char_start_global": 199710, "sentence_char_end_global": 199874, "entities": [{"text": "IL 2", "type": "ENTITY", "char_start": 147, "char_end": 151, "token_start": 28, "token_end": 29}], "entities_global": [{"text": "IL 2", "type": "ENTITY", "char_start": 199857, "char_end": 199861, "token_start": 28, "token_end": 29, "note": null}]}
+{"sentence_id": 1214, "sentence_text": "Glucocorticoid receptors and steroid sensitivity in normal and neoplastic human lymphoid tissues : a review .", "sentence_char_start_global": 199875, "sentence_char_end_global": 199984, "entities": [{"text": "Glucocorticoid receptors", "type": "ENTITY", "char_start": 0, "char_end": 24, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "Glucocorticoid receptors", "type": "ENTITY", "char_start": 199875, "char_end": 199899, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 1215, "sentence_text": "The determination of estrogen and progesterone receptors in breast cancer has been shown to be useful in predicting the response to endocrine therapy .", "sentence_char_start_global": 199985, "sentence_char_end_global": 200136, "entities": [{"text": "estrogen and progesterone receptors", "type": "ENTITY", "char_start": 21, "char_end": 56, "token_start": 3, "token_end": 6}], "entities_global": [{"text": "estrogen and progesterone receptors", "type": "ENTITY", "char_start": 200006, "char_end": 200041, "token_start": 3, "token_end": 6, "note": null}]}
+{"sentence_id": 1216, "sentence_text": "Given their well - known inhibitory effects on lymphoid tissue , glucocorticoids have been used widely in the treatment of leukemia .", "sentence_char_start_global": 200137, "sentence_char_end_global": 200270, "entities": [], "entities_global": []}
+{"sentence_id": 1217, "sentence_text": "Given these facts , over the last 10 years , several investigators have measured the number of glucocorticoid receptors in normal and neoplastic lymphoid tissue to see whether their number correlated with glucocorticoid responsiveness in vitro or in vivo .", "sentence_char_start_global": 200271, "sentence_char_end_global": 200527, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 95, "char_end": 119, "token_start": 17, "token_end": 18}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 200366, "char_end": 200390, "token_start": 17, "token_end": 18, "note": null}]}
+{"sentence_id": 1218, "sentence_text": "No clear correlation could be established between the level of glucocorticoid receptor and the in vitro action of steroids in normal and neoplastic lymphoid tissue .", "sentence_char_start_global": 200528, "sentence_char_end_global": 200693, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 63, "char_end": 86, "token_start": 10, "token_end": 11}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 200591, "char_end": 200614, "token_start": 10, "token_end": 11, "note": null}]}
+{"sentence_id": 1219, "sentence_text": "In contrast , attempts to correlate glucocorticoid receptor levels in acute lymphocytic leukemia to in vivo steroid responsiveness and immunological type using the whole - cell - binding assay for receptor determination and selecting the patients according to age and immunological criteria have been more successful .", "sentence_char_start_global": 200694, "sentence_char_end_global": 201012, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 36, "char_end": 59, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 200730, "char_end": 200753, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 1220, "sentence_text": "[ Glucocorticoid receptors in normal human lymphocytes ]", "sentence_char_start_global": 201013, "sentence_char_end_global": 201069, "entities": [{"text": "Glucocorticoid receptors", "type": "ENTITY", "char_start": 2, "char_end": 26, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "Glucocorticoid receptors", "type": "ENTITY", "char_start": 201015, "char_end": 201039, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 1221, "sentence_text": "Glucocorticoid ( GC ) receptors were studied in intact lymphocytes from 11 donors .", "sentence_char_start_global": 201070, "sentence_char_end_global": 201153, "entities": [], "entities_global": []}
+{"sentence_id": 1222, "sentence_text": "GC binding parameters were found to be highly reproducible in repeated experiments with lymphocytes .", "sentence_char_start_global": 201154, "sentence_char_end_global": 201255, "entities": [], "entities_global": []}
+{"sentence_id": 1223, "sentence_text": "It was shown that GC receptors in donors ' lymphocytes could be distributed into two different classes similarly to the pattern seen in skin fibroblasts .", "sentence_char_start_global": 201256, "sentence_char_end_global": 201410, "entities": [{"text": "GC receptors", "type": "ENTITY", "char_start": 18, "char_end": 30, "token_start": 4, "token_end": 5}], "entities_global": [{"text": "GC receptors", "type": "ENTITY", "char_start": 201274, "char_end": 201286, "token_start": 4, "token_end": 5, "note": null}]}
+{"sentence_id": 1224, "sentence_text": "Human lymphocytes are an adequate object for studying genetically determined variability of GC receptors and its clinical importance .", "sentence_char_start_global": 201411, "sentence_char_end_global": 201545, "entities": [{"text": "GC receptors", "type": "ENTITY", "char_start": 92, "char_end": 104, "token_start": 12, "token_end": 13}], "entities_global": [{"text": "GC receptors", "type": "ENTITY", "char_start": 201503, "char_end": 201515, "token_start": 12, "token_end": 13, "note": null}]}
+{"sentence_id": 1225, "sentence_text": "Specific estrogen binding sites in human lymphoid cells and thymic cells .", "sentence_char_start_global": 201546, "sentence_char_end_global": 201620, "entities": [{"text": "estrogen binding sites", "type": "ENTITY", "char_start": 9, "char_end": 31, "token_start": 1, "token_end": 3}], "entities_global": [{"text": "estrogen binding sites", "type": "ENTITY", "char_start": 201555, "char_end": 201577, "token_start": 1, "token_end": 3, "note": null}]}
+{"sentence_id": 1226, "sentence_text": "The binding of estrogen in preparations of human peripheral blood mononuclear cells , as well as by splenic and thymic cells is demonstrated by three different approaches ( Dextran - coated charcoal method , whole cell assay , and gel filtration on a sepharose 4B column ) .", "sentence_char_start_global": 201621, "sentence_char_end_global": 201895, "entities": [], "entities_global": []}
+{"sentence_id": 1227, "sentence_text": "Scatchard ' s analysis of [ 3H ] - moxestrol ( R2858 ) and [ 3H ] - estradiol binding proves the existence of a single class of receptor sites having a dissociation constant of 0 . 18 - 2 . 4 X 10 ( - 9 ) M .", "sentence_char_start_global": 201896, "sentence_char_end_global": 202104, "entities": [{"text": "receptor sites", "type": "ENTITY", "char_start": 128, "char_end": 142, "token_start": 28, "token_end": 29}], "entities_global": [{"text": "receptor sites", "type": "ENTITY", "char_start": 202024, "char_end": 202038, "token_start": 28, "token_end": 29, "note": null}]}
+{"sentence_id": 1228, "sentence_text": "Physicochemical properties of the binder , including binding capacity and steroid specificity , are quite similar to those reported for the thymus of small mammalian species or human thymoma .", "sentence_char_start_global": 202105, "sentence_char_end_global": 202297, "entities": [], "entities_global": []}
+{"sentence_id": 1229, "sentence_text": "Administration of fibroblast interferon to patients with advanced breast cancer : possible effects on skin metastasis and on hormone receptors .", "sentence_char_start_global": 202298, "sentence_char_end_global": 202442, "entities": [{"text": "fibroblast interferon", "type": "ENTITY", "char_start": 18, "char_end": 39, "token_start": 2, "token_end": 3}, {"text": "hormone receptors", "type": "ENTITY", "char_start": 125, "char_end": 142, "token_start": 18, "token_end": 19}], "entities_global": [{"text": "fibroblast interferon", "type": "ENTITY", "char_start": 202316, "char_end": 202337, "token_start": 2, "token_end": 3, "note": null}, {"text": "hormone receptors", "type": "ENTITY", "char_start": 202423, "char_end": 202440, "token_start": 18, "token_end": 19, "note": null}]}
+{"sentence_id": 1230, "sentence_text": "Eleven patients with metastasized breast cancer received 8 intramuscular injections of 6 x 10 ( 6 ) units of human fibroblast interferon over a period of 40 days .", "sentence_char_start_global": 202443, "sentence_char_end_global": 202606, "entities": [{"text": "human fibroblast interferon", "type": "ENTITY", "char_start": 109, "char_end": 136, "token_start": 19, "token_end": 21}], "entities_global": [{"text": "human fibroblast interferon", "type": "ENTITY", "char_start": 202552, "char_end": 202579, "token_start": 19, "token_end": 21, "note": null}]}
+{"sentence_id": 1231, "sentence_text": "The injections did not cause local irritation or inflammation .", "sentence_char_start_global": 202607, "sentence_char_end_global": 202670, "entities": [], "entities_global": []}
+{"sentence_id": 1232, "sentence_text": "Fever occurred in only 1 of the 11 patients .", "sentence_char_start_global": 202671, "sentence_char_end_global": 202716, "entities": [], "entities_global": []}
+{"sentence_id": 1233, "sentence_text": "Although several types of metastases were monitored , only skin nodules consistently ( 10 out of 11 patients ) exhibited changes that were suggestive of a therapeutic effect of the treatment regimen : either a simple decrease in size of some nodules or central necrosis accompanied by an inflammatory reaction .", "sentence_char_start_global": 202717, "sentence_char_end_global": 203028, "entities": [], "entities_global": []}
+{"sentence_id": 1234, "sentence_text": "NK - activity of peripheral blood leukocytes was significantly increased after administration of the first dose ; the effect of subsequent injections was less clear .", "sentence_char_start_global": 203029, "sentence_char_end_global": 203195, "entities": [], "entities_global": []}
+{"sentence_id": 1235, "sentence_text": "Receptors for estrogens and progestogens were increased in the tumor biopsies of 2 out of 2 and 5 out of 6 patients tested respectively .", "sentence_char_start_global": 203196, "sentence_char_end_global": 203333, "entities": [], "entities_global": []}
+{"sentence_id": 1236, "sentence_text": "Decreased glucocorticoid receptor binding in adrenal insufficiency .", "sentence_char_start_global": 203334, "sentence_char_end_global": 203402, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 10, "char_end": 33, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 203344, "char_end": 203367, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 1237, "sentence_text": "To examine the effect of glucocorticoid deficiency on the glucocorticoid receptor , we examine the binding of [ 3H ] dexamethasone to lymphocytes in normal subjects and patients with adrenal insufficiency before and after glucocorticoid replacement therapy .", "sentence_char_start_global": 203403, "sentence_char_end_global": 203661, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 58, "char_end": 81, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 203461, "char_end": 203484, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 1238, "sentence_text": "Using a whole cell competitive binding assay , normal human lymphocytes had 5977 + / - 1487 ( mean + / - SD ) binding sites / cell and a dissociation constant of 10 + / - 2 nM .", "sentence_char_start_global": 203662, "sentence_char_end_global": 203839, "entities": [], "entities_global": []}
+{"sentence_id": 1239, "sentence_text": "Lymphocytes from patients with untreated adrenal insufficiency had fewer binding sites ( 3364 + / - 322 ) and a 2 - fold increase in binding affinity ( 5 . 4 + / - 0 . 9 mM ) .", "sentence_char_start_global": 203840, "sentence_char_end_global": 204016, "entities": [{"text": "binding sites", "type": "ENTITY", "char_start": 73, "char_end": 86, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "binding sites", "type": "ENTITY", "char_start": 203913, "char_end": 203926, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 1240, "sentence_text": "The administration of conventional replacement doses of cortisone acetate for 6 months caused no change in receptor number , but was associated with a decrease in binding affinity toward normal .", "sentence_char_start_global": 204017, "sentence_char_end_global": 204212, "entities": [], "entities_global": []}
+{"sentence_id": 1241, "sentence_text": "After long term glucocorticoid replacement therapy , binding parameters were similar to those in patients before treatment .", "sentence_char_start_global": 204213, "sentence_char_end_global": 204337, "entities": [], "entities_global": []}
+{"sentence_id": 1242, "sentence_text": "The physiological implications of the decreased receptor number and increased binding affinity in adrenal insufficiency remain to be elucidated .", "sentence_char_start_global": 204338, "sentence_char_end_global": 204483, "entities": [], "entities_global": []}
+{"sentence_id": 1243, "sentence_text": "Glucocorticoid receptor concentrations and terminal transferase activity as indicators of prognosis in acute non - lymphocytic leukaemia .", "sentence_char_start_global": 204484, "sentence_char_end_global": 204622, "entities": [{"text": "Glucocorticoid receptor", "type": "ENTITY", "char_start": 0, "char_end": 23, "token_start": 0, "token_end": 1}, {"text": "transferase", "type": "ENTITY", "char_start": 52, "char_end": 63, "token_start": 5, "token_end": 5}], "entities_global": [{"text": "Glucocorticoid receptor", "type": "ENTITY", "char_start": 204484, "char_end": 204507, "token_start": 0, "token_end": 1, "note": null}, {"text": "transferase", "type": "ENTITY", "char_start": 204536, "char_end": 204547, "token_start": 5, "token_end": 5, "note": null}]}
+{"sentence_id": 1244, "sentence_text": "Activity of terminal deoxynucleotidyl transferase ( TdT ) , adenosine deaminase , and 5 ' nucleotidase and the cellular concentration of glucocorticoid ( dexamethasone ) receptor were determined in 25 patients with acute non - lymphocytic leukaemia .", "sentence_char_start_global": 204623, "sentence_char_end_global": 204873, "entities": [{"text": "terminal deoxynucleotidyl transferase", "type": "ENTITY", "char_start": 12, "char_end": 49, "token_start": 2, "token_end": 4}, {"text": "TdT", "type": "ENTITY", "char_start": 52, "char_end": 55, "token_start": 6, "token_end": 6}, {"text": "adenosine deaminase", "type": "ENTITY", "char_start": 60, "char_end": 79, "token_start": 9, "token_end": 10}, {"text": "5 ' nucleotidase", "type": "ENTITY", "char_start": 86, "char_end": 102, "token_start": 13, "token_end": 15}, {"text": "glucocorticoid ( dexamethasone ) receptor", "type": "ENTITY", "char_start": 137, "char_end": 178, "token_start": 21, "token_end": 25}], "entities_global": [{"text": "terminal deoxynucleotidyl transferase", "type": "ENTITY", "char_start": 204635, "char_end": 204672, "token_start": 2, "token_end": 4, "note": null}, {"text": "TdT", "type": "ENTITY", "char_start": 204675, "char_end": 204678, "token_start": 6, "token_end": 6, "note": null}, {"text": "adenosine deaminase", "type": "ENTITY", "char_start": 204683, "char_end": 204702, "token_start": 9, "token_end": 10, "note": null}, {"text": "5 ' nucleotidase", "type": "ENTITY", "char_start": 204709, "char_end": 204725, "token_start": 13, "token_end": 15, "note": null}, {"text": "glucocorticoid ( dexamethasone ) receptor", "type": "ENTITY", "char_start": 204760, "char_end": 204801, "token_start": 21, "token_end": 25, "note": null}]}
+{"sentence_id": 1245, "sentence_text": "All patients were treated according to a common protocol .", "sentence_char_start_global": 204874, "sentence_char_end_global": 204932, "entities": [], "entities_global": []}
+{"sentence_id": 1246, "sentence_text": "Increased activity of TdT ( greater than 0 . 1 unit / microgram DNA ) was found in 11 patients .", "sentence_char_start_global": 204933, "sentence_char_end_global": 205029, "entities": [{"text": "TdT", "type": "ENTITY", "char_start": 22, "char_end": 25, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "TdT", "type": "ENTITY", "char_start": 204955, "char_end": 204958, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 1247, "sentence_text": "This group of patients was shown to have higher remission and survival rates ( p = 0 . 06 ) compared with patients with low activity of TdT .", "sentence_char_start_global": 205030, "sentence_char_end_global": 205171, "entities": [], "entities_global": []}
+{"sentence_id": 1248, "sentence_text": "The glucocorticoid receptor concentration of the leukaemic blast cells ranged from 0 to 0 . 94 fmol / microgram DNA .", "sentence_char_start_global": 205172, "sentence_char_end_global": 205289, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 4, "char_end": 27, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 205176, "char_end": 205199, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 1249, "sentence_text": "Thirteen patients had blast cells with a glucocorticoid receptor concentration over 0 . 22 fmol / microgram DNA .", "sentence_char_start_global": 205290, "sentence_char_end_global": 205403, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 41, "char_end": 64, "token_start": 7, "token_end": 8}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 205331, "char_end": 205354, "token_start": 7, "token_end": 8, "note": null}]}
+{"sentence_id": 1250, "sentence_text": "These patients had significantly increased remission and survival rates ( p = 0 . 006 ) compared with those with a low receptor concentration .", "sentence_char_start_global": 205404, "sentence_char_end_global": 205547, "entities": [], "entities_global": []}
+{"sentence_id": 1251, "sentence_text": "This finding can not be explained by a difference in sensitivity to glucocorticoids since these were not used as therapeutic agents .", "sentence_char_start_global": 205548, "sentence_char_end_global": 205681, "entities": [], "entities_global": []}
+{"sentence_id": 1252, "sentence_text": "Adenosine deaminase and 5 ' nucleotidase activities both varied within two orders of magnitude .", "sentence_char_start_global": 205682, "sentence_char_end_global": 205778, "entities": [{"text": "Adenosine deaminase", "type": "ENTITY", "char_start": 0, "char_end": 19, "token_start": 0, "token_end": 1}, {"text": "5 ' nucleotidase", "type": "ENTITY", "char_start": 24, "char_end": 40, "token_start": 3, "token_end": 5}], "entities_global": [{"text": "Adenosine deaminase", "type": "ENTITY", "char_start": 205682, "char_end": 205701, "token_start": 0, "token_end": 1, "note": null}, {"text": "5 ' nucleotidase", "type": "ENTITY", "char_start": 205706, "char_end": 205722, "token_start": 3, "token_end": 5, "note": null}]}
+{"sentence_id": 1253, "sentence_text": "No correlation could be found between activities of these enzymes and remission or survival rate .", "sentence_char_start_global": 205779, "sentence_char_end_global": 205877, "entities": [], "entities_global": []}
+{"sentence_id": 1254, "sentence_text": "These results show that measurements of TdT activity and the glucocorticoid receptor concentration yield valuable prognostic information in acute non - lymphocytic leukaemia", "sentence_char_start_global": 205878, "sentence_char_end_global": 206051, "entities": [{"text": "TdT", "type": "ENTITY", "char_start": 40, "char_end": 43, "token_start": 6, "token_end": 6}, {"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 61, "char_end": 84, "token_start": 10, "token_end": 11}], "entities_global": [{"text": "TdT", "type": "ENTITY", "char_start": 205918, "char_end": 205921, "token_start": 6, "token_end": 6, "note": null}, {"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 205939, "char_end": 205962, "token_start": 10, "token_end": 11, "note": null}]}
+{"sentence_id": 1255, "sentence_text": "[ 3H ] cortivazol : a unique high affinity ligand for the glucocorticoid receptor .", "sentence_char_start_global": 206052, "sentence_char_end_global": 206135, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 58, "char_end": 81, "token_start": 12, "token_end": 13}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 206110, "char_end": 206133, "token_start": 12, "token_end": 13, "note": null}]}
+{"sentence_id": 1256, "sentence_text": "Cortivazol ( CVZ ) and deacylcortivazol ( DAC ) are pyrazolosteroids with potent glucocorticoid activity .", "sentence_char_start_global": 206136, "sentence_char_end_global": 206242, "entities": [], "entities_global": []}
+{"sentence_id": 1257, "sentence_text": "In previous work we showed that DAC is 40 - fold more potent than dexamethasone ( DEX ) in lysing leukemic lymphoblasts .", "sentence_char_start_global": 206243, "sentence_char_end_global": 206364, "entities": [], "entities_global": []}
+{"sentence_id": 1258, "sentence_text": "To assess the interaction between these atypical steroids and the glucocorticoid receptor , we examined the binding of [ 3H ] CVZ to cytosol from glucocorticoid - sensitive and - resistant variants of the human leukemic cell line CEM C7 .", "sentence_char_start_global": 206365, "sentence_char_end_global": 206603, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 66, "char_end": 89, "token_start": 10, "token_end": 11}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 206431, "char_end": 206454, "token_start": 10, "token_end": 11, "note": null}]}
+{"sentence_id": 1259, "sentence_text": "In glucocorticoid - sensitive cells [ 3H ] CVZ causes a 2 - fold induction of glutamine synthetase and binds to a protein in the 4 . 6 S region of high salt sucrose gradients .", "sentence_char_start_global": 206604, "sentence_char_end_global": 206780, "entities": [{"text": "glutamine synthetase", "type": "ENTITY", "char_start": 78, "char_end": 98, "token_start": 16, "token_end": 17}], "entities_global": [{"text": "glutamine synthetase", "type": "ENTITY", "char_start": 206682, "char_end": 206702, "token_start": 16, "token_end": 17, "note": null}]}
+{"sentence_id": 1260, "sentence_text": "On DEAE - cellulose chromatography , [ 3H ] CVZ - receptor complexes show a shift from high ( 0 . 25 M KP ) to low salt ( 0 . 09 M KP ) eluting forms upon activation .", "sentence_char_start_global": 206781, "sentence_char_end_global": 206948, "entities": [{"text": "[ 3H ] CVZ - receptor complexes", "type": "ENTITY", "char_start": 37, "char_end": 68, "token_start": 6, "token_end": 12}], "entities_global": [{"text": "[ 3H ] CVZ - receptor complexes", "type": "ENTITY", "char_start": 206818, "char_end": 206849, "token_start": 6, "token_end": 12, "note": null}]}
+{"sentence_id": 1261, "sentence_text": "CVZ competes for a 97 , 000 - dalton protein labeled by [ 3H ] dexamethasone mesylate .", "sentence_char_start_global": 206949, "sentence_char_end_global": 207036, "entities": [], "entities_global": []}
+{"sentence_id": 1262, "sentence_text": "Scatchard analysis of the binding of [ 3H ] CVZ in glucocorticoid - sensitive cells revealed a curvilinear plot which resolved into high ( 0 . 4 nM ) and low ( 11 nM ) affinity components .", "sentence_char_start_global": 207037, "sentence_char_end_global": 207226, "entities": [], "entities_global": []}
+{"sentence_id": 1263, "sentence_text": "The receptor concentration of the low affinity site ( 0 . 30 pmol / mg protein ) was approximately twice that of the high affinity site ( 0 . 14 pmol / mg protein ) .", "sentence_char_start_global": 207227, "sentence_char_end_global": 207393, "entities": [{"text": "high affinity site", "type": "ENTITY", "char_start": 117, "char_end": 135, "token_start": 23, "token_end": 25}], "entities_global": [{"text": "high affinity site", "type": "ENTITY", "char_start": 207344, "char_end": 207362, "token_start": 23, "token_end": 25, "note": null}]}
+{"sentence_id": 1264, "sentence_text": "Dissociation experiments with dilution and / or excess unlabeled CVZ supported the presence of independent sites .", "sentence_char_start_global": 207394, "sentence_char_end_global": 207508, "entities": [], "entities_global": []}
+{"sentence_id": 1265, "sentence_text": "In contrast , the binding of [ 3H ] DEX to C7 cytosol revealed a single class of binding sites ( Kd = 1 . 9 nM ; receptor concentration , 0 . 46 pmol / mg protein ) .", "sentence_char_start_global": 207509, "sentence_char_end_global": 207675, "entities": [], "entities_global": []}
+{"sentence_id": 1266, "sentence_text": "Examination of the binding of [ 3H ] CVZ using 10 ( - 5 ) M DEX as the competing ligand showed that DEX binds only to the low affinity site detected by [ 3H ] CVZ .", "sentence_char_start_global": 207676, "sentence_char_end_global": 207840, "entities": [], "entities_global": []}
+{"sentence_id": 1267, "sentence_text": "In cytosol from a glucocorticoid - resistant cell line with virtually no [ 3H ] DEX binding , [ 3H ] CVZ detected a single high affinity binding site that was similar in dissociation constant ( 0 . 8 nM ) and receptor concentration ( 0 . 13 pmol / mg protein ) to the high affinity site detected in the glucocorticoid - sensitive cell line C7 .", "sentence_char_start_global": 207841, "sentence_char_end_global": 208185, "entities": [{"text": "high affinity binding site", "type": "ENTITY", "char_start": 123, "char_end": 149, "token_start": 25, "token_end": 28}, {"text": "high affinity site", "type": "ENTITY", "char_start": 268, "char_end": 286, "token_start": 55, "token_end": 57}], "entities_global": [{"text": "high affinity binding site", "type": "ENTITY", "char_start": 207964, "char_end": 207990, "token_start": 25, "token_end": 28, "note": null}, {"text": "high affinity site", "type": "ENTITY", "char_start": 208109, "char_end": 208127, "token_start": 55, "token_end": 57, "note": null}]}
+{"sentence_id": 1268, "sentence_text": "A controlled pore glass bead assay for the measurement of cytoplasmic and nuclear glucocorticoid receptors .", "sentence_char_start_global": 208186, "sentence_char_end_global": 208294, "entities": [{"text": "cytoplasmic and nuclear glucocorticoid receptors", "type": "ENTITY", "char_start": 58, "char_end": 106, "token_start": 10, "token_end": 14}], "entities_global": [{"text": "cytoplasmic and nuclear glucocorticoid receptors", "type": "ENTITY", "char_start": 208244, "char_end": 208292, "token_start": 10, "token_end": 14, "note": null}]}
+{"sentence_id": 1269, "sentence_text": "An assay for the quantitation of cytoplasmic and nuclear glucocorticoid receptors in lymphoid tissue has been developed using controlled pore glass ( CPG ) beads .", "sentence_char_start_global": 208295, "sentence_char_end_global": 208458, "entities": [{"text": "cytoplasmic and nuclear glucocorticoid receptors", "type": "ENTITY", "char_start": 33, "char_end": 81, "token_start": 6, "token_end": 10}], "entities_global": [{"text": "cytoplasmic and nuclear glucocorticoid receptors", "type": "ENTITY", "char_start": 208328, "char_end": 208376, "token_start": 6, "token_end": 10, "note": null}]}
+{"sentence_id": 1270, "sentence_text": "Soluble receptor - - 3H - steroid complex ( cytosol or nuclear extract ) is adsorbed quantitatively within the crevasses of porous glass beads .", "sentence_char_start_global": 208459, "sentence_char_end_global": 208603, "entities": [{"text": "receptor - - 3H - steroid complex", "type": "ENTITY", "char_start": 8, "char_end": 41, "token_start": 1, "token_end": 7}], "entities_global": [{"text": "receptor - - 3H - steroid complex", "type": "ENTITY", "char_start": 208467, "char_end": 208500, "token_start": 1, "token_end": 7, "note": null}]}
+{"sentence_id": 1271, "sentence_text": "Excess labeled steroid as well as most non - specifically bound steroid is easily washed away , leaving the hormone - receptor complex retained by the beads .", "sentence_char_start_global": 208604, "sentence_char_end_global": 208762, "entities": [{"text": "hormone - receptor complex", "type": "ENTITY", "char_start": 108, "char_end": 134, "token_start": 19, "token_end": 22}], "entities_global": [{"text": "hormone - receptor complex", "type": "ENTITY", "char_start": 208712, "char_end": 208738, "token_start": 19, "token_end": 22, "note": null}]}
+{"sentence_id": 1272, "sentence_text": "Bound 3H - steroid is eluted with ethanol and measured for radioactivity .", "sentence_char_start_global": 208763, "sentence_char_end_global": 208837, "entities": [], "entities_global": []}
+{"sentence_id": 1273, "sentence_text": "This procedure which is simple , rapid , and highly reproducible is carried out using frozen samples ( stable for many months ) containing as few as 1 X 10 ( 7 ) cells .", "sentence_char_start_global": 208838, "sentence_char_end_global": 209007, "entities": [], "entities_global": []}
+{"sentence_id": 1274, "sentence_text": "A comparison of the CPG assay to dextran coated charcoal and a whole cell assay demonstrates that CPG and dextran coated charcoal give equivalent measurements of cytosolic receptor concentration , while the CPG and whole cell assays provide equivalent values for total receptor content .", "sentence_char_start_global": 209008, "sentence_char_end_global": 209295, "entities": [{"text": "cytosolic receptor", "type": "ENTITY", "char_start": 162, "char_end": 180, "token_start": 26, "token_end": 27}], "entities_global": [{"text": "cytosolic receptor", "type": "ENTITY", "char_start": 209170, "char_end": 209188, "token_start": 26, "token_end": 27, "note": null}]}
+{"sentence_id": 1275, "sentence_text": "Plasmacytoid blast crisis in B - cell chronic lymphocytic leukemia : effect of estradiol on growth and differentiation in vitro .", "sentence_char_start_global": 209296, "sentence_char_end_global": 209425, "entities": [], "entities_global": []}
+{"sentence_id": 1276, "sentence_text": "Evolution of a case of chronic lymphocytic leukemia ( CLL ) into blast crisis was found to be characterized by three unusual features ( 1 ) the phenotype of the emerging blast cells was that of pre - plasmacytoid cells as shown by plasma cell morphology and an immunological phenotype corresponding partially with CLL - or intermediate B - cells , partially with plasma cells ( terminal transferase - , common acute lymphocytic leukemia antigen - , Ia + , surface immunoglobulin heavy chains - , surface kappa light chains + , intracytoplasmic immunoglobulin A + and G + , BA - 1 + , polyclonal gammaglobulin production ) ; ( 2 ) cytogenetic analysis of spontaneous metaphases revealed that in addition to the typical CLL abnormality , trisomy 12 , in all of the cells , an additional translocation between chromosomes 14 and 17 was present in 40 % with a presumptive breakpoint on chromosome 14 ( q12 - 3 ) never described before ( commonly q32 ) and ( 3 ) the progression of the disease was associated with a striking increase in the expression by the transformed cells of specific binding sites for estradiol ( E2 ) due to an actual increase in total cellular receptor proteins and not to a change in receptor affinity for E2 .", "sentence_char_start_global": 209426, "sentence_char_end_global": 210656, "entities": [{"text": "terminal transferase", "type": "ENTITY", "char_start": 378, "char_end": 398, "token_start": 66, "token_end": 67}, {"text": "acute lymphocytic leukemia antigen", "type": "ENTITY", "char_start": 410, "char_end": 444, "token_start": 71, "token_end": 74}, {"text": "Ia +", "type": "ENTITY", "char_start": 449, "char_end": 453, "token_start": 77, "token_end": 78}, {"text": "surface immunoglobulin heavy chains", "type": "ENTITY", "char_start": 456, "char_end": 491, "token_start": 80, "token_end": 83}, {"text": "surface kappa light chains", "type": "ENTITY", "char_start": 496, "char_end": 522, "token_start": 86, "token_end": 89}, {"text": "intracytoplasmic immunoglobulin A + and G +", "type": "ENTITY", "char_start": 527, "char_end": 570, "token_start": 92, "token_end": 98}, {"text": "BA - 1 +", "type": "ENTITY", "char_start": 573, "char_end": 581, "token_start": 100, "token_end": 103}, {"text": "chromosomes 14 and 17", "type": "ENTITY", "char_start": 807, "char_end": 828, "token_start": 141, "token_end": 144}, {"text": "chromosome 14", "type": "ENTITY", "char_start": 882, "char_end": 895, "token_start": 155, "token_end": 156}, {"text": "cellular receptor proteins", "type": "ENTITY", "char_start": 1154, "char_end": 1180, "token_start": 207, "token_end": 209}], "entities_global": [{"text": "terminal transferase", "type": "ENTITY", "char_start": 209804, "char_end": 209824, "token_start": 66, "token_end": 67, "note": null}, {"text": "acute lymphocytic leukemia antigen", "type": "ENTITY", "char_start": 209836, "char_end": 209870, "token_start": 71, "token_end": 74, "note": null}, {"text": "Ia +", "type": "ENTITY", "char_start": 209875, "char_end": 209879, "token_start": 77, "token_end": 78, "note": null}, {"text": "surface immunoglobulin heavy chains", "type": "ENTITY", "char_start": 209882, "char_end": 209917, "token_start": 80, "token_end": 83, "note": null}, {"text": "surface kappa light chains", "type": "ENTITY", "char_start": 209922, "char_end": 209948, "token_start": 86, "token_end": 89, "note": null}, {"text": "intracytoplasmic immunoglobulin A + and G +", "type": "ENTITY", "char_start": 209953, "char_end": 209996, "token_start": 92, "token_end": 98, "note": null}, {"text": "BA - 1 +", "type": "ENTITY", "char_start": 209999, "char_end": 210007, "token_start": 100, "token_end": 103, "note": null}, {"text": "chromosomes 14 and 17", "type": "ENTITY", "char_start": 210233, "char_end": 210254, "token_start": 141, "token_end": 144, "note": null}, {"text": "chromosome 14", "type": "ENTITY", "char_start": 210308, "char_end": 210321, "token_start": 155, "token_end": 156, "note": null}, {"text": "cellular receptor proteins", "type": "ENTITY", "char_start": 210580, "char_end": 210606, "token_start": 207, "token_end": 209, "note": null}]}
+{"sentence_id": 1277, "sentence_text": "The functional status of the steroid receptors was confirmed by nuclear transfer of the cytoplasmic hormone - receptor complex upon temperature activation .", "sentence_char_start_global": 210657, "sentence_char_end_global": 210813, "entities": [{"text": "steroid receptors", "type": "ENTITY", "char_start": 29, "char_end": 46, "token_start": 5, "token_end": 6}, {"text": "cytoplasmic hormone - receptor complex", "type": "ENTITY", "char_start": 88, "char_end": 126, "token_start": 14, "token_end": 18}], "entities_global": [{"text": "steroid receptors", "type": "ENTITY", "char_start": 210686, "char_end": 210703, "token_start": 5, "token_end": 6, "note": null}, {"text": "cytoplasmic hormone - receptor complex", "type": "ENTITY", "char_start": 210745, "char_end": 210783, "token_start": 14, "token_end": 18, "note": null}]}
+{"sentence_id": 1278, "sentence_text": "Since the rise in E2 - receptor display paralleled a large increase in the proliferative activity of the cells as well as a change in their maturation status the question was raised as to whether the E2 - receptor should be considered as a physiological marker of growth rate or of cellular differentiation .", "sentence_char_start_global": 210814, "sentence_char_end_global": 211122, "entities": [{"text": "E2 - receptor", "type": "ENTITY", "char_start": 18, "char_end": 31, "token_start": 4, "token_end": 6}, {"text": "E2 - receptor", "type": "ENTITY", "char_start": 200, "char_end": 213, "token_start": 36, "token_end": 38}], "entities_global": [{"text": "E2 - receptor", "type": "ENTITY", "char_start": 210832, "char_end": 210845, "token_start": 4, "token_end": 6, "note": null}, {"text": "E2 - receptor", "type": "ENTITY", "char_start": 211014, "char_end": 211027, "token_start": 36, "token_end": 38, "note": null}]}
+{"sentence_id": 1279, "sentence_text": "Exposure of the patient ' s blast cells to E2 in vitro resulted in cessation of cell growth following at least one mitosis after addition of the inducer as seen from the replacement of the large blasts by small CLL - like cells without definite signs of alteration of the differentiation status .", "sentence_char_start_global": 211123, "sentence_char_end_global": 211419, "entities": [], "entities_global": []}
+{"sentence_id": 1280, "sentence_text": "This suggests the association of E2 - receptor expression with control of growth rather than cell maturation .", "sentence_char_start_global": 211420, "sentence_char_end_global": 211530, "entities": [{"text": "E2 - receptor", "type": "ENTITY", "char_start": 33, "char_end": 46, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "E2 - receptor", "type": "ENTITY", "char_start": 211453, "char_end": 211466, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 1281, "sentence_text": "Multiple forms and fragments of cytosolic glucocorticoid receptors from human leukemic cells and normal lymphocytes .", "sentence_char_start_global": 211531, "sentence_char_end_global": 211648, "entities": [{"text": "cytosolic glucocorticoid receptors", "type": "ENTITY", "char_start": 32, "char_end": 66, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "cytosolic glucocorticoid receptors", "type": "ENTITY", "char_start": 211563, "char_end": 211597, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 1282, "sentence_text": "Therapy with glucocorticoids is generally more effective in acute lymphoblastic leukemia than in other types of human leukemia .", "sentence_char_start_global": 211649, "sentence_char_end_global": 211777, "entities": [], "entities_global": []}
+{"sentence_id": 1283, "sentence_text": "Previous studies , however , have not revealed any consistent relationship between clinical responsiveness and the cellular or cytosolic concentration of glucocorticoid - binding sites .", "sentence_char_start_global": 211778, "sentence_char_end_global": 211964, "entities": [{"text": "glucocorticoid - binding sites", "type": "ENTITY", "char_start": 154, "char_end": 184, "token_start": 21, "token_end": 24}], "entities_global": [{"text": "glucocorticoid - binding sites", "type": "ENTITY", "char_start": 211932, "char_end": 211962, "token_start": 21, "token_end": 24, "note": null}]}
+{"sentence_id": 1284, "sentence_text": "The objectives of this study were to determine whether there are intrinsic structural differences among the glucocorticoid receptors in various types of leukemic cells and normal lymphocytes and to investigate the role of endogenous peptidases in receptor degradation .", "sentence_char_start_global": 211965, "sentence_char_end_global": 212234, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 108, "char_end": 132, "token_start": 16, "token_end": 17}, {"text": "endogenous peptidases", "type": "ENTITY", "char_start": 222, "char_end": 243, "token_start": 33, "token_end": 34}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 212073, "char_end": 212097, "token_start": 16, "token_end": 17, "note": null}, {"text": "endogenous peptidases", "type": "ENTITY", "char_start": 212187, "char_end": 212208, "token_start": 33, "token_end": 34, "note": null}]}
+{"sentence_id": 1285, "sentence_text": "Cytosols were prepared from fresh or rapidly frozen leukocytes from 6 healthy adults and 35 high - risk leukemia patients ( median white blood cell count , 150 , 000 cells / microliter ; median age , 13 years ) .", "sentence_char_start_global": 212235, "sentence_char_end_global": 212447, "entities": [], "entities_global": []}
+{"sentence_id": 1286, "sentence_text": "Receptors were labeled with [ 3H ] triamcinolone acetonide and quantitated by charcoal - dextran treatment or Sephadex LH - 20 chromatography .", "sentence_char_start_global": 212448, "sentence_char_end_global": 212591, "entities": [], "entities_global": []}
+{"sentence_id": 1287, "sentence_text": "Mean and median cytosolic receptor concentrations in 12 acute lymphoblastic leukemia specimens lacking the standard B - cell or T - cell markers ( ` ` null cells ' ' ) were approximately 4 - fold higher than in 23 other leukemic cell specimens .", "sentence_char_start_global": 212592, "sentence_char_end_global": 212837, "entities": [], "entities_global": []}
+{"sentence_id": 1288, "sentence_text": "No other consistent differences in receptor content were observed .", "sentence_char_start_global": 212838, "sentence_char_end_global": 212905, "entities": [], "entities_global": []}
+{"sentence_id": 1289, "sentence_text": "Agarose filtration and ultracentrifugation in hypotonic buffers containing 20 mM Na2MoO4 revealed complexes of similar size and shape in all clinical specimens tested and two established leukemic cell lines .", "sentence_char_start_global": 212906, "sentence_char_end_global": 213114, "entities": [], "entities_global": []}
+{"sentence_id": 1290, "sentence_text": "They had Stokes radii ( Rs ) of 8 . 1 + / - 0 . 5 ( S . D . ) nm ( n = 50 ) , sedimentation coefficients of 9 . 5 + / - 0 . 3S ( n = 40 ) , molecular weights of approximately 330 , 000 , and axial ratios ( a / b ) of approximately 12 .", "sentence_char_start_global": 213115, "sentence_char_end_global": 213350, "entities": [], "entities_global": []}
+{"sentence_id": 1291, "sentence_text": "In hypertonic , molybdate - free buffer , these oligomeric complexes were dissociated into subunits with Rs of 5 . 9 + / - 0 . 3 nm ( n = 12 ) and a / b of 11 to 12 , as observed previously for other receptors .", "sentence_char_start_global": 213351, "sentence_char_end_global": 213562, "entities": [{"text": "oligomeric complexes", "type": "ENTITY", "char_start": 48, "char_end": 68, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "oligomeric complexes", "type": "ENTITY", "char_start": 213399, "char_end": 213419, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 1292, "sentence_text": "Fragmentation of the oligomer and the subunit was evident in some cytosols .", "sentence_char_start_global": 213563, "sentence_char_end_global": 213639, "entities": [{"text": "oligomer", "type": "ENTITY", "char_start": 21, "char_end": 29, "token_start": 3, "token_end": 3}, {"text": "subunit", "type": "ENTITY", "char_start": 38, "char_end": 45, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "oligomer", "type": "ENTITY", "char_start": 213584, "char_end": 213592, "token_start": 3, "token_end": 3, "note": null}, {"text": "subunit", "type": "ENTITY", "char_start": 213601, "char_end": 213608, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 1293, "sentence_text": "High activities of peptidases of various specificities were detected in leukemic cell cytosols , as in other cytosols , by fluorometric assays with derivatives of 7 - amino - 4 - methylcoumarin .", "sentence_char_start_global": 213640, "sentence_char_end_global": 213835, "entities": [{"text": "peptidases", "type": "ENTITY", "char_start": 19, "char_end": 29, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "peptidases", "type": "ENTITY", "char_start": 213659, "char_end": 213669, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 1294, "sentence_text": "Receptor cleavage by these and other endogenous enzymes may account for previous observations of ` ` abnormal ' ' receptors in cytosols from some leukemic specimens .", "sentence_char_start_global": 213836, "sentence_char_end_global": 214002, "entities": [{"text": "endogenous enzymes", "type": "ENTITY", "char_start": 37, "char_end": 55, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "endogenous enzymes", "type": "ENTITY", "char_start": 213873, "char_end": 213891, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 1295, "sentence_text": "We conclude that intrinsic structural defects in the receptors are unlikely explanations for the unresponsiveness of some types of leukemia to steroid therapy .", "sentence_char_start_global": 214003, "sentence_char_end_global": 214163, "entities": [], "entities_global": []}
+{"sentence_id": 1296, "sentence_text": "Glucocorticoid receptor number and intracellular water space .", "sentence_char_start_global": 214164, "sentence_char_end_global": 214226, "entities": [{"text": "Glucocorticoid receptor", "type": "ENTITY", "char_start": 0, "char_end": 23, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "Glucocorticoid receptor", "type": "ENTITY", "char_start": 214164, "char_end": 214187, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 1297, "sentence_text": "In order to elucidate the relationship between cell water content and number of glucocorticoid receptors , eleven normal and malignant lymphoid or myelomonocytic cell types originating from mouse , rat and man were investigated .", "sentence_char_start_global": 214227, "sentence_char_end_global": 214456, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 80, "char_end": 104, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 214307, "char_end": 214331, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 1298, "sentence_text": "The cellular water space was measured with 3H2O , and glucocorticoid receptor number was measured in a whole - cell binding assay with [ 3H ] dexamethasone at 30 and 37 degrees C .", "sentence_char_start_global": 214457, "sentence_char_end_global": 214637, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 54, "char_end": 77, "token_start": 10, "token_end": 11}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 214511, "char_end": 214534, "token_start": 10, "token_end": 11, "note": null}]}
+{"sentence_id": 1299, "sentence_text": "The intracellular water phase concentration of glucocorticoid receptors ( around 40 nmol / l cell water ) , and the dependence of receptor affinity on temperature were similar in normal and malignant rodent and human cells .", "sentence_char_start_global": 214638, "sentence_char_end_global": 214862, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 47, "char_end": 71, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 214685, "char_end": 214709, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 1300, "sentence_text": "It is concluded that comparisons of glucocorticoid receptor levels are best made on the basis of intracellular receptor concentrations .", "sentence_char_start_global": 214863, "sentence_char_end_global": 214999, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 36, "char_end": 59, "token_start": 6, "token_end": 7}, {"text": "intracellular receptor", "type": "ENTITY", "char_start": 97, "char_end": 119, "token_start": 16, "token_end": 17}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 214899, "char_end": 214922, "token_start": 6, "token_end": 7, "note": null}, {"text": "intracellular receptor", "type": "ENTITY", "char_start": 214960, "char_end": 214982, "token_start": 16, "token_end": 17, "note": null}]}
+{"sentence_id": 1301, "sentence_text": "Covalent labeling of rat thymocyte and human lymphoid glucocorticoid receptor .", "sentence_char_start_global": 215000, "sentence_char_end_global": 215079, "entities": [{"text": "human lymphoid glucocorticoid receptor", "type": "ENTITY", "char_start": 39, "char_end": 77, "token_start": 6, "token_end": 9}], "entities_global": [{"text": "human lymphoid glucocorticoid receptor", "type": "ENTITY", "char_start": 215039, "char_end": 215077, "token_start": 6, "token_end": 9, "note": null}]}
+{"sentence_id": 1302, "sentence_text": "Lymphoid cells contain specific receptors for glucocorticoids .", "sentence_char_start_global": 215080, "sentence_char_end_global": 215143, "entities": [{"text": "receptors", "type": "ENTITY", "char_start": 32, "char_end": 41, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "receptors", "type": "ENTITY", "char_start": 215112, "char_end": 215121, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 1303, "sentence_text": "We have used [ 3H ] dexamethasone - 21 - mesylate to label covalently glucocorticoid receptors in rat thymic lymphocytes and in neoplastic cells obtained from patients with acute lymphoblastic leukemia and malignant lymphoma .", "sentence_char_start_global": 215144, "sentence_char_end_global": 215370, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 70, "char_end": 94, "token_start": 14, "token_end": 15}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 215214, "char_end": 215238, "token_start": 14, "token_end": 15, "note": null}]}
+{"sentence_id": 1304, "sentence_text": "The covalently labeled glucocorticoid receptors were identified by polyacrylamide gel electrophoresis ( in the presence of 0 . 1 % sodium dodecyl sulfate ) .", "sentence_char_start_global": 215371, "sentence_char_end_global": 215528, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 23, "char_end": 47, "token_start": 3, "token_end": 4}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 215394, "char_end": 215418, "token_start": 3, "token_end": 4, "note": null}]}
+{"sentence_id": 1305, "sentence_text": "In cytosolic fractions prepared from rat thymic lymphocytes , [ 3H ] - dexamethasone - 21 - mesylate labels a protein ( Mr approximately equal to 95 , 000 ) which was identified as the glucocorticoid receptor by the following criteria : ( a ) labeling of this moiety is inhibited by treatment with a 100 - fold molar excess of glucocorticoids , such as dexamethasone and triamcinolone acetonide ; and ( b ) the covalently labeled Mr approximately equal to 95 , 000 protein is activated ( by heating at 20 degrees for 30 min ) to a form that binds to DNA - cellulose .", "sentence_char_start_global": 215529, "sentence_char_end_global": 216096, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 185, "char_end": 208, "token_start": 35, "token_end": 36}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 215714, "char_end": 215737, "token_start": 35, "token_end": 36, "note": null}]}
+{"sentence_id": 1306, "sentence_text": "When intact thymocytes are treated with [ 3H ] dexamethasone - 21 - mesylate , an Mr approximately equal to 95 , 000 moiety is also labeled covalently .", "sentence_char_start_global": 216097, "sentence_char_end_global": 216249, "entities": [], "entities_global": []}
+{"sentence_id": 1307, "sentence_text": "Approximately 35 % of the glucocorticoid receptors can be labeled covalently when intact thymocytes are treated with 100 nM [ 3H ] dexamethasone - 21 - mesylate for 30 min at 4 degrees .", "sentence_char_start_global": 216250, "sentence_char_end_global": 216436, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 26, "char_end": 50, "token_start": 5, "token_end": 6}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 216276, "char_end": 216300, "token_start": 5, "token_end": 6, "note": null}]}
+{"sentence_id": 1308, "sentence_text": "Neoplastic cells from acute lymphoblastic leukemia and malignant lymphoma were treated with [ 3H ] dexamethasone - 21 - mesylate .", "sentence_char_start_global": 216437, "sentence_char_end_global": 216567, "entities": [], "entities_global": []}
+{"sentence_id": 1309, "sentence_text": "In all samples , an Mr approximately equal to 95 , 000 moiety was labeled covalently ; labeling was inhibited by excess glucocorticoid .", "sentence_char_start_global": 216568, "sentence_char_end_global": 216704, "entities": [], "entities_global": []}
+{"sentence_id": 1310, "sentence_text": "Smaller moieties were also identified by competition experiments ; these may represent proteolytic fragments of the Mr approximately equal to 95 , 000 receptor .", "sentence_char_start_global": 216705, "sentence_char_end_global": 216866, "entities": [{"text": "Smaller moieties", "type": "ENTITY", "char_start": 0, "char_end": 16, "token_start": 0, "token_end": 1}, {"text": "proteolytic fragments", "type": "ENTITY", "char_start": 87, "char_end": 108, "token_start": 12, "token_end": 13}], "entities_global": [{"text": "Smaller moieties", "type": "ENTITY", "char_start": 216705, "char_end": 216721, "token_start": 0, "token_end": 1, "note": null}, {"text": "proteolytic fragments", "type": "ENTITY", "char_start": 216792, "char_end": 216813, "token_start": 12, "token_end": 13, "note": null}]}
+{"sentence_id": 1311, "sentence_text": "Thus , in rat and human lymphoid cells , [ 3H ] dexamethasone - 21 - mesylate can be used to label covalently the glucocorticoid receptor .", "sentence_char_start_global": 216867, "sentence_char_end_global": 217006, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 114, "char_end": 137, "token_start": 24, "token_end": 25}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 216981, "char_end": 217004, "token_start": 24, "token_end": 25, "note": null}]}
+{"sentence_id": 1312, "sentence_text": "The association of cytosol oestrogen and progesterone receptors with histological features of breast cancer and early recurrence of disease .", "sentence_char_start_global": 217007, "sentence_char_end_global": 217148, "entities": [{"text": "oestrogen and progesterone receptors", "type": "ENTITY", "char_start": 27, "char_end": 63, "token_start": 4, "token_end": 7}], "entities_global": [{"text": "oestrogen and progesterone receptors", "type": "ENTITY", "char_start": 217034, "char_end": 217070, "token_start": 4, "token_end": 7, "note": null}]}
+{"sentence_id": 1313, "sentence_text": "Two hundred and eighty - eight primary breast tumours were examined for the presence or absence of oestrogen ( REc ) and progesterone ( RPc ) receptors .", "sentence_char_start_global": 217149, "sentence_char_end_global": 217302, "entities": [{"text": "oestrogen ( REc ) and progesterone ( RPc ) receptors", "type": "ENTITY", "char_start": 99, "char_end": 151, "token_start": 17, "token_end": 26}], "entities_global": [{"text": "oestrogen ( REc ) and progesterone ( RPc ) receptors", "type": "ENTITY", "char_start": 217248, "char_end": 217300, "token_start": 17, "token_end": 26, "note": null}]}
+{"sentence_id": 1314, "sentence_text": "Analysis has shown a relative interdependence between the steroid receptor status of primary breast cancer and other prognostic variables such as histological grade , lymphocytic infiltration and tumour elastosis .", "sentence_char_start_global": 217303, "sentence_char_end_global": 217517, "entities": [{"text": "steroid receptor", "type": "ENTITY", "char_start": 58, "char_end": 74, "token_start": 8, "token_end": 9}], "entities_global": [{"text": "steroid receptor", "type": "ENTITY", "char_start": 217361, "char_end": 217377, "token_start": 8, "token_end": 9, "note": null}]}
+{"sentence_id": 1315, "sentence_text": "There were significant associations between epithelial cellularity , stromal fibrosis and the value of REc in those tumours in which the receptor was present .", "sentence_char_start_global": 217518, "sentence_char_end_global": 217677, "entities": [{"text": "REc", "type": "ENTITY", "char_start": 103, "char_end": 106, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "REc", "type": "ENTITY", "char_start": 217621, "char_end": 217624, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 1316, "sentence_text": "Cellularity and fibrosis were unrelated to the presence or absence of oestrogen receptor .", "sentence_char_start_global": 217678, "sentence_char_end_global": 217768, "entities": [{"text": "oestrogen receptor", "type": "ENTITY", "char_start": 70, "char_end": 88, "token_start": 11, "token_end": 12}], "entities_global": [{"text": "oestrogen receptor", "type": "ENTITY", "char_start": 217748, "char_end": 217766, "token_start": 11, "token_end": 12, "note": null}]}
+{"sentence_id": 1317, "sentence_text": "By contrast , neither the presence or absence nor the value of RPc could be related to cellularity or fibrosis .", "sentence_char_start_global": 217769, "sentence_char_end_global": 217881, "entities": [{"text": "RPc", "type": "ENTITY", "char_start": 63, "char_end": 66, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "RPc", "type": "ENTITY", "char_start": 217832, "char_end": 217835, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 1318, "sentence_text": "The value of REc and RPc analysis as an indicator of prognosis was examined in a sub - group of 175 patients receiving no additional treatment following mastectomy .", "sentence_char_start_global": 217882, "sentence_char_end_global": 218047, "entities": [{"text": "REc", "type": "ENTITY", "char_start": 13, "char_end": 16, "token_start": 3, "token_end": 3}, {"text": "RPc", "type": "ENTITY", "char_start": 21, "char_end": 24, "token_start": 5, "token_end": 5}], "entities_global": [{"text": "REc", "type": "ENTITY", "char_start": 217895, "char_end": 217898, "token_start": 3, "token_end": 3, "note": null}, {"text": "RPc", "type": "ENTITY", "char_start": 217903, "char_end": 217906, "token_start": 5, "token_end": 5, "note": null}]}
+{"sentence_id": 1319, "sentence_text": "Overall relapse - free survival ( RFS ) was no different for those patients with receptors compared to those without them ( REc P = 0 . 11 , RPc P = 0 . 7 ) .", "sentence_char_start_global": 218048, "sentence_char_end_global": 218206, "entities": [{"text": "REc", "type": "ENTITY", "char_start": 124, "char_end": 127, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "REc", "type": "ENTITY", "char_start": 218172, "char_end": 218175, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 1320, "sentence_text": "There was no difference in RFS of receptor positive and negative tumours when the axillary node status was taken into account .", "sentence_char_start_global": 218207, "sentence_char_end_global": 218334, "entities": [], "entities_global": []}
+{"sentence_id": 1321, "sentence_text": "Clinical implications of glucocorticoid receptors in human leukemia .", "sentence_char_start_global": 218335, "sentence_char_end_global": 218404, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 25, "char_end": 49, "token_start": 3, "token_end": 4}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 218360, "char_end": 218384, "token_start": 3, "token_end": 4, "note": null}]}
+{"sentence_id": 1322, "sentence_text": "Normal lymphoid cells contain glucocorticoid receptor .", "sentence_char_start_global": 218405, "sentence_char_end_global": 218460, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 30, "char_end": 53, "token_start": 4, "token_end": 5}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 218435, "char_end": 218458, "token_start": 4, "token_end": 5, "note": null}]}
+{"sentence_id": 1323, "sentence_text": "A variety of stimuli that activate these cells also induce increases in receptor concentration .", "sentence_char_start_global": 218461, "sentence_char_end_global": 218557, "entities": [], "entities_global": []}
+{"sentence_id": 1324, "sentence_text": "Similar glucocorticoid receptors can be detected in lymphoid cells from patients with acute lymphoblastic leukemia ( ALL ) .", "sentence_char_start_global": 218558, "sentence_char_end_global": 218682, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 8, "char_end": 32, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 218566, "char_end": 218590, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 1325, "sentence_text": "Absence of the glucocorticoid receptor ( usually found in treated patients ) predicts lack of glucocorticoid responsiveness .", "sentence_char_start_global": 218683, "sentence_char_end_global": 218808, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 15, "char_end": 38, "token_start": 3, "token_end": 4}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 218698, "char_end": 218721, "token_start": 3, "token_end": 4, "note": null}]}
+{"sentence_id": 1326, "sentence_text": "Furthermore , in our hands , glucocorticoid receptor levels correlate with the duration of complete remission in ALL ( though not in other forms of leukemia ) .", "sentence_char_start_global": 218809, "sentence_char_end_global": 218969, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 29, "char_end": 52, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 218838, "char_end": 218861, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 1327, "sentence_text": "This association is independent of cell type , age , sex , or initial leukocyte count .", "sentence_char_start_global": 218970, "sentence_char_end_global": 219057, "entities": [], "entities_global": []}
+{"sentence_id": 1328, "sentence_text": "The level of receptor shows a negative correlation with increasing aggressiveness of the tumor ( null - cell leukemia greater than T - cell leukemia greater than Burkitt ' s lymphoma ) .", "sentence_char_start_global": 219058, "sentence_char_end_global": 219244, "entities": [], "entities_global": []}
+{"sentence_id": 1329, "sentence_text": "Corticosteroid - mediated immunoregulation in man .", "sentence_char_start_global": 219245, "sentence_char_end_global": 219296, "entities": [], "entities_global": []}
+{"sentence_id": 1330, "sentence_text": "Glucocorticoids have profound and complex effects on the human immune response .", "sentence_char_start_global": 219297, "sentence_char_end_global": 219377, "entities": [], "entities_global": []}
+{"sentence_id": 1331, "sentence_text": "However , the precise mechanisms of the corticosteroid - induced immunoregulation in man have not been precisely defined .", "sentence_char_start_global": 219378, "sentence_char_end_global": 219500, "entities": [], "entities_global": []}
+{"sentence_id": 1332, "sentence_text": "Intracytoplasmic corticosteroid - specific receptors appear to be an important common pathway for steroid - induced changes , but variations of receptor parameters do not account for the multifaceted effects on the immune system .", "sentence_char_start_global": 219501, "sentence_char_end_global": 219731, "entities": [{"text": "Intracytoplasmic corticosteroid - specific receptors", "type": "ENTITY", "char_start": 0, "char_end": 52, "token_start": 0, "token_end": 4}], "entities_global": [{"text": "Intracytoplasmic corticosteroid - specific receptors", "type": "ENTITY", "char_start": 219501, "char_end": 219553, "token_start": 0, "token_end": 4, "note": null}]}
+{"sentence_id": 1333, "sentence_text": "Human circulating mononuclear cells redistribute out of the intravascular compartment following treatment with corticosteroids .", "sentence_char_start_global": 219732, "sentence_char_end_global": 219860, "entities": [], "entities_global": []}
+{"sentence_id": 1334, "sentence_text": "Although certain components at this redistribution phenomenon have been well - characterized , the importance of this compartmental cellular shift with respect to the mechanisms of corticosteroid - induced immunoregulation are less well - defined .", "sentence_char_start_global": 219861, "sentence_char_end_global": 220109, "entities": [], "entities_global": []}
+{"sentence_id": 1335, "sentence_text": "Recent observations that activated lymphocytes may be sensitive to the lytic effects of glucocorticoids suggest that under certain situations the elimination of selected subsets of cells may be a relevant mechanism of corticosteroid - mediated immunoregulation in man .", "sentence_char_start_global": 220110, "sentence_char_end_global": 220379, "entities": [], "entities_global": []}
+{"sentence_id": 1336, "sentence_text": "Corticosteroid - mediated effects on monocyte function may be an important mechanism of drug - induced immunoregulation in monocyte - dependent responses .", "sentence_char_start_global": 220380, "sentence_char_end_global": 220535, "entities": [], "entities_global": []}
+{"sentence_id": 1337, "sentence_text": "In some experimental conditions , corticosteroids inhibit Interleukin 1 production by monocytes .", "sentence_char_start_global": 220536, "sentence_char_end_global": 220633, "entities": [{"text": "Interleukin 1", "type": "ENTITY", "char_start": 58, "char_end": 71, "token_start": 7, "token_end": 8}], "entities_global": [{"text": "Interleukin 1", "type": "ENTITY", "char_start": 220594, "char_end": 220607, "token_start": 7, "token_end": 8, "note": null}]}
+{"sentence_id": 1338, "sentence_text": "The immunoregulatory effects of corticosteroids on lymphocyte immune responses are complex .", "sentence_char_start_global": 220634, "sentence_char_end_global": 220726, "entities": [], "entities_global": []}
+{"sentence_id": 1339, "sentence_text": "In vitro corticosteroids appear to selectively affect early immunoregulatory events as opposed to altering an established response .", "sentence_char_start_global": 220727, "sentence_char_end_global": 220859, "entities": [], "entities_global": []}
+{"sentence_id": 1340, "sentence_text": "Multiple sites of steroid - induced modulations of human B cell responses have been defined .", "sentence_char_start_global": 220860, "sentence_char_end_global": 220953, "entities": [], "entities_global": []}
+{"sentence_id": 1341, "sentence_text": "Human lymphoid cell lines and glucocorticoids : II .", "sentence_char_start_global": 220954, "sentence_char_end_global": 221006, "entities": [], "entities_global": []}
+{"sentence_id": 1342, "sentence_text": "Whole cell and cytoplasmic binding properties of lymphoblastoid , leukaemia and lymphoma lines .", "sentence_char_start_global": 221007, "sentence_char_end_global": 221103, "entities": [], "entities_global": []}
+{"sentence_id": 1343, "sentence_text": "The glucocorticoid binding properties of 18 human lymphoid cell lines ( HLCL ) have been investigated .", "sentence_char_start_global": 221104, "sentence_char_end_global": 221207, "entities": [], "entities_global": []}
+{"sentence_id": 1344, "sentence_text": "The specificity of steroid binding was confirmed with various glucocorticoid agonists and antagonists .", "sentence_char_start_global": 221208, "sentence_char_end_global": 221311, "entities": [], "entities_global": []}
+{"sentence_id": 1345, "sentence_text": "A gradation in whole cell and cytoplasmic glucocorticoid binding capacity was observed in the different cell line types : lymphoblastoid greater than lymphoma greater than leukaemia .", "sentence_char_start_global": 221312, "sentence_char_end_global": 221495, "entities": [], "entities_global": []}
+{"sentence_id": 1346, "sentence_text": "The cytoplasmic receptors of leukaemia and lymphoblastoid lines appeared to contain both proteinaceous and phospholipid components .", "sentence_char_start_global": 221496, "sentence_char_end_global": 221628, "entities": [{"text": "cytoplasmic receptors", "type": "ENTITY", "char_start": 4, "char_end": 25, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "cytoplasmic receptors", "type": "ENTITY", "char_start": 221500, "char_end": 221521, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 1347, "sentence_text": "Cytoplasmic steroid - receptor complexes exhibited a wide range of sedimentation coefficients ( 8 . 5 - 11 . 3S ) in low ionic strength buffer but there was no correlation with cell line type or glucocorticoid sensitivity .", "sentence_char_start_global": 221629, "sentence_char_end_global": 221852, "entities": [{"text": "Cytoplasmic steroid - receptor complexes", "type": "ENTITY", "char_start": 0, "char_end": 40, "token_start": 0, "token_end": 4}], "entities_global": [{"text": "Cytoplasmic steroid - receptor complexes", "type": "ENTITY", "char_start": 221629, "char_end": 221669, "token_start": 0, "token_end": 4, "note": null}]}
+{"sentence_id": 1348, "sentence_text": "Activation of these complexes by heat ( 37 degrees C ) or exposure to high ionic strength buffer ( 0 . 3 M NaCl ) induced nuclear binding of steroid but only complexes in high ionic strength buffer manifested changes in sedimentation coefficient .", "sentence_char_start_global": 221853, "sentence_char_end_global": 222100, "entities": [], "entities_global": []}
+{"sentence_id": 1349, "sentence_text": "No correlation was observed between the level or nature of glucocorticoid binding and the cytolethal or cytostatic responsiveness of HLCL to glucocorticoid treatment in vitro .", "sentence_char_start_global": 222101, "sentence_char_end_global": 222277, "entities": [], "entities_global": []}
+{"sentence_id": 1350, "sentence_text": "The resistance to cytolethal effects can not be ascribed to a failure of cells to take up and bind steroid or to significant differences in the molecular species of cytoplasmic receptors present .", "sentence_char_start_global": 222278, "sentence_char_end_global": 222474, "entities": [{"text": "cytoplasmic receptors", "type": "ENTITY", "char_start": 165, "char_end": 186, "token_start": 29, "token_end": 30}], "entities_global": [{"text": "cytoplasmic receptors", "type": "ENTITY", "char_start": 222443, "char_end": 222464, "token_start": 29, "token_end": 30, "note": null}]}
+{"sentence_id": 1351, "sentence_text": "The molecular mechanisms by which glucocorticoids achieve cytolethal responses in human lymphoid cells", "sentence_char_start_global": 222475, "sentence_char_end_global": 222577, "entities": [], "entities_global": []}
+{"sentence_id": 1352, "sentence_text": "CD28 - mediated activation in CD45RA + and CD45RO + T cells : enhanced levels of reactive oxygen intermediates and c - Rel nuclear translocation in CD45RA + cells .", "sentence_char_start_global": 222578, "sentence_char_end_global": 222742, "entities": [{"text": "CD28", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}, {"text": "c - Rel", "type": "ENTITY", "char_start": 115, "char_end": 122, "token_start": 20, "token_end": 22}], "entities_global": [{"text": "CD28", "type": "ENTITY", "char_start": 222578, "char_end": 222582, "token_start": 0, "token_end": 0, "note": null}, {"text": "c - Rel", "type": "ENTITY", "char_start": 222693, "char_end": 222700, "token_start": 20, "token_end": 22, "note": null}]}
+{"sentence_id": 1353, "sentence_text": "We have analyzed the effect of complete T cell activation ( anti - CD3 plus anti - CD28 ) on the activation of NF - kappaB in CD45RA + ( naive ) and CD45RO + ( memory / effector ) T cells .", "sentence_char_start_global": 222743, "sentence_char_end_global": 222932, "entities": [{"text": "anti - CD3", "type": "ENTITY", "char_start": 60, "char_end": 70, "token_start": 11, "token_end": 13}, {"text": "anti - CD28", "type": "ENTITY", "char_start": 76, "char_end": 87, "token_start": 15, "token_end": 17}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 111, "char_end": 122, "token_start": 23, "token_end": 25}], "entities_global": [{"text": "anti - CD3", "type": "ENTITY", "char_start": 222803, "char_end": 222813, "token_start": 11, "token_end": 13, "note": null}, {"text": "anti - CD28", "type": "ENTITY", "char_start": 222819, "char_end": 222830, "token_start": 15, "token_end": 17, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 222854, "char_end": 222865, "token_start": 23, "token_end": 25, "note": null}]}
+{"sentence_id": 1354, "sentence_text": "Long exposure ( 24 h ) induced stronger NF - kappaB DNA binding in CD45RA + cells than in CD45RO + cells .", "sentence_char_start_global": 222933, "sentence_char_end_global": 223039, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 40, "char_end": 51, "token_start": 8, "token_end": 10}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 222973, "char_end": 222984, "token_start": 8, "token_end": 10, "note": null}]}
+{"sentence_id": 1355, "sentence_text": "Analysis of the nuclear c - Rel protein indicated that after anti - CD3 + anti - CD28 stimulation the level of c - Rel was higher in CD45RA + cells .", "sentence_char_start_global": 223040, "sentence_char_end_global": 223189, "entities": [{"text": "nuclear c - Rel protein", "type": "ENTITY", "char_start": 16, "char_end": 39, "token_start": 3, "token_end": 7}, {"text": "c - Rel", "type": "ENTITY", "char_start": 111, "char_end": 118, "token_start": 22, "token_end": 24}], "entities_global": [{"text": "nuclear c - Rel protein", "type": "ENTITY", "char_start": 223056, "char_end": 223079, "token_start": 3, "token_end": 7, "note": null}, {"text": "c - Rel", "type": "ENTITY", "char_start": 223151, "char_end": 223158, "token_start": 22, "token_end": 24, "note": null}]}
+{"sentence_id": 1356, "sentence_text": "Analysis of the cytoplasmic inhibitor IkappaBalpha indicated that anti - CD3 + anti - CD28 stimulation induced a long - lasting degradation in CD45RA + cells but in CD45RO + cells the degradation process was more rapid .", "sentence_char_start_global": 223190, "sentence_char_end_global": 223410, "entities": [{"text": "IkappaBalpha", "type": "ENTITY", "char_start": 38, "char_end": 50, "token_start": 5, "token_end": 5}], "entities_global": [{"text": "IkappaBalpha", "type": "ENTITY", "char_start": 223228, "char_end": 223240, "token_start": 5, "token_end": 5, "note": null}]}
+{"sentence_id": 1357, "sentence_text": "Because the CD28 costimulus is known to induce the production of reactive oxygen intermediates ( ROIs ) , the intracellular ROI levels in CD45RA + and CD45RO + cells were compared by flow cytometry .", "sentence_char_start_global": 223411, "sentence_char_end_global": 223610, "entities": [], "entities_global": []}
+{"sentence_id": 1358, "sentence_text": "ROIs were produced in both cell types , but more strongly in CD45RA + cells .", "sentence_char_start_global": 223611, "sentence_char_end_global": 223688, "entities": [], "entities_global": []}
+{"sentence_id": 1359, "sentence_text": "The data presented in this study further emphasize the differences between CD45RA + and CD45RO + T lymphocytes in ROI - dependent signaling pathways .", "sentence_char_start_global": 223689, "sentence_char_end_global": 223839, "entities": [], "entities_global": []}
+{"sentence_id": 1360, "sentence_text": "Ikaros in hemopoietic lineage determination and homeostasis .", "sentence_char_start_global": 223840, "sentence_char_end_global": 223901, "entities": [{"text": "Ikaros", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "Ikaros", "type": "ENTITY", "char_start": 223840, "char_end": 223846, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 1361, "sentence_text": "Studies on the molecular mechanisms that control hemopoietic differentiation have focused on signaling cascades and nuclear effectors that drive this complex developmental system in a regulated fashion .", "sentence_char_start_global": 223902, "sentence_char_end_global": 224105, "entities": [], "entities_global": []}
+{"sentence_id": 1362, "sentence_text": "Here we review the role of Ikaros , the founding member of a unique family of zinc finger transcription factors in this developmental process .", "sentence_char_start_global": 224106, "sentence_char_end_global": 224249, "entities": [{"text": "Ikaros", "type": "ENTITY", "char_start": 27, "char_end": 33, "token_start": 6, "token_end": 6}, {"text": "zinc finger transcription factors", "type": "ENTITY", "char_start": 78, "char_end": 111, "token_start": 16, "token_end": 19}], "entities_global": [{"text": "Ikaros", "type": "ENTITY", "char_start": 224133, "char_end": 224139, "token_start": 6, "token_end": 6, "note": null}, {"text": "zinc finger transcription factors", "type": "ENTITY", "char_start": 224184, "char_end": 224217, "token_start": 16, "token_end": 19, "note": null}]}
+{"sentence_id": 1363, "sentence_text": "Studies on an Ikaros null mutation have revealed an essential role for this factor in lymphoid cell fate determination and at subsequent branch points of the T cell differentiation pathway .", "sentence_char_start_global": 224250, "sentence_char_end_global": 224440, "entities": [{"text": "Ikaros", "type": "ENTITY", "char_start": 14, "char_end": 20, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "Ikaros", "type": "ENTITY", "char_start": 224264, "char_end": 224270, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 1364, "sentence_text": "Differences in the phenotypes of a null and a dominant negative ( DN ) Ikaros mutation provide insight into a regulatory network through which Ikaros proteins exert their effects in development .", "sentence_char_start_global": 224441, "sentence_char_end_global": 224636, "entities": [{"text": "Ikaros proteins", "type": "ENTITY", "char_start": 143, "char_end": 158, "token_start": 24, "token_end": 25}], "entities_global": [{"text": "Ikaros proteins", "type": "ENTITY", "char_start": 224584, "char_end": 224599, "token_start": 24, "token_end": 25, "note": null}]}
+{"sentence_id": 1365, "sentence_text": "In addition a comparative analysis of the hemopoietic stem cell and precursor compartment resulting from the two Ikaros mutations reveals a profound yet not absolute requirement for Ikaros in the production and differentiation of these populations .", "sentence_char_start_global": 224637, "sentence_char_end_global": 224886, "entities": [{"text": "Ikaros", "type": "ENTITY", "char_start": 113, "char_end": 119, "token_start": 17, "token_end": 17}, {"text": "Ikaros", "type": "ENTITY", "char_start": 182, "char_end": 188, "token_start": 27, "token_end": 27}], "entities_global": [{"text": "Ikaros", "type": "ENTITY", "char_start": 224750, "char_end": 224756, "token_start": 17, "token_end": 17, "note": null}, {"text": "Ikaros", "type": "ENTITY", "char_start": 224819, "char_end": 224825, "token_start": 27, "token_end": 27, "note": null}]}
+{"sentence_id": 1366, "sentence_text": "Overexpression of p65 and c - Jun substitutes for B7 - 1 costimulation by targeting the CD28RE within the IL - 2 promoter .", "sentence_char_start_global": 224887, "sentence_char_end_global": 225010, "entities": [{"text": "CD28RE", "type": "ENTITY", "char_start": 88, "char_end": 94, "token_start": 16, "token_end": 16}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 106, "char_end": 121, "token_start": 19, "token_end": 22}], "entities_global": [{"text": "CD28RE", "type": "ENTITY", "char_start": 224975, "char_end": 224981, "token_start": 16, "token_end": 16, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 224993, "char_end": 225008, "token_start": 19, "token_end": 22, "note": null}]}
+{"sentence_id": 1367, "sentence_text": "The role of Rel and activation protein - 1 ( AP - 1 ) in IL - 2 promoter activity in B7 - 1 - and leukocyte function - associated Ag - 3 ( LFA . 3 ) - costimulated T cells has been evaluated .", "sentence_char_start_global": 225011, "sentence_char_end_global": 225203, "entities": [{"text": "Rel", "type": "ENTITY", "char_start": 12, "char_end": 15, "token_start": 3, "token_end": 3}, {"text": "activation protein - 1", "type": "ENTITY", "char_start": 20, "char_end": 42, "token_start": 5, "token_end": 8}, {"text": "AP - 1", "type": "ENTITY", "char_start": 45, "char_end": 51, "token_start": 10, "token_end": 12}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 57, "char_end": 72, "token_start": 15, "token_end": 18}], "entities_global": [{"text": "Rel", "type": "ENTITY", "char_start": 225023, "char_end": 225026, "token_start": 3, "token_end": 3, "note": null}, {"text": "activation protein - 1", "type": "ENTITY", "char_start": 225031, "char_end": 225053, "token_start": 5, "token_end": 8, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 225056, "char_end": 225062, "token_start": 10, "token_end": 12, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 225068, "char_end": 225083, "token_start": 15, "token_end": 18, "note": null}]}
+{"sentence_id": 1368, "sentence_text": "We demonstrate that overexpression of c - Jun but not c - Fos increases IL - 2 promoter activity in both B7 - 1 - and LFA - 3 - costimulated Jurkat T cells .", "sentence_char_start_global": 225204, "sentence_char_end_global": 225361, "entities": [{"text": "c - Jun", "type": "ENTITY", "char_start": 38, "char_end": 45, "token_start": 5, "token_end": 7}, {"text": "c - Fos", "type": "ENTITY", "char_start": 54, "char_end": 61, "token_start": 10, "token_end": 12}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 72, "char_end": 87, "token_start": 14, "token_end": 17}], "entities_global": [{"text": "c - Jun", "type": "ENTITY", "char_start": 225242, "char_end": 225249, "token_start": 5, "token_end": 7, "note": null}, {"text": "c - Fos", "type": "ENTITY", "char_start": 225258, "char_end": 225265, "token_start": 10, "token_end": 12, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 225276, "char_end": 225291, "token_start": 14, "token_end": 17, "note": null}]}
+{"sentence_id": 1369, "sentence_text": "Cotransfection of both c - Jun and c - Fos substitutes for B7 - 1 costimulation in driving an activation protein - 1 response element but not for the IL - 2 promoter .", "sentence_char_start_global": 225362, "sentence_char_end_global": 225529, "entities": [{"text": "activation protein - 1 response element", "type": "ENTITY", "char_start": 94, "char_end": 133, "token_start": 19, "token_end": 24}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 150, "char_end": 165, "token_start": 29, "token_end": 32}], "entities_global": [{"text": "activation protein - 1 response element", "type": "ENTITY", "char_start": 225456, "char_end": 225495, "token_start": 19, "token_end": 24, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 225512, "char_end": 225527, "token_start": 29, "token_end": 32, "note": null}]}
+{"sentence_id": 1370, "sentence_text": "Overexpression of Rel proteins demonstrated that p65 - expressing Jurkat cells transcribed equally well a nuclear factor kappabeta reporter construct when costimulated with B7 - 1 or LFA - 3 , but transcription of IL - 2 promoter or CD28 response element ( CD28RE ) - driven reporters was superior in B7 - 1 - costimulated cells .", "sentence_char_start_global": 225530, "sentence_char_end_global": 225860, "entities": [{"text": "Rel proteins", "type": "ENTITY", "char_start": 18, "char_end": 30, "token_start": 2, "token_end": 3}, {"text": "nuclear factor kappabeta reporter construct", "type": "ENTITY", "char_start": 106, "char_end": 149, "token_start": 15, "token_end": 19}, {"text": "B7 - 1", "type": "ENTITY", "char_start": 173, "char_end": 179, "token_start": 23, "token_end": 25}, {"text": "LFA - 3", "type": "ENTITY", "char_start": 183, "char_end": 190, "token_start": 27, "token_end": 29}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 214, "char_end": 229, "token_start": 34, "token_end": 37}, {"text": "CD28 response element ( CD28RE ) - driven reporters", "type": "ENTITY", "char_start": 233, "char_end": 284, "token_start": 39, "token_end": 47}], "entities_global": [{"text": "Rel proteins", "type": "ENTITY", "char_start": 225548, "char_end": 225560, "token_start": 2, "token_end": 3, "note": null}, {"text": "nuclear factor kappabeta reporter construct", "type": "ENTITY", "char_start": 225636, "char_end": 225679, "token_start": 15, "token_end": 19, "note": null}, {"text": "B7 - 1", "type": "ENTITY", "char_start": 225703, "char_end": 225709, "token_start": 23, "token_end": 25, "note": null}, {"text": "LFA - 3", "type": "ENTITY", "char_start": 225713, "char_end": 225720, "token_start": 27, "token_end": 29, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 225744, "char_end": 225759, "token_start": 34, "token_end": 37, "note": null}, {"text": "CD28 response element ( CD28RE ) - driven reporters", "type": "ENTITY", "char_start": 225763, "char_end": 225814, "token_start": 39, "token_end": 47, "note": null}]}
+{"sentence_id": 1371, "sentence_text": "Combined expression of c - Jun and p65 induced vigorous transcription of IL - 2 promoter - and CD28RE - driven reporter constructs in both LFA - 3 - and B7 - 1 - costimulated Jurkat cells .", "sentence_char_start_global": 225861, "sentence_char_end_global": 226050, "entities": [{"text": "c - Jun", "type": "ENTITY", "char_start": 23, "char_end": 30, "token_start": 3, "token_end": 5}, {"text": "p65", "type": "ENTITY", "char_start": 35, "char_end": 38, "token_start": 7, "token_end": 7}, {"text": "IL - 2 promoter - and CD28RE - driven reporter constructs", "type": "ENTITY", "char_start": 73, "char_end": 130, "token_start": 12, "token_end": 22}], "entities_global": [{"text": "c - Jun", "type": "ENTITY", "char_start": 225884, "char_end": 225891, "token_start": 3, "token_end": 5, "note": null}, {"text": "p65", "type": "ENTITY", "char_start": 225896, "char_end": 225899, "token_start": 7, "token_end": 7, "note": null}, {"text": "IL - 2 promoter - and CD28RE - driven reporter constructs", "type": "ENTITY", "char_start": 225934, "char_end": 225991, "token_start": 12, "token_end": 22, "note": null}]}
+{"sentence_id": 1372, "sentence_text": "Mutating the CD28RE but not the upstream nuclear factor kappabeta - binding site in the IL - 2 promoter reduced B7 - 1 - driven transcription > 90 % .", "sentence_char_start_global": 226051, "sentence_char_end_global": 226201, "entities": [{"text": "CD28RE", "type": "ENTITY", "char_start": 13, "char_end": 19, "token_start": 2, "token_end": 2}, {"text": "upstream nuclear factor kappabeta - binding site", "type": "ENTITY", "char_start": 32, "char_end": 80, "token_start": 6, "token_end": 12}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 88, "char_end": 103, "token_start": 15, "token_end": 18}, {"text": "B7 - 1", "type": "ENTITY", "char_start": 112, "char_end": 118, "token_start": 20, "token_end": 22}], "entities_global": [{"text": "CD28RE", "type": "ENTITY", "char_start": 226064, "char_end": 226070, "token_start": 2, "token_end": 2, "note": null}, {"text": "upstream nuclear factor kappabeta - binding site", "type": "ENTITY", "char_start": 226083, "char_end": 226131, "token_start": 6, "token_end": 12, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 226139, "char_end": 226154, "token_start": 15, "token_end": 18, "note": null}, {"text": "B7 - 1", "type": "ENTITY", "char_start": 226163, "char_end": 226169, "token_start": 20, "token_end": 22, "note": null}]}
+{"sentence_id": 1373, "sentence_text": "The results implicates a major role of the CD28RE in the integration of p65 / c - Jun - mediated transcription within the IL - 2 promoter .", "sentence_char_start_global": 226202, "sentence_char_end_global": 226341, "entities": [{"text": "CD28RE", "type": "ENTITY", "char_start": 43, "char_end": 49, "token_start": 8, "token_end": 8}, {"text": "p65", "type": "ENTITY", "char_start": 72, "char_end": 75, "token_start": 13, "token_end": 13}, {"text": "c - Jun", "type": "ENTITY", "char_start": 78, "char_end": 85, "token_start": 15, "token_end": 17}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 122, "char_end": 137, "token_start": 23, "token_end": 26}], "entities_global": [{"text": "CD28RE", "type": "ENTITY", "char_start": 226245, "char_end": 226251, "token_start": 8, "token_end": 8, "note": null}, {"text": "p65", "type": "ENTITY", "char_start": 226274, "char_end": 226277, "token_start": 13, "token_end": 13, "note": null}, {"text": "c - Jun", "type": "ENTITY", "char_start": 226280, "char_end": 226287, "token_start": 15, "token_end": 17, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 226324, "char_end": 226339, "token_start": 23, "token_end": 26, "note": null}]}
+{"sentence_id": 1374, "sentence_text": "We suggest that the transition from an autocrine LFA - 3 - driven immune response to a B7 - - induced paracrine immune response involves the activation of c - Jun and p65 , which target the CD28RE region of the IL - 2 promoter .", "sentence_char_start_global": 226342, "sentence_char_end_global": 226570, "entities": [{"text": "LFA - 3", "type": "ENTITY", "char_start": 49, "char_end": 56, "token_start": 8, "token_end": 10}, {"text": "c - Jun", "type": "ENTITY", "char_start": 155, "char_end": 162, "token_start": 28, "token_end": 30}, {"text": "p65", "type": "ENTITY", "char_start": 167, "char_end": 170, "token_start": 32, "token_end": 32}, {"text": "CD28RE", "type": "ENTITY", "char_start": 190, "char_end": 196, "token_start": 37, "token_end": 37}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 211, "char_end": 226, "token_start": 41, "token_end": 44}], "entities_global": [{"text": "LFA - 3", "type": "ENTITY", "char_start": 226391, "char_end": 226398, "token_start": 8, "token_end": 10, "note": null}, {"text": "c - Jun", "type": "ENTITY", "char_start": 226497, "char_end": 226504, "token_start": 28, "token_end": 30, "note": null}, {"text": "p65", "type": "ENTITY", "char_start": 226509, "char_end": 226512, "token_start": 32, "token_end": 32, "note": null}, {"text": "CD28RE", "type": "ENTITY", "char_start": 226532, "char_end": 226538, "token_start": 37, "token_end": 37, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 226553, "char_end": 226568, "token_start": 41, "token_end": 44, "note": null}]}
+{"sentence_id": 1375, "sentence_text": "Defects in actin - cap formation in Vav - deficient mice implicate an actin requirement for lymphocyte signal transduction .", "sentence_char_start_global": 226571, "sentence_char_end_global": 226695, "entities": [], "entities_global": []}
+{"sentence_id": 1376, "sentence_text": "BACKGROUND : Antigen - receptor interactions on lymphocytes result in local clustering of actin , receptors and signaling molecules into an asymmetric membrane structure termed a cap .", "sentence_char_start_global": 226696, "sentence_char_end_global": 226880, "entities": [{"text": "actin", "type": "ENTITY", "char_start": 90, "char_end": 95, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "actin", "type": "ENTITY", "char_start": 226786, "char_end": 226791, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 1377, "sentence_text": "Although actin polymerization is known to be required , the mechanisms underlying cap formation are unclear .", "sentence_char_start_global": 226881, "sentence_char_end_global": 226990, "entities": [], "entities_global": []}
+{"sentence_id": 1378, "sentence_text": "We have studied the events underlying cap formation using mice bearing a null mutation in vav ( vav - / - ) , a gene that encodes a guanine - nucleotide exchange factor for the GTPase Rac .", "sentence_char_start_global": 226991, "sentence_char_end_global": 227180, "entities": [{"text": "vav", "type": "ENTITY", "char_start": 90, "char_end": 93, "token_start": 15, "token_end": 15}, {"text": "vav", "type": "ENTITY", "char_start": 96, "char_end": 99, "token_start": 17, "token_end": 17}, {"text": "guanine - nucleotide exchange factor", "type": "ENTITY", "char_start": 132, "char_end": 168, "token_start": 28, "token_end": 32}, {"text": "GTPase Rac", "type": "ENTITY", "char_start": 177, "char_end": 187, "token_start": 35, "token_end": 36}], "entities_global": [{"text": "vav", "type": "ENTITY", "char_start": 227081, "char_end": 227084, "token_start": 15, "token_end": 15, "note": null}, {"text": "vav", "type": "ENTITY", "char_start": 227087, "char_end": 227090, "token_start": 17, "token_end": 17, "note": null}, {"text": "guanine - nucleotide exchange factor", "type": "ENTITY", "char_start": 227123, "char_end": 227159, "token_start": 28, "token_end": 32, "note": null}, {"text": "GTPase Rac", "type": "ENTITY", "char_start": 227168, "char_end": 227178, "token_start": 35, "token_end": 36, "note": null}]}
+{"sentence_id": 1379, "sentence_text": "RESULTS : Lymphocytes from vav - / - mice failed to form T - cell receptor caps following activation and had a defective actin cytoskeleton .", "sentence_char_start_global": 227181, "sentence_char_end_global": 227322, "entities": [{"text": "vav", "type": "ENTITY", "char_start": 27, "char_end": 30, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "vav", "type": "ENTITY", "char_start": 227208, "char_end": 227211, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 1380, "sentence_text": "The vav - / - T cells were deficient in interleukin - 2 ( IL - 2 ) production and proliferation , and the peak of Ca2 + mobilization was reduced although of normal duration .", "sentence_char_start_global": 227323, "sentence_char_end_global": 227497, "entities": [], "entities_global": []}
+{"sentence_id": 1381, "sentence_text": "Activation of Jun N - terminal kinase or stress - activated kinase ( JNK or SAPK ) and mitogen - activated protein kinase ( MAPK ) and the induction of the transcription factor NF - ATc1 and egr - 1 genes was normal .", "sentence_char_start_global": 227498, "sentence_char_end_global": 227715, "entities": [{"text": "Jun N - terminal kinase", "type": "ENTITY", "char_start": 14, "char_end": 37, "token_start": 2, "token_end": 6}, {"text": "stress - activated kinase", "type": "ENTITY", "char_start": 41, "char_end": 66, "token_start": 8, "token_end": 11}, {"text": "JNK", "type": "ENTITY", "char_start": 69, "char_end": 72, "token_start": 13, "token_end": 13}, {"text": "SAPK", "type": "ENTITY", "char_start": 76, "char_end": 80, "token_start": 15, "token_end": 15}, {"text": "mitogen - activated protein kinase", "type": "ENTITY", "char_start": 87, "char_end": 121, "token_start": 18, "token_end": 22}, {"text": "MAPK", "type": "ENTITY", "char_start": 124, "char_end": 128, "token_start": 24, "token_end": 24}, {"text": "transcription factor", "type": "ENTITY", "char_start": 156, "char_end": 176, "token_start": 31, "token_end": 32}, {"text": "NF - ATc1 and egr - 1 genes", "type": "ENTITY", "char_start": 177, "char_end": 204, "token_start": 33, "token_end": 40}], "entities_global": [{"text": "Jun N - terminal kinase", "type": "ENTITY", "char_start": 227512, "char_end": 227535, "token_start": 2, "token_end": 6, "note": null}, {"text": "stress - activated kinase", "type": "ENTITY", "char_start": 227539, "char_end": 227564, "token_start": 8, "token_end": 11, "note": null}, {"text": "JNK", "type": "ENTITY", "char_start": 227567, "char_end": 227570, "token_start": 13, "token_end": 13, "note": null}, {"text": "SAPK", "type": "ENTITY", "char_start": 227574, "char_end": 227578, "token_start": 15, "token_end": 15, "note": null}, {"text": "mitogen - activated protein kinase", "type": "ENTITY", "char_start": 227585, "char_end": 227619, "token_start": 18, "token_end": 22, "note": null}, {"text": "MAPK", "type": "ENTITY", "char_start": 227622, "char_end": 227626, "token_start": 24, "token_end": 24, "note": null}, {"text": "transcription factor", "type": "ENTITY", "char_start": 227654, "char_end": 227674, "token_start": 31, "token_end": 32, "note": null}, {"text": "NF - ATc1 and egr - 1 genes", "type": "ENTITY", "char_start": 227675, "char_end": 227702, "token_start": 33, "token_end": 40, "note": null}]}
+{"sentence_id": 1382, "sentence_text": "Despite the reduced Ca2 + mobilization , translocation of cytoplasmic NF - ATc to the nucleus was normal , reflecting that the lower levels of Ca2 + in vav - / - cells were still sufficient to activate calcineurin .", "sentence_char_start_global": 227716, "sentence_char_end_global": 227931, "entities": [{"text": "cytoplasmic NF - ATc", "type": "ENTITY", "char_start": 58, "char_end": 78, "token_start": 9, "token_end": 12}, {"text": "calcineurin", "type": "ENTITY", "char_start": 202, "char_end": 213, "token_start": 38, "token_end": 38}], "entities_global": [{"text": "cytoplasmic NF - ATc", "type": "ENTITY", "char_start": 227774, "char_end": 227794, "token_start": 9, "token_end": 12, "note": null}, {"text": "calcineurin", "type": "ENTITY", "char_start": 227918, "char_end": 227929, "token_start": 38, "token_end": 38, "note": null}]}
+{"sentence_id": 1383, "sentence_text": "Treatment of lymphocytes with cytochalasin D , which blocks actin polymerization , inhibited cap formation and produced defects in signaling and IL - 2 transcriptional induction in response to antigen - receptor signaling that were nearly identical to those seen in vav - / - cells .", "sentence_char_start_global": 227932, "sentence_char_end_global": 228215, "entities": [], "entities_global": []}
+{"sentence_id": 1384, "sentence_text": "In transfection studies , either constitutively active Vav or Rac could complement constitutively active calcineurin to activate NF - AT - dependent transcription .", "sentence_char_start_global": 228216, "sentence_char_end_global": 228380, "entities": [{"text": "Vav", "type": "ENTITY", "char_start": 55, "char_end": 58, "token_start": 7, "token_end": 7}, {"text": "Rac", "type": "ENTITY", "char_start": 62, "char_end": 65, "token_start": 9, "token_end": 9}, {"text": "calcineurin", "type": "ENTITY", "char_start": 105, "char_end": 116, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "Vav", "type": "ENTITY", "char_start": 228271, "char_end": 228274, "token_start": 7, "token_end": 7, "note": null}, {"text": "Rac", "type": "ENTITY", "char_start": 228278, "char_end": 228281, "token_start": 9, "token_end": 9, "note": null}, {"text": "calcineurin", "type": "ENTITY", "char_start": 228321, "char_end": 228332, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 1385, "sentence_text": "CONCLUSIONS : These results indicate that Vav is required for cap formation in lymphocytes .", "sentence_char_start_global": 228381, "sentence_char_end_global": 228473, "entities": [{"text": "Vav", "type": "ENTITY", "char_start": 42, "char_end": 45, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "Vav", "type": "ENTITY", "char_start": 228423, "char_end": 228426, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 1386, "sentence_text": "Furthermore , the correlation between cap formation , IL - 2 production and proliferation supports the hypothesis that an actin - dependent pathway is a source of specialized growth regulatory signals .", "sentence_char_start_global": 228474, "sentence_char_end_global": 228676, "entities": [], "entities_global": []}
+{"sentence_id": 1387, "sentence_text": "CD14 - dependent activation of human endothelial cells by Bacteroides fragilis outer membrane .", "sentence_char_start_global": 228677, "sentence_char_end_global": 228772, "entities": [{"text": "CD14", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "CD14", "type": "ENTITY", "char_start": 228677, "char_end": 228681, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 1388, "sentence_text": "We studied the capacity of isolated Bacteriodes fragilis outer membrane , B . fragilis NCTC9343 lipopolysaccharide ( LPS ; endotoxin ) , and B . fragilis NCTC9343 capsular polysaccharides to activate human umbilical vein endothelial cell ( HUVEC ) monolayers .", "sentence_char_start_global": 228773, "sentence_char_end_global": 229033, "entities": [], "entities_global": []}
+{"sentence_id": 1389, "sentence_text": "To assess HUVEC activation , E - selectin expression was measured by enzyme - linked immunosorbent assay ( ELISA ) , Northern blot analysis for E - selectin - specific mRNA , and electrophoretic gel mobility shift assay ( EMSA ) for NF - kappa B , a transcription factor necessary for E - selectin gene activation .", "sentence_char_start_global": 229034, "sentence_char_end_global": 229349, "entities": [{"text": "E - selectin", "type": "ENTITY", "char_start": 29, "char_end": 41, "token_start": 5, "token_end": 7}, {"text": "E - selectin - specific mRNA", "type": "ENTITY", "char_start": 144, "char_end": 172, "token_start": 25, "token_end": 30}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 233, "char_end": 245, "token_start": 42, "token_end": 45}, {"text": "transcription factor", "type": "ENTITY", "char_start": 250, "char_end": 270, "token_start": 48, "token_end": 49}, {"text": "E - selectin gene", "type": "ENTITY", "char_start": 285, "char_end": 302, "token_start": 52, "token_end": 55}], "entities_global": [{"text": "E - selectin", "type": "ENTITY", "char_start": 229063, "char_end": 229075, "token_start": 5, "token_end": 7, "note": null}, {"text": "E - selectin - specific mRNA", "type": "ENTITY", "char_start": 229178, "char_end": 229206, "token_start": 25, "token_end": 30, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 229267, "char_end": 229279, "token_start": 42, "token_end": 45, "note": null}, {"text": "transcription factor", "type": "ENTITY", "char_start": 229284, "char_end": 229304, "token_start": 48, "token_end": 49, "note": null}, {"text": "E - selectin gene", "type": "ENTITY", "char_start": 229319, "char_end": 229336, "token_start": 52, "token_end": 55, "note": null}]}
+{"sentence_id": 1390, "sentence_text": "Exposure of HUVECs to B . fragilis outer membrane fractions , separated from other components of the B . fragilis cell wall by isopycnic , sucrose gradient centrifugation , significantly increased surface expression of E - selectin and induced functional endothelial cell - dependent leukocyte adhesion .", "sentence_char_start_global": 229350, "sentence_char_end_global": 229654, "entities": [{"text": "E - selectin", "type": "ENTITY", "char_start": 219, "char_end": 231, "token_start": 34, "token_end": 36}], "entities_global": [{"text": "E - selectin", "type": "ENTITY", "char_start": 229569, "char_end": 229581, "token_start": 34, "token_end": 36, "note": null}]}
+{"sentence_id": 1391, "sentence_text": "B . fragilis outer membranes induced translocation of NF - kappa B to HUVEC nuclei and accumulation of E - selectin mRNA in HUVEC cytoplasm .", "sentence_char_start_global": 229655, "sentence_char_end_global": 229796, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 54, "char_end": 66, "token_start": 8, "token_end": 11}, {"text": "E - selectin mRNA", "type": "ENTITY", "char_start": 103, "char_end": 120, "token_start": 18, "token_end": 21}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 229709, "char_end": 229721, "token_start": 8, "token_end": 11, "note": null}, {"text": "E - selectin mRNA", "type": "ENTITY", "char_start": 229758, "char_end": 229775, "token_start": 18, "token_end": 21, "note": null}]}
+{"sentence_id": 1392, "sentence_text": "E - selectin expression induced by B . fragilis outer membranes was not blocked by polymixin B .", "sentence_char_start_global": 229797, "sentence_char_end_global": 229893, "entities": [], "entities_global": []}
+{"sentence_id": 1393, "sentence_text": "In contrast , E - selectin expression induced by outer membrane fractions purified from E . coli was competitively inhibited by polymixin B .", "sentence_char_start_global": 229894, "sentence_char_end_global": 230035, "entities": [], "entities_global": []}
+{"sentence_id": 1394, "sentence_text": "Neither purified B . fragilis LPS , a prominent constituent of the outer membrane , nor purified B . fragilis capsular polysaccharides induced HUVEC activation .", "sentence_char_start_global": 230036, "sentence_char_end_global": 230197, "entities": [], "entities_global": []}
+{"sentence_id": 1395, "sentence_text": "Two different monoclonal antibodies directed against human CD14 completely inhibited B . fragilis outer membrane - induced NF - kappa B activation , E - selectin transcription , and E - selectin surface expression .", "sentence_char_start_global": 230198, "sentence_char_end_global": 230413, "entities": [{"text": "monoclonal antibodies", "type": "ENTITY", "char_start": 14, "char_end": 35, "token_start": 2, "token_end": 3}, {"text": "human CD14", "type": "ENTITY", "char_start": 53, "char_end": 63, "token_start": 6, "token_end": 7}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 123, "char_end": 135, "token_start": 17, "token_end": 20}], "entities_global": [{"text": "monoclonal antibodies", "type": "ENTITY", "char_start": 230212, "char_end": 230233, "token_start": 2, "token_end": 3, "note": null}, {"text": "human CD14", "type": "ENTITY", "char_start": 230251, "char_end": 230261, "token_start": 6, "token_end": 7, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 230321, "char_end": 230333, "token_start": 17, "token_end": 20, "note": null}]}
+{"sentence_id": 1396, "sentence_text": "We conclude that the outer membrane component of the B . fragilis cell wall contains a proinflammatory factor ( s ) , that is not LPS , which induces human endothelial cell activation by a soluble CD14 - dependent mechanism .", "sentence_char_start_global": 230414, "sentence_char_end_global": 230639, "entities": [{"text": "CD14", "type": "ENTITY", "char_start": 197, "char_end": 201, "token_start": 36, "token_end": 36}], "entities_global": [{"text": "CD14", "type": "ENTITY", "char_start": 230611, "char_end": 230615, "token_start": 36, "token_end": 36, "note": null}]}
+{"sentence_id": 1397, "sentence_text": "NF - kappaB protects HIV - 1 - infected myeloid cells from apoptosis .", "sentence_char_start_global": 230640, "sentence_char_end_global": 230710, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 0, "char_end": 11, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 230640, "char_end": 230651, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 1398, "sentence_text": "HIV - 1 infection of primary monocytic cells and myeloid cell lines results in sustained NF - kappaB activation .", "sentence_char_start_global": 230711, "sentence_char_end_global": 230824, "entities": [], "entities_global": []}
+{"sentence_id": 1399, "sentence_text": "Recently , NF - kappaB induction has been shown to play a role in protecting cells from programmed cell death .", "sentence_char_start_global": 230825, "sentence_char_end_global": 230936, "entities": [], "entities_global": []}
+{"sentence_id": 1400, "sentence_text": "In the present study , we sought to investigate whether constitutive NF - kappaB activity in chronically HIV - 1 - infected promonocytic U937 ( U9 - IIIB ) and myeloblastic PLB - 985 ( PLB - IIIB ) cells affects apoptotic signaling .", "sentence_char_start_global": 230937, "sentence_char_end_global": 231170, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 69, "char_end": 80, "token_start": 11, "token_end": 13}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 231006, "char_end": 231017, "token_start": 11, "token_end": 13, "note": null}]}
+{"sentence_id": 1401, "sentence_text": "TNFalpha and cycloheximide caused infected cells to undergo apoptosis more rapidly than parental U937 and PLB - 985 cells .", "sentence_char_start_global": 231171, "sentence_char_end_global": 231294, "entities": [{"text": "TNFalpha", "type": "ENTITY", "char_start": 0, "char_end": 8, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "TNFalpha", "type": "ENTITY", "char_start": 231171, "char_end": 231179, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 1402, "sentence_text": "Inhibition of TNFalpha - induced NF - kappaB activation using the antioxidant N - acetylcysteine ( NAC ) resulted in increased apoptosis in both U937 and U9 - IIIB cells , while preactivation of NF - kappaB with the non - apoptotic inducer IL - 1beta caused a relative decrease in apoptosis .", "sentence_char_start_global": 231295, "sentence_char_end_global": 231587, "entities": [{"text": "TNFalpha", "type": "ENTITY", "char_start": 14, "char_end": 22, "token_start": 2, "token_end": 2}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 195, "char_end": 206, "token_start": 34, "token_end": 36}, {"text": "non - apoptotic inducer IL - 1beta", "type": "ENTITY", "char_start": 216, "char_end": 250, "token_start": 39, "token_end": 45}], "entities_global": [{"text": "TNFalpha", "type": "ENTITY", "char_start": 231309, "char_end": 231317, "token_start": 2, "token_end": 2, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 231490, "char_end": 231501, "token_start": 34, "token_end": 36, "note": null}, {"text": "non - apoptotic inducer IL - 1beta", "type": "ENTITY", "char_start": 231511, "char_end": 231545, "token_start": 39, "token_end": 45, "note": null}]}
+{"sentence_id": 1403, "sentence_text": "Inhibition of constitutive NF - kappaB activity in U9 - IIIB and PLB - IIIB cells also induced apoptosis , suggesting that NF - kappaB protects cells from a persistent apoptotic signal .", "sentence_char_start_global": 231588, "sentence_char_end_global": 231774, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 27, "char_end": 38, "token_start": 3, "token_end": 5}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 231615, "char_end": 231626, "token_start": 3, "token_end": 5, "note": null}]}
+{"sentence_id": 1404, "sentence_text": "TNFalpha plus NAC treatment resulted in a marked decrease in Bcl - 2 protein levels in HIV - 1 - infected cells , coupled with an increase in Bax protein compared to uninfected cells , suggesting that the difference in susceptibility to TNFalpha - induced apoptosis may relate to the differences in relative levels of Bcl - 2 and Bax .", "sentence_char_start_global": 231775, "sentence_char_end_global": 232110, "entities": [{"text": "TNFalpha", "type": "ENTITY", "char_start": 0, "char_end": 8, "token_start": 0, "token_end": 0}, {"text": "Bcl - 2 protein", "type": "ENTITY", "char_start": 61, "char_end": 76, "token_start": 10, "token_end": 13}, {"text": "Bax protein", "type": "ENTITY", "char_start": 142, "char_end": 153, "token_start": 28, "token_end": 29}, {"text": "TNFalpha", "type": "ENTITY", "char_start": 237, "char_end": 245, "token_start": 42, "token_end": 42}, {"text": "Bcl - 2", "type": "ENTITY", "char_start": 318, "char_end": 325, "token_start": 55, "token_end": 57}, {"text": "Bax", "type": "ENTITY", "char_start": 330, "char_end": 333, "token_start": 59, "token_end": 59}], "entities_global": [{"text": "TNFalpha", "type": "ENTITY", "char_start": 231775, "char_end": 231783, "token_start": 0, "token_end": 0, "note": null}, {"text": "Bcl - 2 protein", "type": "ENTITY", "char_start": 231836, "char_end": 231851, "token_start": 10, "token_end": 13, "note": null}, {"text": "Bax protein", "type": "ENTITY", "char_start": 231917, "char_end": 231928, "token_start": 28, "token_end": 29, "note": null}, {"text": "TNFalpha", "type": "ENTITY", "char_start": 232012, "char_end": 232020, "token_start": 42, "token_end": 42, "note": null}, {"text": "Bcl - 2", "type": "ENTITY", "char_start": 232093, "char_end": 232100, "token_start": 55, "token_end": 57, "note": null}, {"text": "Bax", "type": "ENTITY", "char_start": 232105, "char_end": 232108, "token_start": 59, "token_end": 59, "note": null}]}
+{"sentence_id": 1405, "sentence_text": "The protective role of NF - kappaB in blocking TNFalpha - and HIV - 1 - induced apoptosis was supported by studies in Jurkat T cells engineered to express IkappaB alpha repressor mutants ( TD - IkappaB ) under the control of a tetracycline - responsive promoter .", "sentence_char_start_global": 232111, "sentence_char_end_global": 232374, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 23, "char_end": 34, "token_start": 4, "token_end": 6}, {"text": "IkappaB alpha repressor mutants", "type": "ENTITY", "char_start": 155, "char_end": 186, "token_start": 29, "token_end": 32}, {"text": "TD - IkappaB", "type": "ENTITY", "char_start": 189, "char_end": 201, "token_start": 34, "token_end": 36}, {"text": "tetracycline - responsive promoter", "type": "ENTITY", "char_start": 227, "char_end": 261, "token_start": 43, "token_end": 46}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 232134, "char_end": 232145, "token_start": 4, "token_end": 6, "note": null}, {"text": "IkappaB alpha repressor mutants", "type": "ENTITY", "char_start": 232266, "char_end": 232297, "token_start": 29, "token_end": 32, "note": null}, {"text": "TD - IkappaB", "type": "ENTITY", "char_start": 232300, "char_end": 232312, "token_start": 34, "token_end": 36, "note": null}, {"text": "tetracycline - responsive promoter", "type": "ENTITY", "char_start": 232338, "char_end": 232372, "token_start": 43, "token_end": 46, "note": null}]}
+{"sentence_id": 1406, "sentence_text": "Cells underwent apoptosis in response to TNFalpha only when NF - kappaB activation was inhibited by TD - IkappaB expression .", "sentence_char_start_global": 232375, "sentence_char_end_global": 232500, "entities": [{"text": "TNFalpha", "type": "ENTITY", "char_start": 41, "char_end": 49, "token_start": 6, "token_end": 6}, {"text": "TD - IkappaB", "type": "ENTITY", "char_start": 100, "char_end": 112, "token_start": 16, "token_end": 18}], "entities_global": [{"text": "TNFalpha", "type": "ENTITY", "char_start": 232416, "char_end": 232424, "token_start": 6, "token_end": 6, "note": null}, {"text": "TD - IkappaB", "type": "ENTITY", "char_start": 232475, "char_end": 232487, "token_start": 16, "token_end": 18, "note": null}]}
+{"sentence_id": 1407, "sentence_text": "As was observed for the U9 - IIIB cells , TNFalpha treatment also induced a marked decrease in Bcl - 2 protein levels in TD - IkappaB expressing cells .", "sentence_char_start_global": 232501, "sentence_char_end_global": 232653, "entities": [{"text": "TNFalpha", "type": "ENTITY", "char_start": 42, "char_end": 50, "token_start": 10, "token_end": 10}, {"text": "Bcl - 2 protein", "type": "ENTITY", "char_start": 95, "char_end": 110, "token_start": 18, "token_end": 21}], "entities_global": [{"text": "TNFalpha", "type": "ENTITY", "char_start": 232543, "char_end": 232551, "token_start": 10, "token_end": 10, "note": null}, {"text": "Bcl - 2 protein", "type": "ENTITY", "char_start": 232596, "char_end": 232611, "token_start": 18, "token_end": 21, "note": null}]}
+{"sentence_id": 1408, "sentence_text": "These experiments demonstrate that apoptotic signaling is perturbed in HIV - 1 - infected U9 - IIIB cells and indicate that NF - kappaB activation may play an additional protective role against HIV - 1 - induced apoptosis in myeloid cells .", "sentence_char_start_global": 232654, "sentence_char_end_global": 232894, "entities": [], "entities_global": []}
+{"sentence_id": 1409, "sentence_text": "Human normal peripheral blood B - lymphocytes are deficient in DNA - dependent protein kinase activity due to the expression of a variant form of the Ku86 protein .", "sentence_char_start_global": 232895, "sentence_char_end_global": 233059, "entities": [{"text": "Ku86 protein", "type": "ENTITY", "char_start": 150, "char_end": 162, "token_start": 26, "token_end": 27}], "entities_global": [{"text": "Ku86 protein", "type": "ENTITY", "char_start": 233045, "char_end": 233057, "token_start": 26, "token_end": 27, "note": null}]}
+{"sentence_id": 1410, "sentence_text": "The heterodimeric Ku protein , which comprises a 86 kDa ( Ku86 ) amd a 70 kDa ( Ku70 ) subunits , is an abundant nuclear DNA - binding protein which binds in vitro to DNA termini without sequence specificity .", "sentence_char_start_global": 233060, "sentence_char_end_global": 233269, "entities": [{"text": "Ku protein", "type": "ENTITY", "char_start": 18, "char_end": 28, "token_start": 2, "token_end": 3}, {"text": "86 kDa ( Ku86 )", "type": "ENTITY", "char_start": 49, "char_end": 64, "token_start": 8, "token_end": 12}, {"text": "70 kDa ( Ku70 ) subunits", "type": "ENTITY", "char_start": 71, "char_end": 95, "token_start": 15, "token_end": 20}, {"text": "nuclear DNA - binding protein", "type": "ENTITY", "char_start": 113, "char_end": 142, "token_start": 25, "token_end": 29}, {"text": "DNA termini", "type": "ENTITY", "char_start": 167, "char_end": 178, "token_start": 35, "token_end": 36}], "entities_global": [{"text": "Ku protein", "type": "ENTITY", "char_start": 233078, "char_end": 233088, "token_start": 2, "token_end": 3, "note": null}, {"text": "86 kDa ( Ku86 )", "type": "ENTITY", "char_start": 233109, "char_end": 233124, "token_start": 8, "token_end": 12, "note": null}, {"text": "70 kDa ( Ku70 ) subunits", "type": "ENTITY", "char_start": 233131, "char_end": 233155, "token_start": 15, "token_end": 20, "note": null}, {"text": "nuclear DNA - binding protein", "type": "ENTITY", "char_start": 233173, "char_end": 233202, "token_start": 25, "token_end": 29, "note": null}, {"text": "DNA termini", "type": "ENTITY", "char_start": 233227, "char_end": 233238, "token_start": 35, "token_end": 36, "note": null}]}
+{"sentence_id": 1411, "sentence_text": "Ku is the DNA - targeting component of the large catalytic sub - unit of the DNA - dependent protein kinase complex ( DNA - PK [ CS ] ) , that plays a critical role in mammalian double - strand break repair and lymphoid V ( D ) J recombination .", "sentence_char_start_global": 233270, "sentence_char_end_global": 233515, "entities": [{"text": "Ku", "type": "ENTITY", "char_start": 0, "char_end": 2, "token_start": 0, "token_end": 0}, {"text": "DNA - targeting component", "type": "ENTITY", "char_start": 10, "char_end": 35, "token_start": 3, "token_end": 6}, {"text": "catalytic sub - unit", "type": "ENTITY", "char_start": 49, "char_end": 69, "token_start": 10, "token_end": 13}, {"text": "DNA - dependent protein kinase complex", "type": "ENTITY", "char_start": 77, "char_end": 115, "token_start": 16, "token_end": 21}, {"text": "DNA - PK [ CS ]", "type": "ENTITY", "char_start": 118, "char_end": 133, "token_start": 23, "token_end": 28}], "entities_global": [{"text": "Ku", "type": "ENTITY", "char_start": 233270, "char_end": 233272, "token_start": 0, "token_end": 0, "note": null}, {"text": "DNA - targeting component", "type": "ENTITY", "char_start": 233280, "char_end": 233305, "token_start": 3, "token_end": 6, "note": null}, {"text": "catalytic sub - unit", "type": "ENTITY", "char_start": 233319, "char_end": 233339, "token_start": 10, "token_end": 13, "note": null}, {"text": "DNA - dependent protein kinase complex", "type": "ENTITY", "char_start": 233347, "char_end": 233385, "token_start": 16, "token_end": 21, "note": null}, {"text": "DNA - PK [ CS ]", "type": "ENTITY", "char_start": 233388, "char_end": 233403, "token_start": 23, "token_end": 28, "note": null}]}
+{"sentence_id": 1412, "sentence_text": "By using electrophoretic mobility shift assays , we demonstrated that in addition to the major Ku x DNA complex usually detected in cell line extracts , a second complex with faster electrophoretic mobility was observed in normal peripheral blood lymphocytes ( PBL ) extracts .", "sentence_char_start_global": 233516, "sentence_char_end_global": 233793, "entities": [{"text": "major Ku x DNA complex", "type": "ENTITY", "char_start": 89, "char_end": 111, "token_start": 14, "token_end": 18}], "entities_global": [{"text": "major Ku x DNA complex", "type": "ENTITY", "char_start": 233605, "char_end": 233627, "token_start": 14, "token_end": 18, "note": null}]}
+{"sentence_id": 1413, "sentence_text": "The presence of this faster migrating complex was restricted to B cells among the circulating lymphocyte population .", "sentence_char_start_global": 233794, "sentence_char_end_global": 233911, "entities": [{"text": "faster migrating complex", "type": "ENTITY", "char_start": 21, "char_end": 45, "token_start": 4, "token_end": 6}], "entities_global": [{"text": "faster migrating complex", "type": "ENTITY", "char_start": 233815, "char_end": 233839, "token_start": 4, "token_end": 6, "note": null}]}
+{"sentence_id": 1414, "sentence_text": "Western blot analysis revealed that B cells express a variant form of the Ku86 protein with an apparent molecular weight of 69 kDa , and not the 86 kDa - full - length protein .", "sentence_char_start_global": 233912, "sentence_char_end_global": 234089, "entities": [{"text": "Ku86 protein", "type": "ENTITY", "char_start": 74, "char_end": 86, "token_start": 13, "token_end": 14}, {"text": "86 kDa - full - length protein", "type": "ENTITY", "char_start": 145, "char_end": 175, "token_start": 27, "token_end": 33}], "entities_global": [{"text": "Ku86 protein", "type": "ENTITY", "char_start": 233986, "char_end": 233998, "token_start": 13, "token_end": 14, "note": null}, {"text": "86 kDa - full - length protein", "type": "ENTITY", "char_start": 234057, "char_end": 234087, "token_start": 27, "token_end": 33, "note": null}]}
+{"sentence_id": 1415, "sentence_text": "Although the heterodimer Ku70 / variant - Ku86 binds to DNA - ends , this altered form of the Ku heterodimer has a decreased ability to recruit the catalytic component of the complex , DNA - PK ( CS ) , which contributes to an absence of detectable DNA - PK activity in B cells .", "sentence_char_start_global": 234090, "sentence_char_end_global": 234369, "entities": [{"text": "heterodimer Ku70 / variant - Ku86", "type": "ENTITY", "char_start": 13, "char_end": 46, "token_start": 2, "token_end": 7}, {"text": "DNA - ends", "type": "ENTITY", "char_start": 56, "char_end": 66, "token_start": 10, "token_end": 12}, {"text": "Ku heterodimer", "type": "ENTITY", "char_start": 94, "char_end": 108, "token_start": 19, "token_end": 20}, {"text": "catalytic component", "type": "ENTITY", "char_start": 148, "char_end": 167, "token_start": 28, "token_end": 29}, {"text": "DNA - PK ( CS )", "type": "ENTITY", "char_start": 185, "char_end": 200, "token_start": 34, "token_end": 39}], "entities_global": [{"text": "heterodimer Ku70 / variant - Ku86", "type": "ENTITY", "char_start": 234103, "char_end": 234136, "token_start": 2, "token_end": 7, "note": null}, {"text": "DNA - ends", "type": "ENTITY", "char_start": 234146, "char_end": 234156, "token_start": 10, "token_end": 12, "note": null}, {"text": "Ku heterodimer", "type": "ENTITY", "char_start": 234184, "char_end": 234198, "token_start": 19, "token_end": 20, "note": null}, {"text": "catalytic component", "type": "ENTITY", "char_start": 234238, "char_end": 234257, "token_start": 28, "token_end": 29, "note": null}, {"text": "DNA - PK ( CS )", "type": "ENTITY", "char_start": 234275, "char_end": 234290, "token_start": 34, "token_end": 39, "note": null}]}
+{"sentence_id": 1416, "sentence_text": "These data provide a molecular basis for the increased sensitivity of B cells to ionizing radiation and identify a new mechanism of regulation of DNA - PK activity that operates in vivo .", "sentence_char_start_global": 234370, "sentence_char_end_global": 234557, "entities": [], "entities_global": []}
+{"sentence_id": 1417, "sentence_text": "Co - stimulation of human peripheral blood mononuclear cells with IL - 2 and anti - CD3 monoclonal antibodies induces phosphorylation of CREB .", "sentence_char_start_global": 234558, "sentence_char_end_global": 234701, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 66, "char_end": 72, "token_start": 10, "token_end": 12}, {"text": "anti - CD3 monoclonal antibodies", "type": "ENTITY", "char_start": 77, "char_end": 109, "token_start": 14, "token_end": 18}, {"text": "CREB", "type": "ENTITY", "char_start": 137, "char_end": 141, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 234624, "char_end": 234630, "token_start": 10, "token_end": 12, "note": null}, {"text": "anti - CD3 monoclonal antibodies", "type": "ENTITY", "char_start": 234635, "char_end": 234667, "token_start": 14, "token_end": 18, "note": null}, {"text": "CREB", "type": "ENTITY", "char_start": 234695, "char_end": 234699, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 1418, "sentence_text": "Phosphorylation of the cAMP - response element binding protein CREB within 1 h of CD2 but not CD3 cross - linking of human PBMC was recently demonstrated .", "sentence_char_start_global": 234702, "sentence_char_end_global": 234857, "entities": [{"text": "cAMP - response element binding protein CREB", "type": "ENTITY", "char_start": 23, "char_end": 67, "token_start": 3, "token_end": 9}, {"text": "CD2", "type": "ENTITY", "char_start": 82, "char_end": 85, "token_start": 14, "token_end": 14}, {"text": "CD3", "type": "ENTITY", "char_start": 94, "char_end": 97, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "cAMP - response element binding protein CREB", "type": "ENTITY", "char_start": 234725, "char_end": 234769, "token_start": 3, "token_end": 9, "note": null}, {"text": "CD2", "type": "ENTITY", "char_start": 234784, "char_end": 234787, "token_start": 14, "token_end": 14, "note": null}, {"text": "CD3", "type": "ENTITY", "char_start": 234796, "char_end": 234799, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 1419, "sentence_text": "The absence of P - CREB following CD3 cross - linking was unexpected , as other laboratories reported increased phosphorylation of CREB following CD3 cross - linking of the Jurkat lymphocyte cell line .", "sentence_char_start_global": 234858, "sentence_char_end_global": 235060, "entities": [{"text": "P - CREB", "type": "ENTITY", "char_start": 15, "char_end": 23, "token_start": 3, "token_end": 5}, {"text": "CREB", "type": "ENTITY", "char_start": 131, "char_end": 135, "token_start": 21, "token_end": 21}], "entities_global": [{"text": "P - CREB", "type": "ENTITY", "char_start": 234873, "char_end": 234881, "token_start": 3, "token_end": 5, "note": null}, {"text": "CREB", "type": "ENTITY", "char_start": 234989, "char_end": 234993, "token_start": 21, "token_end": 21, "note": null}]}
+{"sentence_id": 1420, "sentence_text": "Due to Jurkat T - cells being IL - 2 - independent , it was postulated that IL - 2 might provide a necessary co - stimulus for phosphorylation of CREB in primary lymphocytes .", "sentence_char_start_global": 235061, "sentence_char_end_global": 235236, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 76, "char_end": 82, "token_start": 17, "token_end": 19}, {"text": "CREB", "type": "ENTITY", "char_start": 146, "char_end": 150, "token_start": 30, "token_end": 30}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 235137, "char_end": 235143, "token_start": 17, "token_end": 19, "note": null}, {"text": "CREB", "type": "ENTITY", "char_start": 235207, "char_end": 235211, "token_start": 30, "token_end": 30, "note": null}]}
+{"sentence_id": 1421, "sentence_text": "Therefore , P - CREB was evaluated following co - stimulation of human PBMC through the IL - 2 and CD2 or CD3 receptors .", "sentence_char_start_global": 235237, "sentence_char_end_global": 235358, "entities": [{"text": "P - CREB", "type": "ENTITY", "char_start": 12, "char_end": 20, "token_start": 2, "token_end": 4}, {"text": "IL - 2 and CD2 or CD3 receptors", "type": "ENTITY", "char_start": 88, "char_end": 119, "token_start": 16, "token_end": 23}], "entities_global": [{"text": "P - CREB", "type": "ENTITY", "char_start": 235249, "char_end": 235257, "token_start": 2, "token_end": 4, "note": null}, {"text": "IL - 2 and CD2 or CD3 receptors", "type": "ENTITY", "char_start": 235325, "char_end": 235356, "token_start": 16, "token_end": 23, "note": null}]}
+{"sentence_id": 1422, "sentence_text": "IL - 2 did not further augment phosphorylation of CREB following CD2 cross - linking .", "sentence_char_start_global": 235359, "sentence_char_end_global": 235445, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 2}, {"text": "CREB", "type": "ENTITY", "char_start": 50, "char_end": 54, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 235359, "char_end": 235365, "token_start": 0, "token_end": 2, "note": null}, {"text": "CREB", "type": "ENTITY", "char_start": 235409, "char_end": 235413, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 1423, "sentence_text": "However , while neither IL - 2 nor CD3 cross - linking alone induced P - CREB , a 4 . 5 - fold increase in phosphorylation of CREB within 1 h of IL - 2 / CD3 co - stimulation was observed .", "sentence_char_start_global": 235446, "sentence_char_end_global": 235635, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 24, "char_end": 30, "token_start": 4, "token_end": 6}, {"text": "P - CREB", "type": "ENTITY", "char_start": 69, "char_end": 77, "token_start": 14, "token_end": 16}, {"text": "CREB", "type": "ENTITY", "char_start": 126, "char_end": 130, "token_start": 28, "token_end": 28}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 235470, "char_end": 235476, "token_start": 4, "token_end": 6, "note": null}, {"text": "P - CREB", "type": "ENTITY", "char_start": 235515, "char_end": 235523, "token_start": 14, "token_end": 16, "note": null}, {"text": "CREB", "type": "ENTITY", "char_start": 235572, "char_end": 235576, "token_start": 28, "token_end": 28, "note": null}]}
+{"sentence_id": 1424, "sentence_text": "Phosphorylation was not associated with the induction of cAMP , and inhibition of PKA signaling had no effect on P - CREB .", "sentence_char_start_global": 235636, "sentence_char_end_global": 235759, "entities": [{"text": "P - CREB", "type": "ENTITY", "char_start": 113, "char_end": 121, "token_start": 19, "token_end": 21}], "entities_global": [{"text": "P - CREB", "type": "ENTITY", "char_start": 235749, "char_end": 235757, "token_start": 19, "token_end": 21, "note": null}]}
+{"sentence_id": 1425, "sentence_text": "Consistent with signal transduction through p56lck or p59fyn , inhibition of PTK signaling reduced phosphorylation 50 % .", "sentence_char_start_global": 235760, "sentence_char_end_global": 235881, "entities": [{"text": "p56lck", "type": "ENTITY", "char_start": 44, "char_end": 50, "token_start": 5, "token_end": 5}, {"text": "p59fyn", "type": "ENTITY", "char_start": 54, "char_end": 60, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "p56lck", "type": "ENTITY", "char_start": 235804, "char_end": 235810, "token_start": 5, "token_end": 5, "note": null}, {"text": "p59fyn", "type": "ENTITY", "char_start": 235814, "char_end": 235820, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 1426, "sentence_text": "Interestingly , inhibiting PKC signaling with calphostin C further increased P - CREB levels 3 - fold over that observed in IL - 2 / CD3 co - stimulated cells not pretreated with a PKC inhibitor .", "sentence_char_start_global": 235882, "sentence_char_end_global": 236078, "entities": [], "entities_global": []}
+{"sentence_id": 1427, "sentence_text": "In contrast to previous studies performed in the absence of exogenous IL - 2 , no increase in binding of CREB to a 32P - labeled oligonucleotide probe was observed by electrophoretic mobility shift assay .", "sentence_char_start_global": 236079, "sentence_char_end_global": 236284, "entities": [{"text": "exogenous IL - 2", "type": "ENTITY", "char_start": 60, "char_end": 76, "token_start": 10, "token_end": 13}, {"text": "CREB", "type": "ENTITY", "char_start": 105, "char_end": 109, "token_start": 20, "token_end": 20}], "entities_global": [{"text": "exogenous IL - 2", "type": "ENTITY", "char_start": 236139, "char_end": 236155, "token_start": 10, "token_end": 13, "note": null}, {"text": "CREB", "type": "ENTITY", "char_start": 236184, "char_end": 236188, "token_start": 20, "token_end": 20, "note": null}]}
+{"sentence_id": 1428, "sentence_text": "These data suggest that the IL - 2 and CD3 signaling pathways provide a necessary and co - operative stimulus promoting phosphorylation of CREB following receptor cross - linking .", "sentence_char_start_global": 236285, "sentence_char_end_global": 236465, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 28, "char_end": 34, "token_start": 5, "token_end": 7}, {"text": "CD3", "type": "ENTITY", "char_start": 39, "char_end": 42, "token_start": 9, "token_end": 9}, {"text": "CREB", "type": "ENTITY", "char_start": 139, "char_end": 143, "token_start": 23, "token_end": 23}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 236313, "char_end": 236319, "token_start": 5, "token_end": 7, "note": null}, {"text": "CD3", "type": "ENTITY", "char_start": 236324, "char_end": 236327, "token_start": 9, "token_end": 9, "note": null}, {"text": "CREB", "type": "ENTITY", "char_start": 236424, "char_end": 236428, "token_start": 23, "token_end": 23, "note": null}]}
+{"sentence_id": 1429, "sentence_text": "HIV - 1 infection induces a selective reduction in STAT5 protein expression .", "sentence_char_start_global": 236466, "sentence_char_end_global": 236543, "entities": [], "entities_global": []}
+{"sentence_id": 1430, "sentence_text": "HIV - 1 infection is accompanied by qualitative and quantitative defects in CD4 + T lymphocytes .", "sentence_char_start_global": 236544, "sentence_char_end_global": 236641, "entities": [], "entities_global": []}
+{"sentence_id": 1431, "sentence_text": "Loss of immune function in HIV patients is usually associated with a profound dysregulation of cytokine production .", "sentence_char_start_global": 236642, "sentence_char_end_global": 236758, "entities": [{"text": "cytokine", "type": "ENTITY", "char_start": 95, "char_end": 103, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "cytokine", "type": "ENTITY", "char_start": 236737, "char_end": 236745, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 1432, "sentence_text": "To investigate whether cytokine signaling defects occur during HIV infection , PHA blasts from healthy human donors were infected with two strains of HIV - 1 and screened for the expression of STAT proteins used in cytokine signaling .", "sentence_char_start_global": 236759, "sentence_char_end_global": 236994, "entities": [{"text": "cytokine", "type": "ENTITY", "char_start": 23, "char_end": 31, "token_start": 3, "token_end": 3}, {"text": "STAT proteins", "type": "ENTITY", "char_start": 193, "char_end": 206, "token_start": 32, "token_end": 33}, {"text": "cytokine", "type": "ENTITY", "char_start": 215, "char_end": 223, "token_start": 36, "token_end": 36}], "entities_global": [{"text": "cytokine", "type": "ENTITY", "char_start": 236782, "char_end": 236790, "token_start": 3, "token_end": 3, "note": null}, {"text": "STAT proteins", "type": "ENTITY", "char_start": 236952, "char_end": 236965, "token_start": 32, "token_end": 33, "note": null}, {"text": "cytokine", "type": "ENTITY", "char_start": 236974, "char_end": 236982, "token_start": 36, "token_end": 36, "note": null}]}
+{"sentence_id": 1433, "sentence_text": "A selective decrease in STAT5B was seen 8 days after infection with the BZ167 dual - tropic HIV isolate , but not with the Ba - L , M - tropic strain .", "sentence_char_start_global": 236995, "sentence_char_end_global": 237146, "entities": [{"text": "STAT5B", "type": "ENTITY", "char_start": 24, "char_end": 30, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "STAT5B", "type": "ENTITY", "char_start": 237019, "char_end": 237025, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 1434, "sentence_text": "Based on these findings , purified T cells from HIV - infected patients in different stages of disease were also tested for STAT expression ; decreases in STAT5A , STAT5B , and STAT1alpha were observed in all patients .", "sentence_char_start_global": 237147, "sentence_char_end_global": 237366, "entities": [{"text": "STAT5A", "type": "ENTITY", "char_start": 155, "char_end": 161, "token_start": 27, "token_end": 27}, {"text": "STAT5B", "type": "ENTITY", "char_start": 164, "char_end": 170, "token_start": 29, "token_end": 29}, {"text": "STAT1alpha", "type": "ENTITY", "char_start": 177, "char_end": 187, "token_start": 32, "token_end": 32}], "entities_global": [{"text": "STAT5A", "type": "ENTITY", "char_start": 237302, "char_end": 237308, "token_start": 27, "token_end": 27, "note": null}, {"text": "STAT5B", "type": "ENTITY", "char_start": 237311, "char_end": 237317, "token_start": 29, "token_end": 29, "note": null}, {"text": "STAT1alpha", "type": "ENTITY", "char_start": 237324, "char_end": 237334, "token_start": 32, "token_end": 32, "note": null}]}
+{"sentence_id": 1435, "sentence_text": "The reduction in STATs seen in vivo and in vitro after HIV infection may contribute to the loss of T cell function in HIV disease .", "sentence_char_start_global": 237367, "sentence_char_end_global": 237498, "entities": [{"text": "STATs", "type": "ENTITY", "char_start": 17, "char_end": 22, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "STATs", "type": "ENTITY", "char_start": 237384, "char_end": 237389, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 1436, "sentence_text": "Transcription factors that regulate monocyte / macrophage differentiation .", "sentence_char_start_global": 237499, "sentence_char_end_global": 237574, "entities": [{"text": "Transcription factors", "type": "ENTITY", "char_start": 0, "char_end": 21, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "Transcription factors", "type": "ENTITY", "char_start": 237499, "char_end": 237520, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 1437, "sentence_text": "Although all the cells in an organism contain the same genetic information , differences in the cell phenotype arise from the expression of lineage - specific genes .", "sentence_char_start_global": 237575, "sentence_char_end_global": 237741, "entities": [{"text": "lineage - specific genes", "type": "ENTITY", "char_start": 140, "char_end": 164, "token_start": 23, "token_end": 26}], "entities_global": [{"text": "lineage - specific genes", "type": "ENTITY", "char_start": 237715, "char_end": 237739, "token_start": 23, "token_end": 26, "note": null}]}
+{"sentence_id": 1438, "sentence_text": "During myelopoiesis , external differentiating signals regulate the expression of a set of transcription factors .", "sentence_char_start_global": 237742, "sentence_char_end_global": 237856, "entities": [{"text": "transcription factors", "type": "ENTITY", "char_start": 91, "char_end": 112, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "transcription factors", "type": "ENTITY", "char_start": 237833, "char_end": 237854, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 1439, "sentence_text": "The combined action of these transcription factors subsequently determines the expression of myeloid - specific genes and the generation of monocytes and macrophages .", "sentence_char_start_global": 237857, "sentence_char_end_global": 238024, "entities": [{"text": "transcription factors", "type": "ENTITY", "char_start": 29, "char_end": 50, "token_start": 5, "token_end": 6}, {"text": "myeloid - specific genes", "type": "ENTITY", "char_start": 93, "char_end": 117, "token_start": 12, "token_end": 15}], "entities_global": [{"text": "transcription factors", "type": "ENTITY", "char_start": 237886, "char_end": 237907, "token_start": 5, "token_end": 6, "note": null}, {"text": "myeloid - specific genes", "type": "ENTITY", "char_start": 237950, "char_end": 237974, "token_start": 12, "token_end": 15, "note": null}]}
+{"sentence_id": 1440, "sentence_text": "In particular , the transcription factor PU . 1 has a critical role in this process .", "sentence_char_start_global": 238025, "sentence_char_end_global": 238110, "entities": [{"text": "transcription factor PU . 1", "type": "ENTITY", "char_start": 20, "char_end": 47, "token_start": 4, "token_end": 8}], "entities_global": [{"text": "transcription factor PU . 1", "type": "ENTITY", "char_start": 238045, "char_end": 238072, "token_start": 4, "token_end": 8, "note": null}]}
+{"sentence_id": 1441, "sentence_text": "We review the contribution of several transcription factors to the control of macrophage development", "sentence_char_start_global": 238111, "sentence_char_end_global": 238211, "entities": [{"text": "transcription factors", "type": "ENTITY", "char_start": 38, "char_end": 59, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "transcription factors", "type": "ENTITY", "char_start": 238149, "char_end": 238170, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 1442, "sentence_text": "Transcription factor LKLF is sufficient to program T cell quiescence via a c - Myc - - dependent pathway .", "sentence_char_start_global": 238212, "sentence_char_end_global": 238318, "entities": [{"text": "Transcription factor LKLF", "type": "ENTITY", "char_start": 0, "char_end": 25, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "Transcription factor LKLF", "type": "ENTITY", "char_start": 238212, "char_end": 238237, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 1443, "sentence_text": "T lymphocytes circulate in a quiescent state until they encounter cognate antigen bound to the surface of an antigen - presenting cell .", "sentence_char_start_global": 238319, "sentence_char_end_global": 238455, "entities": [{"text": "cognate antigen", "type": "ENTITY", "char_start": 66, "char_end": 81, "token_start": 10, "token_end": 11}], "entities_global": [{"text": "cognate antigen", "type": "ENTITY", "char_start": 238385, "char_end": 238400, "token_start": 10, "token_end": 11, "note": null}]}
+{"sentence_id": 1444, "sentence_text": "The molecular pathways that regulate T cell quiescence remain largely unknown .", "sentence_char_start_global": 238456, "sentence_char_end_global": 238535, "entities": [], "entities_global": []}
+{"sentence_id": 1445, "sentence_text": "Here we show that forced expression of the lung Kruppel - like transcription factor ( LKLF ) in Jurkat T cells is sufficient to program a quiescent phenotype characterized by decreased proliferation , reduced cell size and protein synthesis and decreased surface expression of activation markers .", "sentence_char_start_global": 238536, "sentence_char_end_global": 238833, "entities": [{"text": "lung Kruppel - like transcription factor", "type": "ENTITY", "char_start": 43, "char_end": 83, "token_start": 8, "token_end": 13}, {"text": "LKLF", "type": "ENTITY", "char_start": 86, "char_end": 90, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "lung Kruppel - like transcription factor", "type": "ENTITY", "char_start": 238579, "char_end": 238619, "token_start": 8, "token_end": 13, "note": null}, {"text": "LKLF", "type": "ENTITY", "char_start": 238622, "char_end": 238626, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 1446, "sentence_text": "Conversely , LKLF - deficient peripheral T cells produced by gene targeting showed increased proliferation , increased cell size and enhanced expression of surface activation markers in vivo .", "sentence_char_start_global": 238834, "sentence_char_end_global": 239026, "entities": [], "entities_global": []}
+{"sentence_id": 1447, "sentence_text": "LKLF appeared to function , at least in part , by decreasing expression of the proto - oncogene encoding c - Myc .", "sentence_char_start_global": 239027, "sentence_char_end_global": 239141, "entities": [{"text": "LKLF", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}, {"text": "proto - oncogene", "type": "ENTITY", "char_start": 79, "char_end": 95, "token_start": 15, "token_end": 17}, {"text": "c - Myc", "type": "ENTITY", "char_start": 105, "char_end": 112, "token_start": 19, "token_end": 21}], "entities_global": [{"text": "LKLF", "type": "ENTITY", "char_start": 239027, "char_end": 239031, "token_start": 0, "token_end": 0, "note": null}, {"text": "proto - oncogene", "type": "ENTITY", "char_start": 239106, "char_end": 239122, "token_start": 15, "token_end": 17, "note": null}, {"text": "c - Myc", "type": "ENTITY", "char_start": 239132, "char_end": 239139, "token_start": 19, "token_end": 21, "note": null}]}
+{"sentence_id": 1448, "sentence_text": "Forced expression of LKLF was associated with markedly decreased c - Myc expression .", "sentence_char_start_global": 239142, "sentence_char_end_global": 239227, "entities": [{"text": "LKLF", "type": "ENTITY", "char_start": 21, "char_end": 25, "token_start": 3, "token_end": 3}, {"text": "c - Myc", "type": "ENTITY", "char_start": 65, "char_end": 72, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "LKLF", "type": "ENTITY", "char_start": 239163, "char_end": 239167, "token_start": 3, "token_end": 3, "note": null}, {"text": "c - Myc", "type": "ENTITY", "char_start": 239207, "char_end": 239214, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 1449, "sentence_text": "In addition , many effects of LKLF expression were mimicked by expression of the dominant - negative MadMyc protein and rescued by overexpression of c - Myc .", "sentence_char_start_global": 239228, "sentence_char_end_global": 239386, "entities": [{"text": "LKLF", "type": "ENTITY", "char_start": 30, "char_end": 34, "token_start": 6, "token_end": 6}, {"text": "dominant - negative MadMyc protein", "type": "ENTITY", "char_start": 81, "char_end": 115, "token_start": 14, "token_end": 18}, {"text": "c - Myc", "type": "ENTITY", "char_start": 149, "char_end": 156, "token_start": 24, "token_end": 26}], "entities_global": [{"text": "LKLF", "type": "ENTITY", "char_start": 239258, "char_end": 239262, "token_start": 6, "token_end": 6, "note": null}, {"text": "dominant - negative MadMyc protein", "type": "ENTITY", "char_start": 239309, "char_end": 239343, "token_start": 14, "token_end": 18, "note": null}, {"text": "c - Myc", "type": "ENTITY", "char_start": 239377, "char_end": 239384, "token_start": 24, "token_end": 26, "note": null}]}
+{"sentence_id": 1450, "sentence_text": "Thus , LKLF is both necessary and sufficient to program quiescence in T cells and functions , in part , by negatively regulating a c - Myc - - dependent pathway .", "sentence_char_start_global": 239387, "sentence_char_end_global": 239549, "entities": [{"text": "LKLF", "type": "ENTITY", "char_start": 7, "char_end": 11, "token_start": 2, "token_end": 2}], "entities_global": [{"text": "LKLF", "type": "ENTITY", "char_start": 239394, "char_end": 239398, "token_start": 2, "token_end": 2, "note": null}]}
+{"sentence_id": 1451, "sentence_text": "HTLV - 1 p12 ( I ) protein enhances STAT5 activation and decreases the interleukin - 2 requirement for proliferation of primary human peripheral blood mononuclear cells .", "sentence_char_start_global": 239550, "sentence_char_end_global": 239720, "entities": [{"text": "HTLV - 1 p12 ( I ) protein", "type": "ENTITY", "char_start": 0, "char_end": 26, "token_start": 0, "token_end": 7}, {"text": "interleukin - 2", "type": "ENTITY", "char_start": 71, "char_end": 86, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "HTLV - 1 p12 ( I ) protein", "type": "ENTITY", "char_start": 239550, "char_end": 239576, "token_start": 0, "token_end": 7, "note": null}, {"text": "interleukin - 2", "type": "ENTITY", "char_start": 239621, "char_end": 239636, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 1452, "sentence_text": "The p12 ( I ) protein , encoded by the pX open reading frame I of the human T - lymphotropic virus type 1 ( HTLV - 1 ) , is a hydrophobic protein that localizes to the endoplasmic reticulum and the Golgi .", "sentence_char_start_global": 239721, "sentence_char_end_global": 239926, "entities": [{"text": "p12 ( I ) protein", "type": "ENTITY", "char_start": 4, "char_end": 21, "token_start": 1, "token_end": 5}, {"text": "pX open reading frame I", "type": "ENTITY", "char_start": 39, "char_end": 62, "token_start": 10, "token_end": 14}, {"text": "hydrophobic protein", "type": "ENTITY", "char_start": 126, "char_end": 145, "token_start": 32, "token_end": 33}], "entities_global": [{"text": "p12 ( I ) protein", "type": "ENTITY", "char_start": 239725, "char_end": 239742, "token_start": 1, "token_end": 5, "note": null}, {"text": "pX open reading frame I", "type": "ENTITY", "char_start": 239760, "char_end": 239783, "token_start": 10, "token_end": 14, "note": null}, {"text": "hydrophobic protein", "type": "ENTITY", "char_start": 239847, "char_end": 239866, "token_start": 32, "token_end": 33, "note": null}]}
+{"sentence_id": 1453, "sentence_text": "Although p12 ( I ) contains 4 minimal proline - rich , src homology 3 - binding motifs ( PXXP ) , a characteristic commonly found in proteins involved in signaling pathways , it has not been known whether p12 ( I ) has a role in modulating intracellular signaling pathways .", "sentence_char_start_global": 239927, "sentence_char_end_global": 240201, "entities": [{"text": "p12 ( I )", "type": "ENTITY", "char_start": 9, "char_end": 18, "token_start": 1, "token_end": 4}, {"text": "src homology 3 - binding motifs", "type": "ENTITY", "char_start": 55, "char_end": 86, "token_start": 12, "token_end": 17}, {"text": "PXXP", "type": "ENTITY", "char_start": 89, "char_end": 93, "token_start": 19, "token_end": 19}, {"text": "p12 ( I )", "type": "ENTITY", "char_start": 205, "char_end": 214, "token_start": 39, "token_end": 42}], "entities_global": [{"text": "p12 ( I )", "type": "ENTITY", "char_start": 239936, "char_end": 239945, "token_start": 1, "token_end": 4, "note": null}, {"text": "src homology 3 - binding motifs", "type": "ENTITY", "char_start": 239982, "char_end": 240013, "token_start": 12, "token_end": 17, "note": null}, {"text": "PXXP", "type": "ENTITY", "char_start": 240016, "char_end": 240020, "token_start": 19, "token_end": 19, "note": null}, {"text": "p12 ( I )", "type": "ENTITY", "char_start": 240132, "char_end": 240141, "token_start": 39, "token_end": 42, "note": null}]}
+{"sentence_id": 1454, "sentence_text": "This study demonstrated that p12 ( I ) binds to the cytoplasmic domain of the interleukin - 2 receptor ( IL - 2R ) beta chain that is involved in the recruitment of the Jak1 and Jak3 kinases .", "sentence_char_start_global": 240202, "sentence_char_end_global": 240394, "entities": [{"text": "p12 ( I )", "type": "ENTITY", "char_start": 29, "char_end": 38, "token_start": 4, "token_end": 7}, {"text": "cytoplasmic domain", "type": "ENTITY", "char_start": 52, "char_end": 70, "token_start": 11, "token_end": 12}, {"text": "interleukin - 2 receptor ( IL - 2R ) beta chain", "type": "ENTITY", "char_start": 78, "char_end": 125, "token_start": 15, "token_end": 25}, {"text": "Jak1 and Jak3 kinases", "type": "ENTITY", "char_start": 169, "char_end": 190, "token_start": 34, "token_end": 37}], "entities_global": [{"text": "p12 ( I )", "type": "ENTITY", "char_start": 240231, "char_end": 240240, "token_start": 4, "token_end": 7, "note": null}, {"text": "cytoplasmic domain", "type": "ENTITY", "char_start": 240254, "char_end": 240272, "token_start": 11, "token_end": 12, "note": null}, {"text": "interleukin - 2 receptor ( IL - 2R ) beta chain", "type": "ENTITY", "char_start": 240280, "char_end": 240327, "token_start": 15, "token_end": 25, "note": null}, {"text": "Jak1 and Jak3 kinases", "type": "ENTITY", "char_start": 240371, "char_end": 240392, "token_start": 34, "token_end": 37, "note": null}]}
+{"sentence_id": 1455, "sentence_text": "As a result of this interaction , p12 ( I ) increases signal transducers and activators of transcription 5 ( STAT5 ) DNA binding and transcriptional activity and this effect depends on the presence of both IL - 2R beta and gamma ( c ) chains and Jak3 .", "sentence_char_start_global": 240395, "sentence_char_end_global": 240647, "entities": [{"text": "p12 ( I )", "type": "ENTITY", "char_start": 34, "char_end": 43, "token_start": 7, "token_end": 10}, {"text": "signal transducers and activators of transcription 5", "type": "ENTITY", "char_start": 54, "char_end": 106, "token_start": 12, "token_end": 18}, {"text": "STAT5", "type": "ENTITY", "char_start": 109, "char_end": 114, "token_start": 20, "token_end": 20}, {"text": "IL - 2R beta and gamma ( c ) chains", "type": "ENTITY", "char_start": 206, "char_end": 241, "token_start": 36, "token_end": 45}, {"text": "Jak3", "type": "ENTITY", "char_start": 246, "char_end": 250, "token_start": 47, "token_end": 47}], "entities_global": [{"text": "p12 ( I )", "type": "ENTITY", "char_start": 240429, "char_end": 240438, "token_start": 7, "token_end": 10, "note": null}, {"text": "signal transducers and activators of transcription 5", "type": "ENTITY", "char_start": 240449, "char_end": 240501, "token_start": 12, "token_end": 18, "note": null}, {"text": "STAT5", "type": "ENTITY", "char_start": 240504, "char_end": 240509, "token_start": 20, "token_end": 20, "note": null}, {"text": "IL - 2R beta and gamma ( c ) chains", "type": "ENTITY", "char_start": 240601, "char_end": 240636, "token_start": 36, "token_end": 45, "note": null}, {"text": "Jak3", "type": "ENTITY", "char_start": 240641, "char_end": 240645, "token_start": 47, "token_end": 47, "note": null}]}
+{"sentence_id": 1456, "sentence_text": "Transduction of primary human peripheral blood mononuclear cells ( PBMCs ) with a human immunodeficiency virus type 1 - based retroviral vector expressing p12 ( I ) also resulted in increased STAT5 phosphorylation and DNA binding .", "sentence_char_start_global": 240648, "sentence_char_end_global": 240879, "entities": [{"text": "human immunodeficiency virus type 1 - based retroviral vector", "type": "ENTITY", "char_start": 82, "char_end": 143, "token_start": 13, "token_end": 21}, {"text": "p12 ( I )", "type": "ENTITY", "char_start": 155, "char_end": 164, "token_start": 23, "token_end": 26}, {"text": "STAT5", "type": "ENTITY", "char_start": 192, "char_end": 197, "token_start": 31, "token_end": 31}], "entities_global": [{"text": "human immunodeficiency virus type 1 - based retroviral vector", "type": "ENTITY", "char_start": 240730, "char_end": 240791, "token_start": 13, "token_end": 21, "note": null}, {"text": "p12 ( I )", "type": "ENTITY", "char_start": 240803, "char_end": 240812, "token_start": 23, "token_end": 26, "note": null}, {"text": "STAT5", "type": "ENTITY", "char_start": 240840, "char_end": 240845, "token_start": 31, "token_end": 31, "note": null}]}
+{"sentence_id": 1457, "sentence_text": "However , p12 ( I ) could increase proliferation of human PBMCs only after stimulation of T - cell receptors by treatment of cells with low concentrations of alphaCD3 and alphaCD28 antibodies .", "sentence_char_start_global": 240880, "sentence_char_end_global": 241073, "entities": [{"text": "p12 ( I )", "type": "ENTITY", "char_start": 10, "char_end": 19, "token_start": 2, "token_end": 5}, {"text": "T - cell receptors", "type": "ENTITY", "char_start": 90, "char_end": 108, "token_start": 16, "token_end": 19}, {"text": "alphaCD3 and alphaCD28 antibodies", "type": "ENTITY", "char_start": 158, "char_end": 191, "token_start": 28, "token_end": 31}], "entities_global": [{"text": "p12 ( I )", "type": "ENTITY", "char_start": 240890, "char_end": 240899, "token_start": 2, "token_end": 5, "note": null}, {"text": "T - cell receptors", "type": "ENTITY", "char_start": 240970, "char_end": 240988, "token_start": 16, "token_end": 19, "note": null}, {"text": "alphaCD3 and alphaCD28 antibodies", "type": "ENTITY", "char_start": 241038, "char_end": 241071, "token_start": 28, "token_end": 31, "note": null}]}
+{"sentence_id": 1458, "sentence_text": "In addition , the proliferative advantage of p12 ( I ) - transduced PBMCs was evident mainly at low concentrations of IL - 2 .", "sentence_char_start_global": 241074, "sentence_char_end_global": 241200, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 118, "char_end": 124, "token_start": 21, "token_end": 23}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 241192, "char_end": 241198, "token_start": 21, "token_end": 23, "note": null}]}
+{"sentence_id": 1459, "sentence_text": "Together , these data indicate that p12 ( I ) may confer a proliferative advantage on HTLV - 1 - infected cells in the presence of suboptimal antigen stimulation and that this event may account for the clonal proliferation of infected T cells in vivo .", "sentence_char_start_global": 241201, "sentence_char_end_global": 241453, "entities": [{"text": "p12 ( I )", "type": "ENTITY", "char_start": 36, "char_end": 45, "token_start": 6, "token_end": 9}], "entities_global": [{"text": "p12 ( I )", "type": "ENTITY", "char_start": 241237, "char_end": 241246, "token_start": 6, "token_end": 9, "note": null}]}
+{"sentence_id": 1460, "sentence_text": "( Blood . 2001 ; 98 : 823 - 829 )", "sentence_char_start_global": 241454, "sentence_char_end_global": 241487, "entities": [], "entities_global": []}
+{"sentence_id": 1461, "sentence_text": "Single dose intranasal administration of retinal autoantigen generates a rapid accumulation and cell activation in draining lymph node and spleen : implications for tolerance therapy .", "sentence_char_start_global": 241488, "sentence_char_end_global": 241672, "entities": [{"text": "retinal autoantigen", "type": "ENTITY", "char_start": 41, "char_end": 60, "token_start": 5, "token_end": 6}], "entities_global": [{"text": "retinal autoantigen", "type": "ENTITY", "char_start": 241529, "char_end": 241548, "token_start": 5, "token_end": 6, "note": null}]}
+{"sentence_id": 1462, "sentence_text": "BACKGROUND / AIMS : A single intranasal delivery of retinal autoantigen suppresses effectively experimental autoimmune uveoretinitis ( EAU ) .", "sentence_char_start_global": 241673, "sentence_char_end_global": 241815, "entities": [{"text": "retinal autoantigen", "type": "ENTITY", "char_start": 52, "char_end": 71, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "retinal autoantigen", "type": "ENTITY", "char_start": 241725, "char_end": 241744, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 1463, "sentence_text": "To further unravel underlying mechanisms the authors wished to determine , firstly , the kinetics of antigen delivery and , secondly , the early cellular responses involved in the initial stages of nasal mucosal tolerance induction .", "sentence_char_start_global": 241816, "sentence_char_end_global": 242049, "entities": [], "entities_global": []}
+{"sentence_id": 1464, "sentence_text": "METHODS : Flow cytometry , cell proliferation assays , and microscopy were used to track antigen following a single , intranasal dose of Alexa - 488 labelled retinal antigen .", "sentence_char_start_global": 242050, "sentence_char_end_global": 242225, "entities": [{"text": "antigen", "type": "ENTITY", "char_start": 89, "char_end": 96, "token_start": 15, "token_end": 15}, {"text": "Alexa - 488 labelled retinal antigen", "type": "ENTITY", "char_start": 137, "char_end": 173, "token_start": 23, "token_end": 28}], "entities_global": [{"text": "antigen", "type": "ENTITY", "char_start": 242139, "char_end": 242146, "token_start": 15, "token_end": 15, "note": null}, {"text": "Alexa - 488 labelled retinal antigen", "type": "ENTITY", "char_start": 242187, "char_end": 242223, "token_start": 23, "token_end": 28, "note": null}]}
+{"sentence_id": 1465, "sentence_text": "RESULTS : A rapid accumulation of antigen within both superficial cervical lymph nodes ( SCLN ) and spleen was observed after 30 minutes .", "sentence_char_start_global": 242226, "sentence_char_end_global": 242364, "entities": [{"text": "antigen", "type": "ENTITY", "char_start": 34, "char_end": 41, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "antigen", "type": "ENTITY", "char_start": 242260, "char_end": 242267, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 1466, "sentence_text": "Significant proliferative responses to IRBP were elicited by 48 hours indicating that systemic priming of naive T cells to retinal antigen had occurred .", "sentence_char_start_global": 242365, "sentence_char_end_global": 242518, "entities": [{"text": "retinal antigen", "type": "ENTITY", "char_start": 123, "char_end": 138, "token_start": 19, "token_end": 20}], "entities_global": [{"text": "retinal antigen", "type": "ENTITY", "char_start": 242488, "char_end": 242503, "token_start": 19, "token_end": 20, "note": null}]}
+{"sentence_id": 1467, "sentence_text": "Cell activation was further confirmed by immunoprecipitation studies , which demonstrated phosphorylation of STAT4 but not STAT6 in both lymph nodes and spleen .", "sentence_char_start_global": 242519, "sentence_char_end_global": 242680, "entities": [{"text": "STAT4", "type": "ENTITY", "char_start": 109, "char_end": 114, "token_start": 13, "token_end": 13}, {"text": "STAT6", "type": "ENTITY", "char_start": 123, "char_end": 128, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "STAT4", "type": "ENTITY", "char_start": 242628, "char_end": 242633, "token_start": 13, "token_end": 13, "note": null}, {"text": "STAT6", "type": "ENTITY", "char_start": 242642, "char_end": 242647, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 1468, "sentence_text": "However , at 24 hours , STAT4 heterodimerisation with STAT 3 was only observed in spleen .", "sentence_char_start_global": 242681, "sentence_char_end_global": 242771, "entities": [{"text": "STAT 3", "type": "ENTITY", "char_start": 54, "char_end": 60, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "STAT 3", "type": "ENTITY", "char_start": 242735, "char_end": 242741, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 1469, "sentence_text": "CONCLUSIONS : The results provide novel evidence that following a single intranasal application rapid transfer of antigen occurs .", "sentence_char_start_global": 242772, "sentence_char_end_global": 242902, "entities": [{"text": "antigen", "type": "ENTITY", "char_start": 114, "char_end": 121, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "antigen", "type": "ENTITY", "char_start": 242886, "char_end": 242893, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 1470, "sentence_text": "Resulting T cell proliferation develops consequent to differential cell signalling in SCLN and spleen .", "sentence_char_start_global": 242903, "sentence_char_end_global": 243006, "entities": [], "entities_global": []}
+{"sentence_id": 1471, "sentence_text": "Further understanding of these underlying cellular mechanisms , in particular as is inferred by the results the contribution of local versus systemic tolerance induction , may assist in strategies to clinically apply mucosal tolerance therapy successfully .", "sentence_char_start_global": 243007, "sentence_char_end_global": 243264, "entities": [], "entities_global": []}
+{"sentence_id": 1472, "sentence_text": "Regulation of interleukin ( IL ) - 18 receptor alpha chain expression on CD4 ( + ) T cells during T helper ( Th ) 1 / Th2 differentiation .", "sentence_char_start_global": 243265, "sentence_char_end_global": 243404, "entities": [{"text": "interleukin ( IL ) - 18 receptor alpha chain", "type": "ENTITY", "char_start": 14, "char_end": 58, "token_start": 2, "token_end": 10}], "entities_global": [{"text": "interleukin ( IL ) - 18 receptor alpha chain", "type": "ENTITY", "char_start": 243279, "char_end": 243323, "token_start": 2, "token_end": 10, "note": null}]}
+{"sentence_id": 1473, "sentence_text": "Critical downregulatory role of IL - 4 .", "sentence_char_start_global": 243405, "sentence_char_end_global": 243445, "entities": [{"text": "IL - 4", "type": "ENTITY", "char_start": 32, "char_end": 38, "token_start": 4, "token_end": 6}], "entities_global": [{"text": "IL - 4", "type": "ENTITY", "char_start": 243437, "char_end": 243443, "token_start": 4, "token_end": 6, "note": null}]}
+{"sentence_id": 1474, "sentence_text": "Interleukin ( IL ) - 18 has been well characterized as a costimulatory factor for the induction of IL - 12 - mediated interferon ( IFN ) - gamma production by T helper ( Th ) 1 cells , but also can induce IL - 4 production and thus facilitate the differentiation of Th2 cells .", "sentence_char_start_global": 243446, "sentence_char_end_global": 243723, "entities": [{"text": "Interleukin ( IL ) - 18", "type": "ENTITY", "char_start": 0, "char_end": 23, "token_start": 0, "token_end": 5}, {"text": "costimulatory factor", "type": "ENTITY", "char_start": 57, "char_end": 77, "token_start": 12, "token_end": 13}, {"text": "IL - 12 - mediated interferon ( IFN ) - gamma", "type": "ENTITY", "char_start": 99, "char_end": 144, "token_start": 18, "token_end": 28}], "entities_global": [{"text": "Interleukin ( IL ) - 18", "type": "ENTITY", "char_start": 243446, "char_end": 243469, "token_start": 0, "token_end": 5, "note": null}, {"text": "costimulatory factor", "type": "ENTITY", "char_start": 243503, "char_end": 243523, "token_start": 12, "token_end": 13, "note": null}, {"text": "IL - 12 - mediated interferon ( IFN ) - gamma", "type": "ENTITY", "char_start": 243545, "char_end": 243590, "token_start": 18, "token_end": 28, "note": null}]}
+{"sentence_id": 1475, "sentence_text": "To determine the mechanisms by which IL - 18 might regulate these diametrically distinct immune responses , we have analyzed the role of cytokines in the regulation of IL - 18 receptor alpha chain ( IL - 18Ralpha ) expression .", "sentence_char_start_global": 243724, "sentence_char_end_global": 243951, "entities": [{"text": "IL - 18", "type": "ENTITY", "char_start": 37, "char_end": 44, "token_start": 6, "token_end": 8}, {"text": "cytokines", "type": "ENTITY", "char_start": 137, "char_end": 146, "token_start": 23, "token_end": 23}, {"text": "IL - 18 receptor alpha chain", "type": "ENTITY", "char_start": 168, "char_end": 196, "token_start": 28, "token_end": 33}, {"text": "IL - 18Ralpha", "type": "ENTITY", "char_start": 199, "char_end": 212, "token_start": 35, "token_end": 37}], "entities_global": [{"text": "IL - 18", "type": "ENTITY", "char_start": 243761, "char_end": 243768, "token_start": 6, "token_end": 8, "note": null}, {"text": "cytokines", "type": "ENTITY", "char_start": 243861, "char_end": 243870, "token_start": 23, "token_end": 23, "note": null}, {"text": "IL - 18 receptor alpha chain", "type": "ENTITY", "char_start": 243892, "char_end": 243920, "token_start": 28, "token_end": 33, "note": null}, {"text": "IL - 18Ralpha", "type": "ENTITY", "char_start": 243923, "char_end": 243936, "token_start": 35, "token_end": 37, "note": null}]}
+{"sentence_id": 1476, "sentence_text": "The majority of peripheral CD4 ( + ) T cells constitutively expressed the IL - 18Ralpha .", "sentence_char_start_global": 243952, "sentence_char_end_global": 244041, "entities": [{"text": "IL - 18Ralpha", "type": "ENTITY", "char_start": 74, "char_end": 87, "token_start": 13, "token_end": 15}], "entities_global": [{"text": "IL - 18Ralpha", "type": "ENTITY", "char_start": 244026, "char_end": 244039, "token_start": 13, "token_end": 15, "note": null}]}
+{"sentence_id": 1477, "sentence_text": "Upon antigen stimulation in the presence of IL - 12 , marked enhancement of IL - 18Ralpha expression was observed .", "sentence_char_start_global": 244042, "sentence_char_end_global": 244157, "entities": [{"text": "IL - 12", "type": "ENTITY", "char_start": 44, "char_end": 51, "token_start": 7, "token_end": 9}, {"text": "IL - 18Ralpha", "type": "ENTITY", "char_start": 76, "char_end": 89, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "IL - 12", "type": "ENTITY", "char_start": 244086, "char_end": 244093, "token_start": 7, "token_end": 9, "note": null}, {"text": "IL - 18Ralpha", "type": "ENTITY", "char_start": 244118, "char_end": 244131, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 1478, "sentence_text": "IL - 12 - mediated upregulation of IL - 18Ralpha required IFN - gamma .", "sentence_char_start_global": 244158, "sentence_char_end_global": 244229, "entities": [{"text": "IL - 12", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 2}, {"text": "IL - 18Ralpha", "type": "ENTITY", "char_start": 35, "char_end": 48, "token_start": 7, "token_end": 9}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 58, "char_end": 69, "token_start": 11, "token_end": 13}], "entities_global": [{"text": "IL - 12", "type": "ENTITY", "char_start": 244158, "char_end": 244165, "token_start": 0, "token_end": 2, "note": null}, {"text": "IL - 18Ralpha", "type": "ENTITY", "char_start": 244193, "char_end": 244206, "token_start": 7, "token_end": 9, "note": null}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 244216, "char_end": 244227, "token_start": 11, "token_end": 13, "note": null}]}
+{"sentence_id": 1479, "sentence_text": "Activated CD4 ( + ) T cells that expressed low levels of IL - 18Ralpha could produce IFN - gamma when stimulated with the combination of IL - 12 and IL - 18 , while CD4 ( + ) cells which expressed high levels of IL - 18Ralpha could respond to IL - 18 alone .", "sentence_char_start_global": 244230, "sentence_char_end_global": 244488, "entities": [{"text": "IL - 18Ralpha", "type": "ENTITY", "char_start": 57, "char_end": 70, "token_start": 12, "token_end": 14}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 85, "char_end": 96, "token_start": 17, "token_end": 19}, {"text": "IL - 12", "type": "ENTITY", "char_start": 137, "char_end": 144, "token_start": 26, "token_end": 28}, {"text": "IL - 18", "type": "ENTITY", "char_start": 149, "char_end": 156, "token_start": 30, "token_end": 32}, {"text": "IL - 18Ralpha", "type": "ENTITY", "char_start": 212, "char_end": 225, "token_start": 45, "token_end": 47}, {"text": "IL - 18", "type": "ENTITY", "char_start": 243, "char_end": 250, "token_start": 51, "token_end": 53}], "entities_global": [{"text": "IL - 18Ralpha", "type": "ENTITY", "char_start": 244287, "char_end": 244300, "token_start": 12, "token_end": 14, "note": null}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 244315, "char_end": 244326, "token_start": 17, "token_end": 19, "note": null}, {"text": "IL - 12", "type": "ENTITY", "char_start": 244367, "char_end": 244374, "token_start": 26, "token_end": 28, "note": null}, {"text": "IL - 18", "type": "ENTITY", "char_start": 244379, "char_end": 244386, "token_start": 30, "token_end": 32, "note": null}, {"text": "IL - 18Ralpha", "type": "ENTITY", "char_start": 244442, "char_end": 244455, "token_start": 45, "token_end": 47, "note": null}, {"text": "IL - 18", "type": "ENTITY", "char_start": 244473, "char_end": 244480, "token_start": 51, "token_end": 53, "note": null}]}
+{"sentence_id": 1480, "sentence_text": "In contrast , T cell stimulation in the presence of IL - 4 resulted in a downregulation of IL - 18Ralpha expression .", "sentence_char_start_global": 244489, "sentence_char_end_global": 244606, "entities": [{"text": "IL - 4", "type": "ENTITY", "char_start": 52, "char_end": 58, "token_start": 10, "token_end": 12}, {"text": "IL - 18Ralpha", "type": "ENTITY", "char_start": 91, "char_end": 104, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "IL - 4", "type": "ENTITY", "char_start": 244541, "char_end": 244547, "token_start": 10, "token_end": 12, "note": null}, {"text": "IL - 18Ralpha", "type": "ENTITY", "char_start": 244580, "char_end": 244593, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 1481, "sentence_text": "Both IL - 4 ( - / ) - and signal transducer and activator of transcription ( Stat ) 6 ( - / ) - T cells expressed higher levels of IL - 18Ralpha after TCR stimulation .", "sentence_char_start_global": 244607, "sentence_char_end_global": 244775, "entities": [{"text": "IL - 18Ralpha", "type": "ENTITY", "char_start": 131, "char_end": 144, "token_start": 31, "token_end": 33}], "entities_global": [{"text": "IL - 18Ralpha", "type": "ENTITY", "char_start": 244738, "char_end": 244751, "token_start": 31, "token_end": 33, "note": null}]}
+{"sentence_id": 1482, "sentence_text": "Furthermore , activated T cells from Stat6 ( - / ) - mice produced more IFN - gamma in response to IL - 18 than wild - type controls .", "sentence_char_start_global": 244776, "sentence_char_end_global": 244910, "entities": [{"text": "IFN - gamma", "type": "ENTITY", "char_start": 72, "char_end": 83, "token_start": 15, "token_end": 17}, {"text": "IL - 18", "type": "ENTITY", "char_start": 99, "char_end": 106, "token_start": 21, "token_end": 23}], "entities_global": [{"text": "IFN - gamma", "type": "ENTITY", "char_start": 244848, "char_end": 244859, "token_start": 15, "token_end": 17, "note": null}, {"text": "IL - 18", "type": "ENTITY", "char_start": 244875, "char_end": 244882, "token_start": 21, "token_end": 23, "note": null}]}
+{"sentence_id": 1483, "sentence_text": "Thus , positive / negative regulation of the IL - 18Ralpha by the major inductive cytokines ( IL - 12 and IL - 4 ) determines the capacity of IL - 18 to polarize an immune response .", "sentence_char_start_global": 244911, "sentence_char_end_global": 245093, "entities": [{"text": "IL - 18Ralpha", "type": "ENTITY", "char_start": 45, "char_end": 58, "token_start": 8, "token_end": 10}, {"text": "cytokines", "type": "ENTITY", "char_start": 82, "char_end": 91, "token_start": 15, "token_end": 15}, {"text": "IL - 12", "type": "ENTITY", "char_start": 94, "char_end": 101, "token_start": 17, "token_end": 19}, {"text": "IL - 4", "type": "ENTITY", "char_start": 106, "char_end": 112, "token_start": 21, "token_end": 23}, {"text": "IL - 18", "type": "ENTITY", "char_start": 142, "char_end": 149, "token_start": 29, "token_end": 31}], "entities_global": [{"text": "IL - 18Ralpha", "type": "ENTITY", "char_start": 244956, "char_end": 244969, "token_start": 8, "token_end": 10, "note": null}, {"text": "cytokines", "type": "ENTITY", "char_start": 244993, "char_end": 245002, "token_start": 15, "token_end": 15, "note": null}, {"text": "IL - 12", "type": "ENTITY", "char_start": 245005, "char_end": 245012, "token_start": 17, "token_end": 19, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 245017, "char_end": 245023, "token_start": 21, "token_end": 23, "note": null}, {"text": "IL - 18", "type": "ENTITY", "char_start": 245053, "char_end": 245060, "token_start": 29, "token_end": 31, "note": null}]}
+{"sentence_id": 1484, "sentence_text": "Glucocorticoid - regulated transcription factors .", "sentence_char_start_global": 245094, "sentence_char_end_global": 245144, "entities": [{"text": "Glucocorticoid - regulated transcription factors", "type": "ENTITY", "char_start": 0, "char_end": 48, "token_start": 0, "token_end": 4}], "entities_global": [{"text": "Glucocorticoid - regulated transcription factors", "type": "ENTITY", "char_start": 245094, "char_end": 245142, "token_start": 0, "token_end": 4, "note": null}]}
+{"sentence_id": 1485, "sentence_text": "Glucocorticoids are the most effective antiinflammatory drugs used in the treatment of asthma .", "sentence_char_start_global": 245145, "sentence_char_end_global": 245240, "entities": [], "entities_global": []}
+{"sentence_id": 1486, "sentence_text": "They act by binding to a specific receptor ( GR ) that , upon activation , translocates to the nucleus and either increases ( transactivates ) or decreases ( transrepresses ) gene expression .", "sentence_char_start_global": 245241, "sentence_char_end_global": 245433, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 45, "char_end": 47, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 245286, "char_end": 245288, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 1487, "sentence_text": "Inhibition of pro - inflammatory transcription factors such as activator protein ( AP ) - 1 , signal transducers and activators of transcription ( STATs ) , nuclear factor of activated T cells ( NFAT ) and nuclear factor ( NF ) - kappa B is thought to be a major action of glucocorticoids .", "sentence_char_start_global": 245434, "sentence_char_end_global": 245724, "entities": [{"text": "pro - inflammatory transcription factors", "type": "ENTITY", "char_start": 14, "char_end": 54, "token_start": 2, "token_end": 6}, {"text": "activator protein ( AP ) - 1", "type": "ENTITY", "char_start": 63, "char_end": 91, "token_start": 9, "token_end": 15}, {"text": "signal transducers and activators of transcription", "type": "ENTITY", "char_start": 94, "char_end": 144, "token_start": 17, "token_end": 22}, {"text": "STATs", "type": "ENTITY", "char_start": 147, "char_end": 152, "token_start": 24, "token_end": 24}, {"text": "nuclear factor of activated T cells", "type": "ENTITY", "char_start": 157, "char_end": 192, "token_start": 27, "token_end": 32}, {"text": "NFAT", "type": "ENTITY", "char_start": 195, "char_end": 199, "token_start": 34, "token_end": 34}, {"text": "nuclear factor ( NF ) - kappa B", "type": "ENTITY", "char_start": 206, "char_end": 237, "token_start": 37, "token_end": 44}], "entities_global": [{"text": "pro - inflammatory transcription factors", "type": "ENTITY", "char_start": 245448, "char_end": 245488, "token_start": 2, "token_end": 6, "note": null}, {"text": "activator protein ( AP ) - 1", "type": "ENTITY", "char_start": 245497, "char_end": 245525, "token_start": 9, "token_end": 15, "note": null}, {"text": "signal transducers and activators of transcription", "type": "ENTITY", "char_start": 245528, "char_end": 245578, "token_start": 17, "token_end": 22, "note": null}, {"text": "STATs", "type": "ENTITY", "char_start": 245581, "char_end": 245586, "token_start": 24, "token_end": 24, "note": null}, {"text": "nuclear factor of activated T cells", "type": "ENTITY", "char_start": 245591, "char_end": 245626, "token_start": 27, "token_end": 32, "note": null}, {"text": "NFAT", "type": "ENTITY", "char_start": 245629, "char_end": 245633, "token_start": 34, "token_end": 34, "note": null}, {"text": "nuclear factor ( NF ) - kappa B", "type": "ENTITY", "char_start": 245640, "char_end": 245671, "token_start": 37, "token_end": 44, "note": null}]}
+{"sentence_id": 1488, "sentence_text": "Acetylation of histones allows unwinding of the local DNA structure and enables RNA polymerase II to enhance gene transcription .", "sentence_char_start_global": 245725, "sentence_char_end_global": 245854, "entities": [{"text": "histones", "type": "ENTITY", "char_start": 15, "char_end": 23, "token_start": 2, "token_end": 2}, {"text": "local DNA structure", "type": "ENTITY", "char_start": 48, "char_end": 67, "token_start": 7, "token_end": 9}, {"text": "RNA polymerase II", "type": "ENTITY", "char_start": 80, "char_end": 97, "token_start": 12, "token_end": 14}], "entities_global": [{"text": "histones", "type": "ENTITY", "char_start": 245740, "char_end": 245748, "token_start": 2, "token_end": 2, "note": null}, {"text": "local DNA structure", "type": "ENTITY", "char_start": 245773, "char_end": 245792, "token_start": 7, "token_end": 9, "note": null}, {"text": "RNA polymerase II", "type": "ENTITY", "char_start": 245805, "char_end": 245822, "token_start": 12, "token_end": 14, "note": null}]}
+{"sentence_id": 1489, "sentence_text": "Histone acetylation is regulated by a balance between the activity of histone acetyltransferases ( HATs ) and histone deacetylases ( HDACs ) .", "sentence_char_start_global": 245855, "sentence_char_end_global": 245997, "entities": [{"text": "histone acetyltransferases", "type": "ENTITY", "char_start": 70, "char_end": 96, "token_start": 11, "token_end": 12}, {"text": "HATs", "type": "ENTITY", "char_start": 99, "char_end": 103, "token_start": 14, "token_end": 14}, {"text": "histone deacetylases", "type": "ENTITY", "char_start": 110, "char_end": 130, "token_start": 17, "token_end": 18}, {"text": "HDACs", "type": "ENTITY", "char_start": 133, "char_end": 138, "token_start": 20, "token_end": 20}], "entities_global": [{"text": "histone acetyltransferases", "type": "ENTITY", "char_start": 245925, "char_end": 245951, "token_start": 11, "token_end": 12, "note": null}, {"text": "HATs", "type": "ENTITY", "char_start": 245954, "char_end": 245958, "token_start": 14, "token_end": 14, "note": null}, {"text": "histone deacetylases", "type": "ENTITY", "char_start": 245965, "char_end": 245985, "token_start": 17, "token_end": 18, "note": null}, {"text": "HDACs", "type": "ENTITY", "char_start": 245988, "char_end": 245993, "token_start": 20, "token_end": 20, "note": null}]}
+{"sentence_id": 1490, "sentence_text": "GR acts as a direct inhibitor of NF - kappa B - induced HAT activity and also by recruiting HDAC2 to the NF - kappa B / HAT complex .", "sentence_char_start_global": 245998, "sentence_char_end_global": 246131, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 0, "char_end": 2, "token_start": 0, "token_end": 0}, {"text": "HDAC2", "type": "ENTITY", "char_start": 92, "char_end": 97, "token_start": 19, "token_end": 19}, {"text": "NF - kappa B / HAT complex", "type": "ENTITY", "char_start": 105, "char_end": 131, "token_start": 22, "token_end": 28}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 245998, "char_end": 246000, "token_start": 0, "token_end": 0, "note": null}, {"text": "HDAC2", "type": "ENTITY", "char_start": 246090, "char_end": 246095, "token_start": 19, "token_end": 19, "note": null}, {"text": "NF - kappa B / HAT complex", "type": "ENTITY", "char_start": 246103, "char_end": 246129, "token_start": 22, "token_end": 28, "note": null}]}
+{"sentence_id": 1491, "sentence_text": "A sub - group of patients with glucocorticoid - insensitive asthma have an inability to induce histone acetylation in response to dexamethasone suggesting reduced expression of a GR - specific HAT .", "sentence_char_start_global": 246132, "sentence_char_end_global": 246330, "entities": [{"text": "GR - specific HAT", "type": "ENTITY", "char_start": 179, "char_end": 196, "token_start": 27, "token_end": 30}], "entities_global": [{"text": "GR - specific HAT", "type": "ENTITY", "char_start": 246311, "char_end": 246328, "token_start": 27, "token_end": 30, "note": null}]}
+{"sentence_id": 1492, "sentence_text": "This suggests that pharmacological manipulation of specific histone acetylation status is a potentially useful approach for the treatment of inflammatory diseases .", "sentence_char_start_global": 246331, "sentence_char_end_global": 246495, "entities": [], "entities_global": []}
+{"sentence_id": 1493, "sentence_text": "Identification of the precise mechanism by which activated GR recruits HDAC2 may reveal new targets for the development of drugs that may dissociate the antiinflammatory actions of glucocorticoids from their side effects that are largely due to gene induction .", "sentence_char_start_global": 246496, "sentence_char_end_global": 246757, "entities": [{"text": "activated GR", "type": "ENTITY", "char_start": 49, "char_end": 61, "token_start": 7, "token_end": 8}, {"text": "HDAC2", "type": "ENTITY", "char_start": 71, "char_end": 76, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "activated GR", "type": "ENTITY", "char_start": 246545, "char_end": 246557, "token_start": 7, "token_end": 8, "note": null}, {"text": "HDAC2", "type": "ENTITY", "char_start": 246567, "char_end": 246572, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 1494, "sentence_text": "Copyright Academic Press .", "sentence_char_start_global": 246758, "sentence_char_end_global": 246784, "entities": [], "entities_global": []}
+{"sentence_id": 1495, "sentence_text": "Differential ultraviolet - B - induced immunomodulation in XPA , XPC , and CSB DNA repair - deficient mice .", "sentence_char_start_global": 246785, "sentence_char_end_global": 246893, "entities": [], "entities_global": []}
+{"sentence_id": 1496, "sentence_text": "Ultraviolet B irradiation has serious consequences for cellular immunity and can suppress the rejection of skin tumors and the resistance to infectious diseases .", "sentence_char_start_global": 246894, "sentence_char_end_global": 247056, "entities": [], "entities_global": []}
+{"sentence_id": 1497, "sentence_text": "DNA damage plays a crucial role in these immunomodulatory effects of ultraviolet B , as impaired repair of ultraviolet - B - induced DNA damage has been shown to cause suppression of cellular immunity .", "sentence_char_start_global": 247057, "sentence_char_end_global": 247259, "entities": [], "entities_global": []}
+{"sentence_id": 1498, "sentence_text": "Ultraviolet - B - induced DNA damage is repaired by the nucleotide excision repair mechanism very efficiently .", "sentence_char_start_global": 247260, "sentence_char_end_global": 247371, "entities": [], "entities_global": []}
+{"sentence_id": 1499, "sentence_text": "Nucleotide excision repair comprises two subpathways : transcription - coupled and global genome repair .", "sentence_char_start_global": 247372, "sentence_char_end_global": 247477, "entities": [], "entities_global": []}
+{"sentence_id": 1500, "sentence_text": "In this study the immunologic consequences of specific nucleotide excision repair defects in three mouse models , XPA , XPC , and CSB mutant mice , were investigated .", "sentence_char_start_global": 247478, "sentence_char_end_global": 247645, "entities": [], "entities_global": []}
+{"sentence_id": 1501, "sentence_text": "XPA mice carry a total nucleotide excision repair defect , whereas XPC and CSB mice only lack global genome and transcription - coupled nucleotide excision repair , respectively .", "sentence_char_start_global": 247646, "sentence_char_end_global": 247825, "entities": [], "entities_global": []}
+{"sentence_id": 1502, "sentence_text": "Our data demonstrate that cellular immune parameters in XPA , XPC , and CSB mice are normal compared with their wild - type ( control ) littermates .", "sentence_char_start_global": 247826, "sentence_char_end_global": 247975, "entities": [], "entities_global": []}
+{"sentence_id": 1503, "sentence_text": "This may indicate that the reported altered cellular responses in xeroderma pigmentosum patients are not constitutive but could be due to external factors , such as ultraviolet B .", "sentence_char_start_global": 247976, "sentence_char_end_global": 248156, "entities": [], "entities_global": []}
+{"sentence_id": 1504, "sentence_text": "Upon exposure to ultraviolet B , only XPA mice are very sensitive to ultraviolet - B - induced inhibition of Th1 - mediated contact hypersensitivity responses and interferon - gamma production in skin draining lymph nodes .", "sentence_char_start_global": 248157, "sentence_char_end_global": 248380, "entities": [{"text": "interferon - gamma", "type": "ENTITY", "char_start": 163, "char_end": 181, "token_start": 27, "token_end": 29}], "entities_global": [{"text": "interferon - gamma", "type": "ENTITY", "char_start": 248320, "char_end": 248338, "token_start": 27, "token_end": 29, "note": null}]}
+{"sentence_id": 1505, "sentence_text": "Lipopolysaccharide - stimulated tumor necrosis factor alpha and interleukin - 10 production are significantly augmented in both XPA and CSB mice after ultraviolet B exposure .", "sentence_char_start_global": 248381, "sentence_char_end_global": 248556, "entities": [{"text": "tumor necrosis factor alpha", "type": "ENTITY", "char_start": 32, "char_end": 59, "token_start": 3, "token_end": 6}, {"text": "interleukin - 10", "type": "ENTITY", "char_start": 64, "char_end": 80, "token_start": 8, "token_end": 10}], "entities_global": [{"text": "tumor necrosis factor alpha", "type": "ENTITY", "char_start": 248413, "char_end": 248440, "token_start": 3, "token_end": 6, "note": null}, {"text": "interleukin - 10", "type": "ENTITY", "char_start": 248445, "char_end": 248461, "token_start": 8, "token_end": 10, "note": null}]}
+{"sentence_id": 1506, "sentence_text": "Lymph node cell numbers were increased very significantly in XPA , mildly increased in CSB , and not in XPC mice .", "sentence_char_start_global": 248557, "sentence_char_end_global": 248671, "entities": [], "entities_global": []}
+{"sentence_id": 1507, "sentence_text": "In general XPC mice do not exhibit any indication of enhanced ultraviolet B susceptibility with regard to the immune parameters analyzed .", "sentence_char_start_global": 248672, "sentence_char_end_global": 248810, "entities": [], "entities_global": []}
+{"sentence_id": 1508, "sentence_text": "These data suggest that both global genome repair and transcription - coupled repair are needed to prevent immunomodulation by ultraviolet B , whereas transcription - coupled repair is the major DNA repair subpathway of nucleotide excision repair that prevents the acute ultraviolet - B - induced effects such as erythema .", "sentence_char_start_global": 248811, "sentence_char_end_global": 249134, "entities": [], "entities_global": []}
+{"sentence_id": 1509, "sentence_text": "Biomechanical strain induces class a scavenger receptor expression in human monocyte / macrophages and THP - 1 cells : a potential mechanism of increased atherosclerosis in hypertension .", "sentence_char_start_global": 249135, "sentence_char_end_global": 249322, "entities": [{"text": "scavenger receptor", "type": "ENTITY", "char_start": 37, "char_end": 55, "token_start": 5, "token_end": 6}], "entities_global": [{"text": "scavenger receptor", "type": "ENTITY", "char_start": 249172, "char_end": 249190, "token_start": 5, "token_end": 6, "note": null}]}
+{"sentence_id": 1510, "sentence_text": "BACKGROUND : Although hypertension is an important risk factor for the development of atherosclerosis , the mechanisms for this interaction are incompletely described .", "sentence_char_start_global": 249323, "sentence_char_end_global": 249491, "entities": [], "entities_global": []}
+{"sentence_id": 1511, "sentence_text": "Previous studies have suggested that biomechanical strain regulates macrophage phenotype .", "sentence_char_start_global": 249492, "sentence_char_end_global": 249582, "entities": [], "entities_global": []}
+{"sentence_id": 1512, "sentence_text": "We tested the hypothesis that biomechanical strain can induce expression of the class A scavenger receptor ( SRA ) , an important lipoprotein receptor in atherogenesis .", "sentence_char_start_global": 249583, "sentence_char_end_global": 249752, "entities": [{"text": "class A scavenger receptor", "type": "ENTITY", "char_start": 80, "char_end": 106, "token_start": 12, "token_end": 15}, {"text": "SRA", "type": "ENTITY", "char_start": 109, "char_end": 112, "token_start": 17, "token_end": 17}, {"text": "lipoprotein receptor", "type": "ENTITY", "char_start": 130, "char_end": 150, "token_start": 22, "token_end": 23}], "entities_global": [{"text": "class A scavenger receptor", "type": "ENTITY", "char_start": 249663, "char_end": 249689, "token_start": 12, "token_end": 15, "note": null}, {"text": "SRA", "type": "ENTITY", "char_start": 249692, "char_end": 249695, "token_start": 17, "token_end": 17, "note": null}, {"text": "lipoprotein receptor", "type": "ENTITY", "char_start": 249713, "char_end": 249733, "token_start": 22, "token_end": 23, "note": null}]}
+{"sentence_id": 1513, "sentence_text": "METHODS AND RESULTS : Human monocyte / macrophages or THP - 1 cells were cultured in a device that imposes uniform biaxial cyclic 1 - Hz strains of 0 % , 1 % , 2 % , or 3 % , and SRA expression was analyzed .", "sentence_char_start_global": 249753, "sentence_char_end_global": 249961, "entities": [{"text": "SRA", "type": "ENTITY", "char_start": 179, "char_end": 182, "token_start": 42, "token_end": 42}], "entities_global": [{"text": "SRA", "type": "ENTITY", "char_start": 249932, "char_end": 249935, "token_start": 42, "token_end": 42, "note": null}]}
+{"sentence_id": 1514, "sentence_text": "Mechanical strains induced SRA mRNA ( 3 . 5 + / - 0 . 6 - fold at 3 % strain for 48 hours , P < 0 . 01 ) and SRA protein in THP - 1 cells in an amplitude - dependent manner .", "sentence_char_start_global": 249962, "sentence_char_end_global": 250136, "entities": [{"text": "SRA mRNA", "type": "ENTITY", "char_start": 27, "char_end": 35, "token_start": 3, "token_end": 4}, {"text": "SRA protein", "type": "ENTITY", "char_start": 109, "char_end": 120, "token_start": 32, "token_end": 33}], "entities_global": [{"text": "SRA mRNA", "type": "ENTITY", "char_start": 249989, "char_end": 249997, "token_start": 3, "token_end": 4, "note": null}, {"text": "SRA protein", "type": "ENTITY", "char_start": 250071, "char_end": 250082, "token_start": 32, "token_end": 33, "note": null}]}
+{"sentence_id": 1515, "sentence_text": "This induction was accompanied by augmented expression of the class B scavenger receptor CD36 ( 2 . 8 + / - 0 . 3 - fold , P < 0 . 001 ) but not by increased peroxisome proliferator - activated receptor - gamma expression .", "sentence_char_start_global": 250137, "sentence_char_end_global": 250360, "entities": [{"text": "class B scavenger receptor CD36", "type": "ENTITY", "char_start": 62, "char_end": 93, "token_start": 9, "token_end": 13}, {"text": "peroxisome proliferator - activated receptor - gamma", "type": "ENTITY", "char_start": 158, "char_end": 210, "token_start": 37, "token_end": 43}], "entities_global": [{"text": "class B scavenger receptor CD36", "type": "ENTITY", "char_start": 250199, "char_end": 250230, "token_start": 9, "token_end": 13, "note": null}, {"text": "peroxisome proliferator - activated receptor - gamma", "type": "ENTITY", "char_start": 250295, "char_end": 250347, "token_start": 37, "token_end": 43, "note": null}]}
+{"sentence_id": 1516, "sentence_text": "To evaluate this effect in vivo , apolipoprotein E ( - / - ) mice were randomly assigned to receive standard chow , a high - cholesterol diet , or a high - cholesterol diet with hypertension induced by angiotensin II infusion for 8 weeks .", "sentence_char_start_global": 250361, "sentence_char_end_global": 250600, "entities": [], "entities_global": []}
+{"sentence_id": 1517, "sentence_text": "Immunohistochemistry revealed that among macrophages in atherosclerotic lesions of the aorta , the proportion of macrophages with SRA expression was highest in hypertensive animals on a high - cholesterol diet ( 43 . 9 + / - 0 . 7 % , versus 12 . 0 + / - 2 . 0 % for normotensive animals on a high - cholesterol diet and 4 . 7 + / - 4 . 7 % for animals on standard chow ; P < 0 . 001 ) .", "sentence_char_start_global": 250601, "sentence_char_end_global": 250988, "entities": [{"text": "SRA", "type": "ENTITY", "char_start": 130, "char_end": 133, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "SRA", "type": "ENTITY", "char_start": 250731, "char_end": 250734, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 1518, "sentence_text": "CONCLUSIONS : Biomechanical strain induces SRA expression by monocyte / macrophages , suggesting a novel mechanism for promotion of atherosclerosis in hypertensive patients .", "sentence_char_start_global": 250989, "sentence_char_end_global": 251163, "entities": [{"text": "SRA", "type": "ENTITY", "char_start": 43, "char_end": 46, "token_start": 5, "token_end": 5}], "entities_global": [{"text": "SRA", "type": "ENTITY", "char_start": 251032, "char_end": 251035, "token_start": 5, "token_end": 5, "note": null}]}
+{"sentence_id": 1519, "sentence_text": "High glucose induces MCP - 1 expression partly via tyrosine kinase - AP - 1 pathway in peritoneal mesothelial cells .", "sentence_char_start_global": 251164, "sentence_char_end_global": 251281, "entities": [], "entities_global": []}
+{"sentence_id": 1520, "sentence_text": "BACKGROUND : High glucose in peritoneal dialysis solutions has been implicated in the pathogenesis of peritoneal fibrosis in chronic ambulatory peritoneal dialysis ( CAPD ) patients .", "sentence_char_start_global": 251282, "sentence_char_end_global": 251465, "entities": [], "entities_global": []}
+{"sentence_id": 1521, "sentence_text": "However , the mechanisms are not very clear .", "sentence_char_start_global": 251466, "sentence_char_end_global": 251511, "entities": [], "entities_global": []}
+{"sentence_id": 1522, "sentence_text": "Peritoneal macrophages seem to participate in the process of peritoneal fibrosis and monocyte chemoattractant protein - 1 ( MCP - 1 ) plays a key role in the recruitment of monocytes toward the peritoneal cavity .", "sentence_char_start_global": 251512, "sentence_char_end_global": 251725, "entities": [{"text": "monocyte chemoattractant protein - 1", "type": "ENTITY", "char_start": 85, "char_end": 121, "token_start": 12, "token_end": 16}, {"text": "MCP - 1", "type": "ENTITY", "char_start": 124, "char_end": 131, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "monocyte chemoattractant protein - 1", "type": "ENTITY", "char_start": 251597, "char_end": 251633, "token_start": 12, "token_end": 16, "note": null}, {"text": "MCP - 1", "type": "ENTITY", "char_start": 251636, "char_end": 251643, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 1523, "sentence_text": "However , little is known about the effect of high glucose on MCP - 1 expression and its signal transduction pathway in human peritoneal mesothelial cells .", "sentence_char_start_global": 251726, "sentence_char_end_global": 251882, "entities": [{"text": "MCP - 1", "type": "ENTITY", "char_start": 62, "char_end": 69, "token_start": 12, "token_end": 14}], "entities_global": [{"text": "MCP - 1", "type": "ENTITY", "char_start": 251788, "char_end": 251795, "token_start": 12, "token_end": 14, "note": null}]}
+{"sentence_id": 1524, "sentence_text": "METHODS : Mesothelial cells were cultured with glucose ( 5 to 100 mmol / L ) or mannitol chronically for up to seven days .", "sentence_char_start_global": 251883, "sentence_char_end_global": 252006, "entities": [], "entities_global": []}
+{"sentence_id": 1525, "sentence_text": "MCP - 1 expression of mRNA and protein was measured by Northern blot analysis and enzyme - linked immunosorbent assay ( ELISA ) .", "sentence_char_start_global": 252007, "sentence_char_end_global": 252136, "entities": [{"text": "MCP - 1", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "MCP - 1", "type": "ENTITY", "char_start": 252007, "char_end": 252014, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 1526, "sentence_text": "Chemotactic activity of high - glucose - conditioned culture supernatant was measured by chemotactic assay .", "sentence_char_start_global": 252137, "sentence_char_end_global": 252245, "entities": [], "entities_global": []}
+{"sentence_id": 1527, "sentence_text": "To examine the roles of the transcription factors activator protein - 1 ( AP - 1 ) and nuclear factor - kappaB ( NF - kappaB ) , electrophoretic mobility shift assay ( EMSA ) was performed .", "sentence_char_start_global": 252246, "sentence_char_end_global": 252436, "entities": [{"text": "transcription factors", "type": "ENTITY", "char_start": 28, "char_end": 49, "token_start": 6, "token_end": 7}, {"text": "activator protein - 1", "type": "ENTITY", "char_start": 50, "char_end": 71, "token_start": 8, "token_end": 11}, {"text": "AP - 1", "type": "ENTITY", "char_start": 74, "char_end": 80, "token_start": 13, "token_end": 15}, {"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 87, "char_end": 110, "token_start": 18, "token_end": 21}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 113, "char_end": 124, "token_start": 23, "token_end": 25}], "entities_global": [{"text": "transcription factors", "type": "ENTITY", "char_start": 252274, "char_end": 252295, "token_start": 6, "token_end": 7, "note": null}, {"text": "activator protein - 1", "type": "ENTITY", "char_start": 252296, "char_end": 252317, "token_start": 8, "token_end": 11, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 252320, "char_end": 252326, "token_start": 13, "token_end": 15, "note": null}, {"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 252333, "char_end": 252356, "token_start": 18, "token_end": 21, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 252359, "char_end": 252370, "token_start": 23, "token_end": 25, "note": null}]}
+{"sentence_id": 1528, "sentence_text": "RESULTS : Glucose induced MCP - 1 mRNA expression in a time - and dose - dependent manner .", "sentence_char_start_global": 252437, "sentence_char_end_global": 252528, "entities": [{"text": "MCP - 1 mRNA", "type": "ENTITY", "char_start": 26, "char_end": 38, "token_start": 4, "token_end": 7}], "entities_global": [{"text": "MCP - 1 mRNA", "type": "ENTITY", "char_start": 252463, "char_end": 252475, "token_start": 4, "token_end": 7, "note": null}]}
+{"sentence_id": 1529, "sentence_text": "MCP - 1 protein in cell culture supernant was also increased .", "sentence_char_start_global": 252529, "sentence_char_end_global": 252591, "entities": [{"text": "MCP - 1 protein", "type": "ENTITY", "char_start": 0, "char_end": 15, "token_start": 0, "token_end": 3}], "entities_global": [{"text": "MCP - 1 protein", "type": "ENTITY", "char_start": 252529, "char_end": 252544, "token_start": 0, "token_end": 3, "note": null}]}
+{"sentence_id": 1530, "sentence_text": "Equivalent concentrations of mannitol had no significant effect .", "sentence_char_start_global": 252592, "sentence_char_end_global": 252657, "entities": [], "entities_global": []}
+{"sentence_id": 1531, "sentence_text": "High - glucose - conditioned supernatant possessed an increased chemotactic activity for monocytes , which was neutralized by anti - MCP - 1 antibody .", "sentence_char_start_global": 252658, "sentence_char_end_global": 252809, "entities": [{"text": "anti - MCP - 1 antibody", "type": "ENTITY", "char_start": 126, "char_end": 149, "token_start": 18, "token_end": 23}], "entities_global": [{"text": "anti - MCP - 1 antibody", "type": "ENTITY", "char_start": 252784, "char_end": 252807, "token_start": 18, "token_end": 23, "note": null}]}
+{"sentence_id": 1532, "sentence_text": "EMSA revealed that glucose increased the AP - 1 binding activity in a time - and dose - dependent manner , but not NF - kappaB .", "sentence_char_start_global": 252810, "sentence_char_end_global": 252938, "entities": [{"text": "AP - 1", "type": "ENTITY", "char_start": 41, "char_end": 47, "token_start": 6, "token_end": 8}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 115, "char_end": 126, "token_start": 23, "token_end": 25}], "entities_global": [{"text": "AP - 1", "type": "ENTITY", "char_start": 252851, "char_end": 252857, "token_start": 6, "token_end": 8, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 252925, "char_end": 252936, "token_start": 23, "token_end": 25, "note": null}]}
+{"sentence_id": 1533, "sentence_text": "Curcumin , an inhibitor of AP - 1 , dose - dependently suppressed the induction of MCP - 1 mRNA by high glucose .", "sentence_char_start_global": 252939, "sentence_char_end_global": 253052, "entities": [{"text": "AP - 1", "type": "ENTITY", "char_start": 27, "char_end": 33, "token_start": 5, "token_end": 7}, {"text": "MCP - 1 mRNA", "type": "ENTITY", "char_start": 83, "char_end": 95, "token_start": 16, "token_end": 19}], "entities_global": [{"text": "AP - 1", "type": "ENTITY", "char_start": 252966, "char_end": 252972, "token_start": 5, "token_end": 7, "note": null}, {"text": "MCP - 1 mRNA", "type": "ENTITY", "char_start": 253022, "char_end": 253034, "token_start": 16, "token_end": 19, "note": null}]}
+{"sentence_id": 1534, "sentence_text": "Tyrosine kinase inhibitors such as genistein ( 12 . 5 to 50 micromol / L ) and herbimycin A ( 0 . 1 to 1 micromol / L ) inhibited the high - glucose - induced MCP - 1 mRNA expression in a dose - dependent manner , and also suppressed the high - glucose - induced AP - 1 binding activity .", "sentence_char_start_global": 253053, "sentence_char_end_global": 253341, "entities": [{"text": "MCP - 1 mRNA", "type": "ENTITY", "char_start": 159, "char_end": 171, "token_start": 36, "token_end": 39}, {"text": "AP - 1", "type": "ENTITY", "char_start": 263, "char_end": 269, "token_start": 57, "token_end": 59}], "entities_global": [{"text": "MCP - 1 mRNA", "type": "ENTITY", "char_start": 253212, "char_end": 253224, "token_start": 36, "token_end": 39, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 253316, "char_end": 253322, "token_start": 57, "token_end": 59, "note": null}]}
+{"sentence_id": 1535, "sentence_text": "CONCLUSIONS : : High glucose induced mesothelial MCP - 1 expression partly via the tyrosine kinase - AP - 1 pathway .", "sentence_char_start_global": 253342, "sentence_char_end_global": 253459, "entities": [{"text": "MCP - 1", "type": "ENTITY", "char_start": 49, "char_end": 56, "token_start": 7, "token_end": 9}, {"text": "AP - 1", "type": "ENTITY", "char_start": 101, "char_end": 107, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "MCP - 1", "type": "ENTITY", "char_start": 253391, "char_end": 253398, "token_start": 7, "token_end": 9, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 253443, "char_end": 253449, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 1536, "sentence_text": "Signal thresholds and modular synergy during expression of costimulatory molecules in B lymphocytes .", "sentence_char_start_global": 253460, "sentence_char_end_global": 253561, "entities": [], "entities_global": []}
+{"sentence_id": 1537, "sentence_text": "We analyzed intracellular pathways modulating surface densities of CD80 and CD86 in B cells activated through ligation of the Ag receptor , and the adhesion molecule CD54 .", "sentence_char_start_global": 253562, "sentence_char_end_global": 253734, "entities": [{"text": "CD80", "type": "ENTITY", "char_start": 67, "char_end": 71, "token_start": 8, "token_end": 8}, {"text": "CD86", "type": "ENTITY", "char_start": 76, "char_end": 80, "token_start": 10, "token_end": 10}, {"text": "Ag receptor", "type": "ENTITY", "char_start": 126, "char_end": 137, "token_start": 19, "token_end": 20}, {"text": "adhesion molecule", "type": "ENTITY", "char_start": 148, "char_end": 165, "token_start": 24, "token_end": 25}, {"text": "CD54", "type": "ENTITY", "char_start": 166, "char_end": 170, "token_start": 26, "token_end": 26}], "entities_global": [{"text": "CD80", "type": "ENTITY", "char_start": 253629, "char_end": 253633, "token_start": 8, "token_end": 8, "note": null}, {"text": "CD86", "type": "ENTITY", "char_start": 253638, "char_end": 253642, "token_start": 10, "token_end": 10, "note": null}, {"text": "Ag receptor", "type": "ENTITY", "char_start": 253688, "char_end": 253699, "token_start": 19, "token_end": 20, "note": null}, {"text": "adhesion molecule", "type": "ENTITY", "char_start": 253710, "char_end": 253727, "token_start": 24, "token_end": 25, "note": null}, {"text": "CD54", "type": "ENTITY", "char_start": 253728, "char_end": 253732, "token_start": 26, "token_end": 26, "note": null}]}
+{"sentence_id": 1538, "sentence_text": "Whereas B cell Ag receptor ( BCR ) cross - linking alone stimulated increased expression of CD86 , up - regulation of CD80 required dual stimulation with anti - IgM and anti - CD54 .", "sentence_char_start_global": 253735, "sentence_char_end_global": 253917, "entities": [{"text": "B cell Ag receptor", "type": "ENTITY", "char_start": 8, "char_end": 26, "token_start": 1, "token_end": 4}, {"text": "BCR", "type": "ENTITY", "char_start": 29, "char_end": 32, "token_start": 6, "token_end": 6}, {"text": "CD86", "type": "ENTITY", "char_start": 92, "char_end": 96, "token_start": 16, "token_end": 16}, {"text": "CD80", "type": "ENTITY", "char_start": 118, "char_end": 122, "token_start": 22, "token_end": 22}, {"text": "anti - IgM", "type": "ENTITY", "char_start": 154, "char_end": 164, "token_start": 27, "token_end": 29}, {"text": "anti - CD54", "type": "ENTITY", "char_start": 169, "char_end": 180, "token_start": 31, "token_end": 33}], "entities_global": [{"text": "B cell Ag receptor", "type": "ENTITY", "char_start": 253743, "char_end": 253761, "token_start": 1, "token_end": 4, "note": null}, {"text": "BCR", "type": "ENTITY", "char_start": 253764, "char_end": 253767, "token_start": 6, "token_end": 6, "note": null}, {"text": "CD86", "type": "ENTITY", "char_start": 253827, "char_end": 253831, "token_start": 16, "token_end": 16, "note": null}, {"text": "CD80", "type": "ENTITY", "char_start": 253853, "char_end": 253857, "token_start": 22, "token_end": 22, "note": null}, {"text": "anti - IgM", "type": "ENTITY", "char_start": 253889, "char_end": 253899, "token_start": 27, "token_end": 29, "note": null}, {"text": "anti - CD54", "type": "ENTITY", "char_start": 253904, "char_end": 253915, "token_start": 31, "token_end": 33, "note": null}]}
+{"sentence_id": 1539, "sentence_text": "The principal downstream component contributed by BCR signaling , toward both CD80 and CD86 induction , was the elevated concentration of free cytoplasmic Ca ( 2 + ) , recruited by way of capacitative influx .", "sentence_char_start_global": 253918, "sentence_char_end_global": 254127, "entities": [{"text": "BCR", "type": "ENTITY", "char_start": 50, "char_end": 53, "token_start": 6, "token_end": 6}, {"text": "CD80", "type": "ENTITY", "char_start": 78, "char_end": 82, "token_start": 11, "token_end": 11}, {"text": "CD86", "type": "ENTITY", "char_start": 87, "char_end": 91, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "BCR", "type": "ENTITY", "char_start": 253968, "char_end": 253971, "token_start": 6, "token_end": 6, "note": null}, {"text": "CD80", "type": "ENTITY", "char_start": 253996, "char_end": 254000, "token_start": 11, "token_end": 11, "note": null}, {"text": "CD86", "type": "ENTITY", "char_start": 254005, "char_end": 254009, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 1540, "sentence_text": "This alone was sufficient to generate an increase in CD86 levels .", "sentence_char_start_global": 254128, "sentence_char_end_global": 254194, "entities": [{"text": "CD86", "type": "ENTITY", "char_start": 53, "char_end": 57, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "CD86", "type": "ENTITY", "char_start": 254181, "char_end": 254185, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 1541, "sentence_text": "However , CD80 enhancement required the concerted action of both intracellular Ca ( 2 + ) concentration and CD54 - initiated pathways .", "sentence_char_start_global": 254195, "sentence_char_end_global": 254330, "entities": [{"text": "CD80", "type": "ENTITY", "char_start": 10, "char_end": 14, "token_start": 2, "token_end": 2}], "entities_global": [{"text": "CD80", "type": "ENTITY", "char_start": 254205, "char_end": 254209, "token_start": 2, "token_end": 2, "note": null}]}
+{"sentence_id": 1542, "sentence_text": "The nexus between anti - IgM and anti - CD54 stimulation , in the context of CD80 regulation , was identified to involve a self - propagating process of sequential synergy .", "sentence_char_start_global": 254331, "sentence_char_end_global": 254504, "entities": [{"text": "CD80", "type": "ENTITY", "char_start": 77, "char_end": 81, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "CD80", "type": "ENTITY", "char_start": 254408, "char_end": 254412, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 1543, "sentence_text": "The first step involved amplified accumulation of intracellular cAMP , as a result of cross - talk between BCR - mobilized Ca ( 2 + ) and CD54 - derived signals .", "sentence_char_start_global": 254505, "sentence_char_end_global": 254667, "entities": [{"text": "BCR", "type": "ENTITY", "char_start": 107, "char_end": 110, "token_start": 18, "token_end": 18}], "entities_global": [{"text": "BCR", "type": "ENTITY", "char_start": 254612, "char_end": 254615, "token_start": 18, "token_end": 18, "note": null}]}
+{"sentence_id": 1544, "sentence_text": "This then facilitated a second synergistic interaction between Ca ( 2 + ) and cAMP , culminating in CD80 expression .", "sentence_char_start_global": 254668, "sentence_char_end_global": 254785, "entities": [{"text": "CD80", "type": "ENTITY", "char_start": 100, "char_end": 104, "token_start": 18, "token_end": 18}], "entities_global": [{"text": "CD80", "type": "ENTITY", "char_start": 254768, "char_end": 254772, "token_start": 18, "token_end": 18, "note": null}]}
+{"sentence_id": 1545, "sentence_text": "Our findings of distinct signal transducer requirements , with the added consequences of cross - talk , offers an explanation for variable modulation of costimulatory molecule expression in response to diverse physiological stimuli .", "sentence_char_start_global": 254786, "sentence_char_end_global": 255019, "entities": [], "entities_global": []}
+{"sentence_id": 1546, "sentence_text": "Importantly , these results also reveal how concentration threshold barriers for recruitment of individual second messengers can be overcome by constructive convergence of signaling modules .", "sentence_char_start_global": 255020, "sentence_char_end_global": 255211, "entities": [], "entities_global": []}
+{"sentence_id": 1547, "sentence_text": "The role of Epstein - Barr virus in neoplastic transformation .", "sentence_char_start_global": 255212, "sentence_char_end_global": 255275, "entities": [], "entities_global": []}
+{"sentence_id": 1548, "sentence_text": "In this review , we focus on new data from basic , translational and clinical research relating to the Epstein - Barr virus ( EBV ) .", "sentence_char_start_global": 255276, "sentence_char_end_global": 255409, "entities": [], "entities_global": []}
+{"sentence_id": 1549, "sentence_text": "Beside its well - known tropism for B lymphocytes and epithelial cells , EBV also infects T lymphocytes , monocytes and granulocytes .", "sentence_char_start_global": 255410, "sentence_char_end_global": 255544, "entities": [], "entities_global": []}
+{"sentence_id": 1550, "sentence_text": "After primary infection , EBV persists throughout the life span in resting memory B cells , from where it is reactivated upon breakdown of cellular immunity .", "sentence_char_start_global": 255545, "sentence_char_end_global": 255703, "entities": [], "entities_global": []}
+{"sentence_id": 1551, "sentence_text": "In the process of neoplastic transformation , the EBV - encoded latent membrane protein 1 ( LMP1 ) oncogene represents the major driving force .", "sentence_char_start_global": 255704, "sentence_char_end_global": 255848, "entities": [{"text": "EBV - encoded latent membrane protein 1 ( LMP1 ) oncogene", "type": "ENTITY", "char_start": 50, "char_end": 107, "token_start": 8, "token_end": 18}], "entities_global": [{"text": "EBV - encoded latent membrane protein 1 ( LMP1 ) oncogene", "type": "ENTITY", "char_start": 255754, "char_end": 255811, "token_start": 8, "token_end": 18, "note": null}]}
+{"sentence_id": 1552, "sentence_text": "LMP1 acts like a constitutively activated receptor of the tumor necrosis factor receptor family and allows the amplification or bypassing of physiological regulatory signals through direct and indirect interactions with proteins of the tumor necrosis factor receptor - associated factor ( TRAF ) family .", "sentence_char_start_global": 255849, "sentence_char_end_global": 256153, "entities": [{"text": "LMP1", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}, {"text": "constitutively activated receptor", "type": "ENTITY", "char_start": 17, "char_end": 50, "token_start": 4, "token_end": 6}, {"text": "tumor necrosis factor receptor family", "type": "ENTITY", "char_start": 58, "char_end": 95, "token_start": 9, "token_end": 13}, {"text": "tumor necrosis factor receptor - associated factor ( TRAF ) family", "type": "ENTITY", "char_start": 236, "char_end": 302, "token_start": 33, "token_end": 43}], "entities_global": [{"text": "LMP1", "type": "ENTITY", "char_start": 255849, "char_end": 255853, "token_start": 0, "token_end": 0, "note": null}, {"text": "constitutively activated receptor", "type": "ENTITY", "char_start": 255866, "char_end": 255899, "token_start": 4, "token_end": 6, "note": null}, {"text": "tumor necrosis factor receptor family", "type": "ENTITY", "char_start": 255907, "char_end": 255944, "token_start": 9, "token_end": 13, "note": null}, {"text": "tumor necrosis factor receptor - associated factor ( TRAF ) family", "type": "ENTITY", "char_start": 256085, "char_end": 256151, "token_start": 33, "token_end": 43, "note": null}]}
+{"sentence_id": 1553, "sentence_text": "TRAF2 - mediated NF - kappaB activation , AP - 1 induction and JAK3 / STAT activation may result in sustained proliferation leading to lymphoma .", "sentence_char_start_global": 256154, "sentence_char_end_global": 256299, "entities": [{"text": "TRAF2", "type": "ENTITY", "char_start": 0, "char_end": 5, "token_start": 0, "token_end": 0}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 17, "char_end": 28, "token_start": 3, "token_end": 5}, {"text": "AP - 1", "type": "ENTITY", "char_start": 42, "char_end": 48, "token_start": 8, "token_end": 10}, {"text": "JAK3", "type": "ENTITY", "char_start": 63, "char_end": 67, "token_start": 13, "token_end": 13}, {"text": "STAT", "type": "ENTITY", "char_start": 70, "char_end": 74, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "TRAF2", "type": "ENTITY", "char_start": 256154, "char_end": 256159, "token_start": 0, "token_end": 0, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 256171, "char_end": 256182, "token_start": 3, "token_end": 5, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 256196, "char_end": 256202, "token_start": 8, "token_end": 10, "note": null}, {"text": "JAK3", "type": "ENTITY", "char_start": 256217, "char_end": 256221, "token_start": 13, "token_end": 13, "note": null}, {"text": "STAT", "type": "ENTITY", "char_start": 256224, "char_end": 256228, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 1554, "sentence_text": "The ability of LMP1 to suppress germinal center formation and its capacity to mediate its own transcriptional activation shed new light on the pathogenesis of EBV - associated latency type II lymphoproliferations like Hodgkin ' s disease and angioimmunoblastic lymphadenopathy .", "sentence_char_start_global": 256300, "sentence_char_end_global": 256578, "entities": [{"text": "LMP1", "type": "ENTITY", "char_start": 15, "char_end": 19, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "LMP1", "type": "ENTITY", "char_start": 256315, "char_end": 256319, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 1555, "sentence_text": "The carboxy terminus of LMP1 is also a reliable marker for individual EBV strain identification and thus offers new possibilities in tracing the molecular events leading to posttransplant lymphoproliferative disorders ( PTLDs ) .", "sentence_char_start_global": 256579, "sentence_char_end_global": 256808, "entities": [{"text": "carboxy terminus", "type": "ENTITY", "char_start": 4, "char_end": 20, "token_start": 1, "token_end": 2}, {"text": "LMP1", "type": "ENTITY", "char_start": 24, "char_end": 28, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "carboxy terminus", "type": "ENTITY", "char_start": 256583, "char_end": 256599, "token_start": 1, "token_end": 2, "note": null}, {"text": "LMP1", "type": "ENTITY", "char_start": 256603, "char_end": 256607, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 1556, "sentence_text": "Cytotoxic T lymphocytes directed against well - characterized epitopes of EBV latency genes represent an already successful and promising therapeutic approach to EBV - associated lymphomas , in particular PTLDs", "sentence_char_start_global": 256809, "sentence_char_end_global": 257019, "entities": [{"text": "EBV latency genes", "type": "ENTITY", "char_start": 74, "char_end": 91, "token_start": 10, "token_end": 12}], "entities_global": [{"text": "EBV latency genes", "type": "ENTITY", "char_start": 256883, "char_end": 256900, "token_start": 10, "token_end": 12, "note": null}]}
+{"sentence_id": 1557, "sentence_text": "Interferon - alpha drives T cell - mediated immunopathology in the intestine .", "sentence_char_start_global": 257020, "sentence_char_end_global": 257098, "entities": [{"text": "Interferon - alpha", "type": "ENTITY", "char_start": 0, "char_end": 18, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "Interferon - alpha", "type": "ENTITY", "char_start": 257020, "char_end": 257038, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 1558, "sentence_text": "The ability of interferon ( IFN ) - alpha to induce autoimmunity and exacerbate Th1 diseases is well known .", "sentence_char_start_global": 257099, "sentence_char_end_global": 257207, "entities": [{"text": "interferon ( IFN ) - alpha", "type": "ENTITY", "char_start": 15, "char_end": 41, "token_start": 3, "token_end": 8}], "entities_global": [{"text": "interferon ( IFN ) - alpha", "type": "ENTITY", "char_start": 257114, "char_end": 257140, "token_start": 3, "token_end": 8, "note": null}]}
+{"sentence_id": 1559, "sentence_text": "We have recently described enhanced expression of IFN - alpha in the mucosa of patients with celiac disease ( CD ) , a gluten - sensitive Th1 - mediated enteropathy , characterized by villous atrophy and crypt cell hyperplasia .", "sentence_char_start_global": 257208, "sentence_char_end_global": 257436, "entities": [{"text": "IFN - alpha", "type": "ENTITY", "char_start": 50, "char_end": 61, "token_start": 7, "token_end": 9}], "entities_global": [{"text": "IFN - alpha", "type": "ENTITY", "char_start": 257258, "char_end": 257269, "token_start": 7, "token_end": 9, "note": null}]}
+{"sentence_id": 1560, "sentence_text": "Previous studies from this laboratory have shown that T cell activation in explant cultures of human fetal gut can also result in villous atrophy and crypt cell hyperplasia .", "sentence_char_start_global": 257437, "sentence_char_end_global": 257611, "entities": [], "entities_global": []}
+{"sentence_id": 1561, "sentence_text": "We have , therefore , examined changes that take place in explant cultures of human fetal gut after activation of T cells with anti - CD3 and / or IFN - alpha .", "sentence_char_start_global": 257612, "sentence_char_end_global": 257772, "entities": [{"text": "anti - CD3", "type": "ENTITY", "char_start": 127, "char_end": 137, "token_start": 23, "token_end": 25}, {"text": "IFN - alpha", "type": "ENTITY", "char_start": 147, "char_end": 158, "token_start": 29, "token_end": 31}], "entities_global": [{"text": "anti - CD3", "type": "ENTITY", "char_start": 257739, "char_end": 257749, "token_start": 23, "token_end": 25, "note": null}, {"text": "IFN - alpha", "type": "ENTITY", "char_start": 257759, "char_end": 257770, "token_start": 29, "token_end": 31, "note": null}]}
+{"sentence_id": 1562, "sentence_text": "We show that activation of T cells with anti - CD3 alone elicits a small IFN - gamma and TNF - alpha response with no tissue injury .", "sentence_char_start_global": 257773, "sentence_char_end_global": 257906, "entities": [{"text": "anti - CD3", "type": "ENTITY", "char_start": 40, "char_end": 50, "token_start": 8, "token_end": 10}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 73, "char_end": 84, "token_start": 15, "token_end": 17}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 89, "char_end": 100, "token_start": 19, "token_end": 21}], "entities_global": [{"text": "anti - CD3", "type": "ENTITY", "char_start": 257813, "char_end": 257823, "token_start": 8, "token_end": 10, "note": null}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 257846, "char_end": 257857, "token_start": 15, "token_end": 17, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 257862, "char_end": 257873, "token_start": 19, "token_end": 21, "note": null}]}
+{"sentence_id": 1563, "sentence_text": "Similarly , no changes are seen in explants cultured with IFN - alpha alone .", "sentence_char_start_global": 257907, "sentence_char_end_global": 257984, "entities": [{"text": "IFN - alpha", "type": "ENTITY", "char_start": 58, "char_end": 69, "token_start": 10, "token_end": 12}], "entities_global": [{"text": "IFN - alpha", "type": "ENTITY", "char_start": 257965, "char_end": 257976, "token_start": 10, "token_end": 12, "note": null}]}
+{"sentence_id": 1564, "sentence_text": "However , addition of IFN - alpha with anti - CD3 results in enhanced Th1 response and crypt cell hyperplasia .", "sentence_char_start_global": 257985, "sentence_char_end_global": 258096, "entities": [{"text": "IFN - alpha", "type": "ENTITY", "char_start": 22, "char_end": 33, "token_start": 4, "token_end": 6}, {"text": "anti - CD3", "type": "ENTITY", "char_start": 39, "char_end": 49, "token_start": 8, "token_end": 10}], "entities_global": [{"text": "IFN - alpha", "type": "ENTITY", "char_start": 258007, "char_end": 258018, "token_start": 4, "token_end": 6, "note": null}, {"text": "anti - CD3", "type": "ENTITY", "char_start": 258024, "char_end": 258034, "token_start": 8, "token_end": 10, "note": null}]}
+{"sentence_id": 1565, "sentence_text": "This is associated with enhanced phosphorylation of STAT1 , STAT3 , and Fyn , a Src homology tyrosine kinase , which interacts with both TCR and IFN - alpha signal components .", "sentence_char_start_global": 258097, "sentence_char_end_global": 258273, "entities": [{"text": "STAT1", "type": "ENTITY", "char_start": 52, "char_end": 57, "token_start": 7, "token_end": 7}, {"text": "STAT3", "type": "ENTITY", "char_start": 60, "char_end": 65, "token_start": 9, "token_end": 9}, {"text": "Fyn , a Src homology tyrosine kinase", "type": "ENTITY", "char_start": 72, "char_end": 108, "token_start": 12, "token_end": 18}], "entities_global": [{"text": "STAT1", "type": "ENTITY", "char_start": 258149, "char_end": 258154, "token_start": 7, "token_end": 7, "note": null}, {"text": "STAT3", "type": "ENTITY", "char_start": 258157, "char_end": 258162, "token_start": 9, "token_end": 9, "note": null}, {"text": "Fyn , a Src homology tyrosine kinase", "type": "ENTITY", "char_start": 258169, "char_end": 258205, "token_start": 12, "token_end": 18, "note": null}]}
+{"sentence_id": 1566, "sentence_text": "Together these data indicate that IFN - alpha can facilitate activation of Th1 - reactive cells in the gut and drive immunopathology .", "sentence_char_start_global": 258274, "sentence_char_end_global": 258408, "entities": [{"text": "IFN - alpha", "type": "ENTITY", "char_start": 34, "char_end": 45, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "IFN - alpha", "type": "ENTITY", "char_start": 258308, "char_end": 258319, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 1567, "sentence_text": "Suppression of tumor necrosis factor alpha production by cAMP in human monocytes : dissociation with mRNA level and independent of interleukin - 10 .", "sentence_char_start_global": 258409, "sentence_char_end_global": 258558, "entities": [{"text": "tumor necrosis factor alpha", "type": "ENTITY", "char_start": 15, "char_end": 42, "token_start": 2, "token_end": 5}, {"text": "interleukin - 10", "type": "ENTITY", "char_start": 131, "char_end": 147, "token_start": 20, "token_end": 22}], "entities_global": [{"text": "tumor necrosis factor alpha", "type": "ENTITY", "char_start": 258424, "char_end": 258451, "token_start": 2, "token_end": 5, "note": null}, {"text": "interleukin - 10", "type": "ENTITY", "char_start": 258540, "char_end": 258556, "token_start": 20, "token_end": 22, "note": null}]}
+{"sentence_id": 1568, "sentence_text": "BACKGROUND : Elevation of cellular cAMP inhibits lipopolysaccharide ( LPS ) - stimulated tumor necrosis factor alpha ( TNF - alpha ) production and increases the expression of interleukin ( IL ) - 10 in mononuclear cells .", "sentence_char_start_global": 258559, "sentence_char_end_global": 258781, "entities": [{"text": "tumor necrosis factor alpha", "type": "ENTITY", "char_start": 89, "char_end": 116, "token_start": 13, "token_end": 16}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 119, "char_end": 130, "token_start": 18, "token_end": 20}, {"text": "interleukin ( IL ) - 10", "type": "ENTITY", "char_start": 176, "char_end": 199, "token_start": 28, "token_end": 33}], "entities_global": [{"text": "tumor necrosis factor alpha", "type": "ENTITY", "char_start": 258648, "char_end": 258675, "token_start": 13, "token_end": 16, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 258678, "char_end": 258689, "token_start": 18, "token_end": 20, "note": null}, {"text": "interleukin ( IL ) - 10", "type": "ENTITY", "char_start": 258735, "char_end": 258758, "token_start": 28, "token_end": 33, "note": null}]}
+{"sentence_id": 1569, "sentence_text": "TNF - alpha gene expression obligates activation of the transcription factor nuclear factor kappaB ( NF - kappaB ) .", "sentence_char_start_global": 258782, "sentence_char_end_global": 258898, "entities": [{"text": "TNF - alpha gene", "type": "ENTITY", "char_start": 0, "char_end": 16, "token_start": 0, "token_end": 3}, {"text": "transcription factor", "type": "ENTITY", "char_start": 56, "char_end": 76, "token_start": 9, "token_end": 10}, {"text": "nuclear factor kappaB", "type": "ENTITY", "char_start": 77, "char_end": 98, "token_start": 11, "token_end": 13}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 101, "char_end": 112, "token_start": 15, "token_end": 17}], "entities_global": [{"text": "TNF - alpha gene", "type": "ENTITY", "char_start": 258782, "char_end": 258798, "token_start": 0, "token_end": 3, "note": null}, {"text": "transcription factor", "type": "ENTITY", "char_start": 258838, "char_end": 258858, "token_start": 9, "token_end": 10, "note": null}, {"text": "nuclear factor kappaB", "type": "ENTITY", "char_start": 258859, "char_end": 258880, "token_start": 11, "token_end": 13, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 258883, "char_end": 258894, "token_start": 15, "token_end": 17, "note": null}]}
+{"sentence_id": 1570, "sentence_text": "Exogenous IL - 10 inhibits NF - kappaB in monocytes and thus attenuates TNF - alpha production .", "sentence_char_start_global": 258899, "sentence_char_end_global": 258995, "entities": [{"text": "IL - 10", "type": "ENTITY", "char_start": 10, "char_end": 17, "token_start": 1, "token_end": 3}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 27, "char_end": 38, "token_start": 5, "token_end": 7}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 72, "char_end": 83, "token_start": 13, "token_end": 15}], "entities_global": [{"text": "IL - 10", "type": "ENTITY", "char_start": 258909, "char_end": 258916, "token_start": 1, "token_end": 3, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 258926, "char_end": 258937, "token_start": 5, "token_end": 7, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 258971, "char_end": 258982, "token_start": 13, "token_end": 15, "note": null}]}
+{"sentence_id": 1571, "sentence_text": "We examined the role of endogenous IL - 10 in the regulation of NF - kappaB activation and TNF - alpha production in human monocytes by cAMP .", "sentence_char_start_global": 258996, "sentence_char_end_global": 259138, "entities": [{"text": "IL - 10", "type": "ENTITY", "char_start": 35, "char_end": 42, "token_start": 6, "token_end": 8}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 64, "char_end": 75, "token_start": 13, "token_end": 15}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 91, "char_end": 102, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "IL - 10", "type": "ENTITY", "char_start": 259031, "char_end": 259038, "token_start": 6, "token_end": 8, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 259060, "char_end": 259071, "token_start": 13, "token_end": 15, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 259087, "char_end": 259098, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 1572, "sentence_text": "METHODS : Human monocytes were stimulated with Escherichia coli LPS ( 100 ng / ml ) with and without forskolin ( FSK , 50 microM ) or dibutyryl cyclic AMP ( dbcAMP , 100 microM ) .", "sentence_char_start_global": 259139, "sentence_char_end_global": 259319, "entities": [], "entities_global": []}
+{"sentence_id": 1573, "sentence_text": "Cytokine ( TNF - alpha and IL - 10 ) release was measured by immunoassay .", "sentence_char_start_global": 259320, "sentence_char_end_global": 259394, "entities": [{"text": "Cytokine", "type": "ENTITY", "char_start": 0, "char_end": 8, "token_start": 0, "token_end": 0}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 11, "char_end": 22, "token_start": 2, "token_end": 4}, {"text": "IL - 10", "type": "ENTITY", "char_start": 27, "char_end": 34, "token_start": 6, "token_end": 8}], "entities_global": [{"text": "Cytokine", "type": "ENTITY", "char_start": 259320, "char_end": 259328, "token_start": 0, "token_end": 0, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 259331, "char_end": 259342, "token_start": 2, "token_end": 4, "note": null}, {"text": "IL - 10", "type": "ENTITY", "char_start": 259347, "char_end": 259354, "token_start": 6, "token_end": 8, "note": null}]}
+{"sentence_id": 1574, "sentence_text": "TNF - alpha mRNA was measured by reverse transcription polymerase chain reaction , and NF - kappaB DNA binding activity was assessed by gel mobility shift assay .", "sentence_char_start_global": 259395, "sentence_char_end_global": 259557, "entities": [{"text": "TNF - alpha mRNA", "type": "ENTITY", "char_start": 0, "char_end": 16, "token_start": 0, "token_end": 3}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 87, "char_end": 98, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "TNF - alpha mRNA", "type": "ENTITY", "char_start": 259395, "char_end": 259411, "token_start": 0, "token_end": 3, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 259482, "char_end": 259493, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 1575, "sentence_text": "RESULTS : cAMP - elevating agents inhibited LPS - stimulated TNF - alpha release ( 0 . 77 + / - 0 . 13 ng / 10 ( 6 ) cells in LPS + dbcAMP and 0 . 68 + / - 0 . 19 ng / 10 ( 6 ) cells in LPS + FSK , both P < 0 . 05 vs 1 . 61 + / - 0 . 34 ng / 10 ( 6 ) cells in LPS alone ) .", "sentence_char_start_global": 259558, "sentence_char_end_global": 259831, "entities": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 61, "char_end": 72, "token_start": 10, "token_end": 12}], "entities_global": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 259619, "char_end": 259630, "token_start": 10, "token_end": 12, "note": null}]}
+{"sentence_id": 1576, "sentence_text": "Conversely , cAMP enhanced LPS - stimulated IL - 10 release ( 100 + / - 21 . 5 pg / 10 ( 6 ) cells in LPS + dbcAMP and 110 + / - 25 . 2 pg / 10 ( 6 ) cells in LPS + FSK , both P < 0 . 05 vs 53 . 3 + / - 12 . 8 pg / 10 ( 6 ) cells in LPS alone ) .", "sentence_char_start_global": 259832, "sentence_char_end_global": 260078, "entities": [{"text": "IL - 10", "type": "ENTITY", "char_start": 44, "char_end": 51, "token_start": 7, "token_end": 9}], "entities_global": [{"text": "IL - 10", "type": "ENTITY", "char_start": 259876, "char_end": 259883, "token_start": 7, "token_end": 9, "note": null}]}
+{"sentence_id": 1577, "sentence_text": "Neither TNF - alpha mRNA expression nor NF - kappaB activation stimulated by LPS was inhibited by the cAMP - elevating agents .", "sentence_char_start_global": 260079, "sentence_char_end_global": 260206, "entities": [{"text": "TNF - alpha mRNA", "type": "ENTITY", "char_start": 8, "char_end": 24, "token_start": 1, "token_end": 4}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 40, "char_end": 51, "token_start": 7, "token_end": 9}], "entities_global": [{"text": "TNF - alpha mRNA", "type": "ENTITY", "char_start": 260087, "char_end": 260103, "token_start": 1, "token_end": 4, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 260119, "char_end": 260130, "token_start": 7, "token_end": 9, "note": null}]}
+{"sentence_id": 1578, "sentence_text": "Neutralization of IL - 10 with a specific antibody did not attenuate the effect of cAMP - elevating agents on TNF - alpha production .", "sentence_char_start_global": 260207, "sentence_char_end_global": 260341, "entities": [{"text": "IL - 10", "type": "ENTITY", "char_start": 18, "char_end": 25, "token_start": 2, "token_end": 4}, {"text": "antibody", "type": "ENTITY", "char_start": 42, "char_end": 50, "token_start": 8, "token_end": 8}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 110, "char_end": 121, "token_start": 20, "token_end": 22}], "entities_global": [{"text": "IL - 10", "type": "ENTITY", "char_start": 260225, "char_end": 260232, "token_start": 2, "token_end": 4, "note": null}, {"text": "antibody", "type": "ENTITY", "char_start": 260249, "char_end": 260257, "token_start": 8, "token_end": 8, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 260317, "char_end": 260328, "token_start": 20, "token_end": 22, "note": null}]}
+{"sentence_id": 1579, "sentence_text": "CONCLUSION : The results indicate that cAMP inhibits LPS - stimulated TNF - alpha production through a posttranscriptional mechanism that is independent of endogenous IL - 10 .", "sentence_char_start_global": 260342, "sentence_char_end_global": 260518, "entities": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 70, "char_end": 81, "token_start": 11, "token_end": 13}, {"text": "IL - 10", "type": "ENTITY", "char_start": 167, "char_end": 174, "token_start": 24, "token_end": 26}], "entities_global": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 260412, "char_end": 260423, "token_start": 11, "token_end": 13, "note": null}, {"text": "IL - 10", "type": "ENTITY", "char_start": 260509, "char_end": 260516, "token_start": 24, "token_end": 26, "note": null}]}
+{"sentence_id": 1580, "sentence_text": "Copyright 2001 Academic Press .", "sentence_char_start_global": 260519, "sentence_char_end_global": 260550, "entities": [], "entities_global": []}
+{"sentence_id": 1581, "sentence_text": "Activation of the p21 ( CIP1 / WAF1 ) promoter by bone morphogenetic protein - 2 in mouse B lineage cells .", "sentence_char_start_global": 260551, "sentence_char_end_global": 260658, "entities": [{"text": "p21 ( CIP1 / WAF1 ) promoter", "type": "ENTITY", "char_start": 18, "char_end": 46, "token_start": 3, "token_end": 9}, {"text": "bone morphogenetic protein - 2", "type": "ENTITY", "char_start": 50, "char_end": 80, "token_start": 11, "token_end": 15}], "entities_global": [{"text": "p21 ( CIP1 / WAF1 ) promoter", "type": "ENTITY", "char_start": 260569, "char_end": 260597, "token_start": 3, "token_end": 9, "note": null}, {"text": "bone morphogenetic protein - 2", "type": "ENTITY", "char_start": 260601, "char_end": 260631, "token_start": 11, "token_end": 15, "note": null}]}
+{"sentence_id": 1582, "sentence_text": "BMPs exert a negative growth effect on various types of cells .", "sentence_char_start_global": 260659, "sentence_char_end_global": 260722, "entities": [{"text": "BMPs", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "BMPs", "type": "ENTITY", "char_start": 260659, "char_end": 260663, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 1583, "sentence_text": "We have previously reported that BMP - 2 inhibited the growth of HS - 72 mouse hybridoma cells by inducing p21 ( CIP1 / WAF1 ) expression .", "sentence_char_start_global": 260723, "sentence_char_end_global": 260862, "entities": [{"text": "BMP - 2", "type": "ENTITY", "char_start": 33, "char_end": 40, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "BMP - 2", "type": "ENTITY", "char_start": 260756, "char_end": 260763, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 1584, "sentence_text": "In the present study , we demonstrated that BMP - 2 activated the mouse p21 ( CIP1 / WAF1 ) promoter in HS - 72 cells , and that a 29 - base pair ( b ) region of the promoter ( - 1928 / - 1900 relative to the TATA box ) , conserved between mice and humans , was responsive to BMP - 2 as well as expression of Smad1 , Smad4 , and constitutively active mutants of BMP type I receptors .", "sentence_char_start_global": 260863, "sentence_char_end_global": 261247, "entities": [{"text": "BMP - 2", "type": "ENTITY", "char_start": 44, "char_end": 51, "token_start": 8, "token_end": 10}, {"text": "p21 ( CIP1 / WAF1 ) promoter", "type": "ENTITY", "char_start": 72, "char_end": 100, "token_start": 14, "token_end": 20}, {"text": "29 - base pair ( b ) region", "type": "ENTITY", "char_start": 131, "char_end": 158, "token_start": 30, "token_end": 37}, {"text": "TATA box", "type": "ENTITY", "char_start": 209, "char_end": 217, "token_start": 50, "token_end": 51}, {"text": "BMP - 2", "type": "ENTITY", "char_start": 276, "char_end": 283, "token_start": 63, "token_end": 65}, {"text": "Smad1", "type": "ENTITY", "char_start": 309, "char_end": 314, "token_start": 71, "token_end": 71}, {"text": "Smad4", "type": "ENTITY", "char_start": 317, "char_end": 322, "token_start": 73, "token_end": 73}, {"text": "BMP type I receptors", "type": "ENTITY", "char_start": 362, "char_end": 382, "token_start": 80, "token_end": 83}], "entities_global": [{"text": "BMP - 2", "type": "ENTITY", "char_start": 260907, "char_end": 260914, "token_start": 8, "token_end": 10, "note": null}, {"text": "p21 ( CIP1 / WAF1 ) promoter", "type": "ENTITY", "char_start": 260935, "char_end": 260963, "token_start": 14, "token_end": 20, "note": null}, {"text": "29 - base pair ( b ) region", "type": "ENTITY", "char_start": 260994, "char_end": 261021, "token_start": 30, "token_end": 37, "note": null}, {"text": "TATA box", "type": "ENTITY", "char_start": 261072, "char_end": 261080, "token_start": 50, "token_end": 51, "note": null}, {"text": "BMP - 2", "type": "ENTITY", "char_start": 261139, "char_end": 261146, "token_start": 63, "token_end": 65, "note": null}, {"text": "Smad1", "type": "ENTITY", "char_start": 261172, "char_end": 261177, "token_start": 71, "token_end": 71, "note": null}, {"text": "Smad4", "type": "ENTITY", "char_start": 261180, "char_end": 261185, "token_start": 73, "token_end": 73, "note": null}, {"text": "BMP type I receptors", "type": "ENTITY", "char_start": 261225, "char_end": 261245, "token_start": 80, "token_end": 83, "note": null}]}
+{"sentence_id": 1585, "sentence_text": "Furthermore , an oligonucleotide containing the 29 - b region was found to be associated with Smad4 and phosphorylated Smad1 in the nuclear extract of BMP - 2 - stimulated HS - 72 cells .", "sentence_char_start_global": 261248, "sentence_char_end_global": 261435, "entities": [{"text": "29 - b region", "type": "ENTITY", "char_start": 48, "char_end": 61, "token_start": 6, "token_end": 9}, {"text": "Smad4", "type": "ENTITY", "char_start": 94, "char_end": 99, "token_start": 16, "token_end": 16}, {"text": "phosphorylated Smad1", "type": "ENTITY", "char_start": 104, "char_end": 124, "token_start": 18, "token_end": 19}, {"text": "BMP - 2", "type": "ENTITY", "char_start": 151, "char_end": 158, "token_start": 25, "token_end": 27}], "entities_global": [{"text": "29 - b region", "type": "ENTITY", "char_start": 261296, "char_end": 261309, "token_start": 6, "token_end": 9, "note": null}, {"text": "Smad4", "type": "ENTITY", "char_start": 261342, "char_end": 261347, "token_start": 16, "token_end": 16, "note": null}, {"text": "phosphorylated Smad1", "type": "ENTITY", "char_start": 261352, "char_end": 261372, "token_start": 18, "token_end": 19, "note": null}, {"text": "BMP - 2", "type": "ENTITY", "char_start": 261399, "char_end": 261406, "token_start": 25, "token_end": 27, "note": null}]}
+{"sentence_id": 1586, "sentence_text": "These results suggested that BMP - 2 might activate p21 ( CIP1 / WAF1 ) transcription by inducing a binding of Smad4 and Smad1 to the 29 - b region in HS - 72 cells .", "sentence_char_start_global": 261436, "sentence_char_end_global": 261602, "entities": [{"text": "BMP - 2", "type": "ENTITY", "char_start": 29, "char_end": 36, "token_start": 4, "token_end": 6}, {"text": "Smad4", "type": "ENTITY", "char_start": 111, "char_end": 116, "token_start": 21, "token_end": 21}, {"text": "Smad1", "type": "ENTITY", "char_start": 121, "char_end": 126, "token_start": 23, "token_end": 23}, {"text": "29 - b region", "type": "ENTITY", "char_start": 134, "char_end": 147, "token_start": 26, "token_end": 29}], "entities_global": [{"text": "BMP - 2", "type": "ENTITY", "char_start": 261465, "char_end": 261472, "token_start": 4, "token_end": 6, "note": null}, {"text": "Smad4", "type": "ENTITY", "char_start": 261547, "char_end": 261552, "token_start": 21, "token_end": 21, "note": null}, {"text": "Smad1", "type": "ENTITY", "char_start": 261557, "char_end": 261562, "token_start": 23, "token_end": 23, "note": null}, {"text": "29 - b region", "type": "ENTITY", "char_start": 261570, "char_end": 261583, "token_start": 26, "token_end": 29, "note": null}]}
+{"sentence_id": 1587, "sentence_text": "Dendritic cell development from common myeloid progenitors .", "sentence_char_start_global": 261603, "sentence_char_end_global": 261663, "entities": [], "entities_global": []}
+{"sentence_id": 1588, "sentence_text": "Dendritic cells ( DCs ) are professional antigen - presenting cells which both initiate adaptive immune responses and control tolerance to self - antigens .", "sentence_char_start_global": 261664, "sentence_char_end_global": 261820, "entities": [{"text": "self - antigens", "type": "ENTITY", "char_start": 139, "char_end": 154, "token_start": 21, "token_end": 23}], "entities_global": [{"text": "self - antigens", "type": "ENTITY", "char_start": 261803, "char_end": 261818, "token_start": 21, "token_end": 23, "note": null}]}
+{"sentence_id": 1589, "sentence_text": "It has been suggested that these different effects on responder cells depend on subsets of DCs arising from either myeloid or lymphoid hematopoietic origins .", "sentence_char_start_global": 261821, "sentence_char_end_global": 261979, "entities": [], "entities_global": []}
+{"sentence_id": 1590, "sentence_text": "In this model , CD8 alpha + Mac - 1 - DCs are supposed to be of lymphoid while CD8 alpha - Mac - 1 + DCs are supposed to be of myeloid origin .", "sentence_char_start_global": 261980, "sentence_char_end_global": 262123, "entities": [], "entities_global": []}
+{"sentence_id": 1591, "sentence_text": "Here we summarize our findings that both CD8 alpha + and CD8 alpha - DCs can arise from clonogenic common myeloid progenitors ( CMPs ) in both thymus and spleen .", "sentence_char_start_global": 262124, "sentence_char_end_global": 262286, "entities": [], "entities_global": []}
+{"sentence_id": 1592, "sentence_text": "Therefore CD8 alpha expression DCs does not indicate a lymphoid origin and differences among CD8 alpha + and CD8 alpha - DCs might rather reflect maturation status than ontogeny .", "sentence_char_start_global": 262287, "sentence_char_end_global": 262466, "entities": [{"text": "CD8 alpha", "type": "ENTITY", "char_start": 10, "char_end": 19, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "CD8 alpha", "type": "ENTITY", "char_start": 262297, "char_end": 262306, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 1593, "sentence_text": "On the basis of transplantation studies , it seems likely that most of the DCs in secondary lymphoid organs and a substantial fraction of thymic DCs are myeloid - derived .", "sentence_char_start_global": 262467, "sentence_char_end_global": 262639, "entities": [], "entities_global": []}
+{"sentence_id": 1594, "sentence_text": "Macrophage stimulation with Murabutide , an HIV - suppressive muramyl peptide derivative , selectively activates extracellular signal - regulated kinases 1 and 2 , C / EBPbeta and STAT1 : role of CD14 and Toll - like receptors 2 and 4 .", "sentence_char_start_global": 262640, "sentence_char_end_global": 262876, "entities": [{"text": "extracellular signal - regulated kinases 1 and 2", "type": "ENTITY", "char_start": 113, "char_end": 161, "token_start": 15, "token_end": 22}, {"text": "C / EBPbeta", "type": "ENTITY", "char_start": 164, "char_end": 175, "token_start": 24, "token_end": 26}, {"text": "STAT1", "type": "ENTITY", "char_start": 180, "char_end": 185, "token_start": 28, "token_end": 28}, {"text": "CD14", "type": "ENTITY", "char_start": 196, "char_end": 200, "token_start": 32, "token_end": 32}, {"text": "Toll - like receptors 2 and 4", "type": "ENTITY", "char_start": 205, "char_end": 234, "token_start": 34, "token_end": 40}], "entities_global": [{"text": "extracellular signal - regulated kinases 1 and 2", "type": "ENTITY", "char_start": 262753, "char_end": 262801, "token_start": 15, "token_end": 22, "note": null}, {"text": "C / EBPbeta", "type": "ENTITY", "char_start": 262804, "char_end": 262815, "token_start": 24, "token_end": 26, "note": null}, {"text": "STAT1", "type": "ENTITY", "char_start": 262820, "char_end": 262825, "token_start": 28, "token_end": 28, "note": null}, {"text": "CD14", "type": "ENTITY", "char_start": 262836, "char_end": 262840, "token_start": 32, "token_end": 32, "note": null}, {"text": "Toll - like receptors 2 and 4", "type": "ENTITY", "char_start": 262845, "char_end": 262874, "token_start": 34, "token_end": 40, "note": null}]}
+{"sentence_id": 1595, "sentence_text": "The smallest unit of bacterial peptidoglycans known to be endowed with biological activities is muramyl dipeptide ( MDP ) .", "sentence_char_start_global": 262877, "sentence_char_end_global": 263000, "entities": [], "entities_global": []}
+{"sentence_id": 1596, "sentence_text": "A clinically acceptable synthetic derivative of MDP , namely murabutide ( MB ) , has been found to present interesting pharmacological properties and to suppress HIV - 1 replication in monocyte - derived macrophages ( MDM ) .", "sentence_char_start_global": 263001, "sentence_char_end_global": 263226, "entities": [], "entities_global": []}
+{"sentence_id": 1597, "sentence_text": "We have addressed the signaling events activated in MDM following stimulation with either MB or the potent immunostimulant LPS .", "sentence_char_start_global": 263227, "sentence_char_end_global": 263355, "entities": [], "entities_global": []}
+{"sentence_id": 1598, "sentence_text": "We also examined whether signaling by muramyl peptides involves the use of cell surface receptors , including CD14 and Toll - like receptor 2 ( TLR2 ) or TLR4 that are known to be signal - transducing receptors for other bacterial cell wall components .", "sentence_char_start_global": 263356, "sentence_char_end_global": 263609, "entities": [{"text": "cell surface receptors", "type": "ENTITY", "char_start": 75, "char_end": 97, "token_start": 12, "token_end": 14}, {"text": "CD14", "type": "ENTITY", "char_start": 110, "char_end": 114, "token_start": 17, "token_end": 17}, {"text": "Toll - like receptor 2", "type": "ENTITY", "char_start": 119, "char_end": 141, "token_start": 19, "token_end": 23}, {"text": "TLR2", "type": "ENTITY", "char_start": 144, "char_end": 148, "token_start": 25, "token_end": 25}, {"text": "TLR4", "type": "ENTITY", "char_start": 154, "char_end": 158, "token_start": 28, "token_end": 28}, {"text": "signal - transducing receptors", "type": "ENTITY", "char_start": 180, "char_end": 210, "token_start": 34, "token_end": 37}], "entities_global": [{"text": "cell surface receptors", "type": "ENTITY", "char_start": 263431, "char_end": 263453, "token_start": 12, "token_end": 14, "note": null}, {"text": "CD14", "type": "ENTITY", "char_start": 263466, "char_end": 263470, "token_start": 17, "token_end": 17, "note": null}, {"text": "Toll - like receptor 2", "type": "ENTITY", "char_start": 263475, "char_end": 263497, "token_start": 19, "token_end": 23, "note": null}, {"text": "TLR2", "type": "ENTITY", "char_start": 263500, "char_end": 263504, "token_start": 25, "token_end": 25, "note": null}, {"text": "TLR4", "type": "ENTITY", "char_start": 263510, "char_end": 263514, "token_start": 28, "token_end": 28, "note": null}, {"text": "signal - transducing receptors", "type": "ENTITY", "char_start": 263536, "char_end": 263566, "token_start": 34, "token_end": 37, "note": null}]}
+{"sentence_id": 1599, "sentence_text": "We demonstrate that , unlike LPS , the safe immunomodulator MB selectively activates extracellular signal - regulated kinases ( Erk ) 1 / 2 , in the absence of detectable Jun N - terminal kinase ( JNK ) or p38 mitogen - activated kinase activation .", "sentence_char_start_global": 263610, "sentence_char_end_global": 263859, "entities": [{"text": "extracellular signal - regulated kinases ( Erk ) 1 / 2", "type": "ENTITY", "char_start": 85, "char_end": 139, "token_start": 13, "token_end": 23}, {"text": "Jun N - terminal kinase", "type": "ENTITY", "char_start": 171, "char_end": 194, "token_start": 30, "token_end": 34}, {"text": "JNK", "type": "ENTITY", "char_start": 197, "char_end": 200, "token_start": 36, "token_end": 36}, {"text": "p38 mitogen - activated kinase", "type": "ENTITY", "char_start": 206, "char_end": 236, "token_start": 39, "token_end": 43}], "entities_global": [{"text": "extracellular signal - regulated kinases ( Erk ) 1 / 2", "type": "ENTITY", "char_start": 263695, "char_end": 263749, "token_start": 13, "token_end": 23, "note": null}, {"text": "Jun N - terminal kinase", "type": "ENTITY", "char_start": 263781, "char_end": 263804, "token_start": 30, "token_end": 34, "note": null}, {"text": "JNK", "type": "ENTITY", "char_start": 263807, "char_end": 263810, "token_start": 36, "token_end": 36, "note": null}, {"text": "p38 mitogen - activated kinase", "type": "ENTITY", "char_start": 263816, "char_end": 263846, "token_start": 39, "token_end": 43, "note": null}]}
+{"sentence_id": 1600, "sentence_text": "Furthermore , STAT1 activation but weak or no activation of STAT3 or STAT5 respectively , could be detected in MB - stimulated MDM .", "sentence_char_start_global": 263860, "sentence_char_end_global": 263992, "entities": [{"text": "STAT1", "type": "ENTITY", "char_start": 14, "char_end": 19, "token_start": 2, "token_end": 2}, {"text": "STAT3", "type": "ENTITY", "char_start": 60, "char_end": 65, "token_start": 10, "token_end": 10}, {"text": "STAT5", "type": "ENTITY", "char_start": 69, "char_end": 74, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "STAT1", "type": "ENTITY", "char_start": 263874, "char_end": 263879, "token_start": 2, "token_end": 2, "note": null}, {"text": "STAT3", "type": "ENTITY", "char_start": 263920, "char_end": 263925, "token_start": 10, "token_end": 10, "note": null}, {"text": "STAT5", "type": "ENTITY", "char_start": 263929, "char_end": 263934, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 1601, "sentence_text": "Using MonoMac6 cells , we observed high C / EBPbeta and AP - 1 but weaker and transient NF - kappaB activation by MB .", "sentence_char_start_global": 263993, "sentence_char_end_global": 264111, "entities": [{"text": "C / EBPbeta", "type": "ENTITY", "char_start": 40, "char_end": 51, "token_start": 7, "token_end": 9}, {"text": "AP - 1", "type": "ENTITY", "char_start": 56, "char_end": 62, "token_start": 11, "token_end": 13}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 88, "char_end": 99, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "C / EBPbeta", "type": "ENTITY", "char_start": 264033, "char_end": 264044, "token_start": 7, "token_end": 9, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 264049, "char_end": 264055, "token_start": 11, "token_end": 13, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 264081, "char_end": 264092, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 1602, "sentence_text": "Moreover , the truncated form of C / EBPbeta , known to repress HIV - 1 transcription , was detected in extracts from MB - treated THP - 1 cells .", "sentence_char_start_global": 264112, "sentence_char_end_global": 264258, "entities": [{"text": "C / EBPbeta", "type": "ENTITY", "char_start": 33, "char_end": 44, "token_start": 6, "token_end": 8}], "entities_global": [{"text": "C / EBPbeta", "type": "ENTITY", "char_start": 264145, "char_end": 264156, "token_start": 6, "token_end": 8, "note": null}]}
+{"sentence_id": 1603, "sentence_text": "Surprisingly , neither MB nor MDP were able to transduce signals via CD14 and TLR2 or 4 .", "sentence_char_start_global": 264259, "sentence_char_end_global": 264348, "entities": [{"text": "CD14", "type": "ENTITY", "char_start": 69, "char_end": 73, "token_start": 12, "token_end": 12}, {"text": "TLR2 or 4", "type": "ENTITY", "char_start": 78, "char_end": 87, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "CD14", "type": "ENTITY", "char_start": 264328, "char_end": 264332, "token_start": 12, "token_end": 12, "note": null}, {"text": "TLR2 or 4", "type": "ENTITY", "char_start": 264337, "char_end": 264346, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 1604, "sentence_text": "These findings present major differences in the early cell activation process between LPS and muramyl peptides , and strongly argue for the implication of co - receptors other than TLR2 and TLR4 in mediating the signaling events induced by defined subunits of bacterial peptidoglycans .", "sentence_char_start_global": 264349, "sentence_char_end_global": 264635, "entities": [{"text": "co - receptors", "type": "ENTITY", "char_start": 155, "char_end": 169, "token_start": 24, "token_end": 26}, {"text": "TLR2", "type": "ENTITY", "char_start": 181, "char_end": 185, "token_start": 29, "token_end": 29}, {"text": "TLR4", "type": "ENTITY", "char_start": 190, "char_end": 194, "token_start": 31, "token_end": 31}], "entities_global": [{"text": "co - receptors", "type": "ENTITY", "char_start": 264504, "char_end": 264518, "token_start": 24, "token_end": 26, "note": null}, {"text": "TLR2", "type": "ENTITY", "char_start": 264530, "char_end": 264534, "token_start": 29, "token_end": 29, "note": null}, {"text": "TLR4", "type": "ENTITY", "char_start": 264539, "char_end": 264543, "token_start": 31, "token_end": 31, "note": null}]}
+{"sentence_id": 1605, "sentence_text": "Nuclear peroxisome proliferator - activated receptors alpha and gamma have opposing effects on monocyte chemotaxis in endometriosis .", "sentence_char_start_global": 264636, "sentence_char_end_global": 264769, "entities": [{"text": "Nuclear peroxisome proliferator - activated receptors alpha and gamma", "type": "ENTITY", "char_start": 0, "char_end": 69, "token_start": 0, "token_end": 8}], "entities_global": [{"text": "Nuclear peroxisome proliferator - activated receptors alpha and gamma", "type": "ENTITY", "char_start": 264636, "char_end": 264705, "token_start": 0, "token_end": 8, "note": null}]}
+{"sentence_id": 1606, "sentence_text": "The peroxisome proliferator - activated receptors ( PPARs ) alpha and gamma are nuclear receptors that play important roles in inflammatory diseases like ulcerative colitis and arthritis .", "sentence_char_start_global": 264770, "sentence_char_end_global": 264958, "entities": [{"text": "peroxisome proliferator - activated receptors ( PPARs ) alpha and gamma", "type": "ENTITY", "char_start": 4, "char_end": 75, "token_start": 1, "token_end": 11}, {"text": "nuclear receptors", "type": "ENTITY", "char_start": 80, "char_end": 97, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "peroxisome proliferator - activated receptors ( PPARs ) alpha and gamma", "type": "ENTITY", "char_start": 264774, "char_end": 264845, "token_start": 1, "token_end": 11, "note": null}, {"text": "nuclear receptors", "type": "ENTITY", "char_start": 264850, "char_end": 264867, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 1607, "sentence_text": "In this study , we examined the possible role of PPARs in macrophage attraction into the peritoneal cavity of patients with endometriosis .", "sentence_char_start_global": 264959, "sentence_char_end_global": 265098, "entities": [{"text": "PPARs", "type": "ENTITY", "char_start": 49, "char_end": 54, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "PPARs", "type": "ENTITY", "char_start": 265008, "char_end": 265013, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 1608, "sentence_text": "We identified PPAR - alpha and - gamma messenger RNA by RT - PCR and protein by immunoblotting of lysates of peritoneal macrophages and monocytic U937 cells .", "sentence_char_start_global": 265099, "sentence_char_end_global": 265257, "entities": [{"text": "PPAR - alpha and - gamma", "type": "ENTITY", "char_start": 14, "char_end": 38, "token_start": 2, "token_end": 7}], "entities_global": [{"text": "PPAR - alpha and - gamma", "type": "ENTITY", "char_start": 265113, "char_end": 265137, "token_start": 2, "token_end": 7, "note": null}]}
+{"sentence_id": 1609, "sentence_text": "Using immunocytochemistry , we localized PPAR - alpha and - gamma within the nuclei of both cell types .", "sentence_char_start_global": 265258, "sentence_char_end_global": 265362, "entities": [{"text": "PPAR - alpha and - gamma", "type": "ENTITY", "char_start": 41, "char_end": 65, "token_start": 5, "token_end": 10}], "entities_global": [{"text": "PPAR - alpha and - gamma", "type": "ENTITY", "char_start": 265299, "char_end": 265323, "token_start": 5, "token_end": 10, "note": null}]}
+{"sentence_id": 1610, "sentence_text": "Monocyte chemotactic activity of peritoneal fluid from patients with endometriosis was quantified in Boyden chambers .", "sentence_char_start_global": 265363, "sentence_char_end_global": 265481, "entities": [], "entities_global": []}
+{"sentence_id": 1611, "sentence_text": "Migration of U937 cells was increased by WY 14643 and reduced by rosiglitazone .", "sentence_char_start_global": 265482, "sentence_char_end_global": 265562, "entities": [], "entities_global": []}
+{"sentence_id": 1612, "sentence_text": "Peritoneal fluid from patients with endometriosis activated U937 cells transiently transfected with a PPAR - alpha / GAL4 luciferase reporter .", "sentence_char_start_global": 265563, "sentence_char_end_global": 265706, "entities": [{"text": "PPAR - alpha / GAL4 luciferase reporter", "type": "ENTITY", "char_start": 102, "char_end": 141, "token_start": 13, "token_end": 19}], "entities_global": [{"text": "PPAR - alpha / GAL4 luciferase reporter", "type": "ENTITY", "char_start": 265665, "char_end": 265704, "token_start": 13, "token_end": 19, "note": null}]}
+{"sentence_id": 1613, "sentence_text": "By contrast , peritoneal fluid did not cause significant activation of PPAR - gamma / GAL4 constructs .", "sentence_char_start_global": 265707, "sentence_char_end_global": 265810, "entities": [{"text": "PPAR - gamma / GAL4 constructs", "type": "ENTITY", "char_start": 71, "char_end": 101, "token_start": 11, "token_end": 16}], "entities_global": [{"text": "PPAR - gamma / GAL4 constructs", "type": "ENTITY", "char_start": 265778, "char_end": 265808, "token_start": 11, "token_end": 16, "note": null}]}
+{"sentence_id": 1614, "sentence_text": "The U937 cells transiently transfected with a PPAR response element luciferase reporter showed disease stage - dependent up - regulation when treated with peritoneal fluid from patients with endometriosis .", "sentence_char_start_global": 265811, "sentence_char_end_global": 266017, "entities": [{"text": "PPAR response element luciferase reporter", "type": "ENTITY", "char_start": 46, "char_end": 87, "token_start": 7, "token_end": 11}], "entities_global": [{"text": "PPAR response element luciferase reporter", "type": "ENTITY", "char_start": 265857, "char_end": 265898, "token_start": 7, "token_end": 11, "note": null}]}
+{"sentence_id": 1615, "sentence_text": "Treatment with peritoneal fluid from healthy controls down - regulated PPAR response element transactivation .", "sentence_char_start_global": 266018, "sentence_char_end_global": 266128, "entities": [], "entities_global": []}
+{"sentence_id": 1616, "sentence_text": "We conclude that peritoneal fluid of endometriosis patients contains activators of PPAR - alpha that stimulate macrophage chemotaxis .", "sentence_char_start_global": 266129, "sentence_char_end_global": 266263, "entities": [{"text": "PPAR - alpha", "type": "ENTITY", "char_start": 83, "char_end": 95, "token_start": 11, "token_end": 13}], "entities_global": [{"text": "PPAR - alpha", "type": "ENTITY", "char_start": 266212, "char_end": 266224, "token_start": 11, "token_end": 13, "note": null}]}
+{"sentence_id": 1617, "sentence_text": "Inhibitors of PPAR - alpha or activators of PPAR - gamma could be developed for the treatment of inflammation associated with endometriosis .", "sentence_char_start_global": 266264, "sentence_char_end_global": 266405, "entities": [{"text": "PPAR - alpha", "type": "ENTITY", "char_start": 14, "char_end": 26, "token_start": 2, "token_end": 4}, {"text": "PPAR - gamma", "type": "ENTITY", "char_start": 44, "char_end": 56, "token_start": 8, "token_end": 10}], "entities_global": [{"text": "PPAR - alpha", "type": "ENTITY", "char_start": 266278, "char_end": 266290, "token_start": 2, "token_end": 4, "note": null}, {"text": "PPAR - gamma", "type": "ENTITY", "char_start": 266308, "char_end": 266320, "token_start": 8, "token_end": 10, "note": null}]}
+{"sentence_id": 1618, "sentence_text": "Long - term - impaired expression of nuclear factor - kappa B and I kappa B alpha in peripheral blood mononuclear cells of trauma patients .", "sentence_char_start_global": 266406, "sentence_char_end_global": 266546, "entities": [{"text": "nuclear factor - kappa B", "type": "ENTITY", "char_start": 37, "char_end": 61, "token_start": 7, "token_end": 11}, {"text": "I kappa B alpha", "type": "ENTITY", "char_start": 66, "char_end": 81, "token_start": 13, "token_end": 16}], "entities_global": [{"text": "nuclear factor - kappa B", "type": "ENTITY", "char_start": 266443, "char_end": 266467, "token_start": 7, "token_end": 11, "note": null}, {"text": "I kappa B alpha", "type": "ENTITY", "char_start": 266472, "char_end": 266487, "token_start": 13, "token_end": 16, "note": null}]}
+{"sentence_id": 1619, "sentence_text": "Nuclear factor ( NF ) - kappa B expression and dimer characteristics were studied in peripheral blood mononuclear cells ( PBMCs ) of major - trauma patients and healthy controls .", "sentence_char_start_global": 266547, "sentence_char_end_global": 266726, "entities": [{"text": "Nuclear factor ( NF ) - kappa B", "type": "ENTITY", "char_start": 0, "char_end": 31, "token_start": 0, "token_end": 7}], "entities_global": [{"text": "Nuclear factor ( NF ) - kappa B", "type": "ENTITY", "char_start": 266547, "char_end": 266578, "token_start": 0, "token_end": 7, "note": null}]}
+{"sentence_id": 1620, "sentence_text": "Analysis of PBMCs on days 1 , 3 , 5 , and 10 after trauma revealed that expression of both p65p50 heterodimers and p50p50 homodimers was significantly reduced compared with that in controls .", "sentence_char_start_global": 266727, "sentence_char_end_global": 266918, "entities": [{"text": "p65p50 heterodimers", "type": "ENTITY", "char_start": 91, "char_end": 110, "token_start": 20, "token_end": 21}, {"text": "p50p50 homodimers", "type": "ENTITY", "char_start": 115, "char_end": 132, "token_start": 23, "token_end": 24}], "entities_global": [{"text": "p65p50 heterodimers", "type": "ENTITY", "char_start": 266818, "char_end": 266837, "token_start": 20, "token_end": 21, "note": null}, {"text": "p50p50 homodimers", "type": "ENTITY", "char_start": 266842, "char_end": 266859, "token_start": 23, "token_end": 24, "note": null}]}
+{"sentence_id": 1621, "sentence_text": "In vitro lipopolysaccharide ( LPS ) stimulation of PBMCs induced NF - kappa B translocation .", "sentence_char_start_global": 266919, "sentence_char_end_global": 267012, "entities": [], "entities_global": []}
+{"sentence_id": 1622, "sentence_text": "However , throughout the survey , p65p50 activation remained significantly lower in trauma patients than in controls .", "sentence_char_start_global": 267013, "sentence_char_end_global": 267131, "entities": [], "entities_global": []}
+{"sentence_id": 1623, "sentence_text": "After LPS stimulation in vitro , the p65p50 / p50p50 ratio was significantly lower in PBMCs from trauma patients than from healthy controls .", "sentence_char_start_global": 267132, "sentence_char_end_global": 267273, "entities": [], "entities_global": []}
+{"sentence_id": 1624, "sentence_text": "The ex vivo expression of I kappa B alpha was higher in PBMCs of controls than of trauma patients .", "sentence_char_start_global": 267274, "sentence_char_end_global": 267373, "entities": [{"text": "I kappa B alpha", "type": "ENTITY", "char_start": 26, "char_end": 41, "token_start": 5, "token_end": 8}], "entities_global": [{"text": "I kappa B alpha", "type": "ENTITY", "char_start": 267300, "char_end": 267315, "token_start": 5, "token_end": 8, "note": null}]}
+{"sentence_id": 1625, "sentence_text": "LPS did not induce I kappa B expression in PBMCs from trauma patients , but strong induction was obtained with staphylococci , suggesting that this defect is not universal and depends on the nature of the activating signal .", "sentence_char_start_global": 267374, "sentence_char_end_global": 267598, "entities": [], "entities_global": []}
+{"sentence_id": 1626, "sentence_text": "Although no direct correlation was found between levels of interleukin - 10 or transforming growth factor - beta and NF - kappa B , these immunosuppressive cytokines were significantly elevated in trauma patients by 10 days after admission .", "sentence_char_start_global": 267599, "sentence_char_end_global": 267840, "entities": [{"text": "interleukin - 10", "type": "ENTITY", "char_start": 59, "char_end": 75, "token_start": 9, "token_end": 11}, {"text": "transforming growth factor - beta", "type": "ENTITY", "char_start": 79, "char_end": 112, "token_start": 13, "token_end": 17}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 117, "char_end": 129, "token_start": 19, "token_end": 22}, {"text": "immunosuppressive cytokines", "type": "ENTITY", "char_start": 138, "char_end": 165, "token_start": 25, "token_end": 26}], "entities_global": [{"text": "interleukin - 10", "type": "ENTITY", "char_start": 267658, "char_end": 267674, "token_start": 9, "token_end": 11, "note": null}, {"text": "transforming growth factor - beta", "type": "ENTITY", "char_start": 267678, "char_end": 267711, "token_start": 13, "token_end": 17, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 267716, "char_end": 267728, "token_start": 19, "token_end": 22, "note": null}, {"text": "immunosuppressive cytokines", "type": "ENTITY", "char_start": 267737, "char_end": 267764, "token_start": 25, "token_end": 26, "note": null}]}
+{"sentence_id": 1627, "sentence_text": "The long - term low - basal and LPS - induced nuclear translocation of NF - kappa B recalled long - term immunoparalysis observed in patients with severe inflammatory stress such as trauma .", "sentence_char_start_global": 267841, "sentence_char_end_global": 268031, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 71, "char_end": 83, "token_start": 14, "token_end": 17}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 267912, "char_end": 267924, "token_start": 14, "token_end": 17, "note": null}]}
+{"sentence_id": 1628, "sentence_text": "Hepatic ischemia - reperfusion injury .", "sentence_char_start_global": 268032, "sentence_char_end_global": 268071, "entities": [], "entities_global": []}
+{"sentence_id": 1629, "sentence_text": "BACKGROUND : The morbidity associated with liver transplantation and major hepatic resections is partly a result of ischemia - reperfusion injury .", "sentence_char_start_global": 268072, "sentence_char_end_global": 268219, "entities": [], "entities_global": []}
+{"sentence_id": 1630, "sentence_text": "DATA SOURCES : The entire world literature on the subject was searched via Medline .", "sentence_char_start_global": 268220, "sentence_char_end_global": 268304, "entities": [], "entities_global": []}
+{"sentence_id": 1631, "sentence_text": "Keywords included reperfusion injury , transplantation , liver resection , nitric oxide , endothelin , cytokines , Kupffer cells , ischemic / ischaemic preconditioning , and nuclear factor - kappa B .", "sentence_char_start_global": 268305, "sentence_char_end_global": 268505, "entities": [{"text": "cytokines", "type": "ENTITY", "char_start": 103, "char_end": 112, "token_start": 15, "token_end": 15}, {"text": "nuclear factor - kappa B", "type": "ENTITY", "char_start": 174, "char_end": 198, "token_start": 26, "token_end": 30}], "entities_global": [{"text": "cytokines", "type": "ENTITY", "char_start": 268408, "char_end": 268417, "token_start": 15, "token_end": 15, "note": null}, {"text": "nuclear factor - kappa B", "type": "ENTITY", "char_start": 268479, "char_end": 268503, "token_start": 26, "token_end": 30, "note": null}]}
+{"sentence_id": 1632, "sentence_text": "CONCLUSIONS : An imbalance between endothelin and nitric oxide levels results in failure of the hepatic microcirculation at the onset of reperfusion .", "sentence_char_start_global": 268506, "sentence_char_end_global": 268656, "entities": [], "entities_global": []}
+{"sentence_id": 1633, "sentence_text": "Activation of nuclear factor - kappa B in the liver promotes proinflammatory cytokine and adhesion molecule synthesis .", "sentence_char_start_global": 268657, "sentence_char_end_global": 268776, "entities": [{"text": "nuclear factor - kappa B", "type": "ENTITY", "char_start": 14, "char_end": 38, "token_start": 2, "token_end": 6}, {"text": "proinflammatory cytokine", "type": "ENTITY", "char_start": 61, "char_end": 85, "token_start": 11, "token_end": 12}, {"text": "adhesion molecule", "type": "ENTITY", "char_start": 90, "char_end": 107, "token_start": 14, "token_end": 15}], "entities_global": [{"text": "nuclear factor - kappa B", "type": "ENTITY", "char_start": 268671, "char_end": 268695, "token_start": 2, "token_end": 6, "note": null}, {"text": "proinflammatory cytokine", "type": "ENTITY", "char_start": 268718, "char_end": 268742, "token_start": 11, "token_end": 12, "note": null}, {"text": "adhesion molecule", "type": "ENTITY", "char_start": 268747, "char_end": 268764, "token_start": 14, "token_end": 15, "note": null}]}
+{"sentence_id": 1634, "sentence_text": "These result in oxygen - derived free radical production and neutrophil recruitment , further contributing to cellular injury .", "sentence_char_start_global": 268777, "sentence_char_end_global": 268904, "entities": [], "entities_global": []}
+{"sentence_id": 1635, "sentence_text": "Various therapeutic modalities acting on the above mediators have been successfully used to attenuate reperfusion injury in animal models of hepatic transplantation and resection .", "sentence_char_start_global": 268905, "sentence_char_end_global": 269085, "entities": [], "entities_global": []}
+{"sentence_id": 1636, "sentence_text": "Application of the knowledge gained from animal models of hepatic ischemia - reperfusion to the clinical setting will improve the outcome of hepatic surgery .", "sentence_char_start_global": 269086, "sentence_char_end_global": 269244, "entities": [], "entities_global": []}
+{"sentence_id": 1637, "sentence_text": "Down - regulation of IL - 12 p40 gene in Plasmodium berghei - infected mice .", "sentence_char_start_global": 269245, "sentence_char_end_global": 269322, "entities": [{"text": "IL - 12 p40 gene", "type": "ENTITY", "char_start": 21, "char_end": 37, "token_start": 4, "token_end": 8}], "entities_global": [{"text": "IL - 12 p40 gene", "type": "ENTITY", "char_start": 269266, "char_end": 269282, "token_start": 4, "token_end": 8, "note": null}]}
+{"sentence_id": 1638, "sentence_text": "We analyzed the mechanism that causes suppression of IL - 12 p40 gene induction during Plasmodium berghei infection .", "sentence_char_start_global": 269323, "sentence_char_end_global": 269440, "entities": [{"text": "IL - 12 p40 gene", "type": "ENTITY", "char_start": 53, "char_end": 69, "token_start": 8, "token_end": 12}], "entities_global": [{"text": "IL - 12 p40 gene", "type": "ENTITY", "char_start": 269376, "char_end": 269392, "token_start": 8, "token_end": 12, "note": null}]}
+{"sentence_id": 1639, "sentence_text": "Although IL - 12 together with IFN - gamma plays an important role in protection against pathogenic infection , the IL - 12 p70 protein production of infected macrophages is lower than that by the uninfected macrophages .", "sentence_char_start_global": 269441, "sentence_char_end_global": 269662, "entities": [{"text": "IL - 12", "type": "ENTITY", "char_start": 9, "char_end": 16, "token_start": 1, "token_end": 3}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 31, "char_end": 42, "token_start": 6, "token_end": 8}, {"text": "IL - 12 p70 protein", "type": "ENTITY", "char_start": 116, "char_end": 135, "token_start": 20, "token_end": 24}], "entities_global": [{"text": "IL - 12", "type": "ENTITY", "char_start": 269450, "char_end": 269457, "token_start": 1, "token_end": 3, "note": null}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 269472, "char_end": 269483, "token_start": 6, "token_end": 8, "note": null}, {"text": "IL - 12 p70 protein", "type": "ENTITY", "char_start": 269557, "char_end": 269576, "token_start": 20, "token_end": 24, "note": null}]}
+{"sentence_id": 1640, "sentence_text": "We showed in the present study that the induction of IL - 12 p40 gene but not IL - 12 p35 gene in macrophages of P . berghei - infected mice was profoundly inhibited .", "sentence_char_start_global": 269663, "sentence_char_end_global": 269830, "entities": [{"text": "IL - 12 p40 gene", "type": "ENTITY", "char_start": 53, "char_end": 69, "token_start": 10, "token_end": 14}, {"text": "IL - 12 p35 gene", "type": "ENTITY", "char_start": 78, "char_end": 94, "token_start": 17, "token_end": 21}], "entities_global": [{"text": "IL - 12 p40 gene", "type": "ENTITY", "char_start": 269716, "char_end": 269732, "token_start": 10, "token_end": 14, "note": null}, {"text": "IL - 12 p35 gene", "type": "ENTITY", "char_start": 269741, "char_end": 269757, "token_start": 17, "token_end": 21, "note": null}]}
+{"sentence_id": 1641, "sentence_text": "The inhibition was induced by interaction with macrophages that had contacted with P . berghei - infected erythrocytes and was mediated by a soluble factor , IL - 10 .", "sentence_char_start_global": 269831, "sentence_char_end_global": 269998, "entities": [{"text": "IL - 10", "type": "ENTITY", "char_start": 158, "char_end": 165, "token_start": 26, "token_end": 28}], "entities_global": [{"text": "IL - 10", "type": "ENTITY", "char_start": 269989, "char_end": 269996, "token_start": 26, "token_end": 28, "note": null}]}
+{"sentence_id": 1642, "sentence_text": "There was comparable activation of NF - kappaB in uninfected and infected cells .", "sentence_char_start_global": 269999, "sentence_char_end_global": 270080, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 35, "char_end": 46, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 270034, "char_end": 270045, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 1643, "sentence_text": "The induction of IFN - regulatory factor - 1 gene was comparable in transcription level in uninfected and infected cells , while the unidentified complex formation of IFN - regulatory factor - 1 was observed in infected cells .", "sentence_char_start_global": 270081, "sentence_char_end_global": 270308, "entities": [{"text": "IFN - regulatory factor - 1 gene", "type": "ENTITY", "char_start": 17, "char_end": 49, "token_start": 3, "token_end": 9}, {"text": "IFN - regulatory factor - 1", "type": "ENTITY", "char_start": 167, "char_end": 194, "token_start": 27, "token_end": 32}], "entities_global": [{"text": "IFN - regulatory factor - 1 gene", "type": "ENTITY", "char_start": 270098, "char_end": 270130, "token_start": 3, "token_end": 9, "note": null}, {"text": "IFN - regulatory factor - 1", "type": "ENTITY", "char_start": 270248, "char_end": 270275, "token_start": 27, "token_end": 32, "note": null}]}
+{"sentence_id": 1644, "sentence_text": "Therefore , the inhibition of the IL - 12 p40 gene induction appeared to be regulated at transcriptional regulation level of the gene .", "sentence_char_start_global": 270309, "sentence_char_end_global": 270444, "entities": [{"text": "IL - 12 p40 gene", "type": "ENTITY", "char_start": 34, "char_end": 50, "token_start": 6, "token_end": 10}], "entities_global": [{"text": "IL - 12 p40 gene", "type": "ENTITY", "char_start": 270343, "char_end": 270359, "token_start": 6, "token_end": 10, "note": null}]}
+{"sentence_id": 1645, "sentence_text": "The Friend of GATA proteins U - shaped , FOG - 1 , and FOG - 2 function as negative regulators of blood , heart , and eye development in Drosophila .", "sentence_char_start_global": 270445, "sentence_char_end_global": 270594, "entities": [{"text": "Friend of GATA proteins", "type": "ENTITY", "char_start": 4, "char_end": 27, "token_start": 1, "token_end": 4}, {"text": "FOG - 1", "type": "ENTITY", "char_start": 41, "char_end": 48, "token_start": 9, "token_end": 11}, {"text": "FOG - 2", "type": "ENTITY", "char_start": 55, "char_end": 62, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "Friend of GATA proteins", "type": "ENTITY", "char_start": 270449, "char_end": 270472, "token_start": 1, "token_end": 4, "note": null}, {"text": "FOG - 1", "type": "ENTITY", "char_start": 270486, "char_end": 270493, "token_start": 9, "token_end": 11, "note": null}, {"text": "FOG - 2", "type": "ENTITY", "char_start": 270500, "char_end": 270507, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 1646, "sentence_text": "Friend of GATA ( FOG ) proteins regulate GATA factor - activated gene transcription .", "sentence_char_start_global": 270595, "sentence_char_end_global": 270680, "entities": [{"text": "Friend of GATA ( FOG ) proteins", "type": "ENTITY", "char_start": 0, "char_end": 31, "token_start": 0, "token_end": 6}], "entities_global": [{"text": "Friend of GATA ( FOG ) proteins", "type": "ENTITY", "char_start": 270595, "char_end": 270626, "token_start": 0, "token_end": 6, "note": null}]}
+{"sentence_id": 1647, "sentence_text": "During vertebrate hematopoiesis , FOG and GATA proteins cooperate to promote erythrocyte and megakaryocyte differentiation .", "sentence_char_start_global": 270681, "sentence_char_end_global": 270805, "entities": [{"text": "FOG and GATA proteins", "type": "ENTITY", "char_start": 34, "char_end": 55, "token_start": 4, "token_end": 7}], "entities_global": [{"text": "FOG and GATA proteins", "type": "ENTITY", "char_start": 270715, "char_end": 270736, "token_start": 4, "token_end": 7, "note": null}]}
+{"sentence_id": 1648, "sentence_text": "The Drosophila FOG homologue U - shaped ( Ush ) is expressed similarly in the blood cell anlage during embryogenesis .", "sentence_char_start_global": 270806, "sentence_char_end_global": 270924, "entities": [{"text": "Drosophila FOG homologue U - shaped", "type": "ENTITY", "char_start": 4, "char_end": 39, "token_start": 1, "token_end": 6}, {"text": "Ush", "type": "ENTITY", "char_start": 42, "char_end": 45, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "Drosophila FOG homologue U - shaped", "type": "ENTITY", "char_start": 270810, "char_end": 270845, "token_start": 1, "token_end": 6, "note": null}, {"text": "Ush", "type": "ENTITY", "char_start": 270848, "char_end": 270851, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 1649, "sentence_text": "During hematopoiesis , the acute myeloid leukemia 1 homologue Lozenge and Glial cells missing are required for the production of crystal cells and plasmatocytes , respectively .", "sentence_char_start_global": 270925, "sentence_char_end_global": 271102, "entities": [], "entities_global": []}
+{"sentence_id": 1650, "sentence_text": "However , additional factors have been predicted to control crystal cell proliferation .", "sentence_char_start_global": 271103, "sentence_char_end_global": 271191, "entities": [], "entities_global": []}
+{"sentence_id": 1651, "sentence_text": "In this report , we show that Ush is expressed in hemocyte precursors and plasmatocytes throughout embryogenesis and larval development , and the GATA factor Serpent is essential for Ush embryonic expression .", "sentence_char_start_global": 271192, "sentence_char_end_global": 271401, "entities": [{"text": "Ush", "type": "ENTITY", "char_start": 30, "char_end": 33, "token_start": 7, "token_end": 7}, {"text": "GATA factor Serpent", "type": "ENTITY", "char_start": 146, "char_end": 165, "token_start": 23, "token_end": 25}, {"text": "Ush", "type": "ENTITY", "char_start": 183, "char_end": 186, "token_start": 29, "token_end": 29}], "entities_global": [{"text": "Ush", "type": "ENTITY", "char_start": 271222, "char_end": 271225, "token_start": 7, "token_end": 7, "note": null}, {"text": "GATA factor Serpent", "type": "ENTITY", "char_start": 271338, "char_end": 271357, "token_start": 23, "token_end": 25, "note": null}, {"text": "Ush", "type": "ENTITY", "char_start": 271375, "char_end": 271378, "token_start": 29, "token_end": 29, "note": null}]}
+{"sentence_id": 1652, "sentence_text": "Furthermore , loss of ush function results in an overproduction of crystal cells , whereas forced expression of Ush reduces this cell population .", "sentence_char_start_global": 271402, "sentence_char_end_global": 271548, "entities": [{"text": "Ush", "type": "ENTITY", "char_start": 112, "char_end": 115, "token_start": 18, "token_end": 18}], "entities_global": [{"text": "Ush", "type": "ENTITY", "char_start": 271514, "char_end": 271517, "token_start": 18, "token_end": 18, "note": null}]}
+{"sentence_id": 1653, "sentence_text": "Murine FOG - 1 and FOG - 2 also can repress crystal cell production , but a mutant version of FOG - 2 lacking a conserved motif that binds the corepressor C - terminal binding protein fails to affect the cell lineage .", "sentence_char_start_global": 271549, "sentence_char_end_global": 271767, "entities": [{"text": "Murine FOG - 1 and FOG - 2", "type": "ENTITY", "char_start": 0, "char_end": 26, "token_start": 0, "token_end": 7}, {"text": "FOG - 2", "type": "ENTITY", "char_start": 94, "char_end": 101, "token_start": 20, "token_end": 22}, {"text": "corepressor C - terminal binding protein", "type": "ENTITY", "char_start": 143, "char_end": 183, "token_start": 30, "token_end": 35}], "entities_global": [{"text": "Murine FOG - 1 and FOG - 2", "type": "ENTITY", "char_start": 271549, "char_end": 271575, "token_start": 0, "token_end": 7, "note": null}, {"text": "FOG - 2", "type": "ENTITY", "char_start": 271643, "char_end": 271650, "token_start": 20, "token_end": 22, "note": null}, {"text": "corepressor C - terminal binding protein", "type": "ENTITY", "char_start": 271692, "char_end": 271732, "token_start": 30, "token_end": 35, "note": null}]}
+{"sentence_id": 1654, "sentence_text": "The GATA factor Pannier ( Pnr ) is required for eye and heart development in Drosophila .", "sentence_char_start_global": 271768, "sentence_char_end_global": 271857, "entities": [{"text": "GATA factor Pannier", "type": "ENTITY", "char_start": 4, "char_end": 23, "token_start": 1, "token_end": 3}, {"text": "Pnr", "type": "ENTITY", "char_start": 26, "char_end": 29, "token_start": 5, "token_end": 5}], "entities_global": [{"text": "GATA factor Pannier", "type": "ENTITY", "char_start": 271772, "char_end": 271791, "token_start": 1, "token_end": 3, "note": null}, {"text": "Pnr", "type": "ENTITY", "char_start": 271794, "char_end": 271797, "token_start": 5, "token_end": 5, "note": null}]}
+{"sentence_id": 1655, "sentence_text": "When Ush , FOG - 1 , FOG - 2 , or mutant FOG - 2 is coexpressed with Pnr during these developmental processes , severe eye and heart phenotypes result , consistent with a conserved negative regulation of Pnr function .", "sentence_char_start_global": 271858, "sentence_char_end_global": 272076, "entities": [{"text": "Ush", "type": "ENTITY", "char_start": 5, "char_end": 8, "token_start": 1, "token_end": 1}, {"text": "FOG - 1", "type": "ENTITY", "char_start": 11, "char_end": 18, "token_start": 3, "token_end": 5}, {"text": "FOG - 2", "type": "ENTITY", "char_start": 21, "char_end": 28, "token_start": 7, "token_end": 9}, {"text": "mutant FOG - 2", "type": "ENTITY", "char_start": 34, "char_end": 48, "token_start": 12, "token_end": 15}, {"text": "Pnr", "type": "ENTITY", "char_start": 69, "char_end": 72, "token_start": 19, "token_end": 19}, {"text": "Pnr", "type": "ENTITY", "char_start": 204, "char_end": 207, "token_start": 39, "token_end": 39}], "entities_global": [{"text": "Ush", "type": "ENTITY", "char_start": 271863, "char_end": 271866, "token_start": 1, "token_end": 1, "note": null}, {"text": "FOG - 1", "type": "ENTITY", "char_start": 271869, "char_end": 271876, "token_start": 3, "token_end": 5, "note": null}, {"text": "FOG - 2", "type": "ENTITY", "char_start": 271879, "char_end": 271886, "token_start": 7, "token_end": 9, "note": null}, {"text": "mutant FOG - 2", "type": "ENTITY", "char_start": 271892, "char_end": 271906, "token_start": 12, "token_end": 15, "note": null}, {"text": "Pnr", "type": "ENTITY", "char_start": 271927, "char_end": 271930, "token_start": 19, "token_end": 19, "note": null}, {"text": "Pnr", "type": "ENTITY", "char_start": 272062, "char_end": 272065, "token_start": 39, "token_end": 39, "note": null}]}
+{"sentence_id": 1656, "sentence_text": "These results indicate that the fly and mouse FOG proteins function similarly in three distinct cellular contexts in Drosophila , but may use different mechanisms to regulate genetic events in blood vs . cardial or eye cell lineages", "sentence_char_start_global": 272077, "sentence_char_end_global": 272309, "entities": [{"text": "FOG proteins", "type": "ENTITY", "char_start": 46, "char_end": 58, "token_start": 8, "token_end": 9}], "entities_global": [{"text": "FOG proteins", "type": "ENTITY", "char_start": 272123, "char_end": 272135, "token_start": 8, "token_end": 9, "note": null}]}
+{"sentence_id": 1657, "sentence_text": "The RING finger protein Siah - 1 regulates the level of the transcriptional coactivator OBF - 1 .", "sentence_char_start_global": 272310, "sentence_char_end_global": 272407, "entities": [{"text": "RING finger protein", "type": "ENTITY", "char_start": 4, "char_end": 23, "token_start": 1, "token_end": 3}, {"text": "Siah - 1", "type": "ENTITY", "char_start": 24, "char_end": 32, "token_start": 4, "token_end": 6}, {"text": "transcriptional coactivator", "type": "ENTITY", "char_start": 60, "char_end": 87, "token_start": 12, "token_end": 13}, {"text": "OBF - 1", "type": "ENTITY", "char_start": 88, "char_end": 95, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "RING finger protein", "type": "ENTITY", "char_start": 272314, "char_end": 272333, "token_start": 1, "token_end": 3, "note": null}, {"text": "Siah - 1", "type": "ENTITY", "char_start": 272334, "char_end": 272342, "token_start": 4, "token_end": 6, "note": null}, {"text": "transcriptional coactivator", "type": "ENTITY", "char_start": 272370, "char_end": 272397, "token_start": 12, "token_end": 13, "note": null}, {"text": "OBF - 1", "type": "ENTITY", "char_start": 272398, "char_end": 272405, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 1658, "sentence_text": "The transcriptional coactivator OBF - 1 , which interacts with Oct - 1 and Oct - 2 and the octamer site DNA , has been shown to be critical for development of a normal immune response and the formation of germinal centers in secondary lymphoid organs .", "sentence_char_start_global": 272408, "sentence_char_end_global": 272660, "entities": [{"text": "transcriptional coactivator", "type": "ENTITY", "char_start": 4, "char_end": 31, "token_start": 1, "token_end": 2}, {"text": "OBF - 1", "type": "ENTITY", "char_start": 32, "char_end": 39, "token_start": 3, "token_end": 5}, {"text": "Oct - 1", "type": "ENTITY", "char_start": 63, "char_end": 70, "token_start": 10, "token_end": 12}, {"text": "Oct - 2", "type": "ENTITY", "char_start": 75, "char_end": 82, "token_start": 14, "token_end": 16}, {"text": "octamer site DNA", "type": "ENTITY", "char_start": 91, "char_end": 107, "token_start": 19, "token_end": 21}], "entities_global": [{"text": "transcriptional coactivator", "type": "ENTITY", "char_start": 272412, "char_end": 272439, "token_start": 1, "token_end": 2, "note": null}, {"text": "OBF - 1", "type": "ENTITY", "char_start": 272440, "char_end": 272447, "token_start": 3, "token_end": 5, "note": null}, {"text": "Oct - 1", "type": "ENTITY", "char_start": 272471, "char_end": 272478, "token_start": 10, "token_end": 12, "note": null}, {"text": "Oct - 2", "type": "ENTITY", "char_start": 272483, "char_end": 272490, "token_start": 14, "token_end": 16, "note": null}, {"text": "octamer site DNA", "type": "ENTITY", "char_start": 272499, "char_end": 272515, "token_start": 19, "token_end": 21, "note": null}]}
+{"sentence_id": 1659, "sentence_text": "Here we have identified the RING finger protein Siah - 1 as a protein interacting specifically with OBF - 1 .", "sentence_char_start_global": 272661, "sentence_char_end_global": 272770, "entities": [{"text": "RING finger protein", "type": "ENTITY", "char_start": 28, "char_end": 47, "token_start": 5, "token_end": 7}, {"text": "Siah - 1", "type": "ENTITY", "char_start": 48, "char_end": 56, "token_start": 8, "token_end": 10}, {"text": "OBF - 1", "type": "ENTITY", "char_start": 100, "char_end": 107, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "RING finger protein", "type": "ENTITY", "char_start": 272689, "char_end": 272708, "token_start": 5, "token_end": 7, "note": null}, {"text": "Siah - 1", "type": "ENTITY", "char_start": 272709, "char_end": 272717, "token_start": 8, "token_end": 10, "note": null}, {"text": "OBF - 1", "type": "ENTITY", "char_start": 272761, "char_end": 272768, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 1660, "sentence_text": "This interaction is mediated by the C - terminal part of Siah - 1 and by residues in the N - terminus of OBF - 1 , partly distinct from the residues required for formation of a complex with the Oct POU domains and the DNA .", "sentence_char_start_global": 272771, "sentence_char_end_global": 272994, "entities": [{"text": "C - terminal", "type": "ENTITY", "char_start": 36, "char_end": 48, "token_start": 6, "token_end": 8}, {"text": "Siah - 1", "type": "ENTITY", "char_start": 57, "char_end": 65, "token_start": 11, "token_end": 13}, {"text": "N - terminus", "type": "ENTITY", "char_start": 89, "char_end": 101, "token_start": 19, "token_end": 21}, {"text": "OBF - 1", "type": "ENTITY", "char_start": 105, "char_end": 112, "token_start": 23, "token_end": 25}, {"text": "Oct POU domains", "type": "ENTITY", "char_start": 194, "char_end": 209, "token_start": 40, "token_end": 42}], "entities_global": [{"text": "C - terminal", "type": "ENTITY", "char_start": 272807, "char_end": 272819, "token_start": 6, "token_end": 8, "note": null}, {"text": "Siah - 1", "type": "ENTITY", "char_start": 272828, "char_end": 272836, "token_start": 11, "token_end": 13, "note": null}, {"text": "N - terminus", "type": "ENTITY", "char_start": 272860, "char_end": 272872, "token_start": 19, "token_end": 21, "note": null}, {"text": "OBF - 1", "type": "ENTITY", "char_start": 272876, "char_end": 272883, "token_start": 23, "token_end": 25, "note": null}, {"text": "Oct POU domains", "type": "ENTITY", "char_start": 272965, "char_end": 272980, "token_start": 40, "token_end": 42, "note": null}]}
+{"sentence_id": 1661, "sentence_text": "Interaction between Siah - 1 and OBF - 1 leads to downregulation of OBF - 1 protein level but not mRNA , and to a corresponding reduction in octamer site - dependent transcription activation .", "sentence_char_start_global": 272995, "sentence_char_end_global": 273187, "entities": [{"text": "Siah - 1", "type": "ENTITY", "char_start": 20, "char_end": 28, "token_start": 2, "token_end": 4}, {"text": "OBF - 1", "type": "ENTITY", "char_start": 33, "char_end": 40, "token_start": 6, "token_end": 8}], "entities_global": [{"text": "Siah - 1", "type": "ENTITY", "char_start": 273015, "char_end": 273023, "token_start": 2, "token_end": 4, "note": null}, {"text": "OBF - 1", "type": "ENTITY", "char_start": 273028, "char_end": 273035, "token_start": 6, "token_end": 8, "note": null}]}
+{"sentence_id": 1662, "sentence_text": "Inhibition of the ubiquitin - proteasome pathway in B cells leads to elevated levels of OBF - 1 protein .", "sentence_char_start_global": 273188, "sentence_char_end_global": 273293, "entities": [{"text": "OBF - 1 protein", "type": "ENTITY", "char_start": 88, "char_end": 103, "token_start": 15, "token_end": 18}], "entities_global": [{"text": "OBF - 1 protein", "type": "ENTITY", "char_start": 273276, "char_end": 273291, "token_start": 15, "token_end": 18, "note": null}]}
+{"sentence_id": 1663, "sentence_text": "Furthermore , in immunized mice , OBF - 1 protein amounts are dramatically increased in primary activated B cells , without concomitant increase in OBF - 1 mRNA .", "sentence_char_start_global": 273294, "sentence_char_end_global": 273456, "entities": [{"text": "OBF - 1 protein", "type": "ENTITY", "char_start": 34, "char_end": 49, "token_start": 6, "token_end": 9}, {"text": "OBF - 1 mRNA", "type": "ENTITY", "char_start": 148, "char_end": 160, "token_start": 24, "token_end": 27}], "entities_global": [{"text": "OBF - 1 protein", "type": "ENTITY", "char_start": 273328, "char_end": 273343, "token_start": 6, "token_end": 9, "note": null}, {"text": "OBF - 1 mRNA", "type": "ENTITY", "char_start": 273442, "char_end": 273454, "token_start": 24, "token_end": 27, "note": null}]}
+{"sentence_id": 1664, "sentence_text": "These data suggest that Siah - 1 is part of a novel regulatory loop controlling the level of OBF - 1 protein in B cells .", "sentence_char_start_global": 273457, "sentence_char_end_global": 273578, "entities": [{"text": "Siah - 1", "type": "ENTITY", "char_start": 24, "char_end": 32, "token_start": 4, "token_end": 6}, {"text": "OBF - 1 protein", "type": "ENTITY", "char_start": 93, "char_end": 108, "token_start": 18, "token_end": 21}], "entities_global": [{"text": "Siah - 1", "type": "ENTITY", "char_start": 273481, "char_end": 273489, "token_start": 4, "token_end": 6, "note": null}, {"text": "OBF - 1 protein", "type": "ENTITY", "char_start": 273550, "char_end": 273565, "token_start": 18, "token_end": 21, "note": null}]}
+{"sentence_id": 1665, "sentence_text": "The beta - catenin - - TCF - 1 pathway ensures CD4 ( + ) CD8 ( + ) thymocyte survival .", "sentence_char_start_global": 273579, "sentence_char_end_global": 273666, "entities": [], "entities_global": []}
+{"sentence_id": 1666, "sentence_text": "The association of trans - acting T cell factors ( TCFs ) or lymphoid enhancer factor 1 ( LEF - 1 ) with their coactivator beta - catenin mediates transient transcriptional responses to extracellular Wnt signals .", "sentence_char_start_global": 273667, "sentence_char_end_global": 273880, "entities": [{"text": "trans - acting T cell factors", "type": "ENTITY", "char_start": 19, "char_end": 48, "token_start": 3, "token_end": 8}, {"text": "TCFs", "type": "ENTITY", "char_start": 51, "char_end": 55, "token_start": 10, "token_end": 10}, {"text": "lymphoid enhancer factor 1", "type": "ENTITY", "char_start": 61, "char_end": 87, "token_start": 13, "token_end": 16}, {"text": "LEF - 1", "type": "ENTITY", "char_start": 90, "char_end": 97, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "trans - acting T cell factors", "type": "ENTITY", "char_start": 273686, "char_end": 273715, "token_start": 3, "token_end": 8, "note": null}, {"text": "TCFs", "type": "ENTITY", "char_start": 273718, "char_end": 273722, "token_start": 10, "token_end": 10, "note": null}, {"text": "lymphoid enhancer factor 1", "type": "ENTITY", "char_start": 273728, "char_end": 273754, "token_start": 13, "token_end": 16, "note": null}, {"text": "LEF - 1", "type": "ENTITY", "char_start": 273757, "char_end": 273764, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 1667, "sentence_text": "We show here that T cell maturation depends on the presence of the beta - catenin - - binding domain in TCF - 1 .", "sentence_char_start_global": 273881, "sentence_char_end_global": 273994, "entities": [{"text": "beta - catenin - - binding domain", "type": "ENTITY", "char_start": 67, "char_end": 100, "token_start": 13, "token_end": 19}, {"text": "TCF - 1", "type": "ENTITY", "char_start": 104, "char_end": 111, "token_start": 21, "token_end": 23}], "entities_global": [{"text": "beta - catenin - - binding domain", "type": "ENTITY", "char_start": 273948, "char_end": 273981, "token_start": 13, "token_end": 19, "note": null}, {"text": "TCF - 1", "type": "ENTITY", "char_start": 273985, "char_end": 273992, "token_start": 21, "token_end": 23, "note": null}]}
+{"sentence_id": 1668, "sentence_text": "This domain is necessary to mediate the survival of immature CD4 ( + ) CD8 ( + ) double - positive ( DP ) thymocytes .", "sentence_char_start_global": 273995, "sentence_char_end_global": 274113, "entities": [], "entities_global": []}
+{"sentence_id": 1669, "sentence_text": "Accelerated spontaneous thymocyte death in the absence of TCF - 1 correlates with aberrantly low expression of the anti - apoptotic protein Bcl - x ( L ) .", "sentence_char_start_global": 274114, "sentence_char_end_global": 274269, "entities": [{"text": "TCF - 1", "type": "ENTITY", "char_start": 58, "char_end": 65, "token_start": 8, "token_end": 10}, {"text": "anti - apoptotic protein", "type": "ENTITY", "char_start": 115, "char_end": 139, "token_start": 18, "token_end": 21}, {"text": "Bcl - x ( L )", "type": "ENTITY", "char_start": 140, "char_end": 153, "token_start": 22, "token_end": 27}], "entities_global": [{"text": "TCF - 1", "type": "ENTITY", "char_start": 274172, "char_end": 274179, "token_start": 8, "token_end": 10, "note": null}, {"text": "anti - apoptotic protein", "type": "ENTITY", "char_start": 274229, "char_end": 274253, "token_start": 18, "token_end": 21, "note": null}, {"text": "Bcl - x ( L )", "type": "ENTITY", "char_start": 274254, "char_end": 274267, "token_start": 22, "token_end": 27, "note": null}]}
+{"sentence_id": 1670, "sentence_text": "Increasing anti - apoptotic effectors in thymocytes by the use of a Bcl - 2 transgene rescued TCF - 1 - deficient DP thymocytes from apoptosis .", "sentence_char_start_global": 274270, "sentence_char_end_global": 274414, "entities": [{"text": "Bcl - 2 transgene", "type": "ENTITY", "char_start": 68, "char_end": 85, "token_start": 12, "token_end": 15}], "entities_global": [{"text": "Bcl - 2 transgene", "type": "ENTITY", "char_start": 274338, "char_end": 274355, "token_start": 12, "token_end": 15, "note": null}]}
+{"sentence_id": 1671, "sentence_text": "Thus , TCF - 1 , upon association with beta - catenin , transiently ensures the survival of immature T cells , which enables them to generate and edit T cell receptor ( TCR ) alpha chains and attempt TCR - mediated positive selection .", "sentence_char_start_global": 274415, "sentence_char_end_global": 274650, "entities": [{"text": "TCF - 1", "type": "ENTITY", "char_start": 7, "char_end": 14, "token_start": 2, "token_end": 4}, {"text": "T cell receptor ( TCR ) alpha chains", "type": "ENTITY", "char_start": 151, "char_end": 187, "token_start": 29, "token_end": 36}, {"text": "TCR", "type": "ENTITY", "char_start": 200, "char_end": 203, "token_start": 39, "token_end": 39}], "entities_global": [{"text": "TCF - 1", "type": "ENTITY", "char_start": 274422, "char_end": 274429, "token_start": 2, "token_end": 4, "note": null}, {"text": "T cell receptor ( TCR ) alpha chains", "type": "ENTITY", "char_start": 274566, "char_end": 274602, "token_start": 29, "token_end": 36, "note": null}, {"text": "TCR", "type": "ENTITY", "char_start": 274615, "char_end": 274618, "token_start": 39, "token_end": 39, "note": null}]}
+{"sentence_id": 1672, "sentence_text": "TRAIL / Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma : therapeutic applications .", "sentence_char_start_global": 274651, "sentence_char_end_global": 274780, "entities": [{"text": "TRAIL / Apo2L ligand", "type": "ENTITY", "char_start": 0, "char_end": 20, "token_start": 0, "token_end": 3}], "entities_global": [{"text": "TRAIL / Apo2L ligand", "type": "ENTITY", "char_start": 274651, "char_end": 274671, "token_start": 0, "token_end": 3, "note": null}]}
+{"sentence_id": 1673, "sentence_text": "Multiple myeloma ( MM ) remains incurable and novel treatments are urgently needed .", "sentence_char_start_global": 274781, "sentence_char_end_global": 274865, "entities": [], "entities_global": []}
+{"sentence_id": 1674, "sentence_text": "Preclinical in vitro and in vivo evaluations were performed to assess the potential therapeutic applications of human recombinant tumor necrosis factor ( TNF ) - related apoptosis - inducing ligand / Apo2 ligand ( TRAIL / Apo2L ) in MM .", "sentence_char_start_global": 274866, "sentence_char_end_global": 275103, "entities": [{"text": "tumor necrosis factor ( TNF ) - related apoptosis - inducing ligand / Apo2 ligand", "type": "ENTITY", "char_start": 130, "char_end": 211, "token_start": 18, "token_end": 32}, {"text": "TRAIL / Apo2L", "type": "ENTITY", "char_start": 214, "char_end": 227, "token_start": 34, "token_end": 36}], "entities_global": [{"text": "tumor necrosis factor ( TNF ) - related apoptosis - inducing ligand / Apo2 ligand", "type": "ENTITY", "char_start": 274996, "char_end": 275077, "token_start": 18, "token_end": 32, "note": null}, {"text": "TRAIL / Apo2L", "type": "ENTITY", "char_start": 275080, "char_end": 275093, "token_start": 34, "token_end": 36, "note": null}]}
+{"sentence_id": 1675, "sentence_text": "TRAIL / Apo2L potently induced apoptosis of MM cells from patients and the majority of MM cell lines , including cells sensitive or resistant to dexamethasone ( Dex ) , doxorubicin ( Dox ) , melphalan , and mitoxantrone .", "sentence_char_start_global": 275104, "sentence_char_end_global": 275325, "entities": [{"text": "TRAIL / Apo2L", "type": "ENTITY", "char_start": 0, "char_end": 13, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "TRAIL / Apo2L", "type": "ENTITY", "char_start": 275104, "char_end": 275117, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 1676, "sentence_text": "TRAIL / Apo2L also overcame the survival effect of interleukin 6 on MM cells and did not affect the survival of peripheral blood and bone marrow mononuclear cells and purified B cells from healthy donors .", "sentence_char_start_global": 275326, "sentence_char_end_global": 275531, "entities": [{"text": "TRAIL / Apo2L", "type": "ENTITY", "char_start": 0, "char_end": 13, "token_start": 0, "token_end": 2}, {"text": "interleukin 6", "type": "ENTITY", "char_start": 51, "char_end": 64, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "TRAIL / Apo2L", "type": "ENTITY", "char_start": 275326, "char_end": 275339, "token_start": 0, "token_end": 2, "note": null}, {"text": "interleukin 6", "type": "ENTITY", "char_start": 275377, "char_end": 275390, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 1677, "sentence_text": "The status of the TRAIL receptors ( assessed by immunoblotting and flow cytometry ) could not predict TRAIL sensitivity of MM cells .", "sentence_char_start_global": 275532, "sentence_char_end_global": 275665, "entities": [{"text": "TRAIL receptors", "type": "ENTITY", "char_start": 18, "char_end": 33, "token_start": 4, "token_end": 5}], "entities_global": [{"text": "TRAIL receptors", "type": "ENTITY", "char_start": 275550, "char_end": 275565, "token_start": 4, "token_end": 5, "note": null}]}
+{"sentence_id": 1678, "sentence_text": "The anti - MM activity of TRAIL / Apo2L was confirmed in nu / xid / bg mice xenografted with human MM cells ; TRAIL ( 500 microg intraperitoneally daily for 14 days ) was well tolerated and significantly suppressed the growth of plasmacytomas .", "sentence_char_start_global": 275666, "sentence_char_end_global": 275910, "entities": [{"text": "TRAIL / Apo2L", "type": "ENTITY", "char_start": 26, "char_end": 39, "token_start": 6, "token_end": 8}, {"text": "TRAIL", "type": "ENTITY", "char_start": 110, "char_end": 115, "token_start": 24, "token_end": 24}], "entities_global": [{"text": "TRAIL / Apo2L", "type": "ENTITY", "char_start": 275692, "char_end": 275705, "token_start": 6, "token_end": 8, "note": null}, {"text": "TRAIL", "type": "ENTITY", "char_start": 275776, "char_end": 275781, "token_start": 24, "token_end": 24, "note": null}]}
+{"sentence_id": 1679, "sentence_text": "Dox up - regulated the expression of the TRAIL receptor death receptor 5 ( DR5 ) and synergistically enhanced the effect of TRAIL not only against MM cells sensitive to , but also against those resistant to , Dex - or Dox - induced apoptosis .", "sentence_char_start_global": 275911, "sentence_char_end_global": 276154, "entities": [{"text": "TRAIL receptor", "type": "ENTITY", "char_start": 41, "char_end": 55, "token_start": 8, "token_end": 9}, {"text": "death receptor 5", "type": "ENTITY", "char_start": 56, "char_end": 72, "token_start": 10, "token_end": 12}, {"text": "DR5", "type": "ENTITY", "char_start": 75, "char_end": 78, "token_start": 14, "token_end": 14}, {"text": "TRAIL", "type": "ENTITY", "char_start": 124, "char_end": 129, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "TRAIL receptor", "type": "ENTITY", "char_start": 275952, "char_end": 275966, "token_start": 8, "token_end": 9, "note": null}, {"text": "death receptor 5", "type": "ENTITY", "char_start": 275967, "char_end": 275983, "token_start": 10, "token_end": 12, "note": null}, {"text": "DR5", "type": "ENTITY", "char_start": 275986, "char_end": 275989, "token_start": 14, "token_end": 14, "note": null}, {"text": "TRAIL", "type": "ENTITY", "char_start": 276035, "char_end": 276040, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 1680, "sentence_text": "Nuclear factor ( NF ) - kappaB inhibitors , such as SN50 ( a cell - permeable inhibitor of the nuclear translocation and transcriptional activity of NF - kappaB ) or the proteasome inhibitor PS - 341 , enhanced the proapoptotic activity of TRAIL / Apo2L against TRAIL - sensitive MM cells , whereas SN50 reversed the TRAIL resistance of ARH - 77 and IM - 9 MM cells .", "sentence_char_start_global": 276155, "sentence_char_end_global": 276522, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 149, "char_end": 160, "token_start": 26, "token_end": 28}, {"text": "TRAIL / Apo2L", "type": "ENTITY", "char_start": 240, "char_end": 253, "token_start": 43, "token_end": 45}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 276304, "char_end": 276315, "token_start": 26, "token_end": 28, "note": null}, {"text": "TRAIL / Apo2L", "type": "ENTITY", "char_start": 276395, "char_end": 276408, "token_start": 43, "token_end": 45, "note": null}]}
+{"sentence_id": 1681, "sentence_text": "Importantly , normal B lymphocytes were not sensitized to TRAIL by either Dox , SN50 , or PS - 341 .", "sentence_char_start_global": 276523, "sentence_char_end_global": 276623, "entities": [{"text": "TRAIL", "type": "ENTITY", "char_start": 58, "char_end": 63, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "TRAIL", "type": "ENTITY", "char_start": 276581, "char_end": 276586, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 1682, "sentence_text": "These preclinical studies suggest that TRAIL / Apo2L can overcome conventional drug resistance and provide the basis for clinical trials of TRAIL - based treatment regimens to improve outcome in patients with MM .", "sentence_char_start_global": 276624, "sentence_char_end_global": 276837, "entities": [{"text": "TRAIL / Apo2L", "type": "ENTITY", "char_start": 39, "char_end": 52, "token_start": 5, "token_end": 7}, {"text": "TRAIL", "type": "ENTITY", "char_start": 140, "char_end": 145, "token_start": 21, "token_end": 21}], "entities_global": [{"text": "TRAIL / Apo2L", "type": "ENTITY", "char_start": 276663, "char_end": 276676, "token_start": 5, "token_end": 7, "note": null}, {"text": "TRAIL", "type": "ENTITY", "char_start": 276764, "char_end": 276769, "token_start": 21, "token_end": 21, "note": null}]}
+{"sentence_id": 1683, "sentence_text": "( Blood . 2001 ; 98 : 795 - 804 )", "sentence_char_start_global": 276838, "sentence_char_end_global": 276871, "entities": [], "entities_global": []}
+{"sentence_id": 1684, "sentence_text": "CD28 costimulation is required not only to induce IL - 12 receptor but also to render janus kinases / STAT4 responsive to IL - 12 stimulation in TCR - triggered T cells .", "sentence_char_start_global": 276872, "sentence_char_end_global": 277042, "entities": [{"text": "CD28", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}, {"text": "IL - 12 receptor", "type": "ENTITY", "char_start": 50, "char_end": 66, "token_start": 8, "token_end": 11}, {"text": "janus kinases / STAT4", "type": "ENTITY", "char_start": 86, "char_end": 107, "token_start": 16, "token_end": 19}, {"text": "IL - 12", "type": "ENTITY", "char_start": 122, "char_end": 129, "token_start": 22, "token_end": 24}], "entities_global": [{"text": "CD28", "type": "ENTITY", "char_start": 276872, "char_end": 276876, "token_start": 0, "token_end": 0, "note": null}, {"text": "IL - 12 receptor", "type": "ENTITY", "char_start": 276922, "char_end": 276938, "token_start": 8, "token_end": 11, "note": null}, {"text": "janus kinases / STAT4", "type": "ENTITY", "char_start": 276958, "char_end": 276979, "token_start": 16, "token_end": 19, "note": null}, {"text": "IL - 12", "type": "ENTITY", "char_start": 276994, "char_end": 277001, "token_start": 22, "token_end": 24, "note": null}]}
+{"sentence_id": 1685, "sentence_text": "The activation of resting T cells for the acquisition of various functions depends on whether CD28 costimulatory signals are provided upon T cell receptor stimulation .", "sentence_char_start_global": 277043, "sentence_char_end_global": 277211, "entities": [], "entities_global": []}
+{"sentence_id": 1686, "sentence_text": "Here , we investigated how CD28 costimulation functions to allow TCR - triggered resting T cells to acquire IL - 12 responsiveness .", "sentence_char_start_global": 277212, "sentence_char_end_global": 277344, "entities": [{"text": "TCR", "type": "ENTITY", "char_start": 65, "char_end": 68, "token_start": 10, "token_end": 10}, {"text": "IL - 12", "type": "ENTITY", "char_start": 108, "char_end": 115, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "TCR", "type": "ENTITY", "char_start": 277277, "char_end": 277280, "token_start": 10, "token_end": 10, "note": null}, {"text": "IL - 12", "type": "ENTITY", "char_start": 277320, "char_end": 277327, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 1687, "sentence_text": "When T cells are stimulated with low doses of anti - CD3 mAb , CD28 costimulation was required for the optimal levels of IL - 12 receptor ( IL - 12R ) expression .", "sentence_char_start_global": 277345, "sentence_char_end_global": 277508, "entities": [{"text": "anti - CD3 mAb", "type": "ENTITY", "char_start": 46, "char_end": 60, "token_start": 9, "token_end": 12}, {"text": "IL - 12 receptor", "type": "ENTITY", "char_start": 121, "char_end": 137, "token_start": 23, "token_end": 26}, {"text": "IL - 12R", "type": "ENTITY", "char_start": 140, "char_end": 148, "token_start": 28, "token_end": 30}], "entities_global": [{"text": "anti - CD3 mAb", "type": "ENTITY", "char_start": 277391, "char_end": 277405, "token_start": 9, "token_end": 12, "note": null}, {"text": "IL - 12 receptor", "type": "ENTITY", "char_start": 277466, "char_end": 277482, "token_start": 23, "token_end": 26, "note": null}, {"text": "IL - 12R", "type": "ENTITY", "char_start": 277485, "char_end": 277493, "token_start": 28, "token_end": 30, "note": null}]}
+{"sentence_id": 1688, "sentence_text": "However , stimulation of T cells with high doses of anti - CD3 alone induced comparable levels of IL - 12R expression to those induced upon CD28 costimulation .", "sentence_char_start_global": 277509, "sentence_char_end_global": 277669, "entities": [{"text": "anti - CD3", "type": "ENTITY", "char_start": 52, "char_end": 62, "token_start": 10, "token_end": 12}, {"text": "IL - 12R", "type": "ENTITY", "char_start": 98, "char_end": 106, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "anti - CD3", "type": "ENTITY", "char_start": 277561, "char_end": 277571, "token_start": 10, "token_end": 12, "note": null}, {"text": "IL - 12R", "type": "ENTITY", "char_start": 277607, "char_end": 277615, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 1689, "sentence_text": "Nevertheless , there was a substantial difference in IL - 12 responsiveness between these two groups of T cells : compared to anti - CD28 - costimulated T cells , T cells that were not costimulated with anti - CD28 exhibited decreased levels of Janus kinases ( JAK ) JAK2 / TYK2 and STAT4 phosphorylation and IFN - y production following IL - 12 stimulation .", "sentence_char_start_global": 277670, "sentence_char_end_global": 278029, "entities": [{"text": "IL - 12", "type": "ENTITY", "char_start": 53, "char_end": 60, "token_start": 8, "token_end": 10}, {"text": "anti - CD28", "type": "ENTITY", "char_start": 203, "char_end": 214, "token_start": 37, "token_end": 39}, {"text": "Janus kinases", "type": "ENTITY", "char_start": 245, "char_end": 258, "token_start": 44, "token_end": 45}, {"text": "JAK", "type": "ENTITY", "char_start": 261, "char_end": 264, "token_start": 47, "token_end": 47}, {"text": "JAK2 / TYK2", "type": "ENTITY", "char_start": 267, "char_end": 278, "token_start": 49, "token_end": 51}, {"text": "STAT4", "type": "ENTITY", "char_start": 283, "char_end": 288, "token_start": 53, "token_end": 53}, {"text": "IL - 12", "type": "ENTITY", "char_start": 338, "char_end": 345, "token_start": 61, "token_end": 63}], "entities_global": [{"text": "IL - 12", "type": "ENTITY", "char_start": 277723, "char_end": 277730, "token_start": 8, "token_end": 10, "note": null}, {"text": "anti - CD28", "type": "ENTITY", "char_start": 277873, "char_end": 277884, "token_start": 37, "token_end": 39, "note": null}, {"text": "Janus kinases", "type": "ENTITY", "char_start": 277915, "char_end": 277928, "token_start": 44, "token_end": 45, "note": null}, {"text": "JAK", "type": "ENTITY", "char_start": 277931, "char_end": 277934, "token_start": 47, "token_end": 47, "note": null}, {"text": "JAK2 / TYK2", "type": "ENTITY", "char_start": 277937, "char_end": 277948, "token_start": 49, "token_end": 51, "note": null}, {"text": "STAT4", "type": "ENTITY", "char_start": 277953, "char_end": 277958, "token_start": 53, "token_end": 53, "note": null}, {"text": "IL - 12", "type": "ENTITY", "char_start": 278008, "char_end": 278015, "token_start": 61, "token_end": 63, "note": null}]}
+{"sentence_id": 1690, "sentence_text": "Importantly , STAT6 phosphorylation following IL - 4 stimulation was not decreased in anti - CD28 - uncostimulated T cells .", "sentence_char_start_global": 278030, "sentence_char_end_global": 278154, "entities": [], "entities_global": []}
+{"sentence_id": 1691, "sentence_text": "These resutls indicate that CD28 costimulation not only contributes to up - regulating IL - 12R expression but is also required to render JAKs / STAT4 responsive to IL - 12 stimulation .", "sentence_char_start_global": 278155, "sentence_char_end_global": 278341, "entities": [{"text": "IL - 12R", "type": "ENTITY", "char_start": 87, "char_end": 95, "token_start": 13, "token_end": 15}, {"text": "JAKs / STAT4", "type": "ENTITY", "char_start": 138, "char_end": 150, "token_start": 23, "token_end": 25}, {"text": "IL - 12", "type": "ENTITY", "char_start": 165, "char_end": 172, "token_start": 28, "token_end": 30}], "entities_global": [{"text": "IL - 12R", "type": "ENTITY", "char_start": 278242, "char_end": 278250, "token_start": 13, "token_end": 15, "note": null}, {"text": "JAKs / STAT4", "type": "ENTITY", "char_start": 278293, "char_end": 278305, "token_start": 23, "token_end": 25, "note": null}, {"text": "IL - 12", "type": "ENTITY", "char_start": 278320, "char_end": 278327, "token_start": 28, "token_end": 30, "note": null}]}
+{"sentence_id": 1692, "sentence_text": "Constitutively activated Akt - 1 is vital for the survival of human monocyte - differentiated macrophages .", "sentence_char_start_global": 278342, "sentence_char_end_global": 278449, "entities": [{"text": "Akt - 1", "type": "ENTITY", "char_start": 25, "char_end": 32, "token_start": 2, "token_end": 4}], "entities_global": [{"text": "Akt - 1", "type": "ENTITY", "char_start": 278367, "char_end": 278374, "token_start": 2, "token_end": 4, "note": null}]}
+{"sentence_id": 1693, "sentence_text": "Role of Mcl - 1 , independent of nuclear factor ( NF ) - kappaB , Bad , or caspase activation .", "sentence_char_start_global": 278450, "sentence_char_end_global": 278545, "entities": [{"text": "Mcl - 1", "type": "ENTITY", "char_start": 8, "char_end": 15, "token_start": 2, "token_end": 4}, {"text": "nuclear factor ( NF ) - kappaB", "type": "ENTITY", "char_start": 33, "char_end": 63, "token_start": 8, "token_end": 14}, {"text": "Bad", "type": "ENTITY", "char_start": 66, "char_end": 69, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "Mcl - 1", "type": "ENTITY", "char_start": 278458, "char_end": 278465, "token_start": 2, "token_end": 4, "note": null}, {"text": "nuclear factor ( NF ) - kappaB", "type": "ENTITY", "char_start": 278483, "char_end": 278513, "token_start": 8, "token_end": 14, "note": null}, {"text": "Bad", "type": "ENTITY", "char_start": 278516, "char_end": 278519, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 1694, "sentence_text": "Recent data from mice deficient for phosphatase and tensin homologue deleted from chromosome 10 or src homology 2 domain - containing 5 ' inositol phosphatase , phosphatases that negatively regulate the phosphatidylinositol 3 - kinase ( PI3K ) pathway , revealed an increased number of macrophages in these animals , suggesting an essential role for the PI3K pathway for macro - phage survival .", "sentence_char_start_global": 278546, "sentence_char_end_global": 278941, "entities": [{"text": "phosphatase", "type": "ENTITY", "char_start": 36, "char_end": 47, "token_start": 6, "token_end": 6}, {"text": "tensin homologue", "type": "ENTITY", "char_start": 52, "char_end": 68, "token_start": 8, "token_end": 9}, {"text": "chromosome 10", "type": "ENTITY", "char_start": 82, "char_end": 95, "token_start": 12, "token_end": 13}, {"text": "src homology 2 domain - containing 5 ' inositol phosphatase", "type": "ENTITY", "char_start": 99, "char_end": 158, "token_start": 15, "token_end": 24}, {"text": "phosphatases", "type": "ENTITY", "char_start": 161, "char_end": 173, "token_start": 26, "token_end": 26}, {"text": "phosphatidylinositol 3 - kinase", "type": "ENTITY", "char_start": 203, "char_end": 234, "token_start": 31, "token_end": 34}, {"text": "PI3K", "type": "ENTITY", "char_start": 237, "char_end": 241, "token_start": 36, "token_end": 36}, {"text": "PI3K", "type": "ENTITY", "char_start": 354, "char_end": 358, "token_start": 56, "token_end": 56}], "entities_global": [{"text": "phosphatase", "type": "ENTITY", "char_start": 278582, "char_end": 278593, "token_start": 6, "token_end": 6, "note": null}, {"text": "tensin homologue", "type": "ENTITY", "char_start": 278598, "char_end": 278614, "token_start": 8, "token_end": 9, "note": null}, {"text": "chromosome 10", "type": "ENTITY", "char_start": 278628, "char_end": 278641, "token_start": 12, "token_end": 13, "note": null}, {"text": "src homology 2 domain - containing 5 ' inositol phosphatase", "type": "ENTITY", "char_start": 278645, "char_end": 278704, "token_start": 15, "token_end": 24, "note": null}, {"text": "phosphatases", "type": "ENTITY", "char_start": 278707, "char_end": 278719, "token_start": 26, "token_end": 26, "note": null}, {"text": "phosphatidylinositol 3 - kinase", "type": "ENTITY", "char_start": 278749, "char_end": 278780, "token_start": 31, "token_end": 34, "note": null}, {"text": "PI3K", "type": "ENTITY", "char_start": 278783, "char_end": 278787, "token_start": 36, "token_end": 36, "note": null}, {"text": "PI3K", "type": "ENTITY", "char_start": 278900, "char_end": 278904, "token_start": 56, "token_end": 56, "note": null}]}
+{"sentence_id": 1695, "sentence_text": "Here , we focused on the role of the PI3K - regulated serine / threonine kinase Akt - 1 in modulating macrophage survival .", "sentence_char_start_global": 278942, "sentence_char_end_global": 279065, "entities": [{"text": "PI3K - regulated serine / threonine kinase", "type": "ENTITY", "char_start": 37, "char_end": 79, "token_start": 9, "token_end": 15}, {"text": "Akt - 1", "type": "ENTITY", "char_start": 80, "char_end": 87, "token_start": 16, "token_end": 18}], "entities_global": [{"text": "PI3K - regulated serine / threonine kinase", "type": "ENTITY", "char_start": 278979, "char_end": 279021, "token_start": 9, "token_end": 15, "note": null}, {"text": "Akt - 1", "type": "ENTITY", "char_start": 279022, "char_end": 279029, "token_start": 16, "token_end": 18, "note": null}]}
+{"sentence_id": 1696, "sentence_text": "Akt - 1 was constitutively activated in human macrophages and addition of the PI3K inhibitor , LY294002 , suppressed the activation of Akt - 1 and induced cell death .", "sentence_char_start_global": 279066, "sentence_char_end_global": 279233, "entities": [{"text": "Akt - 1", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 2}, {"text": "PI3K", "type": "ENTITY", "char_start": 78, "char_end": 82, "token_start": 13, "token_end": 13}, {"text": "Akt - 1", "type": "ENTITY", "char_start": 135, "char_end": 142, "token_start": 22, "token_end": 24}], "entities_global": [{"text": "Akt - 1", "type": "ENTITY", "char_start": 279066, "char_end": 279073, "token_start": 0, "token_end": 2, "note": null}, {"text": "PI3K", "type": "ENTITY", "char_start": 279144, "char_end": 279148, "token_start": 13, "token_end": 13, "note": null}, {"text": "Akt - 1", "type": "ENTITY", "char_start": 279201, "char_end": 279208, "token_start": 22, "token_end": 24, "note": null}]}
+{"sentence_id": 1697, "sentence_text": "Furthermore , suppression of Akt - 1 by inhibition of PI3K or a dominant negative ( DN ) Akt - 1 resulted in loss of mitochondrial transmembrane potential , activation of caspases - 9 and - 3 , and DNA fragmentation .", "sentence_char_start_global": 279234, "sentence_char_end_global": 279451, "entities": [{"text": "Akt - 1", "type": "ENTITY", "char_start": 29, "char_end": 36, "token_start": 4, "token_end": 6}, {"text": "PI3K", "type": "ENTITY", "char_start": 54, "char_end": 58, "token_start": 10, "token_end": 10}, {"text": "dominant negative ( DN ) Akt - 1", "type": "ENTITY", "char_start": 64, "char_end": 96, "token_start": 13, "token_end": 20}, {"text": "caspases - 9 and - 3", "type": "ENTITY", "char_start": 171, "char_end": 191, "token_start": 31, "token_end": 36}], "entities_global": [{"text": "Akt - 1", "type": "ENTITY", "char_start": 279263, "char_end": 279270, "token_start": 4, "token_end": 6, "note": null}, {"text": "PI3K", "type": "ENTITY", "char_start": 279288, "char_end": 279292, "token_start": 10, "token_end": 10, "note": null}, {"text": "dominant negative ( DN ) Akt - 1", "type": "ENTITY", "char_start": 279298, "char_end": 279330, "token_start": 13, "token_end": 20, "note": null}, {"text": "caspases - 9 and - 3", "type": "ENTITY", "char_start": 279405, "char_end": 279425, "token_start": 31, "token_end": 36, "note": null}]}
+{"sentence_id": 1698, "sentence_text": "The effects of PI3K inhibition were reversed by the ectopic expression of constitutively activated Akt - 1 or Bcl - x ( L ) .", "sentence_char_start_global": 279452, "sentence_char_end_global": 279577, "entities": [{"text": "PI3K", "type": "ENTITY", "char_start": 15, "char_end": 19, "token_start": 3, "token_end": 3}, {"text": "Akt - 1", "type": "ENTITY", "char_start": 99, "char_end": 106, "token_start": 14, "token_end": 16}, {"text": "Bcl - x ( L )", "type": "ENTITY", "char_start": 110, "char_end": 123, "token_start": 18, "token_end": 23}], "entities_global": [{"text": "PI3K", "type": "ENTITY", "char_start": 279467, "char_end": 279471, "token_start": 3, "token_end": 3, "note": null}, {"text": "Akt - 1", "type": "ENTITY", "char_start": 279551, "char_end": 279558, "token_start": 14, "token_end": 16, "note": null}, {"text": "Bcl - x ( L )", "type": "ENTITY", "char_start": 279562, "char_end": 279575, "token_start": 18, "token_end": 23, "note": null}]}
+{"sentence_id": 1699, "sentence_text": "Inhibition of PI3K / Akt - 1 pathway either by LY294002 or DN Akt - 1 had no effect on the constitutive or inducible activation of nuclear factor ( NF ) - kappaB in human macrophages .", "sentence_char_start_global": 279578, "sentence_char_end_global": 279762, "entities": [{"text": "PI3K", "type": "ENTITY", "char_start": 14, "char_end": 18, "token_start": 2, "token_end": 2}, {"text": "DN Akt - 1", "type": "ENTITY", "char_start": 59, "char_end": 69, "token_start": 12, "token_end": 15}, {"text": "nuclear factor ( NF ) - kappaB", "type": "ENTITY", "char_start": 131, "char_end": 161, "token_start": 26, "token_end": 32}], "entities_global": [{"text": "PI3K", "type": "ENTITY", "char_start": 279592, "char_end": 279596, "token_start": 2, "token_end": 2, "note": null}, {"text": "DN Akt - 1", "type": "ENTITY", "char_start": 279637, "char_end": 279647, "token_start": 12, "token_end": 15, "note": null}, {"text": "nuclear factor ( NF ) - kappaB", "type": "ENTITY", "char_start": 279709, "char_end": 279739, "token_start": 26, "token_end": 32, "note": null}]}
+{"sentence_id": 1700, "sentence_text": "However , after inhibition of the PI3K / Akt - 1 pathway , a marked decrease in the expression of the antiapoptotic molecule Mcl - 1 , but not other Bcl - 2 family members was observed , and Mcl - 1 rescued macrophages from LY294002 - induced cell death .", "sentence_char_start_global": 279763, "sentence_char_end_global": 280018, "entities": [{"text": "PI3K", "type": "ENTITY", "char_start": 34, "char_end": 38, "token_start": 6, "token_end": 6}, {"text": "Akt - 1", "type": "ENTITY", "char_start": 41, "char_end": 48, "token_start": 8, "token_end": 10}, {"text": "antiapoptotic molecule", "type": "ENTITY", "char_start": 102, "char_end": 124, "token_start": 21, "token_end": 22}, {"text": "Mcl - 1", "type": "ENTITY", "char_start": 125, "char_end": 132, "token_start": 23, "token_end": 25}, {"text": "Bcl - 2 family members", "type": "ENTITY", "char_start": 149, "char_end": 171, "token_start": 30, "token_end": 34}, {"text": "Mcl - 1", "type": "ENTITY", "char_start": 191, "char_end": 198, "token_start": 39, "token_end": 41}], "entities_global": [{"text": "PI3K", "type": "ENTITY", "char_start": 279797, "char_end": 279801, "token_start": 6, "token_end": 6, "note": null}, {"text": "Akt - 1", "type": "ENTITY", "char_start": 279804, "char_end": 279811, "token_start": 8, "token_end": 10, "note": null}, {"text": "antiapoptotic molecule", "type": "ENTITY", "char_start": 279865, "char_end": 279887, "token_start": 21, "token_end": 22, "note": null}, {"text": "Mcl - 1", "type": "ENTITY", "char_start": 279888, "char_end": 279895, "token_start": 23, "token_end": 25, "note": null}, {"text": "Bcl - 2 family members", "type": "ENTITY", "char_start": 279912, "char_end": 279934, "token_start": 30, "token_end": 34, "note": null}, {"text": "Mcl - 1", "type": "ENTITY", "char_start": 279954, "char_end": 279961, "token_start": 39, "token_end": 41, "note": null}]}
+{"sentence_id": 1701, "sentence_text": "Further , inhibition of Mcl - 1 by antisense oligonucleotides , also resulted in macrophage apoptosis .", "sentence_char_start_global": 280019, "sentence_char_end_global": 280122, "entities": [{"text": "Mcl - 1", "type": "ENTITY", "char_start": 24, "char_end": 31, "token_start": 4, "token_end": 6}], "entities_global": [{"text": "Mcl - 1", "type": "ENTITY", "char_start": 280043, "char_end": 280050, "token_start": 4, "token_end": 6, "note": null}]}
+{"sentence_id": 1702, "sentence_text": "Thus , our findings demonstrate that the constitutive activation of Akt - 1 regulates macrophage survival through Mcl - 1 , which is independent of caspases , NF - kappaB , or Bad .", "sentence_char_start_global": 280123, "sentence_char_end_global": 280304, "entities": [{"text": "Akt - 1", "type": "ENTITY", "char_start": 68, "char_end": 75, "token_start": 10, "token_end": 12}, {"text": "Mcl - 1", "type": "ENTITY", "char_start": 114, "char_end": 121, "token_start": 17, "token_end": 19}, {"text": "caspases", "type": "ENTITY", "char_start": 148, "char_end": 156, "token_start": 25, "token_end": 25}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 159, "char_end": 170, "token_start": 27, "token_end": 29}, {"text": "Bad", "type": "ENTITY", "char_start": 176, "char_end": 179, "token_start": 32, "token_end": 32}], "entities_global": [{"text": "Akt - 1", "type": "ENTITY", "char_start": 280191, "char_end": 280198, "token_start": 10, "token_end": 12, "note": null}, {"text": "Mcl - 1", "type": "ENTITY", "char_start": 280237, "char_end": 280244, "token_start": 17, "token_end": 19, "note": null}, {"text": "caspases", "type": "ENTITY", "char_start": 280271, "char_end": 280279, "token_start": 25, "token_end": 25, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 280282, "char_end": 280293, "token_start": 27, "token_end": 29, "note": null}, {"text": "Bad", "type": "ENTITY", "char_start": 280299, "char_end": 280302, "token_start": 32, "token_end": 32, "note": null}]}
+{"sentence_id": 1703, "sentence_text": "GRbeta expression in nasal polyp inflammatory cells and its relationship to the anti - inflammatory effects of intranasal fluticasone .", "sentence_char_start_global": 280305, "sentence_char_end_global": 280440, "entities": [], "entities_global": []}
+{"sentence_id": 1704, "sentence_text": "BACKGROUND : Nasal polyposis disease is an inflammatory disorder with intense eosinophilic infiltration of respiratory mucosa that is often difficult to control with topical steroids .", "sentence_char_start_global": 280441, "sentence_char_end_global": 280625, "entities": [], "entities_global": []}
+{"sentence_id": 1705, "sentence_text": "Recent evidence suggests that overexpression of the glucocorticoid receptor splice variant GRbeta in inflammatory cells might contribute to steroid insensitivity in diseases such as asthma .", "sentence_char_start_global": 280626, "sentence_char_end_global": 280816, "entities": [{"text": "glucocorticoid receptor splice variant", "type": "ENTITY", "char_start": 52, "char_end": 90, "token_start": 7, "token_end": 10}, {"text": "GRbeta", "type": "ENTITY", "char_start": 91, "char_end": 97, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "glucocorticoid receptor splice variant", "type": "ENTITY", "char_start": 280678, "char_end": 280716, "token_start": 7, "token_end": 10, "note": null}, {"text": "GRbeta", "type": "ENTITY", "char_start": 280717, "char_end": 280723, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 1706, "sentence_text": "OBJECTIVE : The purposes of this investigation were to determine whether nasal polyp ( NP ) inflammatory cells overexpress GRbeta and to examine whether GRbeta overexpression is associated with insensitivity to the potent topical steroid fluticasone propionate ( FP ) .", "sentence_char_start_global": 280817, "sentence_char_end_global": 281086, "entities": [{"text": "GRbeta", "type": "ENTITY", "char_start": 123, "char_end": 129, "token_start": 19, "token_end": 19}, {"text": "GRbeta", "type": "ENTITY", "char_start": 153, "char_end": 159, "token_start": 24, "token_end": 24}], "entities_global": [{"text": "GRbeta", "type": "ENTITY", "char_start": 280940, "char_end": 280946, "token_start": 19, "token_end": 19, "note": null}, {"text": "GRbeta", "type": "ENTITY", "char_start": 280970, "char_end": 280976, "token_start": 24, "token_end": 24, "note": null}]}
+{"sentence_id": 1707, "sentence_text": "METHODS : Biopsies were obtained from 10 subjects with NPs before and 4 weeks after treatment with intranasal FP .", "sentence_char_start_global": 281087, "sentence_char_end_global": 281201, "entities": [], "entities_global": []}
+{"sentence_id": 1708, "sentence_text": "Middle turbinates biopsies from 6 healthy , nonallergic subjects served as normal controls .", "sentence_char_start_global": 281202, "sentence_char_end_global": 281294, "entities": [], "entities_global": []}
+{"sentence_id": 1709, "sentence_text": "Biopsies were immunostained for inflammatory cell markers as well as GRbeta and probed for various cytokine mRNA .", "sentence_char_start_global": 281295, "sentence_char_end_global": 281409, "entities": [{"text": "GRbeta", "type": "ENTITY", "char_start": 69, "char_end": 75, "token_start": 10, "token_end": 10}, {"text": "cytokine mRNA", "type": "ENTITY", "char_start": 99, "char_end": 112, "token_start": 15, "token_end": 16}], "entities_global": [{"text": "GRbeta", "type": "ENTITY", "char_start": 281364, "char_end": 281370, "token_start": 10, "token_end": 10, "note": null}, {"text": "cytokine mRNA", "type": "ENTITY", "char_start": 281394, "char_end": 281407, "token_start": 15, "token_end": 16, "note": null}]}
+{"sentence_id": 1710, "sentence_text": "The anti - inflammatory response to FP was examined in relation to pretreatment levels of GRbeta expression .", "sentence_char_start_global": 281410, "sentence_char_end_global": 281519, "entities": [], "entities_global": []}
+{"sentence_id": 1711, "sentence_text": "RESULTS : The total numbers of inflammatory cells were increased in NPs .", "sentence_char_start_global": 281520, "sentence_char_end_global": 281593, "entities": [], "entities_global": []}
+{"sentence_id": 1712, "sentence_text": "The percentage of inflammatory cells expressing GRbeta was also increased ( 40 . 5 % + / - 19 . 2 % vs 16 . 1 % + / - 4 . 0 % , P = . 009 ) .", "sentence_char_start_global": 281594, "sentence_char_end_global": 281735, "entities": [{"text": "GRbeta", "type": "ENTITY", "char_start": 48, "char_end": 54, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "GRbeta", "type": "ENTITY", "char_start": 281642, "char_end": 281648, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 1713, "sentence_text": "GRbeta expression in NPs was almost exclusive to T lymphocytes , eosinophils , and macrophages .", "sentence_char_start_global": 281736, "sentence_char_end_global": 281832, "entities": [{"text": "GRbeta", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "GRbeta", "type": "ENTITY", "char_start": 281736, "char_end": 281742, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 1714, "sentence_text": "An inverse correlation was observed between the baseline inflammatory cell GRbeta expression and the reduction after FP treatment in EG2 - positive eosinophils , CD4 - positive T lymphocytes , endothelial VCAM - 1 expression , and IL - 4 mRNA - positive cells .", "sentence_char_start_global": 281833, "sentence_char_end_global": 282094, "entities": [{"text": "GRbeta", "type": "ENTITY", "char_start": 75, "char_end": 81, "token_start": 10, "token_end": 10}, {"text": "VCAM - 1", "type": "ENTITY", "char_start": 205, "char_end": 213, "token_start": 31, "token_end": 33}], "entities_global": [{"text": "GRbeta", "type": "ENTITY", "char_start": 281908, "char_end": 281914, "token_start": 10, "token_end": 10, "note": null}, {"text": "VCAM - 1", "type": "ENTITY", "char_start": 282038, "char_end": 282046, "token_start": 31, "token_end": 33, "note": null}]}
+{"sentence_id": 1715, "sentence_text": "NPs that were ` ` FP - insensitive ' ' in terms of suppression of eosinophil numbers ( major basic protein - positive ) had a significantly greater percentage of GRbeta - positive inflammatory cells , a higher ratio of GRbeta - positive / GRalpha - positive cells , and increased numbers of GRbeta - positive eosinophils and macrophages in comparison with those that were ` ` FP - sensitive . ' '", "sentence_char_start_global": 282095, "sentence_char_end_global": 282491, "entities": [{"text": "major basic protein", "type": "ENTITY", "char_start": 87, "char_end": 106, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "major basic protein", "type": "ENTITY", "char_start": 282182, "char_end": 282201, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 1716, "sentence_text": "` ` FP - insensitive ' ' NPs also demonstrated a higher percentage of IL - 5 - positive inflammatory cells expressing GRbeta before and after FP treatment .", "sentence_char_start_global": 282492, "sentence_char_end_global": 282648, "entities": [{"text": "GRbeta", "type": "ENTITY", "char_start": 118, "char_end": 124, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "GRbeta", "type": "ENTITY", "char_start": 282610, "char_end": 282616, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 1717, "sentence_text": "CONCLUSION : GRbeta expression appears to be a marker of steroid insensitivity in NPs .", "sentence_char_start_global": 282649, "sentence_char_end_global": 282736, "entities": [{"text": "GRbeta", "type": "ENTITY", "char_start": 13, "char_end": 19, "token_start": 2, "token_end": 2}], "entities_global": [{"text": "GRbeta", "type": "ENTITY", "char_start": 282662, "char_end": 282668, "token_start": 2, "token_end": 2, "note": null}]}
+{"sentence_id": 1718, "sentence_text": "Expression of GRbeta by NP inflammatory cells , particularly T cells and eosinophils , might render them resistant to suppression by topical steroids and thereby contribute to persistent NP inflammation .", "sentence_char_start_global": 282737, "sentence_char_end_global": 282941, "entities": [{"text": "GRbeta", "type": "ENTITY", "char_start": 14, "char_end": 20, "token_start": 2, "token_end": 2}], "entities_global": [{"text": "GRbeta", "type": "ENTITY", "char_start": 282751, "char_end": 282757, "token_start": 2, "token_end": 2, "note": null}]}
+{"sentence_id": 1719, "sentence_text": "Transcriptional regulation of galectin - 10 ( eosinophil Charcot - Leyden crystal protein ) : a GC box ( - 44 to - 50 ) controls butyric acid induction of gene expression .", "sentence_char_start_global": 282942, "sentence_char_end_global": 283114, "entities": [{"text": "galectin - 10", "type": "ENTITY", "char_start": 30, "char_end": 43, "token_start": 3, "token_end": 5}, {"text": "eosinophil Charcot - Leyden crystal protein", "type": "ENTITY", "char_start": 46, "char_end": 89, "token_start": 7, "token_end": 12}, {"text": "GC box", "type": "ENTITY", "char_start": 96, "char_end": 102, "token_start": 16, "token_end": 17}], "entities_global": [{"text": "galectin - 10", "type": "ENTITY", "char_start": 282972, "char_end": 282985, "token_start": 3, "token_end": 5, "note": null}, {"text": "eosinophil Charcot - Leyden crystal protein", "type": "ENTITY", "char_start": 282988, "char_end": 283031, "token_start": 7, "token_end": 12, "note": null}, {"text": "GC box", "type": "ENTITY", "char_start": 283038, "char_end": 283044, "token_start": 16, "token_end": 17, "note": null}]}
+{"sentence_id": 1720, "sentence_text": "Galectin - 10 ( gal - 10 , also known as Charcot - Leyden crystal protein ) is a member of the galectin family of beta - galactoside binding proteins that is expressed uniquely in eosinophilic and basophilic leukocytes .", "sentence_char_start_global": 283115, "sentence_char_end_global": 283335, "entities": [{"text": "Galectin - 10", "type": "ENTITY", "char_start": 0, "char_end": 13, "token_start": 0, "token_end": 2}, {"text": "gal - 10", "type": "ENTITY", "char_start": 16, "char_end": 24, "token_start": 4, "token_end": 6}, {"text": "Charcot - Leyden crystal protein", "type": "ENTITY", "char_start": 41, "char_end": 73, "token_start": 11, "token_end": 15}, {"text": "galectin family", "type": "ENTITY", "char_start": 95, "char_end": 110, "token_start": 22, "token_end": 23}, {"text": "beta - galactoside binding proteins", "type": "ENTITY", "char_start": 114, "char_end": 149, "token_start": 25, "token_end": 29}], "entities_global": [{"text": "Galectin - 10", "type": "ENTITY", "char_start": 283115, "char_end": 283128, "token_start": 0, "token_end": 2, "note": null}, {"text": "gal - 10", "type": "ENTITY", "char_start": 283131, "char_end": 283139, "token_start": 4, "token_end": 6, "note": null}, {"text": "Charcot - Leyden crystal protein", "type": "ENTITY", "char_start": 283156, "char_end": 283188, "token_start": 11, "token_end": 15, "note": null}, {"text": "galectin family", "type": "ENTITY", "char_start": 283210, "char_end": 283225, "token_start": 22, "token_end": 23, "note": null}, {"text": "beta - galactoside binding proteins", "type": "ENTITY", "char_start": 283229, "char_end": 283264, "token_start": 25, "token_end": 29, "note": null}]}
+{"sentence_id": 1721, "sentence_text": "To gain a better understanding of galectin gene expression , we present an analysis of the transcriptional regulation of the gene encoding gal - 10 .", "sentence_char_start_global": 283336, "sentence_char_end_global": 283485, "entities": [{"text": "gal - 10", "type": "ENTITY", "char_start": 139, "char_end": 147, "token_start": 22, "token_end": 24}], "entities_global": [{"text": "gal - 10", "type": "ENTITY", "char_start": 283475, "char_end": 283483, "token_start": 22, "token_end": 24, "note": null}]}
+{"sentence_id": 1722, "sentence_text": "Analysis of the minimal promoter revealed nine consensus - binding sites for transcription factors , including several that are also found in the minimal promoters of galectins - 1 , - 2 , and - 3 .", "sentence_char_start_global": 283486, "sentence_char_end_global": 283684, "entities": [{"text": "minimal promoter", "type": "ENTITY", "char_start": 16, "char_end": 32, "token_start": 3, "token_end": 4}, {"text": "consensus - binding sites", "type": "ENTITY", "char_start": 47, "char_end": 72, "token_start": 7, "token_end": 10}, {"text": "transcription factors", "type": "ENTITY", "char_start": 77, "char_end": 98, "token_start": 12, "token_end": 13}, {"text": "minimal promoters", "type": "ENTITY", "char_start": 146, "char_end": 163, "token_start": 23, "token_end": 24}, {"text": "galectins - 1 , - 2 , and - 3", "type": "ENTITY", "char_start": 167, "char_end": 196, "token_start": 26, "token_end": 35}], "entities_global": [{"text": "minimal promoter", "type": "ENTITY", "char_start": 283502, "char_end": 283518, "token_start": 3, "token_end": 4, "note": null}, {"text": "consensus - binding sites", "type": "ENTITY", "char_start": 283533, "char_end": 283558, "token_start": 7, "token_end": 10, "note": null}, {"text": "transcription factors", "type": "ENTITY", "char_start": 283563, "char_end": 283584, "token_start": 12, "token_end": 13, "note": null}, {"text": "minimal promoters", "type": "ENTITY", "char_start": 283632, "char_end": 283649, "token_start": 23, "token_end": 24, "note": null}, {"text": "galectins - 1 , - 2 , and - 3", "type": "ENTITY", "char_start": 283653, "char_end": 283682, "token_start": 26, "token_end": 35, "note": null}]}
+{"sentence_id": 1723, "sentence_text": "The decrease in gal - 10 promoter activity after disruption of either the GC box ( - 44 to - 50 ) or the Oct site ( - 255 to - 261 ) suggests that these sites , along with the previously characterized GATA and EoTF sites , are necessary for full promoter activity .", "sentence_char_start_global": 283685, "sentence_char_end_global": 283950, "entities": [{"text": "GC box", "type": "ENTITY", "char_start": 74, "char_end": 80, "token_start": 13, "token_end": 14}, {"text": "Oct site", "type": "ENTITY", "char_start": 105, "char_end": 113, "token_start": 24, "token_end": 25}, {"text": "GATA and EoTF sites", "type": "ENTITY", "char_start": 201, "char_end": 220, "token_start": 43, "token_end": 46}], "entities_global": [{"text": "GC box", "type": "ENTITY", "char_start": 283759, "char_end": 283765, "token_start": 13, "token_end": 14, "note": null}, {"text": "Oct site", "type": "ENTITY", "char_start": 283790, "char_end": 283798, "token_start": 24, "token_end": 25, "note": null}, {"text": "GATA and EoTF sites", "type": "ENTITY", "char_start": 283886, "char_end": 283905, "token_start": 43, "token_end": 46, "note": null}]}
+{"sentence_id": 1724, "sentence_text": "By supershift analysis , we demonstrate binding of the transcription factors Sp1 and Oct1 to the consensus GC box and the Oct site , respectively .", "sentence_char_start_global": 283951, "sentence_char_end_global": 284098, "entities": [{"text": "transcription factors", "type": "ENTITY", "char_start": 55, "char_end": 76, "token_start": 9, "token_end": 10}, {"text": "Sp1", "type": "ENTITY", "char_start": 77, "char_end": 80, "token_start": 11, "token_end": 11}, {"text": "Oct1", "type": "ENTITY", "char_start": 85, "char_end": 89, "token_start": 13, "token_end": 13}, {"text": "consensus GC box", "type": "ENTITY", "char_start": 97, "char_end": 113, "token_start": 16, "token_end": 18}, {"text": "Oct site", "type": "ENTITY", "char_start": 122, "char_end": 130, "token_start": 21, "token_end": 22}], "entities_global": [{"text": "transcription factors", "type": "ENTITY", "char_start": 284006, "char_end": 284027, "token_start": 9, "token_end": 10, "note": null}, {"text": "Sp1", "type": "ENTITY", "char_start": 284028, "char_end": 284031, "token_start": 11, "token_end": 11, "note": null}, {"text": "Oct1", "type": "ENTITY", "char_start": 284036, "char_end": 284040, "token_start": 13, "token_end": 13, "note": null}, {"text": "consensus GC box", "type": "ENTITY", "char_start": 284048, "char_end": 284064, "token_start": 16, "token_end": 18, "note": null}, {"text": "Oct site", "type": "ENTITY", "char_start": 284073, "char_end": 284081, "token_start": 21, "token_end": 22, "note": null}]}
+{"sentence_id": 1725, "sentence_text": "Similar to gal - 1 , gal - 10 expression is induced by butyric acid , an effect that is lost upon ablation of the GC box .", "sentence_char_start_global": 284099, "sentence_char_end_global": 284221, "entities": [{"text": "gal - 1", "type": "ENTITY", "char_start": 11, "char_end": 18, "token_start": 2, "token_end": 4}, {"text": "GC box", "type": "ENTITY", "char_start": 114, "char_end": 120, "token_start": 25, "token_end": 26}], "entities_global": [{"text": "gal - 1", "type": "ENTITY", "char_start": 284110, "char_end": 284117, "token_start": 2, "token_end": 4, "note": null}, {"text": "GC box", "type": "ENTITY", "char_start": 284213, "char_end": 284219, "token_start": 25, "token_end": 26, "note": null}]}
+{"sentence_id": 1726, "sentence_text": "Additionally , we demonstrate AML3 binding to the consensus AML site and YY1 binding to the Inr sequence , both elements functioning as silencers in the gal - 10 promoter .", "sentence_char_start_global": 284222, "sentence_char_end_global": 284394, "entities": [{"text": "consensus AML site", "type": "ENTITY", "char_start": 50, "char_end": 68, "token_start": 8, "token_end": 10}, {"text": "YY1 binding", "type": "ENTITY", "char_start": 73, "char_end": 84, "token_start": 12, "token_end": 13}, {"text": "Inr sequence", "type": "ENTITY", "char_start": 92, "char_end": 104, "token_start": 16, "token_end": 17}, {"text": "gal - 10 promoter", "type": "ENTITY", "char_start": 153, "char_end": 170, "token_start": 26, "token_end": 29}], "entities_global": [{"text": "consensus AML site", "type": "ENTITY", "char_start": 284272, "char_end": 284290, "token_start": 8, "token_end": 10, "note": null}, {"text": "YY1 binding", "type": "ENTITY", "char_start": 284295, "char_end": 284306, "token_start": 12, "token_end": 13, "note": null}, {"text": "Inr sequence", "type": "ENTITY", "char_start": 284314, "char_end": 284326, "token_start": 16, "token_end": 17, "note": null}, {"text": "gal - 10 promoter", "type": "ENTITY", "char_start": 284375, "char_end": 284392, "token_start": 26, "token_end": 29, "note": null}]}
+{"sentence_id": 1727, "sentence_text": "Tumour - stromal interactions .", "sentence_char_start_global": 284395, "sentence_char_end_global": 284426, "entities": [], "entities_global": []}
+{"sentence_id": 1728, "sentence_text": "Role of the stroma in mammary development .", "sentence_char_start_global": 284427, "sentence_char_end_global": 284470, "entities": [], "entities_global": []}
+{"sentence_id": 1729, "sentence_text": "Mammary development depends on branching morphogenesis , namely the bifurcation and extension of ductal growth points ( end buds ) and secretory lobules into a more or less fatty stroma .", "sentence_char_start_global": 284471, "sentence_char_end_global": 284658, "entities": [], "entities_global": []}
+{"sentence_id": 1730, "sentence_text": "Because breast carcinomas are overwhelmingly ductal in origin , this review focuses on stromal influences guiding postnatal ductal development and there is only the briefest account of the role of embryonic stroma ( mesenchyme ) .", "sentence_char_start_global": 284659, "sentence_char_end_global": 284889, "entities": [], "entities_global": []}
+{"sentence_id": 1731, "sentence_text": "The stroma as the necessary target for endocrine mammogens and the source of stimulatory growth factors is described and the importance of mammary epithelium - induced modifications of the periductal stroma is emphasized .", "sentence_char_start_global": 284890, "sentence_char_end_global": 285112, "entities": [], "entities_global": []}
+{"sentence_id": 1732, "sentence_text": "Evidence is presented that if they are to grow , end buds must condition proximal fatty stroma by recruiting white blood cells as well as inducing stromal cell division and , possibly , estrogen receptors .", "sentence_char_start_global": 285113, "sentence_char_end_global": 285319, "entities": [{"text": "estrogen receptors", "type": "ENTITY", "char_start": 186, "char_end": 204, "token_start": 33, "token_end": 34}], "entities_global": [{"text": "estrogen receptors", "type": "ENTITY", "char_start": 285299, "char_end": 285317, "token_start": 33, "token_end": 34, "note": null}]}
+{"sentence_id": 1733, "sentence_text": "The induction of a fibrous stromal tunic around the end bud is described and its likely role as a complex ductal morphogen is discussed ; a possible role in growth inhibition is also considered .", "sentence_char_start_global": 285320, "sentence_char_end_global": 285515, "entities": [], "entities_global": []}
+{"sentence_id": 1734, "sentence_text": "Although the signals governing fibrotic induction , ductal morphogenesis , and growth inhibition are unknown , a role for transforming growth factor - beta is highly likely and is discussed .", "sentence_char_start_global": 285516, "sentence_char_end_global": 285707, "entities": [{"text": "growth factor - beta", "type": "ENTITY", "char_start": 135, "char_end": 155, "token_start": 20, "token_end": 23}], "entities_global": [{"text": "growth factor - beta", "type": "ENTITY", "char_start": 285651, "char_end": 285671, "token_start": 20, "token_end": 23, "note": null}]}
+{"sentence_id": 1735, "sentence_text": "Finally , a need for new conceptual and experimental approaches to understanding stromal - epithelial signaling is discussed .", "sentence_char_start_global": 285708, "sentence_char_end_global": 285834, "entities": [], "entities_global": []}
+{"sentence_id": 1736, "sentence_text": "Adipophilin is a sensitive marker for lipid loading in human blood monocytes .", "sentence_char_start_global": 285835, "sentence_char_end_global": 285913, "entities": [{"text": "Adipophilin", "type": "ENTITY", "char_start": 0, "char_end": 11, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "Adipophilin", "type": "ENTITY", "char_start": 285835, "char_end": 285846, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 1737, "sentence_text": "Adipophilin , a marker of lipid accumulation initially described in adipocytes , was recently shown to be induced in macrophage foam cells .", "sentence_char_start_global": 285914, "sentence_char_end_global": 286054, "entities": [{"text": "Adipophilin", "type": "ENTITY", "char_start": 0, "char_end": 11, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "Adipophilin", "type": "ENTITY", "char_start": 285914, "char_end": 285925, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 1738, "sentence_text": "We found that even freshly isolated blood monocytes express adipophilin and that the amount of adipophilin protein is variable in monocytes from different healthy individuals .", "sentence_char_start_global": 286055, "sentence_char_end_global": 286231, "entities": [{"text": "adipophilin", "type": "ENTITY", "char_start": 60, "char_end": 71, "token_start": 9, "token_end": 9}, {"text": "adipophilin protein", "type": "ENTITY", "char_start": 95, "char_end": 114, "token_start": 15, "token_end": 16}], "entities_global": [{"text": "adipophilin", "type": "ENTITY", "char_start": 286115, "char_end": 286126, "token_start": 9, "token_end": 9, "note": null}, {"text": "adipophilin protein", "type": "ENTITY", "char_start": 286150, "char_end": 286169, "token_start": 15, "token_end": 16, "note": null}]}
+{"sentence_id": 1739, "sentence_text": "However , the physiological expression of adipophilin does not correlate with the levels of free fatty acids , cholesterylesters or free cholesterol .", "sentence_char_start_global": 286232, "sentence_char_end_global": 286382, "entities": [{"text": "adipophilin", "type": "ENTITY", "char_start": 42, "char_end": 53, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "adipophilin", "type": "ENTITY", "char_start": 286274, "char_end": 286285, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 1740, "sentence_text": "Enzymatically modified low - density lipoprotein ( E - LDL ) induces rapid foam cell formation in monocytes and upregulates adipophilin mRNA and protein within 2 h of incubation .", "sentence_char_start_global": 286383, "sentence_char_end_global": 286562, "entities": [{"text": "Enzymatically modified low - density lipoprotein", "type": "ENTITY", "char_start": 0, "char_end": 48, "token_start": 0, "token_end": 5}, {"text": "E - LDL", "type": "ENTITY", "char_start": 51, "char_end": 58, "token_start": 7, "token_end": 9}, {"text": "adipophilin", "type": "ENTITY", "char_start": 124, "char_end": 135, "token_start": 20, "token_end": 20}], "entities_global": [{"text": "Enzymatically modified low - density lipoprotein", "type": "ENTITY", "char_start": 286383, "char_end": 286431, "token_start": 0, "token_end": 5, "note": null}, {"text": "E - LDL", "type": "ENTITY", "char_start": 286434, "char_end": 286441, "token_start": 7, "token_end": 9, "note": null}, {"text": "adipophilin", "type": "ENTITY", "char_start": 286507, "char_end": 286518, "token_start": 20, "token_end": 20, "note": null}]}
+{"sentence_id": 1741, "sentence_text": "This rapid induction of adipophilin is accompanied by a significant increase of free fatty acids in monocytes incubated with E - LDL .", "sentence_char_start_global": 286563, "sentence_char_end_global": 286697, "entities": [{"text": "adipophilin", "type": "ENTITY", "char_start": 24, "char_end": 35, "token_start": 4, "token_end": 4}, {"text": "E - LDL", "type": "ENTITY", "char_start": 125, "char_end": 132, "token_start": 19, "token_end": 21}], "entities_global": [{"text": "adipophilin", "type": "ENTITY", "char_start": 286587, "char_end": 286598, "token_start": 4, "token_end": 4, "note": null}, {"text": "E - LDL", "type": "ENTITY", "char_start": 286688, "char_end": 286695, "token_start": 19, "token_end": 21, "note": null}]}
+{"sentence_id": 1742, "sentence_text": "Adipophilin facilitates the uptake of free fatty acids , and here we demonstrate that free fatty acids increase is related to the early upregulation of adipophilin expression in blood monocytes .", "sentence_char_start_global": 286698, "sentence_char_end_global": 286893, "entities": [{"text": "Adipophilin", "type": "ENTITY", "char_start": 0, "char_end": 11, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "Adipophilin", "type": "ENTITY", "char_start": 286698, "char_end": 286709, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 1743, "sentence_text": "Fatty acids are ligands for peroxisome proliferator - activated receptor - gamma ( PPARgamma ) , and the upregulation of adipophilin mRNA by PPARgamma agonists like 15d - PGJ ( 2 ) and ciglitazone indicates that PPARgamma may mediate the induction of adipophilin expression in human blood monocytes .", "sentence_char_start_global": 286894, "sentence_char_end_global": 287194, "entities": [{"text": "peroxisome proliferator - activated receptor - gamma", "type": "ENTITY", "char_start": 28, "char_end": 80, "token_start": 5, "token_end": 11}, {"text": "PPARgamma", "type": "ENTITY", "char_start": 83, "char_end": 92, "token_start": 13, "token_end": 13}, {"text": "adipophilin mRNA", "type": "ENTITY", "char_start": 121, "char_end": 137, "token_start": 20, "token_end": 21}, {"text": "PPARgamma", "type": "ENTITY", "char_start": 141, "char_end": 150, "token_start": 23, "token_end": 23}, {"text": "PPARgamma", "type": "ENTITY", "char_start": 212, "char_end": 221, "token_start": 36, "token_end": 36}], "entities_global": [{"text": "peroxisome proliferator - activated receptor - gamma", "type": "ENTITY", "char_start": 286922, "char_end": 286974, "token_start": 5, "token_end": 11, "note": null}, {"text": "PPARgamma", "type": "ENTITY", "char_start": 286977, "char_end": 286986, "token_start": 13, "token_end": 13, "note": null}, {"text": "adipophilin mRNA", "type": "ENTITY", "char_start": 287015, "char_end": 287031, "token_start": 20, "token_end": 21, "note": null}, {"text": "PPARgamma", "type": "ENTITY", "char_start": 287035, "char_end": 287044, "token_start": 23, "token_end": 23, "note": null}, {"text": "PPARgamma", "type": "ENTITY", "char_start": 287106, "char_end": 287115, "token_start": 36, "token_end": 36, "note": null}]}
+{"sentence_id": 1744, "sentence_text": "Constitutive expression of MHC class II genes in melanoma cell lines results from the transcription of class II transactivator abnormally initiated from its B cell - specific promoter .", "sentence_char_start_global": 287195, "sentence_char_end_global": 287380, "entities": [{"text": "MHC class II genes", "type": "ENTITY", "char_start": 27, "char_end": 45, "token_start": 3, "token_end": 6}, {"text": "class II transactivator", "type": "ENTITY", "char_start": 103, "char_end": 126, "token_start": 16, "token_end": 18}, {"text": "B cell - specific promoter", "type": "ENTITY", "char_start": 157, "char_end": 183, "token_start": 23, "token_end": 27}], "entities_global": [{"text": "MHC class II genes", "type": "ENTITY", "char_start": 287222, "char_end": 287240, "token_start": 3, "token_end": 6, "note": null}, {"text": "class II transactivator", "type": "ENTITY", "char_start": 287298, "char_end": 287321, "token_start": 16, "token_end": 18, "note": null}, {"text": "B cell - specific promoter", "type": "ENTITY", "char_start": 287352, "char_end": 287378, "token_start": 23, "token_end": 27, "note": null}]}
+{"sentence_id": 1745, "sentence_text": "In melanoma cell lines , two different patterns of MHC class II expression have been described , either an IFN gamma - inducible expression of HLA - DR and HLA - DP , with a faint or null expression of HLA - DQ , resembling that described for melanocytes , or a constitutive expression , i . e . , IFN - gamma independent , of all three HLA - D isotypes .", "sentence_char_start_global": 287381, "sentence_char_end_global": 287736, "entities": [{"text": "HLA - DR", "type": "ENTITY", "char_start": 143, "char_end": 151, "token_start": 25, "token_end": 27}, {"text": "HLA - DP", "type": "ENTITY", "char_start": 156, "char_end": 164, "token_start": 29, "token_end": 31}, {"text": "HLA - DQ", "type": "ENTITY", "char_start": 202, "char_end": 210, "token_start": 40, "token_end": 42}, {"text": "HLA - D isotypes", "type": "ENTITY", "char_start": 337, "char_end": 353, "token_start": 68, "token_end": 71}], "entities_global": [{"text": "HLA - DR", "type": "ENTITY", "char_start": 287524, "char_end": 287532, "token_start": 25, "token_end": 27, "note": null}, {"text": "HLA - DP", "type": "ENTITY", "char_start": 287537, "char_end": 287545, "token_start": 29, "token_end": 31, "note": null}, {"text": "HLA - DQ", "type": "ENTITY", "char_start": 287583, "char_end": 287591, "token_start": 40, "token_end": 42, "note": null}, {"text": "HLA - D isotypes", "type": "ENTITY", "char_start": 287718, "char_end": 287734, "token_start": 68, "token_end": 71, "note": null}]}
+{"sentence_id": 1746, "sentence_text": "As this latter phenotype has been associated with a more rapid progression of melanoma tumors , we have analyzed in different melanoma cell lines the molecular mechanisms leading to this abnormal pattern of MHC class II expression .", "sentence_char_start_global": 287737, "sentence_char_end_global": 287969, "entities": [], "entities_global": []}
+{"sentence_id": 1747, "sentence_text": "In agreement with the evidence of a coordinate transcription of the HLA - D genes in these cell lines , we have shown the constitutive expression of CIITA ( class II transactivator ) transcripts , CIITA being known as the master switch of MHC class II expression .", "sentence_char_start_global": 287970, "sentence_char_end_global": 288234, "entities": [{"text": "HLA - D genes", "type": "ENTITY", "char_start": 68, "char_end": 81, "token_start": 11, "token_end": 14}, {"text": "CIITA ( class II transactivator ) transcripts", "type": "ENTITY", "char_start": 149, "char_end": 194, "token_start": 27, "token_end": 33}, {"text": "CIITA", "type": "ENTITY", "char_start": 197, "char_end": 202, "token_start": 35, "token_end": 35}], "entities_global": [{"text": "HLA - D genes", "type": "ENTITY", "char_start": 288038, "char_end": 288051, "token_start": 11, "token_end": 14, "note": null}, {"text": "CIITA ( class II transactivator ) transcripts", "type": "ENTITY", "char_start": 288119, "char_end": 288164, "token_start": 27, "token_end": 33, "note": null}, {"text": "CIITA", "type": "ENTITY", "char_start": 288167, "char_end": 288172, "token_start": 35, "token_end": 35, "note": null}]}
+{"sentence_id": 1748, "sentence_text": "Unexpectedly , these transcripts initiate from promoter III of the CIITA gene , a promoter that is mainly used constitutively in B lymphocytes .", "sentence_char_start_global": 288235, "sentence_char_end_global": 288379, "entities": [{"text": "promoter III", "type": "ENTITY", "char_start": 47, "char_end": 59, "token_start": 6, "token_end": 7}, {"text": "CIITA gene", "type": "ENTITY", "char_start": 67, "char_end": 77, "token_start": 10, "token_end": 11}], "entities_global": [{"text": "promoter III", "type": "ENTITY", "char_start": 288282, "char_end": 288294, "token_start": 6, "token_end": 7, "note": null}, {"text": "CIITA gene", "type": "ENTITY", "char_start": 288302, "char_end": 288312, "token_start": 10, "token_end": 11, "note": null}]}
+{"sentence_id": 1749, "sentence_text": "This expression was further shown to occur through factor ( s ) acting on the enhancer located upstream of CIITA promoter III , which was previously described in epithelioid cells as an IFN - gamma - response sequence .", "sentence_char_start_global": 288380, "sentence_char_end_global": 288599, "entities": [{"text": "CIITA promoter III", "type": "ENTITY", "char_start": 107, "char_end": 125, "token_start": 19, "token_end": 21}], "entities_global": [{"text": "CIITA promoter III", "type": "ENTITY", "char_start": 288487, "char_end": 288505, "token_start": 19, "token_end": 21, "note": null}]}
+{"sentence_id": 1750, "sentence_text": "The hypothesis of a general abnormality of the IFN - gamma transduction pathway was dismissed .", "sentence_char_start_global": 288600, "sentence_char_end_global": 288695, "entities": [], "entities_global": []}
+{"sentence_id": 1751, "sentence_text": "Constitutive transcription of CIITA from promoter III having been observed in unrelated melanoma cell lines , we propose the hypothesis that this phenomenon might not be a random event , but could be linked to the neoplasic state of the melanoma cells", "sentence_char_start_global": 288696, "sentence_char_end_global": 288947, "entities": [{"text": "CIITA", "type": "ENTITY", "char_start": 30, "char_end": 35, "token_start": 3, "token_end": 3}, {"text": "promoter III", "type": "ENTITY", "char_start": 41, "char_end": 53, "token_start": 5, "token_end": 6}], "entities_global": [{"text": "CIITA", "type": "ENTITY", "char_start": 288726, "char_end": 288731, "token_start": 3, "token_end": 3, "note": null}, {"text": "promoter III", "type": "ENTITY", "char_start": 288737, "char_end": 288749, "token_start": 5, "token_end": 6, "note": null}]}
+{"sentence_id": 1752, "sentence_text": "Caspase - mediated calcineurin activation contributes to IL - 2 release during T cell activation .", "sentence_char_start_global": 288948, "sentence_char_end_global": 289046, "entities": [{"text": "Caspase", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 0}, {"text": "IL - 2", "type": "ENTITY", "char_start": 57, "char_end": 63, "token_start": 7, "token_end": 9}], "entities_global": [{"text": "Caspase", "type": "ENTITY", "char_start": 288948, "char_end": 288955, "token_start": 0, "token_end": 0, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 289005, "char_end": 289011, "token_start": 7, "token_end": 9, "note": null}]}
+{"sentence_id": 1753, "sentence_text": "Calcineurin , a Ca ( 2 + ) / calmodulin - dependent Ser / Thr phosphatase ( protein phosphatase 2B ) , plays a critical role in IL - 2 production during T cell activation .", "sentence_char_start_global": 289047, "sentence_char_end_global": 289219, "entities": [{"text": "Calcineurin", "type": "ENTITY", "char_start": 0, "char_end": 11, "token_start": 0, "token_end": 0}, {"text": "Ca ( 2 + ) / calmodulin - dependent Ser / Thr phosphatase ( protein phosphatase 2B )", "type": "ENTITY", "char_start": 16, "char_end": 100, "token_start": 3, "token_end": 20}], "entities_global": [{"text": "Calcineurin", "type": "ENTITY", "char_start": 289047, "char_end": 289058, "token_start": 0, "token_end": 0, "note": null}, {"text": "Ca ( 2 + ) / calmodulin - dependent Ser / Thr phosphatase ( protein phosphatase 2B )", "type": "ENTITY", "char_start": 289063, "char_end": 289147, "token_start": 3, "token_end": 20, "note": null}]}
+{"sentence_id": 1754, "sentence_text": "It has been previously reported that IL - 2 release in activated Jurkat T requires caspase - like activity ( Posmantur et al . ( 1998 ) Exp . Cell . Res . 244 , 302 - 309 ) .", "sentence_char_start_global": 289220, "sentence_char_end_global": 289394, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 37, "char_end": 43, "token_start": 6, "token_end": 8}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 289257, "char_end": 289263, "token_start": 6, "token_end": 8, "note": null}]}
+{"sentence_id": 1755, "sentence_text": "We report here that the 60 - kDa catalytic subunit of calcineurin A ( Cn A ) was partially cleaved to a 45 - kDa form in phytohemagglutinin A ( PHA ) or phorbol ester + ionomycin ( P + I ) - activated Jurkat cells .", "sentence_char_start_global": 289395, "sentence_char_end_global": 289610, "entities": [{"text": "60 - kDa catalytic subunit", "type": "ENTITY", "char_start": 24, "char_end": 50, "token_start": 5, "token_end": 9}, {"text": "calcineurin A", "type": "ENTITY", "char_start": 54, "char_end": 67, "token_start": 11, "token_end": 12}, {"text": "Cn A", "type": "ENTITY", "char_start": 70, "char_end": 74, "token_start": 14, "token_end": 15}, {"text": "45 - kDa", "type": "ENTITY", "char_start": 104, "char_end": 112, "token_start": 22, "token_end": 24}], "entities_global": [{"text": "60 - kDa catalytic subunit", "type": "ENTITY", "char_start": 289419, "char_end": 289445, "token_start": 5, "token_end": 9, "note": null}, {"text": "calcineurin A", "type": "ENTITY", "char_start": 289449, "char_end": 289462, "token_start": 11, "token_end": 12, "note": null}, {"text": "Cn A", "type": "ENTITY", "char_start": 289465, "char_end": 289469, "token_start": 14, "token_end": 15, "note": null}, {"text": "45 - kDa", "type": "ENTITY", "char_start": 289499, "char_end": 289507, "token_start": 22, "token_end": 24, "note": null}]}
+{"sentence_id": 1756, "sentence_text": "In parallel , proteolytic activation of upstream caspases ( caspase - 8 and - 9 ) as well as effector caspase - 3 was also observed .", "sentence_char_start_global": 289611, "sentence_char_end_global": 289744, "entities": [{"text": "caspases", "type": "ENTITY", "char_start": 49, "char_end": 57, "token_start": 7, "token_end": 7}, {"text": "effector caspase - 3", "type": "ENTITY", "char_start": 93, "char_end": 113, "token_start": 19, "token_end": 22}], "entities_global": [{"text": "caspases", "type": "ENTITY", "char_start": 289660, "char_end": 289668, "token_start": 7, "token_end": 7, "note": null}, {"text": "effector caspase - 3", "type": "ENTITY", "char_start": 289704, "char_end": 289724, "token_start": 19, "token_end": 22, "note": null}]}
+{"sentence_id": 1757, "sentence_text": "Cn A cleavage was caspase mediated , since it was inhibitable by pan - caspase inhibitor Cbz - Asp - CH ( 2 ) OC ( O ) - 2 , 6 - dichlorobenzene ( Z - D - DCB ) .", "sentence_char_start_global": 289745, "sentence_char_end_global": 289907, "entities": [{"text": "Cn A", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "Cn A", "type": "ENTITY", "char_start": 289745, "char_end": 289749, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 1758, "sentence_text": "Cn A cleavage was also observed when purified calcineurin was digested in vitro with caspase - 3 .", "sentence_char_start_global": 289908, "sentence_char_end_global": 290006, "entities": [{"text": "Cn A", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 1}, {"text": "calcineurin", "type": "ENTITY", "char_start": 46, "char_end": 57, "token_start": 8, "token_end": 8}, {"text": "caspase - 3", "type": "ENTITY", "char_start": 85, "char_end": 96, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "Cn A", "type": "ENTITY", "char_start": 289908, "char_end": 289912, "token_start": 0, "token_end": 1, "note": null}, {"text": "calcineurin", "type": "ENTITY", "char_start": 289954, "char_end": 289965, "token_start": 8, "token_end": 8, "note": null}, {"text": "caspase - 3", "type": "ENTITY", "char_start": 289993, "char_end": 290004, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 1759, "sentence_text": "Truncated Cn A was associated with enhanced phosphatase activity and reduced calmodulin sensitivity .", "sentence_char_start_global": 290007, "sentence_char_end_global": 290108, "entities": [{"text": "Truncated Cn A", "type": "ENTITY", "char_start": 0, "char_end": 14, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "Truncated Cn A", "type": "ENTITY", "char_start": 290007, "char_end": 290021, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 1760, "sentence_text": "Furthermore , in PHA or P + I - activated Jurkat cells , dephosphorylation of calcineurin substrate NFATc ( a transcription factor known to be involved in transactivation of the IL - 2 gene ) , was also suppressed by Z - D - DCB .", "sentence_char_start_global": 290109, "sentence_char_end_global": 290339, "entities": [{"text": "calcineurin", "type": "ENTITY", "char_start": 78, "char_end": 89, "token_start": 15, "token_end": 15}, {"text": "NFATc", "type": "ENTITY", "char_start": 100, "char_end": 105, "token_start": 17, "token_end": 17}, {"text": "transcription factor", "type": "ENTITY", "char_start": 110, "char_end": 130, "token_start": 20, "token_end": 21}, {"text": "IL - 2 gene", "type": "ENTITY", "char_start": 178, "char_end": 189, "token_start": 30, "token_end": 33}], "entities_global": [{"text": "calcineurin", "type": "ENTITY", "char_start": 290187, "char_end": 290198, "token_start": 15, "token_end": 15, "note": null}, {"text": "NFATc", "type": "ENTITY", "char_start": 290209, "char_end": 290214, "token_start": 17, "token_end": 17, "note": null}, {"text": "transcription factor", "type": "ENTITY", "char_start": 290219, "char_end": 290239, "token_start": 20, "token_end": 21, "note": null}, {"text": "IL - 2 gene", "type": "ENTITY", "char_start": 290287, "char_end": 290298, "token_start": 30, "token_end": 33, "note": null}]}
+{"sentence_id": 1761, "sentence_text": "Taken together , our results suggest that caspase - mediated cleavage of Cn A contributes to IL - 2 production during T cell activation .", "sentence_char_start_global": 290340, "sentence_char_end_global": 290477, "entities": [{"text": "Cn A", "type": "ENTITY", "char_start": 73, "char_end": 77, "token_start": 12, "token_end": 13}], "entities_global": [{"text": "Cn A", "type": "ENTITY", "char_start": 290413, "char_end": 290417, "token_start": 12, "token_end": 13, "note": null}]}
+{"sentence_id": 1762, "sentence_text": "Copyright 2001 Academic Press .", "sentence_char_start_global": 290478, "sentence_char_end_global": 290509, "entities": [], "entities_global": []}
+{"sentence_id": 1763, "sentence_text": "Maturation of human dendritic cells as sulfasalazine target .", "sentence_char_start_global": 290510, "sentence_char_end_global": 290571, "entities": [], "entities_global": []}
+{"sentence_id": 1764, "sentence_text": "AIM : Sulfasalazine , a nonsteroidal anti - inflammatory drug , is effective in treating some autoimmune diseases , but its mechanism of action is unclear .", "sentence_char_start_global": 290572, "sentence_char_end_global": 290728, "entities": [], "entities_global": []}
+{"sentence_id": 1765, "sentence_text": "To determine whether dendritic cells could be a possible target of the drug , we studied the effects of sulfasalazine and its metabolites , aminosalicylate and sulfapyridine , on in vitro maturation ( terminal differentiation ) of human myeloid dendritic cells .", "sentence_char_start_global": 290729, "sentence_char_end_global": 290991, "entities": [], "entities_global": []}
+{"sentence_id": 1766, "sentence_text": "METHODS : We prepared immature dendritic cells by incubating CD14 - positive cells in the presence of granulocyte - macrophage colony - stimulating factor and interleukin ( IL ) - 4 .", "sentence_char_start_global": 290992, "sentence_char_end_global": 291175, "entities": [{"text": "granulocyte - macrophage colony - stimulating factor", "type": "ENTITY", "char_start": 102, "char_end": 154, "token_start": 17, "token_end": 23}, {"text": "interleukin ( IL ) - 4", "type": "ENTITY", "char_start": 159, "char_end": 181, "token_start": 25, "token_end": 30}], "entities_global": [{"text": "granulocyte - macrophage colony - stimulating factor", "type": "ENTITY", "char_start": 291094, "char_end": 291146, "token_start": 17, "token_end": 23, "note": null}, {"text": "interleukin ( IL ) - 4", "type": "ENTITY", "char_start": 291151, "char_end": 291173, "token_start": 25, "token_end": 30, "note": null}]}
+{"sentence_id": 1767, "sentence_text": "The cells were matured by addition of tumor necrosis factor ( TNF ) - a , IL - 1 beta , and prostaglandin E2 in the presence of sulfasalazine or its metabolites - - aminosalicylate and sulfapyridine , or their combinations .", "sentence_char_start_global": 291176, "sentence_char_end_global": 291400, "entities": [{"text": "tumor necrosis factor ( TNF ) - a", "type": "ENTITY", "char_start": 38, "char_end": 71, "token_start": 7, "token_end": 14}, {"text": "IL - 1 beta", "type": "ENTITY", "char_start": 74, "char_end": 85, "token_start": 16, "token_end": 19}, {"text": "prostaglandin E2", "type": "ENTITY", "char_start": 92, "char_end": 108, "token_start": 22, "token_end": 23}], "entities_global": [{"text": "tumor necrosis factor ( TNF ) - a", "type": "ENTITY", "char_start": 291214, "char_end": 291247, "token_start": 7, "token_end": 14, "note": null}, {"text": "IL - 1 beta", "type": "ENTITY", "char_start": 291250, "char_end": 291261, "token_start": 16, "token_end": 19, "note": null}, {"text": "prostaglandin E2", "type": "ENTITY", "char_start": 291268, "char_end": 291284, "token_start": 22, "token_end": 23, "note": null}]}
+{"sentence_id": 1768, "sentence_text": "We quantified the effect of drugs on the dendritic cell characteristics , such as stimulation of autologous and allogeneic pan - T cell proliferation , surface marker phenotype , IL - 12 p40 subunit secretion , and activation of nuclear transcription factor ( NF ) - kappa B .", "sentence_char_start_global": 291401, "sentence_char_end_global": 291677, "entities": [{"text": "nuclear transcription factor ( NF ) - kappa B", "type": "ENTITY", "char_start": 229, "char_end": 274, "token_start": 39, "token_end": 47}], "entities_global": [{"text": "nuclear transcription factor ( NF ) - kappa B", "type": "ENTITY", "char_start": 291630, "char_end": 291675, "token_start": 39, "token_end": 47, "note": null}]}
+{"sentence_id": 1769, "sentence_text": "RESULTS : Dendritic cells treated with sulfasalazine ( 1 . 25 micromol / L or 2 . 5 micromol / L ) could not stimulate T cells ( p < 0 . 028 , two - sided paired t - test ) .", "sentence_char_start_global": 291678, "sentence_char_end_global": 291852, "entities": [], "entities_global": []}
+{"sentence_id": 1770, "sentence_text": "In distinction to drug - free maturing dendritic cells , 2 . 5 micromol / L sulfasalazine upregulated the levels of CD14 and CD68 and downregulated the levels of CD40 , CD80 , and CD83 ( for all CD markers , p < 0 . 03 for difference between measurements in the absence and the presence of sulfasalazine ) .", "sentence_char_start_global": 291853, "sentence_char_end_global": 292160, "entities": [{"text": "CD14", "type": "ENTITY", "char_start": 116, "char_end": 120, "token_start": 21, "token_end": 21}, {"text": "CD68", "type": "ENTITY", "char_start": 125, "char_end": 129, "token_start": 23, "token_end": 23}, {"text": "CD40", "type": "ENTITY", "char_start": 162, "char_end": 166, "token_start": 29, "token_end": 29}, {"text": "CD80", "type": "ENTITY", "char_start": 169, "char_end": 173, "token_start": 31, "token_end": 31}, {"text": "CD83", "type": "ENTITY", "char_start": 180, "char_end": 184, "token_start": 34, "token_end": 34}], "entities_global": [{"text": "CD14", "type": "ENTITY", "char_start": 291969, "char_end": 291973, "token_start": 21, "token_end": 21, "note": null}, {"text": "CD68", "type": "ENTITY", "char_start": 291978, "char_end": 291982, "token_start": 23, "token_end": 23, "note": null}, {"text": "CD40", "type": "ENTITY", "char_start": 292015, "char_end": 292019, "token_start": 29, "token_end": 29, "note": null}, {"text": "CD80", "type": "ENTITY", "char_start": 292022, "char_end": 292026, "token_start": 31, "token_end": 31, "note": null}, {"text": "CD83", "type": "ENTITY", "char_start": 292033, "char_end": 292037, "token_start": 34, "token_end": 34, "note": null}]}
+{"sentence_id": 1771, "sentence_text": "From concentration - dependent changes in CD83 expression , we found an apparent ID50 > > 1 . 5 micromol / L sulfasalazine .", "sentence_char_start_global": 292161, "sentence_char_end_global": 292285, "entities": [], "entities_global": []}
+{"sentence_id": 1772, "sentence_text": "The apparent ID50 value for aminosalicylate - inhibited maturation was 4 micromol / L .", "sentence_char_start_global": 292286, "sentence_char_end_global": 292373, "entities": [], "entities_global": []}
+{"sentence_id": 1773, "sentence_text": "Sulfapyridine had no effect .", "sentence_char_start_global": 292374, "sentence_char_end_global": 292403, "entities": [], "entities_global": []}
+{"sentence_id": 1774, "sentence_text": "At 1 . 25 micromol / L , sulfasalazine largely inhibited NF - kB activation in dendritic cells .", "sentence_char_start_global": 292404, "sentence_char_end_global": 292500, "entities": [], "entities_global": []}
+{"sentence_id": 1775, "sentence_text": "CONCLUSION : Maturing human dendritic cells are hundred - fold more sensitive to sulfasalazine than T cells and NK cells and the most sensitive human cells described so far .", "sentence_char_start_global": 292501, "sentence_char_end_global": 292675, "entities": [], "entities_global": []}
+{"sentence_id": 1776, "sentence_text": "Thus , dendritic cell maturation is an important target of sulfasalazine .", "sentence_char_start_global": 292676, "sentence_char_end_global": 292750, "entities": [], "entities_global": []}
+{"sentence_id": 1777, "sentence_text": "Because of the role of dendritic cells in ( auto ) immunity , inhibition of their maturation might provide a target for further optimization of sulfasalazine therapy .", "sentence_char_start_global": 292751, "sentence_char_end_global": 292918, "entities": [], "entities_global": []}
+{"sentence_id": 1778, "sentence_text": "Defective function of the proteasome in autoimmunity : involvement of impaired NF - kappaB activation .", "sentence_char_start_global": 292919, "sentence_char_end_global": 293022, "entities": [{"text": "proteasome", "type": "ENTITY", "char_start": 26, "char_end": 36, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "proteasome", "type": "ENTITY", "char_start": 292945, "char_end": 292955, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 1779, "sentence_text": "Type 1 diabetes ( also known as insulin - dependent diabetes mellitus or juvenile - onset diabetes ) is usually caused by T cell - mediated autoimmunity , with a prediabetic state characterized by the production of autoantibodies specific for proteins expressed by pancreatic beta cells .", "sentence_char_start_global": 293023, "sentence_char_end_global": 293311, "entities": [{"text": "autoantibodies", "type": "ENTITY", "char_start": 215, "char_end": 229, "token_start": 37, "token_end": 37}], "entities_global": [{"text": "autoantibodies", "type": "ENTITY", "char_start": 293238, "char_end": 293252, "token_start": 37, "token_end": 37, "note": null}]}
+{"sentence_id": 1780, "sentence_text": "The nonobese patient with diabetes ( NOD ) mouse is a spontaneous model of type 1 diabetes with a strong genetic component that maps to the major histocompatibility complex ( MHC ) region of the genome .", "sentence_char_start_global": 293312, "sentence_char_end_global": 293515, "entities": [{"text": "major histocompatibility complex ( MHC ) region", "type": "ENTITY", "char_start": 140, "char_end": 187, "token_start": 26, "token_end": 32}, {"text": "genome", "type": "ENTITY", "char_start": 195, "char_end": 201, "token_start": 35, "token_end": 35}], "entities_global": [{"text": "major histocompatibility complex ( MHC ) region", "type": "ENTITY", "char_start": 293452, "char_end": 293499, "token_start": 26, "token_end": 32, "note": null}, {"text": "genome", "type": "ENTITY", "char_start": 293507, "char_end": 293513, "token_start": 35, "token_end": 35, "note": null}]}
+{"sentence_id": 1781, "sentence_text": "A specific proteasome defect has been identified in NOD mouse in select lymphocytic and monocytic lineages that results from down - regulation of expression of the proteasome subunit LMP2 , which is encoded by a gene in the MHC genomic region .", "sentence_char_start_global": 293516, "sentence_char_end_global": 293760, "entities": [{"text": "proteasome", "type": "ENTITY", "char_start": 11, "char_end": 21, "token_start": 2, "token_end": 2}, {"text": "proteasome subunit LMP2", "type": "ENTITY", "char_start": 164, "char_end": 187, "token_start": 26, "token_end": 28}, {"text": "MHC genomic region", "type": "ENTITY", "char_start": 224, "char_end": 242, "token_start": 38, "token_end": 40}], "entities_global": [{"text": "proteasome", "type": "ENTITY", "char_start": 293527, "char_end": 293537, "token_start": 2, "token_end": 2, "note": null}, {"text": "proteasome subunit LMP2", "type": "ENTITY", "char_start": 293680, "char_end": 293703, "token_start": 26, "token_end": 28, "note": null}, {"text": "MHC genomic region", "type": "ENTITY", "char_start": 293740, "char_end": 293758, "token_start": 38, "token_end": 40, "note": null}]}
+{"sentence_id": 1782, "sentence_text": "This defect prevents the proteolytic processing required for the production and activation of the transcription factor nuclear factor - kappaB ( NF - kappaB ) , which plays important roles in immune and inflammatory responses , as well as increases the susceptibility of the affected cells to apoptosis induced by tumor necrosis factor - alpha ( TNF - alpha ) .", "sentence_char_start_global": 293761, "sentence_char_end_global": 294122, "entities": [{"text": "transcription factor nuclear factor - kappaB", "type": "ENTITY", "char_start": 98, "char_end": 142, "token_start": 14, "token_end": 19}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 145, "char_end": 156, "token_start": 21, "token_end": 23}, {"text": "tumor necrosis factor - alpha", "type": "ENTITY", "char_start": 314, "char_end": 343, "token_start": 50, "token_end": 54}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 346, "char_end": 357, "token_start": 56, "token_end": 58}], "entities_global": [{"text": "transcription factor nuclear factor - kappaB", "type": "ENTITY", "char_start": 293859, "char_end": 293903, "token_start": 14, "token_end": 19, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 293906, "char_end": 293917, "token_start": 21, "token_end": 23, "note": null}, {"text": "tumor necrosis factor - alpha", "type": "ENTITY", "char_start": 294075, "char_end": 294104, "token_start": 50, "token_end": 54, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 294107, "char_end": 294118, "token_start": 56, "token_end": 58, "note": null}]}
+{"sentence_id": 1783, "sentence_text": "The novel role of the proteasome in dysfunction in autoimmunity is presented and documented to be both tissue and developmental stage specific .", "sentence_char_start_global": 294123, "sentence_char_end_global": 294267, "entities": [{"text": "proteasome", "type": "ENTITY", "char_start": 22, "char_end": 32, "token_start": 5, "token_end": 5}], "entities_global": [{"text": "proteasome", "type": "ENTITY", "char_start": 294145, "char_end": 294155, "token_start": 5, "token_end": 5, "note": null}]}
+{"sentence_id": 1784, "sentence_text": "We propose a role of the proteasome as a step in disease pathogenesis and tissue targeting .", "sentence_char_start_global": 294268, "sentence_char_end_global": 294360, "entities": [{"text": "proteasome", "type": "ENTITY", "char_start": 25, "char_end": 35, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "proteasome", "type": "ENTITY", "char_start": 294293, "char_end": 294303, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 1785, "sentence_text": "Down - regulation of TDT transcription in CD4 ( + ) CD8 ( + ) thymocytes by Ikaros proteins in direct competition with an Ets activator .", "sentence_char_start_global": 294361, "sentence_char_end_global": 294498, "entities": [{"text": "Ikaros proteins", "type": "ENTITY", "char_start": 76, "char_end": 91, "token_start": 17, "token_end": 18}, {"text": "Ets activator", "type": "ENTITY", "char_start": 122, "char_end": 135, "token_start": 24, "token_end": 25}], "entities_global": [{"text": "Ikaros proteins", "type": "ENTITY", "char_start": 294437, "char_end": 294452, "token_start": 17, "token_end": 18, "note": null}, {"text": "Ets activator", "type": "ENTITY", "char_start": 294483, "char_end": 294496, "token_start": 24, "token_end": 25, "note": null}]}
+{"sentence_id": 1786, "sentence_text": "Ikaros is a unique regulator of lymphopoiesis that associates with pericentromeric heterochromatin and has been implicated in heritable gene inactivation .", "sentence_char_start_global": 294499, "sentence_char_end_global": 294654, "entities": [{"text": "Ikaros", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 0}, {"text": "pericentromeric heterochromatin", "type": "ENTITY", "char_start": 67, "char_end": 98, "token_start": 10, "token_end": 11}], "entities_global": [{"text": "Ikaros", "type": "ENTITY", "char_start": 294499, "char_end": 294505, "token_start": 0, "token_end": 0, "note": null}, {"text": "pericentromeric heterochromatin", "type": "ENTITY", "char_start": 294566, "char_end": 294597, "token_start": 10, "token_end": 11, "note": null}]}
+{"sentence_id": 1787, "sentence_text": "Binding and competition experiments demonstrate that Ikaros dimers compete with an Ets activator for occupancy of the lymphocyte - specific TdT promoter .", "sentence_char_start_global": 294655, "sentence_char_end_global": 294809, "entities": [{"text": "Ikaros dimers", "type": "ENTITY", "char_start": 53, "char_end": 66, "token_start": 6, "token_end": 7}, {"text": "Ets activator", "type": "ENTITY", "char_start": 83, "char_end": 96, "token_start": 11, "token_end": 12}, {"text": "lymphocyte - specific TdT promoter", "type": "ENTITY", "char_start": 118, "char_end": 152, "token_start": 17, "token_end": 21}], "entities_global": [{"text": "Ikaros dimers", "type": "ENTITY", "char_start": 294708, "char_end": 294721, "token_start": 6, "token_end": 7, "note": null}, {"text": "Ets activator", "type": "ENTITY", "char_start": 294738, "char_end": 294751, "token_start": 11, "token_end": 12, "note": null}, {"text": "lymphocyte - specific TdT promoter", "type": "ENTITY", "char_start": 294773, "char_end": 294807, "token_start": 17, "token_end": 21, "note": null}]}
+{"sentence_id": 1788, "sentence_text": "Mutations that selectively disrupt Ikaros binding to an integrated TdT promoter had no effect on promoter function in a CD4 ( + ) CD8 ( + ) thymocyte line .", "sentence_char_start_global": 294810, "sentence_char_end_global": 294966, "entities": [{"text": "integrated TdT promoter", "type": "ENTITY", "char_start": 56, "char_end": 79, "token_start": 8, "token_end": 10}], "entities_global": [{"text": "integrated TdT promoter", "type": "ENTITY", "char_start": 294866, "char_end": 294889, "token_start": 8, "token_end": 10, "note": null}]}
+{"sentence_id": 1789, "sentence_text": "However , these mutations abolished down - regulation on differentiation , providing evidence that Ikaros plays a direct role in repression .", "sentence_char_start_global": 294967, "sentence_char_end_global": 295108, "entities": [{"text": "Ikaros", "type": "ENTITY", "char_start": 99, "char_end": 105, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "Ikaros", "type": "ENTITY", "char_start": 295066, "char_end": 295072, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 1790, "sentence_text": "Reduced access to restriction enzyme cleavage suggested that chromatin alterations accompany down - regulation .", "sentence_char_start_global": 295109, "sentence_char_end_global": 295221, "entities": [], "entities_global": []}
+{"sentence_id": 1791, "sentence_text": "The Ikaros - dependent down - regulation event and the observed chromatin alterations appear to precede pericentromeric repositioning .", "sentence_char_start_global": 295222, "sentence_char_end_global": 295357, "entities": [], "entities_global": []}
+{"sentence_id": 1792, "sentence_text": "Current models propose that the functions of Ikaros should be disrupted by a small isoform that retains the dimerization domain and lacks the DNA - binding domain .", "sentence_char_start_global": 295358, "sentence_char_end_global": 295522, "entities": [{"text": "Ikaros", "type": "ENTITY", "char_start": 45, "char_end": 51, "token_start": 7, "token_end": 7}, {"text": "isoform", "type": "ENTITY", "char_start": 83, "char_end": 90, "token_start": 14, "token_end": 14}, {"text": "dimerization domain", "type": "ENTITY", "char_start": 108, "char_end": 127, "token_start": 18, "token_end": 19}, {"text": "DNA - binding domain", "type": "ENTITY", "char_start": 142, "char_end": 162, "token_start": 23, "token_end": 26}], "entities_global": [{"text": "Ikaros", "type": "ENTITY", "char_start": 295403, "char_end": 295409, "token_start": 7, "token_end": 7, "note": null}, {"text": "isoform", "type": "ENTITY", "char_start": 295441, "char_end": 295448, "token_start": 14, "token_end": 14, "note": null}, {"text": "dimerization domain", "type": "ENTITY", "char_start": 295466, "char_end": 295485, "token_start": 18, "token_end": 19, "note": null}, {"text": "DNA - binding domain", "type": "ENTITY", "char_start": 295500, "char_end": 295520, "token_start": 23, "token_end": 26, "note": null}]}
+{"sentence_id": 1793, "sentence_text": "Surprisingly , in the CD4 ( + ) CD8 ( + ) thymocyte line , overexpression of a small Ikaros isoform had no effect on differentiation or on the pericentromeric targeting and DNA - binding properties of Ikaros .", "sentence_char_start_global": 295523, "sentence_char_end_global": 295732, "entities": [{"text": "small Ikaros isoform", "type": "ENTITY", "char_start": 79, "char_end": 99, "token_start": 18, "token_end": 20}, {"text": "Ikaros", "type": "ENTITY", "char_start": 201, "char_end": 207, "token_start": 37, "token_end": 37}], "entities_global": [{"text": "small Ikaros isoform", "type": "ENTITY", "char_start": 295602, "char_end": 295622, "token_start": 18, "token_end": 20, "note": null}, {"text": "Ikaros", "type": "ENTITY", "char_start": 295724, "char_end": 295730, "token_start": 37, "token_end": 37, "note": null}]}
+{"sentence_id": 1794, "sentence_text": "Rather , the small isoform assembled into multimeric complexes with DNA - bound Ikaros at the pericentromeric foci .", "sentence_char_start_global": 295733, "sentence_char_end_global": 295849, "entities": [{"text": "isoform", "type": "ENTITY", "char_start": 19, "char_end": 26, "token_start": 4, "token_end": 4}, {"text": "multimeric complexes", "type": "ENTITY", "char_start": 42, "char_end": 62, "token_start": 7, "token_end": 8}, {"text": "DNA - bound Ikaros", "type": "ENTITY", "char_start": 68, "char_end": 86, "token_start": 10, "token_end": 13}], "entities_global": [{"text": "isoform", "type": "ENTITY", "char_start": 295752, "char_end": 295759, "token_start": 4, "token_end": 4, "note": null}, {"text": "multimeric complexes", "type": "ENTITY", "char_start": 295775, "char_end": 295795, "token_start": 7, "token_end": 8, "note": null}, {"text": "DNA - bound Ikaros", "type": "ENTITY", "char_start": 295801, "char_end": 295819, "token_start": 10, "token_end": 13, "note": null}]}
+{"sentence_id": 1795, "sentence_text": "The capacity for in vivo multimer formation suggests that interactions between Ikaros dimers bound to the TdT promoter and those bound to pericentromeric repeat sequences may contribute to the pericentromeric repositioning of the inactive gene .", "sentence_char_start_global": 295850, "sentence_char_end_global": 296095, "entities": [{"text": "Ikaros dimers", "type": "ENTITY", "char_start": 79, "char_end": 92, "token_start": 11, "token_end": 12}, {"text": "TdT promoter", "type": "ENTITY", "char_start": 106, "char_end": 118, "token_start": 16, "token_end": 17}, {"text": "pericentromeric repeat sequences", "type": "ENTITY", "char_start": 138, "char_end": 170, "token_start": 22, "token_end": 24}, {"text": "inactive gene", "type": "ENTITY", "char_start": 230, "char_end": 243, "token_start": 33, "token_end": 34}], "entities_global": [{"text": "Ikaros dimers", "type": "ENTITY", "char_start": 295929, "char_end": 295942, "token_start": 11, "token_end": 12, "note": null}, {"text": "TdT promoter", "type": "ENTITY", "char_start": 295956, "char_end": 295968, "token_start": 16, "token_end": 17, "note": null}, {"text": "pericentromeric repeat sequences", "type": "ENTITY", "char_start": 295988, "char_end": 296020, "token_start": 22, "token_end": 24, "note": null}, {"text": "inactive gene", "type": "ENTITY", "char_start": 296080, "char_end": 296093, "token_start": 33, "token_end": 34, "note": null}]}
+{"sentence_id": 1796, "sentence_text": "Type I interferons and IL - 12 : convergence and cross - regulation among mediators of cellular immunity .", "sentence_char_start_global": 296096, "sentence_char_end_global": 296202, "entities": [{"text": "Type I interferons", "type": "ENTITY", "char_start": 0, "char_end": 18, "token_start": 0, "token_end": 2}, {"text": "IL - 12", "type": "ENTITY", "char_start": 23, "char_end": 30, "token_start": 4, "token_end": 6}], "entities_global": [{"text": "Type I interferons", "type": "ENTITY", "char_start": 296096, "char_end": 296114, "token_start": 0, "token_end": 2, "note": null}, {"text": "IL - 12", "type": "ENTITY", "char_start": 296119, "char_end": 296126, "token_start": 4, "token_end": 6, "note": null}]}
+{"sentence_id": 1797, "sentence_text": "Therapeutic use of type I IFN ( IFN - alpha / beta ) has become common .", "sentence_char_start_global": 296203, "sentence_char_end_global": 296275, "entities": [{"text": "type I IFN", "type": "ENTITY", "char_start": 19, "char_end": 29, "token_start": 3, "token_end": 5}, {"text": "IFN - alpha / beta", "type": "ENTITY", "char_start": 32, "char_end": 50, "token_start": 7, "token_end": 11}], "entities_global": [{"text": "type I IFN", "type": "ENTITY", "char_start": 296222, "char_end": 296232, "token_start": 3, "token_end": 5, "note": null}, {"text": "IFN - alpha / beta", "type": "ENTITY", "char_start": 296235, "char_end": 296253, "token_start": 7, "token_end": 11, "note": null}]}
+{"sentence_id": 1798, "sentence_text": "Many of the diverse diseases targeted are marked by pathogenetic abnormalities in cell - mediated immunity ( CMI ) , these cellular immune responses either causing injury to the host , lacking sufficient vigor for virus or tumor clearance , or both .", "sentence_char_start_global": 296276, "sentence_char_end_global": 296526, "entities": [], "entities_global": []}
+{"sentence_id": 1799, "sentence_text": "In general , therapeutic efficacy is limited .", "sentence_char_start_global": 296527, "sentence_char_end_global": 296573, "entities": [], "entities_global": []}
+{"sentence_id": 1800, "sentence_text": "It is thus notable that the pleiotropic effects of type I IFN on CMI remain poorly understood .", "sentence_char_start_global": 296574, "sentence_char_end_global": 296669, "entities": [{"text": "type I IFN", "type": "ENTITY", "char_start": 51, "char_end": 61, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "type I IFN", "type": "ENTITY", "char_start": 296625, "char_end": 296635, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 1801, "sentence_text": "We characterized the effects of type I IFN on the production of IL - 12 , the central immunoregulatory cytokine of the CD4 ( + ) T cell arm of CMI .", "sentence_char_start_global": 296670, "sentence_char_end_global": 296818, "entities": [{"text": "type I IFN", "type": "ENTITY", "char_start": 32, "char_end": 42, "token_start": 5, "token_end": 7}, {"text": "IL - 12", "type": "ENTITY", "char_start": 64, "char_end": 71, "token_start": 12, "token_end": 14}, {"text": "central immunoregulatory cytokine", "type": "ENTITY", "char_start": 78, "char_end": 111, "token_start": 17, "token_end": 19}, {"text": "CD4 ( + ) T cell arm", "type": "ENTITY", "char_start": 119, "char_end": 139, "token_start": 22, "token_end": 28}], "entities_global": [{"text": "type I IFN", "type": "ENTITY", "char_start": 296702, "char_end": 296712, "token_start": 5, "token_end": 7, "note": null}, {"text": "IL - 12", "type": "ENTITY", "char_start": 296734, "char_end": 296741, "token_start": 12, "token_end": 14, "note": null}, {"text": "central immunoregulatory cytokine", "type": "ENTITY", "char_start": 296748, "char_end": 296781, "token_start": 17, "token_end": 19, "note": null}, {"text": "CD4 ( + ) T cell arm", "type": "ENTITY", "char_start": 296789, "char_end": 296809, "token_start": 22, "token_end": 28, "note": null}]}
+{"sentence_id": 1802, "sentence_text": "We show that type I IFN are potent inhibitors of IL - 12 production by human monocytes / macrophages .", "sentence_char_start_global": 296819, "sentence_char_end_global": 296921, "entities": [{"text": "type I IFN", "type": "ENTITY", "char_start": 13, "char_end": 23, "token_start": 3, "token_end": 5}], "entities_global": [{"text": "type I IFN", "type": "ENTITY", "char_start": 296832, "char_end": 296842, "token_start": 3, "token_end": 5, "note": null}]}
+{"sentence_id": 1803, "sentence_text": "The underlying mechanism involves transcriptional inhibition of the IL - 12p40 gene , marked by down - regulation of PU . 1 binding activity at the upstream Ets site of the IL - 12p40 promoter .", "sentence_char_start_global": 296922, "sentence_char_end_global": 297116, "entities": [{"text": "IL - 12p40 gene", "type": "ENTITY", "char_start": 68, "char_end": 83, "token_start": 8, "token_end": 11}, {"text": "upstream Ets site", "type": "ENTITY", "char_start": 148, "char_end": 165, "token_start": 26, "token_end": 28}, {"text": "IL - 12p40 promoter", "type": "ENTITY", "char_start": 173, "char_end": 192, "token_start": 31, "token_end": 34}], "entities_global": [{"text": "IL - 12p40 gene", "type": "ENTITY", "char_start": 296990, "char_end": 297005, "token_start": 8, "token_end": 11, "note": null}, {"text": "upstream Ets site", "type": "ENTITY", "char_start": 297070, "char_end": 297087, "token_start": 26, "token_end": 28, "note": null}, {"text": "IL - 12p40 promoter", "type": "ENTITY", "char_start": 297095, "char_end": 297114, "token_start": 31, "token_end": 34, "note": null}]}
+{"sentence_id": 1804, "sentence_text": "Type I IFN have previously been shown to be able to substitute for IL - 12 in driving IFN - gamma production from T and NK cells .", "sentence_char_start_global": 297117, "sentence_char_end_global": 297247, "entities": [{"text": "Type I IFN", "type": "ENTITY", "char_start": 0, "char_end": 10, "token_start": 0, "token_end": 2}, {"text": "IL - 12", "type": "ENTITY", "char_start": 67, "char_end": 74, "token_start": 13, "token_end": 15}], "entities_global": [{"text": "Type I IFN", "type": "ENTITY", "char_start": 297117, "char_end": 297127, "token_start": 0, "token_end": 2, "note": null}, {"text": "IL - 12", "type": "ENTITY", "char_start": 297184, "char_end": 297191, "token_start": 13, "token_end": 15, "note": null}]}
+{"sentence_id": 1805, "sentence_text": "The ability of IFN - alpha / beta to suppress IL - 12 production while up - regulating IFN - gamma production suggests a possible mechanistic basis for the difficulties of employing these cytokines in diseases involving abnormalities of CMI .", "sentence_char_start_global": 297248, "sentence_char_end_global": 297490, "entities": [{"text": "IFN - alpha / beta", "type": "ENTITY", "char_start": 15, "char_end": 33, "token_start": 3, "token_end": 7}, {"text": "cytokines", "type": "ENTITY", "char_start": 188, "char_end": 197, "token_start": 33, "token_end": 33}], "entities_global": [{"text": "IFN - alpha / beta", "type": "ENTITY", "char_start": 297263, "char_end": 297281, "token_start": 3, "token_end": 7, "note": null}, {"text": "cytokines", "type": "ENTITY", "char_start": 297436, "char_end": 297445, "token_start": 33, "token_end": 33, "note": null}]}
+{"sentence_id": 1806, "sentence_text": "Nuclear factor - kappaB suppressive and inhibitor - kappaB stimulatory effects of troglitazone in obese patients with type 2 diabetes : evidence of an antiinflammatory action ?", "sentence_char_start_global": 297491, "sentence_char_end_global": 297667, "entities": [{"text": "Nuclear factor - kappaB", "type": "ENTITY", "char_start": 0, "char_end": 23, "token_start": 0, "token_end": 3}, {"text": "inhibitor - kappaB", "type": "ENTITY", "char_start": 40, "char_end": 58, "token_start": 6, "token_end": 8}], "entities_global": [{"text": "Nuclear factor - kappaB", "type": "ENTITY", "char_start": 297491, "char_end": 297514, "token_start": 0, "token_end": 3, "note": null}, {"text": "inhibitor - kappaB", "type": "ENTITY", "char_start": 297531, "char_end": 297549, "token_start": 6, "token_end": 8, "note": null}]}
+{"sentence_id": 1807, "sentence_text": "It has been shown recently that troglitazone exerts an anti - inflammatory effect , in vitro , and in experimental animals .", "sentence_char_start_global": 297668, "sentence_char_end_global": 297792, "entities": [], "entities_global": []}
+{"sentence_id": 1808, "sentence_text": "To test these properties in humans , we investigated the effect of troglitazone on the proinflammatory transcription factor nuclear factor - kappaB and its inhibitory protein IkappaB in mononuclear cells ( MNC ) and plasma soluble intracellular adhesion molecule - 1 , monocyte chemoattractant protein - 1 , plasminogen activator inhibitor - 1 , and C - reactive protein .", "sentence_char_start_global": 297793, "sentence_char_end_global": 298165, "entities": [{"text": "proinflammatory transcription factor nuclear factor - kappaB", "type": "ENTITY", "char_start": 87, "char_end": 147, "token_start": 15, "token_end": 21}, {"text": "inhibitory protein IkappaB", "type": "ENTITY", "char_start": 156, "char_end": 182, "token_start": 24, "token_end": 26}, {"text": "plasma soluble intracellular adhesion molecule - 1", "type": "ENTITY", "char_start": 216, "char_end": 266, "token_start": 34, "token_end": 40}, {"text": "monocyte chemoattractant protein - 1", "type": "ENTITY", "char_start": 269, "char_end": 305, "token_start": 42, "token_end": 46}, {"text": "plasminogen activator inhibitor - 1", "type": "ENTITY", "char_start": 308, "char_end": 343, "token_start": 48, "token_end": 52}, {"text": "C - reactive protein", "type": "ENTITY", "char_start": 350, "char_end": 370, "token_start": 55, "token_end": 58}], "entities_global": [{"text": "proinflammatory transcription factor nuclear factor - kappaB", "type": "ENTITY", "char_start": 297880, "char_end": 297940, "token_start": 15, "token_end": 21, "note": null}, {"text": "inhibitory protein IkappaB", "type": "ENTITY", "char_start": 297949, "char_end": 297975, "token_start": 24, "token_end": 26, "note": null}, {"text": "plasma soluble intracellular adhesion molecule - 1", "type": "ENTITY", "char_start": 298009, "char_end": 298059, "token_start": 34, "token_end": 40, "note": null}, {"text": "monocyte chemoattractant protein - 1", "type": "ENTITY", "char_start": 298062, "char_end": 298098, "token_start": 42, "token_end": 46, "note": null}, {"text": "plasminogen activator inhibitor - 1", "type": "ENTITY", "char_start": 298101, "char_end": 298136, "token_start": 48, "token_end": 52, "note": null}, {"text": "C - reactive protein", "type": "ENTITY", "char_start": 298143, "char_end": 298163, "token_start": 55, "token_end": 58, "note": null}]}
+{"sentence_id": 1809, "sentence_text": "We also examined the effect of troglitazone on reactive oxygen species generation , p47 ( phox ) subunit expression , 9 - hydroxyoctadecadieno acid ( 9 - HODE ) , 13 - HODE , o - tyrosine , and m - tyrosine in obese patients with type 2 diabetes .", "sentence_char_start_global": 298166, "sentence_char_end_global": 298413, "entities": [], "entities_global": []}
+{"sentence_id": 1810, "sentence_text": "Seven obese patients with type 2 diabetes were treated with troglitazone ( 400 mg / day ) for 4 weeks .", "sentence_char_start_global": 298414, "sentence_char_end_global": 298517, "entities": [], "entities_global": []}
+{"sentence_id": 1811, "sentence_text": "Blood samples were obtained at weekly intervals .", "sentence_char_start_global": 298518, "sentence_char_end_global": 298567, "entities": [], "entities_global": []}
+{"sentence_id": 1812, "sentence_text": "Nuclear factor - kappaB binding activity in MNC nuclear extracts was significantly inhibited after troglitazone treatment at week 1 and continued to be inhibited up to week 4 .", "sentence_char_start_global": 298568, "sentence_char_end_global": 298744, "entities": [{"text": "Nuclear factor - kappaB", "type": "ENTITY", "char_start": 0, "char_end": 23, "token_start": 0, "token_end": 3}], "entities_global": [{"text": "Nuclear factor - kappaB", "type": "ENTITY", "char_start": 298568, "char_end": 298591, "token_start": 0, "token_end": 3, "note": null}]}
+{"sentence_id": 1813, "sentence_text": "On the other hand , IkappaB protein levels increased significantly after troglitazone treatment at week 1 , and this increase persisted throughout the study .", "sentence_char_start_global": 298745, "sentence_char_end_global": 298903, "entities": [], "entities_global": []}
+{"sentence_id": 1814, "sentence_text": "Plasma monocyte chemoattractant protein - 1 and soluble intracellular adhesion molecule - 1 concentrations did not decrease significantly after troglitazone treatment , although there was a trend toward inhibition .", "sentence_char_start_global": 298904, "sentence_char_end_global": 299119, "entities": [{"text": "Plasma monocyte chemoattractant protein - 1", "type": "ENTITY", "char_start": 0, "char_end": 43, "token_start": 0, "token_end": 5}, {"text": "soluble intracellular adhesion molecule - 1", "type": "ENTITY", "char_start": 48, "char_end": 91, "token_start": 7, "token_end": 12}], "entities_global": [{"text": "Plasma monocyte chemoattractant protein - 1", "type": "ENTITY", "char_start": 298904, "char_end": 298947, "token_start": 0, "token_end": 5, "note": null}, {"text": "soluble intracellular adhesion molecule - 1", "type": "ENTITY", "char_start": 298952, "char_end": 298995, "token_start": 7, "token_end": 12, "note": null}]}
+{"sentence_id": 1815, "sentence_text": "Reactive oxygen species generation by polymorphonuclear cells and MNC , p47 ( phox ) subunit protein quantities , plasminogen activator inhibitor - 1 , and C - reactive protein levels decreased significantly after troglitazone intake .", "sentence_char_start_global": 299120, "sentence_char_end_global": 299355, "entities": [{"text": "p47 ( phox ) subunit protein", "type": "ENTITY", "char_start": 72, "char_end": 100, "token_start": 10, "token_end": 15}, {"text": "plasminogen activator inhibitor - 1", "type": "ENTITY", "char_start": 114, "char_end": 149, "token_start": 18, "token_end": 22}, {"text": "C - reactive protein", "type": "ENTITY", "char_start": 156, "char_end": 176, "token_start": 25, "token_end": 28}], "entities_global": [{"text": "p47 ( phox ) subunit protein", "type": "ENTITY", "char_start": 299192, "char_end": 299220, "token_start": 10, "token_end": 15, "note": null}, {"text": "plasminogen activator inhibitor - 1", "type": "ENTITY", "char_start": 299234, "char_end": 299269, "token_start": 18, "token_end": 22, "note": null}, {"text": "C - reactive protein", "type": "ENTITY", "char_start": 299276, "char_end": 299296, "token_start": 25, "token_end": 28, "note": null}]}
+{"sentence_id": 1816, "sentence_text": "13 - HODE / linoleic acid and 9 - HODE / linoleic acid ratios also decreased after troglitazone intake .", "sentence_char_start_global": 299356, "sentence_char_end_global": 299460, "entities": [], "entities_global": []}
+{"sentence_id": 1817, "sentence_text": "However , o - tyrosine / phenylalanine and m - tyrosine / phenylalanine ratios did not change significantly .", "sentence_char_start_global": 299461, "sentence_char_end_global": 299570, "entities": [], "entities_global": []}
+{"sentence_id": 1818, "sentence_text": "These data show that troglitazone has profound antiinflammatory effects in addition to antioxidant effects in obese type 2 diabetics ; these effects may be relevant to the recently described beneficial antiatherosclerotic effects of troglitazone at the vascular level .", "sentence_char_start_global": 299571, "sentence_char_end_global": 299840, "entities": [], "entities_global": []}
+{"sentence_id": 1819, "sentence_text": "OX40 stimulation by gp34 / OX40 ligand enhances productive human immunodeficiency virus type 1 infection .", "sentence_char_start_global": 299841, "sentence_char_end_global": 299947, "entities": [{"text": "gp34 / OX40 ligand", "type": "ENTITY", "char_start": 20, "char_end": 38, "token_start": 3, "token_end": 6}], "entities_global": [{"text": "gp34 / OX40 ligand", "type": "ENTITY", "char_start": 299861, "char_end": 299879, "token_start": 3, "token_end": 6, "note": null}]}
+{"sentence_id": 1820, "sentence_text": "OX40 is a member of the tumor necrosis factor ( TNF ) receptor superfamily and known to be an important costimulatory molecule expressed on activated T cells .", "sentence_char_start_global": 299948, "sentence_char_end_global": 300107, "entities": [{"text": "OX40", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}, {"text": "tumor necrosis factor ( TNF ) receptor superfamily", "type": "ENTITY", "char_start": 24, "char_end": 74, "token_start": 6, "token_end": 13}, {"text": "costimulatory molecule", "type": "ENTITY", "char_start": 104, "char_end": 126, "token_start": 20, "token_end": 21}], "entities_global": [{"text": "OX40", "type": "ENTITY", "char_start": 299948, "char_end": 299952, "token_start": 0, "token_end": 0, "note": null}, {"text": "tumor necrosis factor ( TNF ) receptor superfamily", "type": "ENTITY", "char_start": 299972, "char_end": 300022, "token_start": 6, "token_end": 13, "note": null}, {"text": "costimulatory molecule", "type": "ENTITY", "char_start": 300052, "char_end": 300074, "token_start": 20, "token_end": 21, "note": null}]}
+{"sentence_id": 1821, "sentence_text": "To investigate the role of costimulation of OX40 in human immunodeficiency virus type 1 ( HIV - 1 ) infection by its natural ligand , gp34 , the OX40 - transfected ACH - 2 cell line , ACH - 2 / OX40 , chronically infected with HIV - 1 , was cocultured with paraformaldehyde ( PFA ) - fixed gp34 - transfected mouse cell line , SV - T2 / gp34 .", "sentence_char_start_global": 300108, "sentence_char_end_global": 300451, "entities": [{"text": "OX40", "type": "ENTITY", "char_start": 44, "char_end": 48, "token_start": 7, "token_end": 7}, {"text": "gp34", "type": "ENTITY", "char_start": 134, "char_end": 138, "token_start": 25, "token_end": 25}], "entities_global": [{"text": "OX40", "type": "ENTITY", "char_start": 300152, "char_end": 300156, "token_start": 7, "token_end": 7, "note": null}, {"text": "gp34", "type": "ENTITY", "char_start": 300242, "char_end": 300246, "token_start": 25, "token_end": 25, "note": null}]}
+{"sentence_id": 1822, "sentence_text": "The results showed that HIV - 1 production was strongly induced .", "sentence_char_start_global": 300452, "sentence_char_end_global": 300517, "entities": [], "entities_global": []}
+{"sentence_id": 1823, "sentence_text": "This was followed by apparent apoptosis , and both processes were specifically inhibited by the gp34 - specific neutralizing monoclonal antibody 5A8 .", "sentence_char_start_global": 300518, "sentence_char_end_global": 300668, "entities": [{"text": "gp34", "type": "ENTITY", "char_start": 96, "char_end": 100, "token_start": 15, "token_end": 15}, {"text": "neutralizing monoclonal antibody 5A8", "type": "ENTITY", "char_start": 112, "char_end": 148, "token_start": 18, "token_end": 21}], "entities_global": [{"text": "gp34", "type": "ENTITY", "char_start": 300614, "char_end": 300618, "token_start": 15, "token_end": 15, "note": null}, {"text": "neutralizing monoclonal antibody 5A8", "type": "ENTITY", "char_start": 300630, "char_end": 300666, "token_start": 18, "token_end": 21, "note": null}]}
+{"sentence_id": 1824, "sentence_text": "Endogenous TNF alpha ( TNF - alpha ) and TNF - beta production were not involved in the enhanced HIV - 1 production .", "sentence_char_start_global": 300669, "sentence_char_end_global": 300786, "entities": [{"text": "TNF alpha", "type": "ENTITY", "char_start": 11, "char_end": 20, "token_start": 1, "token_end": 2}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 23, "char_end": 34, "token_start": 4, "token_end": 6}, {"text": "TNF - beta", "type": "ENTITY", "char_start": 41, "char_end": 51, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "TNF alpha", "type": "ENTITY", "char_start": 300680, "char_end": 300689, "token_start": 1, "token_end": 2, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 300692, "char_end": 300703, "token_start": 4, "token_end": 6, "note": null}, {"text": "TNF - beta", "type": "ENTITY", "char_start": 300710, "char_end": 300720, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 1825, "sentence_text": "Furthermore , enhanced HIV - 1 transcription in gp34 - stimulated ACH - 2 / OX40 cells was dependent on the kappa B site of the HIV - 1 long terminal repeat , and the OX40 - gp34 interaction activated NF - kappa B consisting of p50 and p65 subunits .", "sentence_char_start_global": 300787, "sentence_char_end_global": 301037, "entities": [{"text": "gp34", "type": "ENTITY", "char_start": 48, "char_end": 52, "token_start": 8, "token_end": 8}, {"text": "kappa B site", "type": "ENTITY", "char_start": 108, "char_end": 120, "token_start": 21, "token_end": 23}, {"text": "HIV - 1 long terminal repeat", "type": "ENTITY", "char_start": 128, "char_end": 156, "token_start": 26, "token_end": 31}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 201, "char_end": 213, "token_start": 40, "token_end": 43}, {"text": "p50 and p65 subunits", "type": "ENTITY", "char_start": 228, "char_end": 248, "token_start": 46, "token_end": 49}], "entities_global": [{"text": "gp34", "type": "ENTITY", "char_start": 300835, "char_end": 300839, "token_start": 8, "token_end": 8, "note": null}, {"text": "kappa B site", "type": "ENTITY", "char_start": 300895, "char_end": 300907, "token_start": 21, "token_end": 23, "note": null}, {"text": "HIV - 1 long terminal repeat", "type": "ENTITY", "char_start": 300915, "char_end": 300943, "token_start": 26, "token_end": 31, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 300988, "char_end": 301000, "token_start": 40, "token_end": 43, "note": null}, {"text": "p50 and p65 subunits", "type": "ENTITY", "char_start": 301015, "char_end": 301035, "token_start": 46, "token_end": 49, "note": null}]}
+{"sentence_id": 1826, "sentence_text": "When primary activated CD4 ( + ) T cells acutely infected with HIV - 1 ( NL4 - 3 ) ( CXCR4 - using T - cell - line - tropic ) were cocultured with PFA - fixed gp34 ( + ) human T - cell leukemia virus type 1 - bearing MT - 2 cells or SV - T2 / gp34 cells , HIV - 1 production was also markedly enhanced .", "sentence_char_start_global": 301038, "sentence_char_end_global": 301341, "entities": [], "entities_global": []}
+{"sentence_id": 1827, "sentence_text": "The enhancement was again significantly inhibited by 5A8 .", "sentence_char_start_global": 301342, "sentence_char_end_global": 301400, "entities": [{"text": "5A8", "type": "ENTITY", "char_start": 53, "char_end": 56, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "5A8", "type": "ENTITY", "char_start": 301395, "char_end": 301398, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 1828, "sentence_text": "The present study first shows that OX40 - gp34 interaction stimulates HIV - 1 expression and suggests that OX40 triggering by gp34 may play an important role in enhancing HIV - 1 production in both acutely and latently infected CD4 ( + ) T cells in vivo .", "sentence_char_start_global": 301401, "sentence_char_end_global": 301656, "entities": [{"text": "gp34", "type": "ENTITY", "char_start": 126, "char_end": 130, "token_start": 21, "token_end": 21}], "entities_global": [{"text": "gp34", "type": "ENTITY", "char_start": 301527, "char_end": 301531, "token_start": 21, "token_end": 21, "note": null}]}
+{"sentence_id": 1829, "sentence_text": "Troglitazone , a PPARgamma ligand , inhibits osteopontin gene expression in human monocytes / macrophage THP - 1 cells .", "sentence_char_start_global": 301657, "sentence_char_end_global": 301777, "entities": [], "entities_global": []}
+{"sentence_id": 1830, "sentence_text": "Peroxizome proliferator - activated receptor - gamma ( PPARgamma ) is a member of the nuclear receptor family of transcription factors that regulate adipocyte differentiation .", "sentence_char_start_global": 301778, "sentence_char_end_global": 301954, "entities": [{"text": "Peroxizome proliferator - activated receptor - gamma", "type": "ENTITY", "char_start": 0, "char_end": 52, "token_start": 0, "token_end": 6}, {"text": "PPARgamma", "type": "ENTITY", "char_start": 55, "char_end": 64, "token_start": 8, "token_end": 8}, {"text": "nuclear receptor family", "type": "ENTITY", "char_start": 86, "char_end": 109, "token_start": 15, "token_end": 17}, {"text": "transcription factors", "type": "ENTITY", "char_start": 113, "char_end": 134, "token_start": 19, "token_end": 20}], "entities_global": [{"text": "Peroxizome proliferator - activated receptor - gamma", "type": "ENTITY", "char_start": 301778, "char_end": 301830, "token_start": 0, "token_end": 6, "note": null}, {"text": "PPARgamma", "type": "ENTITY", "char_start": 301833, "char_end": 301842, "token_start": 8, "token_end": 8, "note": null}, {"text": "nuclear receptor family", "type": "ENTITY", "char_start": 301864, "char_end": 301887, "token_start": 15, "token_end": 17, "note": null}, {"text": "transcription factors", "type": "ENTITY", "char_start": 301891, "char_end": 301912, "token_start": 19, "token_end": 20, "note": null}]}
+{"sentence_id": 1831, "sentence_text": "Recent studies indicate that liganded PPARgamma not only promotes differentiation but also inhibits the activation of macrophages .", "sentence_char_start_global": 301955, "sentence_char_end_global": 302086, "entities": [{"text": "liganded PPARgamma", "type": "ENTITY", "char_start": 29, "char_end": 47, "token_start": 4, "token_end": 5}], "entities_global": [{"text": "liganded PPARgamma", "type": "ENTITY", "char_start": 301984, "char_end": 302002, "token_start": 4, "token_end": 5, "note": null}]}
+{"sentence_id": 1832, "sentence_text": "Osteopontin , a component of extracellular matrix , is synthesized by macrophages in atherosclerotic plaques .", "sentence_char_start_global": 302087, "sentence_char_end_global": 302197, "entities": [{"text": "Osteopontin", "type": "ENTITY", "char_start": 0, "char_end": 11, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "Osteopontin", "type": "ENTITY", "char_start": 302087, "char_end": 302098, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 1833, "sentence_text": "In this study , we examined whether PPARgamma ligand regulates osteopontin gene expression in THP - 1 cells , a cell line derived from human monocytic leukemia cells which can differentiate to macrophage upon stimulation with phorbol ester PMA .", "sentence_char_start_global": 302198, "sentence_char_end_global": 302443, "entities": [{"text": "PPARgamma", "type": "ENTITY", "char_start": 36, "char_end": 45, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "PPARgamma", "type": "ENTITY", "char_start": 302234, "char_end": 302243, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 1834, "sentence_text": "Northern blot analysis showed that osteopontin expression is markedly induced in response to PMA .", "sentence_char_start_global": 302444, "sentence_char_end_global": 302542, "entities": [], "entities_global": []}
+{"sentence_id": 1835, "sentence_text": "Troglitazone , a PPARgamma ligand , dramatically attenuated the PMA - induced osteopontin expression .", "sentence_char_start_global": 302543, "sentence_char_end_global": 302645, "entities": [{"text": "PPARgamma", "type": "ENTITY", "char_start": 17, "char_end": 26, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "PPARgamma", "type": "ENTITY", "char_start": 302560, "char_end": 302569, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 1836, "sentence_text": "Transient transfection assays of the human osteopontin promoter / luciferase construct which contains a 5 ' - flanking region between - 1500 and + 87 relative to the transcription start site demonstrate that either treatment with troglitazone or cotransfection of PPARgamma expression vector inhibits osteopontin promoter activity .", "sentence_char_start_global": 302646, "sentence_char_end_global": 302978, "entities": [{"text": "human osteopontin promoter / luciferase construct", "type": "ENTITY", "char_start": 37, "char_end": 86, "token_start": 5, "token_end": 10}, {"text": "5 ' - flanking region", "type": "ENTITY", "char_start": 104, "char_end": 125, "token_start": 14, "token_end": 18}, {"text": "transcription start site", "type": "ENTITY", "char_start": 166, "char_end": 190, "token_start": 28, "token_end": 30}, {"text": "PPARgamma expression vector", "type": "ENTITY", "char_start": 264, "char_end": 291, "token_start": 40, "token_end": 42}], "entities_global": [{"text": "human osteopontin promoter / luciferase construct", "type": "ENTITY", "char_start": 302683, "char_end": 302732, "token_start": 5, "token_end": 10, "note": null}, {"text": "5 ' - flanking region", "type": "ENTITY", "char_start": 302750, "char_end": 302771, "token_start": 14, "token_end": 18, "note": null}, {"text": "transcription start site", "type": "ENTITY", "char_start": 302812, "char_end": 302836, "token_start": 28, "token_end": 30, "note": null}, {"text": "PPARgamma expression vector", "type": "ENTITY", "char_start": 302910, "char_end": 302937, "token_start": 40, "token_end": 42, "note": null}]}
+{"sentence_id": 1837, "sentence_text": "These data indicate that troglitazone reduces osteopontin gene expression at transcriptional level through PPARgamma activation , and suggest the role of troglitazone in inhibiting the ability of macrophages to produce extracellular matrix , which is particularly relevant to atherosclerotic plaque formation .", "sentence_char_start_global": 302979, "sentence_char_end_global": 303289, "entities": [{"text": "PPARgamma", "type": "ENTITY", "char_start": 107, "char_end": 116, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "PPARgamma", "type": "ENTITY", "char_start": 303086, "char_end": 303095, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 1838, "sentence_text": "Transcription factor NF - kappa B regulates Ig lambda light chain gene rearrangement .", "sentence_char_start_global": 303290, "sentence_char_end_global": 303376, "entities": [{"text": "Transcription factor NF - kappa B", "type": "ENTITY", "char_start": 0, "char_end": 33, "token_start": 0, "token_end": 5}, {"text": "Ig lambda", "type": "ENTITY", "char_start": 44, "char_end": 53, "token_start": 7, "token_end": 8}], "entities_global": [{"text": "Transcription factor NF - kappa B", "type": "ENTITY", "char_start": 303290, "char_end": 303323, "token_start": 0, "token_end": 5, "note": null}, {"text": "Ig lambda", "type": "ENTITY", "char_start": 303334, "char_end": 303343, "token_start": 7, "token_end": 8, "note": null}]}
+{"sentence_id": 1839, "sentence_text": "The tissue - and stage - specific assembly of Ig and TCR genes is mediated by a common V ( D ) J recombinase complex in precursor lymphocytes .", "sentence_char_start_global": 303377, "sentence_char_end_global": 303520, "entities": [{"text": "Ig and TCR genes", "type": "ENTITY", "char_start": 46, "char_end": 62, "token_start": 9, "token_end": 12}, {"text": "V ( D ) J recombinase complex", "type": "ENTITY", "char_start": 87, "char_end": 116, "token_start": 18, "token_end": 24}], "entities_global": [{"text": "Ig and TCR genes", "type": "ENTITY", "char_start": 303423, "char_end": 303439, "token_start": 9, "token_end": 12, "note": null}, {"text": "V ( D ) J recombinase complex", "type": "ENTITY", "char_start": 303464, "char_end": 303493, "token_start": 18, "token_end": 24, "note": null}]}
+{"sentence_id": 1840, "sentence_text": "Directed alterations in the accessibility of V , D , and J gene segments target the recombinase to specific Ag receptor loci .", "sentence_char_start_global": 303521, "sentence_char_end_global": 303647, "entities": [{"text": "V , D , and J gene segments", "type": "ENTITY", "char_start": 45, "char_end": 72, "token_start": 6, "token_end": 13}, {"text": "recombinase", "type": "ENTITY", "char_start": 84, "char_end": 95, "token_start": 16, "token_end": 16}, {"text": "Ag receptor loci", "type": "ENTITY", "char_start": 108, "char_end": 124, "token_start": 19, "token_end": 21}], "entities_global": [{"text": "V , D , and J gene segments", "type": "ENTITY", "char_start": 303566, "char_end": 303593, "token_start": 6, "token_end": 13, "note": null}, {"text": "recombinase", "type": "ENTITY", "char_start": 303605, "char_end": 303616, "token_start": 16, "token_end": 16, "note": null}, {"text": "Ag receptor loci", "type": "ENTITY", "char_start": 303629, "char_end": 303645, "token_start": 19, "token_end": 21, "note": null}]}
+{"sentence_id": 1841, "sentence_text": "Accessibility within a given locus is regulated by the functional interaction of transcription factors with cognate enhancer elements and correlates with the transcriptional activity of unrearranged gene segments .", "sentence_char_start_global": 303648, "sentence_char_end_global": 303862, "entities": [{"text": "locus", "type": "ENTITY", "char_start": 29, "char_end": 34, "token_start": 4, "token_end": 4}, {"text": "transcription factors", "type": "ENTITY", "char_start": 81, "char_end": 102, "token_start": 12, "token_end": 13}, {"text": "cognate enhancer elements", "type": "ENTITY", "char_start": 108, "char_end": 133, "token_start": 15, "token_end": 17}, {"text": "gene segments", "type": "ENTITY", "char_start": 199, "char_end": 212, "token_start": 26, "token_end": 27}], "entities_global": [{"text": "locus", "type": "ENTITY", "char_start": 303677, "char_end": 303682, "token_start": 4, "token_end": 4, "note": null}, {"text": "transcription factors", "type": "ENTITY", "char_start": 303729, "char_end": 303750, "token_start": 12, "token_end": 13, "note": null}, {"text": "cognate enhancer elements", "type": "ENTITY", "char_start": 303756, "char_end": 303781, "token_start": 15, "token_end": 17, "note": null}, {"text": "gene segments", "type": "ENTITY", "char_start": 303847, "char_end": 303860, "token_start": 26, "token_end": 27, "note": null}]}
+{"sentence_id": 1842, "sentence_text": "As demonstrated in our prior studies , rearrangement of the Igkappa locus is regulated by the inducible transcription factor NF - kappaB .", "sentence_char_start_global": 303863, "sentence_char_end_global": 304001, "entities": [{"text": "Igkappa locus", "type": "ENTITY", "char_start": 60, "char_end": 73, "token_start": 10, "token_end": 11}, {"text": "inducible transcription factor", "type": "ENTITY", "char_start": 94, "char_end": 124, "token_start": 16, "token_end": 18}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 125, "char_end": 136, "token_start": 19, "token_end": 21}], "entities_global": [{"text": "Igkappa locus", "type": "ENTITY", "char_start": 303923, "char_end": 303936, "token_start": 10, "token_end": 11, "note": null}, {"text": "inducible transcription factor", "type": "ENTITY", "char_start": 303957, "char_end": 303987, "token_start": 16, "token_end": 18, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 303988, "char_end": 303999, "token_start": 19, "token_end": 21, "note": null}]}
+{"sentence_id": 1843, "sentence_text": "In contrast to the Igkappa locus , known transcriptional control elements in the Iglambda locus lack functional NF - kappaB binding sites .", "sentence_char_start_global": 304002, "sentence_char_end_global": 304141, "entities": [{"text": "Igkappa locus", "type": "ENTITY", "char_start": 19, "char_end": 32, "token_start": 4, "token_end": 5}, {"text": "transcriptional control elements", "type": "ENTITY", "char_start": 41, "char_end": 73, "token_start": 8, "token_end": 10}, {"text": "Iglambda locus", "type": "ENTITY", "char_start": 81, "char_end": 95, "token_start": 13, "token_end": 14}, {"text": "NF - kappaB binding sites", "type": "ENTITY", "char_start": 112, "char_end": 137, "token_start": 17, "token_end": 21}], "entities_global": [{"text": "Igkappa locus", "type": "ENTITY", "char_start": 304021, "char_end": 304034, "token_start": 4, "token_end": 5, "note": null}, {"text": "transcriptional control elements", "type": "ENTITY", "char_start": 304043, "char_end": 304075, "token_start": 8, "token_end": 10, "note": null}, {"text": "Iglambda locus", "type": "ENTITY", "char_start": 304083, "char_end": 304097, "token_start": 13, "token_end": 14, "note": null}, {"text": "NF - kappaB binding sites", "type": "ENTITY", "char_start": 304114, "char_end": 304139, "token_start": 17, "token_end": 21, "note": null}]}
+{"sentence_id": 1844, "sentence_text": "Consistent with this observation , the expression of assembled Iglambda genes in mature B cells has been shown to be NF - kappaB independent .", "sentence_char_start_global": 304142, "sentence_char_end_global": 304284, "entities": [{"text": "Iglambda genes", "type": "ENTITY", "char_start": 63, "char_end": 77, "token_start": 9, "token_end": 10}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 117, "char_end": 128, "token_start": 20, "token_end": 22}], "entities_global": [{"text": "Iglambda genes", "type": "ENTITY", "char_start": 304205, "char_end": 304219, "token_start": 9, "token_end": 10, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 304259, "char_end": 304270, "token_start": 20, "token_end": 22, "note": null}]}
+{"sentence_id": 1845, "sentence_text": "Nonetheless , we now show that specific repression of NF - kappaB inhibits germline transcription and recombination of Iglambda gene segments in precursor B cells .", "sentence_char_start_global": 304285, "sentence_char_end_global": 304449, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 54, "char_end": 65, "token_start": 9, "token_end": 11}, {"text": "Iglambda gene segments", "type": "ENTITY", "char_start": 119, "char_end": 141, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 304339, "char_end": 304350, "token_start": 9, "token_end": 11, "note": null}, {"text": "Iglambda gene segments", "type": "ENTITY", "char_start": 304404, "char_end": 304426, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 1846, "sentence_text": "Molecular analyses indicate that the block in NF - kappaB impairs Iglambda rearrangement at the level of recombinase accessibility .", "sentence_char_start_global": 304450, "sentence_char_end_global": 304582, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 46, "char_end": 57, "token_start": 7, "token_end": 9}, {"text": "recombinase", "type": "ENTITY", "char_start": 105, "char_end": 116, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 304496, "char_end": 304507, "token_start": 7, "token_end": 9, "note": null}, {"text": "recombinase", "type": "ENTITY", "char_start": 304555, "char_end": 304566, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 1847, "sentence_text": "In contrast , the activities of known Iglambda promoter and enhancer elements are unaffected in the same cellular background .", "sentence_char_start_global": 304583, "sentence_char_end_global": 304709, "entities": [{"text": "Iglambda promoter", "type": "ENTITY", "char_start": 38, "char_end": 55, "token_start": 7, "token_end": 8}, {"text": "enhancer elements", "type": "ENTITY", "char_start": 60, "char_end": 77, "token_start": 10, "token_end": 11}], "entities_global": [{"text": "Iglambda promoter", "type": "ENTITY", "char_start": 304621, "char_end": 304638, "token_start": 7, "token_end": 8, "note": null}, {"text": "enhancer elements", "type": "ENTITY", "char_start": 304643, "char_end": 304660, "token_start": 10, "token_end": 11, "note": null}]}
+{"sentence_id": 1848, "sentence_text": "These findings expand the range of NF - kappaB action in precursor B cells beyond Igkappa to include the control of recombinational accessibility at both L chain loci .", "sentence_char_start_global": 304710, "sentence_char_end_global": 304878, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 35, "char_end": 46, "token_start": 6, "token_end": 8}, {"text": "Igkappa", "type": "ENTITY", "char_start": 82, "char_end": 89, "token_start": 15, "token_end": 15}, {"text": "L chain loci", "type": "ENTITY", "char_start": 154, "char_end": 166, "token_start": 25, "token_end": 27}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 304745, "char_end": 304756, "token_start": 6, "token_end": 8, "note": null}, {"text": "Igkappa", "type": "ENTITY", "char_start": 304792, "char_end": 304799, "token_start": 15, "token_end": 15, "note": null}, {"text": "L chain loci", "type": "ENTITY", "char_start": 304864, "char_end": 304876, "token_start": 25, "token_end": 27, "note": null}]}
+{"sentence_id": 1849, "sentence_text": "Moreover , our results strongly suggest the existence of a novel Iglambda regulatory element that is either directly or indirectly activated by NF - kappaB during the early stages of B cell development .", "sentence_char_start_global": 304879, "sentence_char_end_global": 305082, "entities": [{"text": "Iglambda regulatory element", "type": "ENTITY", "char_start": 65, "char_end": 92, "token_start": 11, "token_end": 13}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 144, "char_end": 155, "token_start": 22, "token_end": 24}], "entities_global": [{"text": "Iglambda regulatory element", "type": "ENTITY", "char_start": 304944, "char_end": 304971, "token_start": 11, "token_end": 13, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 305023, "char_end": 305034, "token_start": 22, "token_end": 24, "note": null}]}
+{"sentence_id": 1850, "sentence_text": "Transcription factor STAT5A is a substrate of Bruton ' s tyrosine kinase in B cells .", "sentence_char_start_global": 305083, "sentence_char_end_global": 305168, "entities": [{"text": "Transcription factor", "type": "ENTITY", "char_start": 0, "char_end": 20, "token_start": 0, "token_end": 1}, {"text": "STAT5A", "type": "ENTITY", "char_start": 21, "char_end": 27, "token_start": 2, "token_end": 2}, {"text": "Bruton ' s tyrosine kinase", "type": "ENTITY", "char_start": 46, "char_end": 72, "token_start": 7, "token_end": 11}], "entities_global": [{"text": "Transcription factor", "type": "ENTITY", "char_start": 305083, "char_end": 305103, "token_start": 0, "token_end": 1, "note": null}, {"text": "STAT5A", "type": "ENTITY", "char_start": 305104, "char_end": 305110, "token_start": 2, "token_end": 2, "note": null}, {"text": "Bruton ' s tyrosine kinase", "type": "ENTITY", "char_start": 305129, "char_end": 305155, "token_start": 7, "token_end": 11, "note": null}]}
+{"sentence_id": 1851, "sentence_text": "STAT5A is a molecular regulator of proliferation , differentiation , and apoptosis in lymphohematopoietic cells .", "sentence_char_start_global": 305169, "sentence_char_end_global": 305282, "entities": [{"text": "STAT5A", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "STAT5A", "type": "ENTITY", "char_start": 305169, "char_end": 305175, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 1852, "sentence_text": "Here we show that STAT5A can serve as a functional substrate of Bruton ' s tyrosine kinase ( BTK ) .", "sentence_char_start_global": 305283, "sentence_char_end_global": 305383, "entities": [{"text": "STAT5A", "type": "ENTITY", "char_start": 18, "char_end": 24, "token_start": 4, "token_end": 4}, {"text": "Bruton ' s tyrosine kinase", "type": "ENTITY", "char_start": 64, "char_end": 90, "token_start": 12, "token_end": 16}, {"text": "BTK", "type": "ENTITY", "char_start": 93, "char_end": 96, "token_start": 18, "token_end": 18}], "entities_global": [{"text": "STAT5A", "type": "ENTITY", "char_start": 305301, "char_end": 305307, "token_start": 4, "token_end": 4, "note": null}, {"text": "Bruton ' s tyrosine kinase", "type": "ENTITY", "char_start": 305347, "char_end": 305373, "token_start": 12, "token_end": 16, "note": null}, {"text": "BTK", "type": "ENTITY", "char_start": 305376, "char_end": 305379, "token_start": 18, "token_end": 18, "note": null}]}
+{"sentence_id": 1853, "sentence_text": "Purified recombinant BTK was capable of directly binding purified recombinant STAT5A with high affinity ( K ( d ) = 44 nm ) , as determined by surface plasmon resonance using a BIAcore biosensor system .", "sentence_char_start_global": 305384, "sentence_char_end_global": 305587, "entities": [{"text": "Purified recombinant BTK", "type": "ENTITY", "char_start": 0, "char_end": 24, "token_start": 0, "token_end": 2}, {"text": "purified recombinant STAT5A", "type": "ENTITY", "char_start": 57, "char_end": 84, "token_start": 8, "token_end": 10}], "entities_global": [{"text": "Purified recombinant BTK", "type": "ENTITY", "char_start": 305384, "char_end": 305408, "token_start": 0, "token_end": 2, "note": null}, {"text": "purified recombinant STAT5A", "type": "ENTITY", "char_start": 305441, "char_end": 305468, "token_start": 8, "token_end": 10, "note": null}]}
+{"sentence_id": 1854, "sentence_text": "BTK was also capable of tyrosine - phosphorylating ectopically expressed recombinant STAT5A on Tyr ( 694 ) both in vitro and in vivo in a Janus kinase 3 - independent fashion .", "sentence_char_start_global": 305588, "sentence_char_end_global": 305764, "entities": [{"text": "BTK", "type": "ENTITY", "char_start": 0, "char_end": 3, "token_start": 0, "token_end": 0}, {"text": "recombinant STAT5A", "type": "ENTITY", "char_start": 73, "char_end": 91, "token_start": 10, "token_end": 11}, {"text": "Janus kinase 3", "type": "ENTITY", "char_start": 138, "char_end": 152, "token_start": 25, "token_end": 27}], "entities_global": [{"text": "BTK", "type": "ENTITY", "char_start": 305588, "char_end": 305591, "token_start": 0, "token_end": 0, "note": null}, {"text": "recombinant STAT5A", "type": "ENTITY", "char_start": 305661, "char_end": 305679, "token_start": 10, "token_end": 11, "note": null}, {"text": "Janus kinase 3", "type": "ENTITY", "char_start": 305726, "char_end": 305740, "token_start": 25, "token_end": 27, "note": null}]}
+{"sentence_id": 1855, "sentence_text": "BTK phosphorylated the Y665F , Y668F , and Y682F , Y683F mutants but not the Y694F mutant of STAT5A .", "sentence_char_start_global": 305765, "sentence_char_end_global": 305866, "entities": [{"text": "BTK", "type": "ENTITY", "char_start": 0, "char_end": 3, "token_start": 0, "token_end": 0}, {"text": "Y665F , Y668F , and Y682F , Y683F mutants", "type": "ENTITY", "char_start": 23, "char_end": 64, "token_start": 3, "token_end": 11}, {"text": "Y694F mutant", "type": "ENTITY", "char_start": 77, "char_end": 89, "token_start": 15, "token_end": 16}, {"text": "STAT5A", "type": "ENTITY", "char_start": 93, "char_end": 99, "token_start": 18, "token_end": 18}], "entities_global": [{"text": "BTK", "type": "ENTITY", "char_start": 305765, "char_end": 305768, "token_start": 0, "token_end": 0, "note": null}, {"text": "Y665F , Y668F , and Y682F , Y683F mutants", "type": "ENTITY", "char_start": 305788, "char_end": 305829, "token_start": 3, "token_end": 11, "note": null}, {"text": "Y694F mutant", "type": "ENTITY", "char_start": 305842, "char_end": 305854, "token_start": 15, "token_end": 16, "note": null}, {"text": "STAT5A", "type": "ENTITY", "char_start": 305858, "char_end": 305864, "token_start": 18, "token_end": 18, "note": null}]}
+{"sentence_id": 1856, "sentence_text": "STAT5A mutations in the Src homology 2 ( SH2 ) and SH3 domains did not alter the BTK - mediated tyrosine phosphorylation .", "sentence_char_start_global": 305867, "sentence_char_end_global": 305989, "entities": [{"text": "Src homology 2 ( SH2 ) and SH3 domains", "type": "ENTITY", "char_start": 24, "char_end": 62, "token_start": 4, "token_end": 12}, {"text": "BTK", "type": "ENTITY", "char_start": 81, "char_end": 84, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "Src homology 2 ( SH2 ) and SH3 domains", "type": "ENTITY", "char_start": 305891, "char_end": 305929, "token_start": 4, "token_end": 12, "note": null}, {"text": "BTK", "type": "ENTITY", "char_start": 305948, "char_end": 305951, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 1857, "sentence_text": "Recombinant BTK proteins with mutant pleckstrin homology , SH2 , or SH3 domains were capable of phosphorylating STAT5A , whereas recombinant BTK proteins with SH1 / kinase domain mutations were not .", "sentence_char_start_global": 305990, "sentence_char_end_global": 306189, "entities": [{"text": "Recombinant BTK proteins", "type": "ENTITY", "char_start": 0, "char_end": 24, "token_start": 0, "token_end": 2}, {"text": "SH2 , or SH3 domains", "type": "ENTITY", "char_start": 59, "char_end": 79, "token_start": 8, "token_end": 12}, {"text": "STAT5A", "type": "ENTITY", "char_start": 112, "char_end": 118, "token_start": 17, "token_end": 17}, {"text": "recombinant BTK proteins", "type": "ENTITY", "char_start": 129, "char_end": 153, "token_start": 20, "token_end": 22}], "entities_global": [{"text": "Recombinant BTK proteins", "type": "ENTITY", "char_start": 305990, "char_end": 306014, "token_start": 0, "token_end": 2, "note": null}, {"text": "SH2 , or SH3 domains", "type": "ENTITY", "char_start": 306049, "char_end": 306069, "token_start": 8, "token_end": 12, "note": null}, {"text": "STAT5A", "type": "ENTITY", "char_start": 306102, "char_end": 306108, "token_start": 17, "token_end": 17, "note": null}, {"text": "recombinant BTK proteins", "type": "ENTITY", "char_start": 306119, "char_end": 306143, "token_start": 20, "token_end": 22, "note": null}]}
+{"sentence_id": 1858, "sentence_text": "In pull - down experiments , only full - length BTK and its SH1 / kinase domain ( but not the pleckstrin homology , SH2 , or SH3 domains ) were capable of binding STAT5A .", "sentence_char_start_global": 306190, "sentence_char_end_global": 306361, "entities": [{"text": "full - length BTK", "type": "ENTITY", "char_start": 34, "char_end": 51, "token_start": 7, "token_end": 10}, {"text": "SH1 / kinase domain", "type": "ENTITY", "char_start": 60, "char_end": 79, "token_start": 13, "token_end": 16}, {"text": "SH2 , or SH3 domains", "type": "ENTITY", "char_start": 116, "char_end": 136, "token_start": 24, "token_end": 28}, {"text": "STAT5A", "type": "ENTITY", "char_start": 163, "char_end": 169, "token_start": 34, "token_end": 34}], "entities_global": [{"text": "full - length BTK", "type": "ENTITY", "char_start": 306224, "char_end": 306241, "token_start": 7, "token_end": 10, "note": null}, {"text": "SH1 / kinase domain", "type": "ENTITY", "char_start": 306250, "char_end": 306269, "token_start": 13, "token_end": 16, "note": null}, {"text": "SH2 , or SH3 domains", "type": "ENTITY", "char_start": 306306, "char_end": 306326, "token_start": 24, "token_end": 28, "note": null}, {"text": "STAT5A", "type": "ENTITY", "char_start": 306353, "char_end": 306359, "token_start": 34, "token_end": 34, "note": null}]}
+{"sentence_id": 1859, "sentence_text": "Ectopically expressed BTK kinase domain was capable of tyrosine - phosphorylating STAT5A both in vitro and in vivo .", "sentence_char_start_global": 306362, "sentence_char_end_global": 306478, "entities": [{"text": "BTK kinase domain", "type": "ENTITY", "char_start": 22, "char_end": 39, "token_start": 2, "token_end": 4}, {"text": "STAT5A", "type": "ENTITY", "char_start": 82, "char_end": 88, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "BTK kinase domain", "type": "ENTITY", "char_start": 306384, "char_end": 306401, "token_start": 2, "token_end": 4, "note": null}, {"text": "STAT5A", "type": "ENTITY", "char_start": 306444, "char_end": 306450, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 1860, "sentence_text": "BTK - mediated tyrosine phosphorylation of ectopically expressed wild type ( but not Tyr ( 694 ) mutant ) STAT5A enhanced its DNA binding activity .", "sentence_char_start_global": 306479, "sentence_char_end_global": 306627, "entities": [{"text": "BTK", "type": "ENTITY", "char_start": 0, "char_end": 3, "token_start": 0, "token_end": 0}, {"text": "Tyr ( 694 ) mutant", "type": "ENTITY", "char_start": 85, "char_end": 103, "token_start": 13, "token_end": 17}, {"text": "STAT5A", "type": "ENTITY", "char_start": 106, "char_end": 112, "token_start": 19, "token_end": 19}], "entities_global": [{"text": "BTK", "type": "ENTITY", "char_start": 306479, "char_end": 306482, "token_start": 0, "token_end": 0, "note": null}, {"text": "Tyr ( 694 ) mutant", "type": "ENTITY", "char_start": 306564, "char_end": 306582, "token_start": 13, "token_end": 17, "note": null}, {"text": "STAT5A", "type": "ENTITY", "char_start": 306585, "char_end": 306591, "token_start": 19, "token_end": 19, "note": null}]}
+{"sentence_id": 1861, "sentence_text": "In BTK - competent chicken B cells , anti - IgM - stimulated tyrosine phosphorylation of STAT5 protein was prevented by pretreatment with the BTK inhibitor LFM - A13 but not by pretreatment with the JAK3 inhibitor HI - P131 .", "sentence_char_start_global": 306628, "sentence_char_end_global": 306853, "entities": [{"text": "BTK", "type": "ENTITY", "char_start": 3, "char_end": 6, "token_start": 1, "token_end": 1}, {"text": "STAT5 protein", "type": "ENTITY", "char_start": 89, "char_end": 102, "token_start": 16, "token_end": 17}, {"text": "BTK", "type": "ENTITY", "char_start": 142, "char_end": 145, "token_start": 24, "token_end": 24}], "entities_global": [{"text": "BTK", "type": "ENTITY", "char_start": 306631, "char_end": 306634, "token_start": 1, "token_end": 1, "note": null}, {"text": "STAT5 protein", "type": "ENTITY", "char_start": 306717, "char_end": 306730, "token_start": 16, "token_end": 17, "note": null}, {"text": "BTK", "type": "ENTITY", "char_start": 306770, "char_end": 306773, "token_start": 24, "token_end": 24, "note": null}]}
+{"sentence_id": 1862, "sentence_text": "B cell antigen receptor ligation resulted in enhanced tyrosine phosphorylation of STAT5 in BTK - deficient chicken B cells reconstituted with wild type human BTK but not in BTK - deficient chicken B cells reconstituted with kinase - inactive mutant BTK .", "sentence_char_start_global": 306854, "sentence_char_end_global": 307108, "entities": [{"text": "STAT5", "type": "ENTITY", "char_start": 82, "char_end": 87, "token_start": 11, "token_end": 11}, {"text": "BTK", "type": "ENTITY", "char_start": 91, "char_end": 94, "token_start": 13, "token_end": 13}, {"text": "wild type human BTK", "type": "ENTITY", "char_start": 142, "char_end": 161, "token_start": 21, "token_end": 24}, {"text": "BTK", "type": "ENTITY", "char_start": 173, "char_end": 176, "token_start": 28, "token_end": 28}, {"text": "kinase - inactive mutant BTK", "type": "ENTITY", "char_start": 224, "char_end": 252, "token_start": 36, "token_end": 40}], "entities_global": [{"text": "STAT5", "type": "ENTITY", "char_start": 306936, "char_end": 306941, "token_start": 11, "token_end": 11, "note": null}, {"text": "BTK", "type": "ENTITY", "char_start": 306945, "char_end": 306948, "token_start": 13, "token_end": 13, "note": null}, {"text": "wild type human BTK", "type": "ENTITY", "char_start": 306996, "char_end": 307015, "token_start": 21, "token_end": 24, "note": null}, {"text": "BTK", "type": "ENTITY", "char_start": 307027, "char_end": 307030, "token_start": 28, "token_end": 28, "note": null}, {"text": "kinase - inactive mutant BTK", "type": "ENTITY", "char_start": 307078, "char_end": 307106, "token_start": 36, "token_end": 40, "note": null}]}
+{"sentence_id": 1863, "sentence_text": "Similarly , anti - IgM stimulation resulted in enhanced tyrosine phosphorylation of STAT5A in BTK - competent B cells from wild type mice but not in BTK - deficient B cells from XID mice .", "sentence_char_start_global": 307109, "sentence_char_end_global": 307297, "entities": [{"text": "STAT5A", "type": "ENTITY", "char_start": 84, "char_end": 90, "token_start": 12, "token_end": 12}, {"text": "BTK", "type": "ENTITY", "char_start": 94, "char_end": 97, "token_start": 14, "token_end": 14}, {"text": "BTK", "type": "ENTITY", "char_start": 149, "char_end": 152, "token_start": 26, "token_end": 26}], "entities_global": [{"text": "STAT5A", "type": "ENTITY", "char_start": 307193, "char_end": 307199, "token_start": 12, "token_end": 12, "note": null}, {"text": "BTK", "type": "ENTITY", "char_start": 307203, "char_end": 307206, "token_start": 14, "token_end": 14, "note": null}, {"text": "BTK", "type": "ENTITY", "char_start": 307258, "char_end": 307261, "token_start": 26, "token_end": 26, "note": null}]}
+{"sentence_id": 1864, "sentence_text": "In contrast to B cells from XID mice , B cells from JAK3 knockout mice showed a normal STAT5A phosphorylation response to anti - IgM stimulation .", "sentence_char_start_global": 307298, "sentence_char_end_global": 307444, "entities": [], "entities_global": []}
+{"sentence_id": 1865, "sentence_text": "These findings provide unprecedented experimental evidence that BTK plays a nonredundant and pivotal role in B cell antigen receptor - mediated STAT5A activation in B cells", "sentence_char_start_global": 307445, "sentence_char_end_global": 307617, "entities": [{"text": "BTK", "type": "ENTITY", "char_start": 64, "char_end": 67, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "BTK", "type": "ENTITY", "char_start": 307509, "char_end": 307512, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 1866, "sentence_text": "Role of T - bet in commitment of TH1 cells before IL - 12 - dependent selection .", "sentence_char_start_global": 307618, "sentence_char_end_global": 307699, "entities": [{"text": "T - bet", "type": "ENTITY", "char_start": 8, "char_end": 15, "token_start": 2, "token_end": 4}, {"text": "IL - 12", "type": "ENTITY", "char_start": 50, "char_end": 57, "token_start": 11, "token_end": 13}], "entities_global": [{"text": "T - bet", "type": "ENTITY", "char_start": 307626, "char_end": 307633, "token_start": 2, "token_end": 4, "note": null}, {"text": "IL - 12", "type": "ENTITY", "char_start": 307668, "char_end": 307675, "token_start": 11, "token_end": 13, "note": null}]}
+{"sentence_id": 1867, "sentence_text": "How cytokines control differentiation of helper T ( TH ) cells is controversial .", "sentence_char_start_global": 307700, "sentence_char_end_global": 307781, "entities": [{"text": "cytokines", "type": "ENTITY", "char_start": 4, "char_end": 13, "token_start": 1, "token_end": 1}], "entities_global": [{"text": "cytokines", "type": "ENTITY", "char_start": 307704, "char_end": 307713, "token_start": 1, "token_end": 1, "note": null}]}
+{"sentence_id": 1868, "sentence_text": "We show that T - bet , without apparent assistance from interleukin 12 ( IL - 12 ) / STAT4 , specifies TH1 effector fate by targeting chromatin remodeling to individual interferon - gamma ( IFN - gamma ) alleles and by inducing IL - 12 receptor beta2 expression .", "sentence_char_start_global": 307782, "sentence_char_end_global": 308045, "entities": [{"text": "T - bet", "type": "ENTITY", "char_start": 13, "char_end": 20, "token_start": 3, "token_end": 5}, {"text": "interleukin 12 ( IL - 12 )", "type": "ENTITY", "char_start": 56, "char_end": 82, "token_start": 11, "token_end": 17}, {"text": "STAT4", "type": "ENTITY", "char_start": 85, "char_end": 90, "token_start": 19, "token_end": 19}, {"text": "interferon - gamma ( IFN - gamma ) alleles", "type": "ENTITY", "char_start": 169, "char_end": 211, "token_start": 31, "token_end": 39}, {"text": "IL - 12 receptor beta2", "type": "ENTITY", "char_start": 228, "char_end": 250, "token_start": 43, "token_end": 47}], "entities_global": [{"text": "T - bet", "type": "ENTITY", "char_start": 307795, "char_end": 307802, "token_start": 3, "token_end": 5, "note": null}, {"text": "interleukin 12 ( IL - 12 )", "type": "ENTITY", "char_start": 307838, "char_end": 307864, "token_start": 11, "token_end": 17, "note": null}, {"text": "STAT4", "type": "ENTITY", "char_start": 307867, "char_end": 307872, "token_start": 19, "token_end": 19, "note": null}, {"text": "interferon - gamma ( IFN - gamma ) alleles", "type": "ENTITY", "char_start": 307951, "char_end": 307993, "token_start": 31, "token_end": 39, "note": null}, {"text": "IL - 12 receptor beta2", "type": "ENTITY", "char_start": 308010, "char_end": 308032, "token_start": 43, "token_end": 47, "note": null}]}
+{"sentence_id": 1869, "sentence_text": "Subsequently , it appears that IL - 12 / STAT4 serves two essential functions in the development of TH1 cells : as growth signal , inducing survival and cell division ; and as trans - activator , prolonging IFN - gamma synthesis through a genetic interaction with the coactivator , CREB - binding protein .", "sentence_char_start_global": 308046, "sentence_char_end_global": 308352, "entities": [{"text": "IL - 12", "type": "ENTITY", "char_start": 31, "char_end": 38, "token_start": 5, "token_end": 7}, {"text": "STAT4", "type": "ENTITY", "char_start": 41, "char_end": 46, "token_start": 9, "token_end": 9}, {"text": "growth signal", "type": "ENTITY", "char_start": 115, "char_end": 128, "token_start": 22, "token_end": 23}, {"text": "trans - activator", "type": "ENTITY", "char_start": 176, "char_end": 193, "token_start": 33, "token_end": 35}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 207, "char_end": 218, "token_start": 38, "token_end": 40}, {"text": "coactivator", "type": "ENTITY", "char_start": 268, "char_end": 279, "token_start": 48, "token_end": 48}, {"text": "CREB - binding protein", "type": "ENTITY", "char_start": 282, "char_end": 304, "token_start": 50, "token_end": 53}], "entities_global": [{"text": "IL - 12", "type": "ENTITY", "char_start": 308077, "char_end": 308084, "token_start": 5, "token_end": 7, "note": null}, {"text": "STAT4", "type": "ENTITY", "char_start": 308087, "char_end": 308092, "token_start": 9, "token_end": 9, "note": null}, {"text": "growth signal", "type": "ENTITY", "char_start": 308161, "char_end": 308174, "token_start": 22, "token_end": 23, "note": null}, {"text": "trans - activator", "type": "ENTITY", "char_start": 308222, "char_end": 308239, "token_start": 33, "token_end": 35, "note": null}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 308253, "char_end": 308264, "token_start": 38, "token_end": 40, "note": null}, {"text": "coactivator", "type": "ENTITY", "char_start": 308314, "char_end": 308325, "token_start": 48, "token_end": 48, "note": null}, {"text": "CREB - binding protein", "type": "ENTITY", "char_start": 308328, "char_end": 308350, "token_start": 50, "token_end": 53, "note": null}]}
+{"sentence_id": 1870, "sentence_text": "These results suggest that a cytokine does not simply induce TH fate choice but instead may act as an essential secondary stimulus that mediates selective survival of a lineage .", "sentence_char_start_global": 308353, "sentence_char_end_global": 308531, "entities": [{"text": "cytokine", "type": "ENTITY", "char_start": 29, "char_end": 37, "token_start": 5, "token_end": 5}], "entities_global": [{"text": "cytokine", "type": "ENTITY", "char_start": 308382, "char_end": 308390, "token_start": 5, "token_end": 5, "note": null}]}
+{"sentence_id": 1871, "sentence_text": "Stat6 is necessary and sufficient for IL - 4 ' s role in Th2 differentiation and cell expansion .", "sentence_char_start_global": 308532, "sentence_char_end_global": 308629, "entities": [{"text": "Stat6", "type": "ENTITY", "char_start": 0, "char_end": 5, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "Stat6", "type": "ENTITY", "char_start": 308532, "char_end": 308537, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 1872, "sentence_text": "IL - 4 plays a critical role in the differentiation of T CR - stimulated naive CD4 T cells to the Th2 phenotype .", "sentence_char_start_global": 308630, "sentence_char_end_global": 308743, "entities": [{"text": "IL - 4", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "IL - 4", "type": "ENTITY", "char_start": 308630, "char_end": 308636, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 1873, "sentence_text": "In response to IL - 4 , the IL - 4R activates a set of phosphotyrosine binding domain - containing proteins , including insulin receptor substrate 1 / 2 , Shc , and IL - 4R interacting protein , as well as Stat6 .", "sentence_char_start_global": 308744, "sentence_char_end_global": 308957, "entities": [{"text": "IL - 4", "type": "ENTITY", "char_start": 15, "char_end": 21, "token_start": 3, "token_end": 5}, {"text": "IL - 4R", "type": "ENTITY", "char_start": 28, "char_end": 35, "token_start": 8, "token_end": 10}, {"text": "phosphotyrosine binding domain - containing proteins", "type": "ENTITY", "char_start": 55, "char_end": 107, "token_start": 15, "token_end": 20}, {"text": "insulin receptor substrate 1 / 2", "type": "ENTITY", "char_start": 120, "char_end": 152, "token_start": 23, "token_end": 28}, {"text": "Shc", "type": "ENTITY", "char_start": 155, "char_end": 158, "token_start": 30, "token_end": 30}, {"text": "IL - 4R interacting protein", "type": "ENTITY", "char_start": 165, "char_end": 192, "token_start": 33, "token_end": 37}, {"text": "Stat6", "type": "ENTITY", "char_start": 206, "char_end": 211, "token_start": 42, "token_end": 42}], "entities_global": [{"text": "IL - 4", "type": "ENTITY", "char_start": 308759, "char_end": 308765, "token_start": 3, "token_end": 5, "note": null}, {"text": "IL - 4R", "type": "ENTITY", "char_start": 308772, "char_end": 308779, "token_start": 8, "token_end": 10, "note": null}, {"text": "phosphotyrosine binding domain - containing proteins", "type": "ENTITY", "char_start": 308799, "char_end": 308851, "token_start": 15, "token_end": 20, "note": null}, {"text": "insulin receptor substrate 1 / 2", "type": "ENTITY", "char_start": 308864, "char_end": 308896, "token_start": 23, "token_end": 28, "note": null}, {"text": "Shc", "type": "ENTITY", "char_start": 308899, "char_end": 308902, "token_start": 30, "token_end": 30, "note": null}, {"text": "IL - 4R interacting protein", "type": "ENTITY", "char_start": 308909, "char_end": 308936, "token_start": 33, "token_end": 37, "note": null}, {"text": "Stat6", "type": "ENTITY", "char_start": 308950, "char_end": 308955, "token_start": 42, "token_end": 42, "note": null}]}
+{"sentence_id": 1874, "sentence_text": "Stat6 has been shown to be required for Th2 differentiation .", "sentence_char_start_global": 308958, "sentence_char_end_global": 309019, "entities": [{"text": "Stat6", "type": "ENTITY", "char_start": 0, "char_end": 5, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "Stat6", "type": "ENTITY", "char_start": 308958, "char_end": 308963, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 1875, "sentence_text": "To determine the roles of the phosphotyrosine binding adaptors in Th2 differentiation , we prepared a retrovirus containing a mutant of the human ( h ) IL - 4R alpha - chain , Y497F , which is unable to recruit these adaptors .", "sentence_char_start_global": 309020, "sentence_char_end_global": 309247, "entities": [{"text": "phosphotyrosine binding adaptors", "type": "ENTITY", "char_start": 30, "char_end": 62, "token_start": 6, "token_end": 8}, {"text": "human ( h ) IL - 4R alpha - chain", "type": "ENTITY", "char_start": 140, "char_end": 173, "token_start": 22, "token_end": 31}, {"text": "Y497F", "type": "ENTITY", "char_start": 176, "char_end": 181, "token_start": 33, "token_end": 33}], "entities_global": [{"text": "phosphotyrosine binding adaptors", "type": "ENTITY", "char_start": 309050, "char_end": 309082, "token_start": 6, "token_end": 8, "note": null}, {"text": "human ( h ) IL - 4R alpha - chain", "type": "ENTITY", "char_start": 309160, "char_end": 309193, "token_start": 22, "token_end": 31, "note": null}, {"text": "Y497F", "type": "ENTITY", "char_start": 309196, "char_end": 309201, "token_start": 33, "token_end": 33, "note": null}]}
+{"sentence_id": 1876, "sentence_text": "The mutant hIL - 4Ralpha , as well as the wild - type ( WT ) hIL - 4Ralpha , was introduced into naive CD4 T cells .", "sentence_char_start_global": 309248, "sentence_char_end_global": 309364, "entities": [{"text": "mutant hIL - 4Ralpha", "type": "ENTITY", "char_start": 4, "char_end": 24, "token_start": 1, "token_end": 4}, {"text": "wild - type ( WT ) hIL - 4Ralpha", "type": "ENTITY", "char_start": 42, "char_end": 74, "token_start": 10, "token_end": 18}], "entities_global": [{"text": "mutant hIL - 4Ralpha", "type": "ENTITY", "char_start": 309252, "char_end": 309272, "token_start": 1, "token_end": 4, "note": null}, {"text": "wild - type ( WT ) hIL - 4Ralpha", "type": "ENTITY", "char_start": 309290, "char_end": 309322, "token_start": 10, "token_end": 18, "note": null}]}
+{"sentence_id": 1877, "sentence_text": "Upon hIL - 4 stimulation , Y497F worked as well as the WT hIL - 4Ralpha in driving Th2 differentiation , as measured by Gata3 up - regulation and IL - 4 production .", "sentence_char_start_global": 309365, "sentence_char_end_global": 309530, "entities": [{"text": "Y497F", "type": "ENTITY", "char_start": 27, "char_end": 32, "token_start": 6, "token_end": 6}, {"text": "WT hIL - 4Ralpha", "type": "ENTITY", "char_start": 55, "char_end": 71, "token_start": 12, "token_end": 15}], "entities_global": [{"text": "Y497F", "type": "ENTITY", "char_start": 309392, "char_end": 309397, "token_start": 6, "token_end": 6, "note": null}, {"text": "WT hIL - 4Ralpha", "type": "ENTITY", "char_start": 309420, "char_end": 309436, "token_start": 12, "token_end": 15, "note": null}]}
+{"sentence_id": 1878, "sentence_text": "Furthermore , IL - 4 - driven cell expansion was also normal in the cells infected with Y497F , although cells infected with Y497F were not capable of phosphorylating insulin receptor substrate 2 .", "sentence_char_start_global": 309531, "sentence_char_end_global": 309728, "entities": [{"text": "Y497F", "type": "ENTITY", "char_start": 88, "char_end": 93, "token_start": 17, "token_end": 17}, {"text": "Y497F", "type": "ENTITY", "char_start": 125, "char_end": 130, "token_start": 23, "token_end": 23}, {"text": "insulin receptor substrate 2", "type": "ENTITY", "char_start": 167, "char_end": 195, "token_start": 29, "token_end": 32}], "entities_global": [{"text": "Y497F", "type": "ENTITY", "char_start": 309619, "char_end": 309624, "token_start": 17, "token_end": 17, "note": null}, {"text": "Y497F", "type": "ENTITY", "char_start": 309656, "char_end": 309661, "token_start": 23, "token_end": 23, "note": null}, {"text": "insulin receptor substrate 2", "type": "ENTITY", "char_start": 309698, "char_end": 309726, "token_start": 29, "token_end": 32, "note": null}]}
+{"sentence_id": 1879, "sentence_text": "These results suggest that the signal pathway mediated by Y497 is dispensable for both IL - 4 - driven Th2 differentiation and cell expansion .", "sentence_char_start_global": 309729, "sentence_char_end_global": 309872, "entities": [{"text": "Y497", "type": "ENTITY", "char_start": 58, "char_end": 62, "token_start": 9, "token_end": 9}, {"text": "IL - 4", "type": "ENTITY", "char_start": 87, "char_end": 93, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "Y497", "type": "ENTITY", "char_start": 309787, "char_end": 309791, "token_start": 9, "token_end": 9, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 309816, "char_end": 309822, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 1880, "sentence_text": "Both WT and Y497F hIL - 4Ralpha lose the ability to drive Th2 differentiation and cell expansion in Stat6 - knockout CD4 T cells .", "sentence_char_start_global": 309873, "sentence_char_end_global": 310003, "entities": [{"text": "WT and Y497F hIL - 4Ralpha", "type": "ENTITY", "char_start": 5, "char_end": 31, "token_start": 1, "token_end": 6}], "entities_global": [{"text": "WT and Y497F hIL - 4Ralpha", "type": "ENTITY", "char_start": 309878, "char_end": 309904, "token_start": 1, "token_end": 6, "note": null}]}
+{"sentence_id": 1881, "sentence_text": "A constitutively activated form of Stat6 introduced into CD4 T cells resulted in both Th2 differentiation and enhanced cell expansion .", "sentence_char_start_global": 310004, "sentence_char_end_global": 310139, "entities": [{"text": "Stat6", "type": "ENTITY", "char_start": 35, "char_end": 40, "token_start": 5, "token_end": 5}], "entities_global": [{"text": "Stat6", "type": "ENTITY", "char_start": 310039, "char_end": 310044, "token_start": 5, "token_end": 5, "note": null}]}
+{"sentence_id": 1882, "sentence_text": "Thus , activated Stat6 is necessary and sufficient to mediate both IL - 4 - driven Th2 differentiation and cell expansion in CD4 T cells .", "sentence_char_start_global": 310140, "sentence_char_end_global": 310278, "entities": [{"text": "activated Stat6", "type": "ENTITY", "char_start": 7, "char_end": 22, "token_start": 2, "token_end": 3}, {"text": "IL - 4", "type": "ENTITY", "char_start": 67, "char_end": 73, "token_start": 11, "token_end": 13}], "entities_global": [{"text": "activated Stat6", "type": "ENTITY", "char_start": 310147, "char_end": 310162, "token_start": 2, "token_end": 3, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 310207, "char_end": 310213, "token_start": 11, "token_end": 13, "note": null}]}
+{"sentence_id": 1883, "sentence_text": "The effect of HIV - 1 regulatory proteins on cellular genes : derepression of the IL - 2 promoter by Tat .", "sentence_char_start_global": 310279, "sentence_char_end_global": 310385, "entities": [{"text": "HIV - 1 regulatory proteins", "type": "ENTITY", "char_start": 14, "char_end": 41, "token_start": 3, "token_end": 7}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 82, "char_end": 97, "token_start": 15, "token_end": 18}, {"text": "Tat", "type": "ENTITY", "char_start": 101, "char_end": 104, "token_start": 20, "token_end": 20}], "entities_global": [{"text": "HIV - 1 regulatory proteins", "type": "ENTITY", "char_start": 310293, "char_end": 310320, "token_start": 3, "token_end": 7, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 310361, "char_end": 310376, "token_start": 15, "token_end": 18, "note": null}, {"text": "Tat", "type": "ENTITY", "char_start": 310380, "char_end": 310383, "token_start": 20, "token_end": 20, "note": null}]}
+{"sentence_id": 1884, "sentence_text": "In HIV - infected individuals dysregulation of the immune system is characterized by severe disorders of the cytokine network .", "sentence_char_start_global": 310386, "sentence_char_end_global": 310513, "entities": [], "entities_global": []}
+{"sentence_id": 1885, "sentence_text": "Increase secretion of IL - 2 , the major T cell growth and differentiation cytokine , may play a decisive role in sensitization of T cells for activation induced apoptosis and indirect death of activated T cells through augmented virus replication .", "sentence_char_start_global": 310514, "sentence_char_end_global": 310763, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 22, "char_end": 28, "token_start": 3, "token_end": 5}, {"text": "cytokine", "type": "ENTITY", "char_start": 75, "char_end": 83, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 310536, "char_end": 310542, "token_start": 3, "token_end": 5, "note": null}, {"text": "cytokine", "type": "ENTITY", "char_start": 310589, "char_end": 310597, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 1886, "sentence_text": "We investigated the cause of enhanced IL - 2 secretion and found that the HIV Tat induces this effect .", "sentence_char_start_global": 310764, "sentence_char_end_global": 310867, "entities": [{"text": "HIV Tat", "type": "ENTITY", "char_start": 74, "char_end": 81, "token_start": 14, "token_end": 15}], "entities_global": [{"text": "HIV Tat", "type": "ENTITY", "char_start": 310838, "char_end": 310845, "token_start": 14, "token_end": 15, "note": null}]}
+{"sentence_id": 1887, "sentence_text": "We demonstrate that increased IL - 2 secretion is due to Tat - enhanced IL - 2 promoter activation .", "sentence_char_start_global": 310868, "sentence_char_end_global": 310968, "entities": [{"text": "Tat", "type": "ENTITY", "char_start": 57, "char_end": 60, "token_start": 11, "token_end": 11}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 72, "char_end": 87, "token_start": 14, "token_end": 17}], "entities_global": [{"text": "Tat", "type": "ENTITY", "char_start": 310925, "char_end": 310928, "token_start": 11, "token_end": 11, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 310940, "char_end": 310955, "token_start": 14, "token_end": 17, "note": null}]}
+{"sentence_id": 1888, "sentence_text": "Tat derepresses and activates the distal AP - 1 site ( position - 185 to - 177 ) in the IL - 2 promoter .", "sentence_char_start_global": 310969, "sentence_char_end_global": 311074, "entities": [{"text": "Tat", "type": "ENTITY", "char_start": 0, "char_end": 3, "token_start": 0, "token_end": 0}, {"text": "distal AP - 1 site", "type": "ENTITY", "char_start": 34, "char_end": 52, "token_start": 5, "token_end": 9}, {"text": "position - 185 to - 177", "type": "ENTITY", "char_start": 55, "char_end": 78, "token_start": 11, "token_end": 16}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 88, "char_end": 103, "token_start": 20, "token_end": 23}], "entities_global": [{"text": "Tat", "type": "ENTITY", "char_start": 310969, "char_end": 310972, "token_start": 0, "token_end": 0, "note": null}, {"text": "distal AP - 1 site", "type": "ENTITY", "char_start": 311003, "char_end": 311021, "token_start": 5, "token_end": 9, "note": null}, {"text": "position - 185 to - 177", "type": "ENTITY", "char_start": 311024, "char_end": 311047, "token_start": 11, "token_end": 16, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 311057, "char_end": 311072, "token_start": 20, "token_end": 23, "note": null}]}
+{"sentence_id": 1889, "sentence_text": "In nonstimulated T cells a repressor complex containing NF - IL6 , JunB , c - Fos and Fra - 1 is formed on the AP - 1 ( IL - 2 / d ) site and represses IL - 2 promoter activity .", "sentence_char_start_global": 311075, "sentence_char_end_global": 311253, "entities": [{"text": "NF - IL6", "type": "ENTITY", "char_start": 56, "char_end": 64, "token_start": 8, "token_end": 10}, {"text": "JunB", "type": "ENTITY", "char_start": 67, "char_end": 71, "token_start": 12, "token_end": 12}, {"text": "c - Fos", "type": "ENTITY", "char_start": 74, "char_end": 81, "token_start": 14, "token_end": 16}, {"text": "Fra - 1", "type": "ENTITY", "char_start": 86, "char_end": 93, "token_start": 18, "token_end": 20}, {"text": "AP - 1 ( IL - 2 / d ) site", "type": "ENTITY", "char_start": 111, "char_end": 137, "token_start": 25, "token_end": 35}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 152, "char_end": 167, "token_start": 38, "token_end": 41}], "entities_global": [{"text": "NF - IL6", "type": "ENTITY", "char_start": 311131, "char_end": 311139, "token_start": 8, "token_end": 10, "note": null}, {"text": "JunB", "type": "ENTITY", "char_start": 311142, "char_end": 311146, "token_start": 12, "token_end": 12, "note": null}, {"text": "c - Fos", "type": "ENTITY", "char_start": 311149, "char_end": 311156, "token_start": 14, "token_end": 16, "note": null}, {"text": "Fra - 1", "type": "ENTITY", "char_start": 311161, "char_end": 311168, "token_start": 18, "token_end": 20, "note": null}, {"text": "AP - 1 ( IL - 2 / d ) site", "type": "ENTITY", "char_start": 311186, "char_end": 311212, "token_start": 25, "token_end": 35, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 311227, "char_end": 311242, "token_start": 38, "token_end": 41, "note": null}]}
+{"sentence_id": 1890, "sentence_text": "After T cell activation , a heterodimeric activator containing p65 and c - Jun binds to the AP - 1 ( IL - 2 / d ) site .", "sentence_char_start_global": 311254, "sentence_char_end_global": 311374, "entities": [{"text": "heterodimeric activator", "type": "ENTITY", "char_start": 28, "char_end": 51, "token_start": 6, "token_end": 7}, {"text": "p65", "type": "ENTITY", "char_start": 63, "char_end": 66, "token_start": 9, "token_end": 9}, {"text": "c - Jun", "type": "ENTITY", "char_start": 71, "char_end": 78, "token_start": 11, "token_end": 13}, {"text": "AP - 1 ( IL - 2 / d ) site", "type": "ENTITY", "char_start": 92, "char_end": 118, "token_start": 17, "token_end": 27}], "entities_global": [{"text": "heterodimeric activator", "type": "ENTITY", "char_start": 311282, "char_end": 311305, "token_start": 6, "token_end": 7, "note": null}, {"text": "p65", "type": "ENTITY", "char_start": 311317, "char_end": 311320, "token_start": 9, "token_end": 9, "note": null}, {"text": "c - Jun", "type": "ENTITY", "char_start": 311325, "char_end": 311332, "token_start": 11, "token_end": 13, "note": null}, {"text": "AP - 1 ( IL - 2 / d ) site", "type": "ENTITY", "char_start": 311346, "char_end": 311372, "token_start": 17, "token_end": 27, "note": null}]}
+{"sentence_id": 1891, "sentence_text": "HIV Tat enhances activation of NF - kappaB and consequently , activates the AP - 1 ( IL - 2 / d ) site .", "sentence_char_start_global": 311375, "sentence_char_end_global": 311479, "entities": [{"text": "HIV Tat", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 1}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 31, "char_end": 42, "token_start": 5, "token_end": 7}, {"text": "AP - 1 ( IL - 2 / d ) site", "type": "ENTITY", "char_start": 76, "char_end": 102, "token_start": 13, "token_end": 23}], "entities_global": [{"text": "HIV Tat", "type": "ENTITY", "char_start": 311375, "char_end": 311382, "token_start": 0, "token_end": 1, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 311406, "char_end": 311417, "token_start": 5, "token_end": 7, "note": null}, {"text": "AP - 1 ( IL - 2 / d ) site", "type": "ENTITY", "char_start": 311451, "char_end": 311477, "token_start": 13, "token_end": 23, "note": null}]}
+{"sentence_id": 1892, "sentence_text": "Our data provide evidence for a novel mechanism by which HIV Tat dysregulates IL - 2 production and therefore may contribute to the HIV - 1 infection in a way yet to be clarified .", "sentence_char_start_global": 311480, "sentence_char_end_global": 311660, "entities": [{"text": "HIV Tat", "type": "ENTITY", "char_start": 57, "char_end": 64, "token_start": 10, "token_end": 11}], "entities_global": [{"text": "HIV Tat", "type": "ENTITY", "char_start": 311537, "char_end": 311544, "token_start": 10, "token_end": 11, "note": null}]}
+{"sentence_id": 1893, "sentence_text": "Transforming growth factor - beta1 interferes with thrombopoietin - induced signal transduction in megakaryoblastic and erythroleukemic cells .", "sentence_char_start_global": 311661, "sentence_char_end_global": 311804, "entities": [{"text": "Transforming growth factor - beta1", "type": "ENTITY", "char_start": 0, "char_end": 34, "token_start": 0, "token_end": 4}], "entities_global": [{"text": "Transforming growth factor - beta1", "type": "ENTITY", "char_start": 311661, "char_end": 311695, "token_start": 0, "token_end": 4, "note": null}]}
+{"sentence_id": 1894, "sentence_text": "OBJECTIVE : Thrombopoietin ( TPO ) and transforming growth factor - beta ( 1 ) ( TGF - beta ( 1 ) ) have been shown to exert opposite effects on proliferation and megakaryocytic differentiation of hematopoietic cells .", "sentence_char_start_global": 311805, "sentence_char_end_global": 312023, "entities": [{"text": "Thrombopoietin", "type": "ENTITY", "char_start": 12, "char_end": 26, "token_start": 2, "token_end": 2}, {"text": "TPO", "type": "ENTITY", "char_start": 29, "char_end": 32, "token_start": 4, "token_end": 4}, {"text": "transforming growth factor - beta ( 1 )", "type": "ENTITY", "char_start": 39, "char_end": 78, "token_start": 7, "token_end": 14}, {"text": "TGF - beta ( 1 )", "type": "ENTITY", "char_start": 81, "char_end": 97, "token_start": 16, "token_end": 21}], "entities_global": [{"text": "Thrombopoietin", "type": "ENTITY", "char_start": 311817, "char_end": 311831, "token_start": 2, "token_end": 2, "note": null}, {"text": "TPO", "type": "ENTITY", "char_start": 311834, "char_end": 311837, "token_start": 4, "token_end": 4, "note": null}, {"text": "transforming growth factor - beta ( 1 )", "type": "ENTITY", "char_start": 311844, "char_end": 311883, "token_start": 7, "token_end": 14, "note": null}, {"text": "TGF - beta ( 1 )", "type": "ENTITY", "char_start": 311886, "char_end": 311902, "token_start": 16, "token_end": 21, "note": null}]}
+{"sentence_id": 1895, "sentence_text": "To determine whether TGF - beta ( 1 ) interferes directly with TPO - induced signal transduction in hematopoietic cells , we compared the regulatory effects in the TPO - responsive cell lines Mo - 7e and HEL .", "sentence_char_start_global": 312024, "sentence_char_end_global": 312233, "entities": [{"text": "TGF - beta ( 1 )", "type": "ENTITY", "char_start": 21, "char_end": 37, "token_start": 3, "token_end": 8}, {"text": "TPO", "type": "ENTITY", "char_start": 63, "char_end": 66, "token_start": 12, "token_end": 12}, {"text": "TPO", "type": "ENTITY", "char_start": 164, "char_end": 167, "token_start": 28, "token_end": 28}], "entities_global": [{"text": "TGF - beta ( 1 )", "type": "ENTITY", "char_start": 312045, "char_end": 312061, "token_start": 3, "token_end": 8, "note": null}, {"text": "TPO", "type": "ENTITY", "char_start": 312087, "char_end": 312090, "token_start": 12, "token_end": 12, "note": null}, {"text": "TPO", "type": "ENTITY", "char_start": 312188, "char_end": 312191, "token_start": 28, "token_end": 28, "note": null}]}
+{"sentence_id": 1896, "sentence_text": "MATERIALS AND METHODS : The cells were stimulated by 100 ng / mL TPO and / or 100 ng / mL TGF - beta1 and analyzed for proliferation ( 3H thymidine incorporation ) , viability ( trypan blue exclusion ) , and protein expression and phosphorylation ( Western blot ) .", "sentence_char_start_global": 312234, "sentence_char_end_global": 312499, "entities": [{"text": "TPO", "type": "ENTITY", "char_start": 65, "char_end": 68, "token_start": 13, "token_end": 13}, {"text": "TGF - beta1", "type": "ENTITY", "char_start": 90, "char_end": 101, "token_start": 21, "token_end": 23}], "entities_global": [{"text": "TPO", "type": "ENTITY", "char_start": 312299, "char_end": 312302, "token_start": 13, "token_end": 13, "note": null}, {"text": "TGF - beta1", "type": "ENTITY", "char_start": 312324, "char_end": 312335, "token_start": 21, "token_end": 23, "note": null}]}
+{"sentence_id": 1897, "sentence_text": "RESULTS : TPO enhanced the proliferation of Mo - 7e cells as determined by 3H - thymidine incorporation , whereas TGF - beta1 suppressed baseline cell growth and antagonized the proliferative effect of TPO .", "sentence_char_start_global": 312500, "sentence_char_end_global": 312707, "entities": [{"text": "TPO", "type": "ENTITY", "char_start": 10, "char_end": 13, "token_start": 2, "token_end": 2}, {"text": "TGF - beta1", "type": "ENTITY", "char_start": 114, "char_end": 125, "token_start": 20, "token_end": 22}, {"text": "TPO", "type": "ENTITY", "char_start": 202, "char_end": 205, "token_start": 33, "token_end": 33}], "entities_global": [{"text": "TPO", "type": "ENTITY", "char_start": 312510, "char_end": 312513, "token_start": 2, "token_end": 2, "note": null}, {"text": "TGF - beta1", "type": "ENTITY", "char_start": 312614, "char_end": 312625, "token_start": 20, "token_end": 22, "note": null}, {"text": "TPO", "type": "ENTITY", "char_start": 312702, "char_end": 312705, "token_start": 33, "token_end": 33, "note": null}]}
+{"sentence_id": 1898, "sentence_text": "TPO - induced proliferation also was reduced by a specific inhibitor of the mitogen - activated protein kinase ( MAPK ) pathway ( PD098059 ) , which inhibits activation of the MAPK extracellular signal - regulated kinases ( ERK ) ERK1 and ERK2 , and AG490 , an inhibitor of Janus kinase - 2 , which completely blocked TPO - induced proliferation .", "sentence_char_start_global": 312708, "sentence_char_end_global": 313055, "entities": [{"text": "TPO", "type": "ENTITY", "char_start": 0, "char_end": 3, "token_start": 0, "token_end": 0}, {"text": "mitogen - activated protein kinase", "type": "ENTITY", "char_start": 76, "char_end": 110, "token_start": 13, "token_end": 17}, {"text": "MAPK", "type": "ENTITY", "char_start": 113, "char_end": 117, "token_start": 19, "token_end": 19}, {"text": "MAPK extracellular signal - regulated kinases", "type": "ENTITY", "char_start": 176, "char_end": 221, "token_start": 31, "token_end": 36}, {"text": "ERK", "type": "ENTITY", "char_start": 224, "char_end": 227, "token_start": 38, "token_end": 38}, {"text": "ERK1", "type": "ENTITY", "char_start": 230, "char_end": 234, "token_start": 40, "token_end": 40}, {"text": "ERK2", "type": "ENTITY", "char_start": 239, "char_end": 243, "token_start": 42, "token_end": 42}, {"text": "Janus kinase - 2", "type": "ENTITY", "char_start": 274, "char_end": 290, "token_start": 50, "token_end": 53}, {"text": "TPO", "type": "ENTITY", "char_start": 318, "char_end": 321, "token_start": 58, "token_end": 58}], "entities_global": [{"text": "TPO", "type": "ENTITY", "char_start": 312708, "char_end": 312711, "token_start": 0, "token_end": 0, "note": null}, {"text": "mitogen - activated protein kinase", "type": "ENTITY", "char_start": 312784, "char_end": 312818, "token_start": 13, "token_end": 17, "note": null}, {"text": "MAPK", "type": "ENTITY", "char_start": 312821, "char_end": 312825, "token_start": 19, "token_end": 19, "note": null}, {"text": "MAPK extracellular signal - regulated kinases", "type": "ENTITY", "char_start": 312884, "char_end": 312929, "token_start": 31, "token_end": 36, "note": null}, {"text": "ERK", "type": "ENTITY", "char_start": 312932, "char_end": 312935, "token_start": 38, "token_end": 38, "note": null}, {"text": "ERK1", "type": "ENTITY", "char_start": 312938, "char_end": 312942, "token_start": 40, "token_end": 40, "note": null}, {"text": "ERK2", "type": "ENTITY", "char_start": 312947, "char_end": 312951, "token_start": 42, "token_end": 42, "note": null}, {"text": "Janus kinase - 2", "type": "ENTITY", "char_start": 312982, "char_end": 312998, "token_start": 50, "token_end": 53, "note": null}, {"text": "TPO", "type": "ENTITY", "char_start": 313026, "char_end": 313029, "token_start": 58, "token_end": 58, "note": null}]}
+{"sentence_id": 1899, "sentence_text": "As demonstrated by Western blotting , TGF - beta1 reduced the TPO - stimulated ERK1 / ERK2 and STAT5 phosphorylation in Mo - 7e and HEL cells .", "sentence_char_start_global": 313056, "sentence_char_end_global": 313199, "entities": [{"text": "TGF - beta1", "type": "ENTITY", "char_start": 38, "char_end": 49, "token_start": 6, "token_end": 8}, {"text": "TPO", "type": "ENTITY", "char_start": 62, "char_end": 65, "token_start": 11, "token_end": 11}, {"text": "ERK1", "type": "ENTITY", "char_start": 79, "char_end": 83, "token_start": 14, "token_end": 14}, {"text": "ERK2", "type": "ENTITY", "char_start": 86, "char_end": 90, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "TGF - beta1", "type": "ENTITY", "char_start": 313094, "char_end": 313105, "token_start": 6, "token_end": 8, "note": null}, {"text": "TPO", "type": "ENTITY", "char_start": 313118, "char_end": 313121, "token_start": 11, "token_end": 11, "note": null}, {"text": "ERK1", "type": "ENTITY", "char_start": 313135, "char_end": 313139, "token_start": 14, "token_end": 14, "note": null}, {"text": "ERK2", "type": "ENTITY", "char_start": 313142, "char_end": 313146, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 1900, "sentence_text": "This effect was completely reversed by preincubation with a tyrosine phosphatase inhibitor ( Na3VO4 ) , which suggests that TGF - beta1 activated a phosphatase .", "sentence_char_start_global": 313200, "sentence_char_end_global": 313361, "entities": [{"text": "TGF - beta1", "type": "ENTITY", "char_start": 124, "char_end": 135, "token_start": 19, "token_end": 21}, {"text": "phosphatase", "type": "ENTITY", "char_start": 148, "char_end": 159, "token_start": 24, "token_end": 24}], "entities_global": [{"text": "TGF - beta1", "type": "ENTITY", "char_start": 313324, "char_end": 313335, "token_start": 19, "token_end": 21, "note": null}, {"text": "phosphatase", "type": "ENTITY", "char_start": 313348, "char_end": 313359, "token_start": 24, "token_end": 24, "note": null}]}
+{"sentence_id": 1901, "sentence_text": "Although STAT3 also was activated by TPO , STAT3 activation remained unaltered by TGF - beta1 .", "sentence_char_start_global": 313362, "sentence_char_end_global": 313457, "entities": [{"text": "STAT3", "type": "ENTITY", "char_start": 9, "char_end": 14, "token_start": 1, "token_end": 1}, {"text": "TPO", "type": "ENTITY", "char_start": 37, "char_end": 40, "token_start": 6, "token_end": 6}, {"text": "STAT3", "type": "ENTITY", "char_start": 43, "char_end": 48, "token_start": 8, "token_end": 8}, {"text": "TGF - beta1", "type": "ENTITY", "char_start": 82, "char_end": 93, "token_start": 13, "token_end": 15}], "entities_global": [{"text": "STAT3", "type": "ENTITY", "char_start": 313371, "char_end": 313376, "token_start": 1, "token_end": 1, "note": null}, {"text": "TPO", "type": "ENTITY", "char_start": 313399, "char_end": 313402, "token_start": 6, "token_end": 6, "note": null}, {"text": "STAT3", "type": "ENTITY", "char_start": 313405, "char_end": 313410, "token_start": 8, "token_end": 8, "note": null}, {"text": "TGF - beta1", "type": "ENTITY", "char_start": 313444, "char_end": 313455, "token_start": 13, "token_end": 15, "note": null}]}
+{"sentence_id": 1902, "sentence_text": "CONCLUSION : Taken together , these data suggest that TGF - beta1 modulates TPO - mediated effects on megakaryocytic proliferation by interfering with TPO - induced signal transduction , particularly by reducing the activities of MAPK ERK1 / ERK2 and STAT5 .", "sentence_char_start_global": 313458, "sentence_char_end_global": 313716, "entities": [{"text": "TGF - beta1", "type": "ENTITY", "char_start": 54, "char_end": 65, "token_start": 9, "token_end": 11}, {"text": "TPO", "type": "ENTITY", "char_start": 76, "char_end": 79, "token_start": 13, "token_end": 13}, {"text": "TPO", "type": "ENTITY", "char_start": 151, "char_end": 154, "token_start": 23, "token_end": 23}, {"text": "MAPK ERK1 / ERK2 and STAT5", "type": "ENTITY", "char_start": 230, "char_end": 256, "token_start": 35, "token_end": 40}], "entities_global": [{"text": "TGF - beta1", "type": "ENTITY", "char_start": 313512, "char_end": 313523, "token_start": 9, "token_end": 11, "note": null}, {"text": "TPO", "type": "ENTITY", "char_start": 313534, "char_end": 313537, "token_start": 13, "token_end": 13, "note": null}, {"text": "TPO", "type": "ENTITY", "char_start": 313609, "char_end": 313612, "token_start": 23, "token_end": 23, "note": null}, {"text": "MAPK ERK1 / ERK2 and STAT5", "type": "ENTITY", "char_start": 313688, "char_end": 313714, "token_start": 35, "token_end": 40, "note": null}]}
+{"sentence_id": 1903, "sentence_text": "Invariant chain induces B cell maturation by activating a TAF ( II ) 105 - NF - kappaB - dependent transcription program .", "sentence_char_start_global": 313717, "sentence_char_end_global": 313839, "entities": [{"text": "Invariant chain", "type": "ENTITY", "char_start": 0, "char_end": 15, "token_start": 0, "token_end": 1}, {"text": "TAF ( II ) 105 - NF - kappaB", "type": "ENTITY", "char_start": 58, "char_end": 86, "token_start": 9, "token_end": 17}], "entities_global": [{"text": "Invariant chain", "type": "ENTITY", "char_start": 313717, "char_end": 313732, "token_start": 0, "token_end": 1, "note": null}, {"text": "TAF ( II ) 105 - NF - kappaB", "type": "ENTITY", "char_start": 313775, "char_end": 313803, "token_start": 9, "token_end": 17, "note": null}]}
+{"sentence_id": 1904, "sentence_text": "Early stages of B cell development occur in the bone marrow , resulting in formation of immature B cells .", "sentence_char_start_global": 313840, "sentence_char_end_global": 313946, "entities": [], "entities_global": []}
+{"sentence_id": 1905, "sentence_text": "From there these immature cells migrate to the spleen where they differentiate to mature cells .", "sentence_char_start_global": 313947, "sentence_char_end_global": 314043, "entities": [], "entities_global": []}
+{"sentence_id": 1906, "sentence_text": "This final maturation step is crucial for the B cells to become responsive to antigens and to participate in the immune response .", "sentence_char_start_global": 314044, "sentence_char_end_global": 314174, "entities": [{"text": "antigens", "type": "ENTITY", "char_start": 78, "char_end": 86, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "antigens", "type": "ENTITY", "char_start": 314122, "char_end": 314130, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 1907, "sentence_text": "Recently , invariant chain ( Ii ) , a major histocompatibility complex class II chaperone , as well as the transcription factors c - Rel and p65 / RelA , were found to play a role in the final antigen - independent differentiation stage of B cells in the spleen .", "sentence_char_start_global": 314175, "sentence_char_end_global": 314438, "entities": [{"text": "invariant chain", "type": "ENTITY", "char_start": 11, "char_end": 26, "token_start": 2, "token_end": 3}, {"text": "Ii", "type": "ENTITY", "char_start": 29, "char_end": 31, "token_start": 5, "token_end": 5}, {"text": "major histocompatibility complex class II chaperone", "type": "ENTITY", "char_start": 38, "char_end": 89, "token_start": 9, "token_end": 14}, {"text": "transcription factors", "type": "ENTITY", "char_start": 107, "char_end": 128, "token_start": 20, "token_end": 21}, {"text": "c - Rel", "type": "ENTITY", "char_start": 129, "char_end": 136, "token_start": 22, "token_end": 24}, {"text": "p65 / RelA", "type": "ENTITY", "char_start": 141, "char_end": 151, "token_start": 26, "token_end": 28}], "entities_global": [{"text": "invariant chain", "type": "ENTITY", "char_start": 314186, "char_end": 314201, "token_start": 2, "token_end": 3, "note": null}, {"text": "Ii", "type": "ENTITY", "char_start": 314204, "char_end": 314206, "token_start": 5, "token_end": 5, "note": null}, {"text": "major histocompatibility complex class II chaperone", "type": "ENTITY", "char_start": 314213, "char_end": 314264, "token_start": 9, "token_end": 14, "note": null}, {"text": "transcription factors", "type": "ENTITY", "char_start": 314282, "char_end": 314303, "token_start": 20, "token_end": 21, "note": null}, {"text": "c - Rel", "type": "ENTITY", "char_start": 314304, "char_end": 314311, "token_start": 22, "token_end": 24, "note": null}, {"text": "p65 / RelA", "type": "ENTITY", "char_start": 314316, "char_end": 314326, "token_start": 26, "token_end": 28, "note": null}]}
+{"sentence_id": 1908, "sentence_text": "In this study , we investigated a possible link between Ii - dependent B cell maturation and the NF - kappaB pathway .", "sentence_char_start_global": 314439, "sentence_char_end_global": 314557, "entities": [{"text": "Ii", "type": "ENTITY", "char_start": 56, "char_end": 58, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "Ii", "type": "ENTITY", "char_start": 314495, "char_end": 314497, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 1909, "sentence_text": "Our studies indicate that Ii - induced B cell maturation involves activation of transcription mediated by the NF - kappaB p65 / RelA homodimer and requires the B cell - enriched coactivator TBP - associated factor ( II ) 105 .", "sentence_char_start_global": 314558, "sentence_char_end_global": 314784, "entities": [{"text": "Ii", "type": "ENTITY", "char_start": 26, "char_end": 28, "token_start": 4, "token_end": 4}, {"text": "NF - kappaB p65 / RelA homodimer", "type": "ENTITY", "char_start": 110, "char_end": 142, "token_start": 17, "token_end": 23}, {"text": "B cell - enriched coactivator", "type": "ENTITY", "char_start": 160, "char_end": 189, "token_start": 27, "token_end": 31}, {"text": "TBP - associated factor ( II ) 105", "type": "ENTITY", "char_start": 190, "char_end": 224, "token_start": 32, "token_end": 39}], "entities_global": [{"text": "Ii", "type": "ENTITY", "char_start": 314584, "char_end": 314586, "token_start": 4, "token_end": 4, "note": null}, {"text": "NF - kappaB p65 / RelA homodimer", "type": "ENTITY", "char_start": 314668, "char_end": 314700, "token_start": 17, "token_end": 23, "note": null}, {"text": "B cell - enriched coactivator", "type": "ENTITY", "char_start": 314718, "char_end": 314747, "token_start": 27, "token_end": 31, "note": null}, {"text": "TBP - associated factor ( II ) 105", "type": "ENTITY", "char_start": 314748, "char_end": 314782, "token_start": 32, "token_end": 39, "note": null}]}
+{"sentence_id": 1910, "sentence_text": "Androgens indirectly accelerate thymocyte apoptosis .", "sentence_char_start_global": 314785, "sentence_char_end_global": 314838, "entities": [], "entities_global": []}
+{"sentence_id": 1911, "sentence_text": "Apoptotic processes , or the disturbance of the natural regulation of these processes , may be involved in the pathogenesis of autoimmune diseases ( AID ) .", "sentence_char_start_global": 314839, "sentence_char_end_global": 314995, "entities": [], "entities_global": []}
+{"sentence_id": 1912, "sentence_text": "Women are , in general , more susceptible than men to develop AID like rheumatoid arthritis .", "sentence_char_start_global": 314996, "sentence_char_end_global": 315089, "entities": [], "entities_global": []}
+{"sentence_id": 1913, "sentence_text": "Androgens and glucocorticoids , in contrast to oestrogens , have favourable effects in AID models as well as in human AID .", "sentence_char_start_global": 315090, "sentence_char_end_global": 315213, "entities": [], "entities_global": []}
+{"sentence_id": 1914, "sentence_text": "It is known that glucocorticoids ( GC ) , used for treatment of AID , increase apoptosis in the thymus resulting in decreased numbers of CD4 + CD8 + thymocytes .", "sentence_char_start_global": 315214, "sentence_char_end_global": 315375, "entities": [], "entities_global": []}
+{"sentence_id": 1915, "sentence_text": "It was asked whether androgens , in contrast to oestrogens , exert their favourable effects in the treatment of AID by a mechanism comparable to that described for GC by eliminating the apoptosis prone CD4 + CD8 + population in the thymus .", "sentence_char_start_global": 315376, "sentence_char_end_global": 315616, "entities": [], "entities_global": []}
+{"sentence_id": 1916, "sentence_text": "Although both androgens and oestrogens proved thymolytic , a significantly decreased percentage of CD4 + CD8 + thymocytes was observed by flow cytometry after treatment of mice with the androgen methyltestosterone , but not with the oestrogen ethinylestradiol .", "sentence_char_start_global": 315617, "sentence_char_end_global": 315878, "entities": [], "entities_global": []}
+{"sentence_id": 1917, "sentence_text": "To investigate whether the observed thymolytic effects were due to the presence of hormone receptors on thymocytes , cells were isolated from the thymus and incubated with androgens or oestrogens to measure apoptosis .", "sentence_char_start_global": 315879, "sentence_char_end_global": 316097, "entities": [{"text": "hormone receptors", "type": "ENTITY", "char_start": 83, "char_end": 100, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "hormone receptors", "type": "ENTITY", "char_start": 315962, "char_end": 315979, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 1918, "sentence_text": "Several techniques were used to determine thymocyte apoptosis in vitro , but no enhanced apoptotic signal was observed .", "sentence_char_start_global": 316098, "sentence_char_end_global": 316218, "entities": [], "entities_global": []}
+{"sentence_id": 1919, "sentence_text": "Using the very sensitive TUNEL assay , no direct effect of androgens on thymocytes in vitro could be observed .", "sentence_char_start_global": 316219, "sentence_char_end_global": 316330, "entities": [], "entities_global": []}
+{"sentence_id": 1920, "sentence_text": "This is in sharp contrast to the high signal observed with GC .", "sentence_char_start_global": 316331, "sentence_char_end_global": 316394, "entities": [], "entities_global": []}
+{"sentence_id": 1921, "sentence_text": "Therefore , upon in vivo androgen treatment , other cells containing androgen receptors than thymocytes are probably involved in inducing the increase in thymic apoptosis .", "sentence_char_start_global": 316395, "sentence_char_end_global": 316567, "entities": [{"text": "androgen receptors", "type": "ENTITY", "char_start": 69, "char_end": 87, "token_start": 11, "token_end": 12}], "entities_global": [{"text": "androgen receptors", "type": "ENTITY", "char_start": 316464, "char_end": 316482, "token_start": 11, "token_end": 12, "note": null}]}
+{"sentence_id": 1922, "sentence_text": "To study the role of the androgen receptor on thymocyte apoptosis , androgen receptor mutant ( Tfm / Y ) mice were treated with androgens .", "sentence_char_start_global": 316568, "sentence_char_end_global": 316707, "entities": [{"text": "androgen receptor", "type": "ENTITY", "char_start": 25, "char_end": 42, "token_start": 6, "token_end": 7}, {"text": "androgen receptor", "type": "ENTITY", "char_start": 68, "char_end": 85, "token_start": 12, "token_end": 13}], "entities_global": [{"text": "androgen receptor", "type": "ENTITY", "char_start": 316593, "char_end": 316610, "token_start": 6, "token_end": 7, "note": null}, {"text": "androgen receptor", "type": "ENTITY", "char_start": 316636, "char_end": 316653, "token_start": 12, "token_end": 13, "note": null}]}
+{"sentence_id": 1923, "sentence_text": "No alterations of thymocyte subpopulations were seen , suggesting that changes in the percentage of CD4 + CD8 + thymocytes after administration of androgens depend on the presence of functional androgen receptors .", "sentence_char_start_global": 316708, "sentence_char_end_global": 316922, "entities": [{"text": "androgen receptors", "type": "ENTITY", "char_start": 194, "char_end": 212, "token_start": 30, "token_end": 31}], "entities_global": [{"text": "androgen receptors", "type": "ENTITY", "char_start": 316902, "char_end": 316920, "token_start": 30, "token_end": 31, "note": null}]}
+{"sentence_id": 1924, "sentence_text": "Thus , it is concluded that androgens indirectly accelerate thymocyte apoptosis in vivo .", "sentence_char_start_global": 316923, "sentence_char_end_global": 317012, "entities": [], "entities_global": []}
+{"sentence_id": 1925, "sentence_text": "Inhibition of the transcription factors AP - 1 and NF - kappaB in CD4 T cells by peroxisome proliferator - activated receptor gamma ligands .", "sentence_char_start_global": 317013, "sentence_char_end_global": 317154, "entities": [{"text": "transcription factors", "type": "ENTITY", "char_start": 18, "char_end": 39, "token_start": 3, "token_end": 4}, {"text": "AP - 1", "type": "ENTITY", "char_start": 40, "char_end": 46, "token_start": 5, "token_end": 7}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 51, "char_end": 62, "token_start": 9, "token_end": 11}, {"text": "peroxisome proliferator - activated receptor gamma ligands", "type": "ENTITY", "char_start": 81, "char_end": 139, "token_start": 17, "token_end": 23}], "entities_global": [{"text": "transcription factors", "type": "ENTITY", "char_start": 317031, "char_end": 317052, "token_start": 3, "token_end": 4, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 317053, "char_end": 317059, "token_start": 5, "token_end": 7, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 317064, "char_end": 317075, "token_start": 9, "token_end": 11, "note": null}, {"text": "peroxisome proliferator - activated receptor gamma ligands", "type": "ENTITY", "char_start": 317094, "char_end": 317152, "token_start": 17, "token_end": 23, "note": null}]}
+{"sentence_id": 1926, "sentence_text": "The peroxisome proliferator - activated receptor gamma ( PPARgamma ) , a member of the nuclear hormone receptor superfamily , is essential for adipocyte differentiation and glucose homeostasis .", "sentence_char_start_global": 317155, "sentence_char_end_global": 317349, "entities": [{"text": "peroxisome proliferator - activated receptor gamma", "type": "ENTITY", "char_start": 4, "char_end": 54, "token_start": 1, "token_end": 6}, {"text": "PPARgamma", "type": "ENTITY", "char_start": 57, "char_end": 66, "token_start": 8, "token_end": 8}, {"text": "nuclear hormone receptor superfamily", "type": "ENTITY", "char_start": 87, "char_end": 123, "token_start": 15, "token_end": 18}], "entities_global": [{"text": "peroxisome proliferator - activated receptor gamma", "type": "ENTITY", "char_start": 317159, "char_end": 317209, "token_start": 1, "token_end": 6, "note": null}, {"text": "PPARgamma", "type": "ENTITY", "char_start": 317212, "char_end": 317221, "token_start": 8, "token_end": 8, "note": null}, {"text": "nuclear hormone receptor superfamily", "type": "ENTITY", "char_start": 317242, "char_end": 317278, "token_start": 15, "token_end": 18, "note": null}]}
+{"sentence_id": 1927, "sentence_text": "PPARgamma has been found recently to regulate macrophage activation in response to mitogens and inflammation .", "sentence_char_start_global": 317350, "sentence_char_end_global": 317460, "entities": [{"text": "PPARgamma", "type": "ENTITY", "char_start": 0, "char_end": 9, "token_start": 0, "token_end": 0}, {"text": "mitogens", "type": "ENTITY", "char_start": 83, "char_end": 91, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "PPARgamma", "type": "ENTITY", "char_start": 317350, "char_end": 317359, "token_start": 0, "token_end": 0, "note": null}, {"text": "mitogens", "type": "ENTITY", "char_start": 317433, "char_end": 317441, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 1928, "sentence_text": "Our study shows PPARgamma to be preferentially expressed in the nuclei of resting T cells and to increase upon activation of T cells by either anti - CD3 and anti - CD28 or phorbol myristyl acetate ( PMA ) .", "sentence_char_start_global": 317461, "sentence_char_end_global": 317668, "entities": [{"text": "PPARgamma", "type": "ENTITY", "char_start": 16, "char_end": 25, "token_start": 3, "token_end": 3}, {"text": "anti - CD3", "type": "ENTITY", "char_start": 143, "char_end": 153, "token_start": 25, "token_end": 27}, {"text": "anti - CD28", "type": "ENTITY", "char_start": 158, "char_end": 169, "token_start": 29, "token_end": 31}], "entities_global": [{"text": "PPARgamma", "type": "ENTITY", "char_start": 317477, "char_end": 317486, "token_start": 3, "token_end": 3, "note": null}, {"text": "anti - CD3", "type": "ENTITY", "char_start": 317604, "char_end": 317614, "token_start": 25, "token_end": 27, "note": null}, {"text": "anti - CD28", "type": "ENTITY", "char_start": 317619, "char_end": 317630, "token_start": 29, "token_end": 31, "note": null}]}
+{"sentence_id": 1929, "sentence_text": "We also found the PPARgamma ligand ciglitizone to attenuate the activation of T cells by inhibiting cytokine gene expression and anti - CD3 and anti - CD28 or PMA - induced proliferative responses .", "sentence_char_start_global": 317669, "sentence_char_end_global": 317867, "entities": [{"text": "PPARgamma ligand", "type": "ENTITY", "char_start": 18, "char_end": 34, "token_start": 4, "token_end": 5}, {"text": "anti - CD3", "type": "ENTITY", "char_start": 129, "char_end": 139, "token_start": 20, "token_end": 22}, {"text": "anti - CD28", "type": "ENTITY", "char_start": 144, "char_end": 155, "token_start": 24, "token_end": 26}], "entities_global": [{"text": "PPARgamma ligand", "type": "ENTITY", "char_start": 317687, "char_end": 317703, "token_start": 4, "token_end": 5, "note": null}, {"text": "anti - CD3", "type": "ENTITY", "char_start": 317798, "char_end": 317808, "token_start": 20, "token_end": 22, "note": null}, {"text": "anti - CD28", "type": "ENTITY", "char_start": 317813, "char_end": 317824, "token_start": 24, "token_end": 26, "note": null}]}
+{"sentence_id": 1930, "sentence_text": "Inhibition of both the proliferative response and inflammatory cytokine expression in CD4 T cells was correlated with suppression of the activated transcription factors AP1 and NF - kappaB .", "sentence_char_start_global": 317868, "sentence_char_end_global": 318058, "entities": [{"text": "transcription factors", "type": "ENTITY", "char_start": 147, "char_end": 168, "token_start": 21, "token_end": 22}, {"text": "AP1", "type": "ENTITY", "char_start": 169, "char_end": 172, "token_start": 23, "token_end": 23}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 177, "char_end": 188, "token_start": 25, "token_end": 27}], "entities_global": [{"text": "transcription factors", "type": "ENTITY", "char_start": 318015, "char_end": 318036, "token_start": 21, "token_end": 22, "note": null}, {"text": "AP1", "type": "ENTITY", "char_start": 318037, "char_end": 318040, "token_start": 23, "token_end": 23, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 318045, "char_end": 318056, "token_start": 25, "token_end": 27, "note": null}]}
+{"sentence_id": 1931, "sentence_text": "PPARgamma ligands also strongly inhibited SEA - induced Vbeta3 T cell activation in vivo .", "sentence_char_start_global": 318059, "sentence_char_end_global": 318149, "entities": [{"text": "PPARgamma ligands", "type": "ENTITY", "char_start": 0, "char_end": 17, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "PPARgamma ligands", "type": "ENTITY", "char_start": 318059, "char_end": 318076, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 1932, "sentence_text": "These results , together with previous findings of the inhibitory effect of PPARgamma ligands on activated macrophages , provide clear evidence for PPARgamma as a negative regulator of the inflammatory activation of both macrophage and T cells .", "sentence_char_start_global": 318150, "sentence_char_end_global": 318395, "entities": [{"text": "PPARgamma ligands", "type": "ENTITY", "char_start": 76, "char_end": 93, "token_start": 12, "token_end": 13}, {"text": "PPARgamma", "type": "ENTITY", "char_start": 148, "char_end": 157, "token_start": 22, "token_end": 22}, {"text": "negative regulator", "type": "ENTITY", "char_start": 163, "char_end": 181, "token_start": 25, "token_end": 26}], "entities_global": [{"text": "PPARgamma ligands", "type": "ENTITY", "char_start": 318226, "char_end": 318243, "token_start": 12, "token_end": 13, "note": null}, {"text": "PPARgamma", "type": "ENTITY", "char_start": 318298, "char_end": 318307, "token_start": 22, "token_end": 22, "note": null}, {"text": "negative regulator", "type": "ENTITY", "char_start": 318313, "char_end": 318331, "token_start": 25, "token_end": 26, "note": null}]}
+{"sentence_id": 1933, "sentence_text": "PPARgamma may thus be a potential therapeutic target for the treatment of autoimmunity .", "sentence_char_start_global": 318396, "sentence_char_end_global": 318484, "entities": [{"text": "PPARgamma", "type": "ENTITY", "char_start": 0, "char_end": 9, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "PPARgamma", "type": "ENTITY", "char_start": 318396, "char_end": 318405, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 1934, "sentence_text": "A prominent role for activator protein - 1 in the transcription of the human 2B4 ( CD244 ) gene in NK cells .", "sentence_char_start_global": 318485, "sentence_char_end_global": 318594, "entities": [{"text": "activator protein - 1", "type": "ENTITY", "char_start": 21, "char_end": 42, "token_start": 4, "token_end": 7}, {"text": "human 2B4 ( CD244 ) gene", "type": "ENTITY", "char_start": 71, "char_end": 95, "token_start": 13, "token_end": 18}], "entities_global": [{"text": "activator protein - 1", "type": "ENTITY", "char_start": 318506, "char_end": 318527, "token_start": 4, "token_end": 7, "note": null}, {"text": "human 2B4 ( CD244 ) gene", "type": "ENTITY", "char_start": 318556, "char_end": 318580, "token_start": 13, "token_end": 18, "note": null}]}
+{"sentence_id": 1935, "sentence_text": "The cell surface glycoprotein 2B4 ( CD244 ) of the Ig superfamily is involved in the regulation of NK and T lymphocyte functions .", "sentence_char_start_global": 318595, "sentence_char_end_global": 318725, "entities": [{"text": "cell surface glycoprotein 2B4", "type": "ENTITY", "char_start": 4, "char_end": 33, "token_start": 1, "token_end": 4}, {"text": "CD244", "type": "ENTITY", "char_start": 36, "char_end": 41, "token_start": 6, "token_end": 6}, {"text": "Ig superfamily", "type": "ENTITY", "char_start": 51, "char_end": 65, "token_start": 10, "token_end": 11}], "entities_global": [{"text": "cell surface glycoprotein 2B4", "type": "ENTITY", "char_start": 318599, "char_end": 318628, "token_start": 1, "token_end": 4, "note": null}, {"text": "CD244", "type": "ENTITY", "char_start": 318631, "char_end": 318636, "token_start": 6, "token_end": 6, "note": null}, {"text": "Ig superfamily", "type": "ENTITY", "char_start": 318646, "char_end": 318660, "token_start": 10, "token_end": 11, "note": null}]}
+{"sentence_id": 1936, "sentence_text": "We have recently identified CD48 as the high affinity counterreceptor for 2B4 in both mice and humans .", "sentence_char_start_global": 318726, "sentence_char_end_global": 318829, "entities": [{"text": "CD48", "type": "ENTITY", "char_start": 28, "char_end": 32, "token_start": 4, "token_end": 4}, {"text": "high affinity counterreceptor", "type": "ENTITY", "char_start": 40, "char_end": 69, "token_start": 7, "token_end": 9}, {"text": "2B4", "type": "ENTITY", "char_start": 74, "char_end": 77, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "CD48", "type": "ENTITY", "char_start": 318754, "char_end": 318758, "token_start": 4, "token_end": 4, "note": null}, {"text": "high affinity counterreceptor", "type": "ENTITY", "char_start": 318766, "char_end": 318795, "token_start": 7, "token_end": 9, "note": null}, {"text": "2B4", "type": "ENTITY", "char_start": 318800, "char_end": 318803, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 1937, "sentence_text": "The cytoplasmic domain of 2B4 associates with src homology 2 domain - containing protein or signaling lymphocyte activation molecule - associated protein , whose mutation is the underlying genetic defect in the X - linked lymphoproliferative syndrome .", "sentence_char_start_global": 318830, "sentence_char_end_global": 319082, "entities": [{"text": "cytoplasmic domain", "type": "ENTITY", "char_start": 4, "char_end": 22, "token_start": 1, "token_end": 2}, {"text": "2B4", "type": "ENTITY", "char_start": 26, "char_end": 29, "token_start": 4, "token_end": 4}, {"text": "src homology 2 domain - containing protein", "type": "ENTITY", "char_start": 46, "char_end": 88, "token_start": 7, "token_end": 13}, {"text": "signaling lymphocyte activation molecule - associated protein", "type": "ENTITY", "char_start": 92, "char_end": 153, "token_start": 15, "token_end": 21}], "entities_global": [{"text": "cytoplasmic domain", "type": "ENTITY", "char_start": 318834, "char_end": 318852, "token_start": 1, "token_end": 2, "note": null}, {"text": "2B4", "type": "ENTITY", "char_start": 318856, "char_end": 318859, "token_start": 4, "token_end": 4, "note": null}, {"text": "src homology 2 domain - containing protein", "type": "ENTITY", "char_start": 318876, "char_end": 318918, "token_start": 7, "token_end": 13, "note": null}, {"text": "signaling lymphocyte activation molecule - associated protein", "type": "ENTITY", "char_start": 318922, "char_end": 318983, "token_start": 15, "token_end": 21, "note": null}]}
+{"sentence_id": 1938, "sentence_text": "In this study , we report the molecular cloning and characterization of the human 2B4 ( h2B4 ) promoter .", "sentence_char_start_global": 319083, "sentence_char_end_global": 319188, "entities": [{"text": "human 2B4 ( h2B4 ) promoter", "type": "ENTITY", "char_start": 76, "char_end": 103, "token_start": 13, "token_end": 18}], "entities_global": [{"text": "human 2B4 ( h2B4 ) promoter", "type": "ENTITY", "char_start": 319159, "char_end": 319186, "token_start": 13, "token_end": 18, "note": null}]}
+{"sentence_id": 1939, "sentence_text": "Through primer extension analysis , we found that the transcription of the h2B4 gene initiates at multiple start sites .", "sentence_char_start_global": 319189, "sentence_char_end_global": 319309, "entities": [{"text": "h2B4 gene", "type": "ENTITY", "char_start": 75, "char_end": 84, "token_start": 12, "token_end": 13}], "entities_global": [{"text": "h2B4 gene", "type": "ENTITY", "char_start": 319264, "char_end": 319273, "token_start": 12, "token_end": 13, "note": null}]}
+{"sentence_id": 1940, "sentence_text": "We isolated h2B4 genomic clones and PCR amplified the 5 ' untranslated region containing the promoter elements .", "sentence_char_start_global": 319310, "sentence_char_end_global": 319422, "entities": [{"text": "h2B4 genomic clones", "type": "ENTITY", "char_start": 12, "char_end": 31, "token_start": 2, "token_end": 4}, {"text": "5 ' untranslated region", "type": "ENTITY", "char_start": 54, "char_end": 77, "token_start": 9, "token_end": 12}, {"text": "promoter elements", "type": "ENTITY", "char_start": 93, "char_end": 110, "token_start": 15, "token_end": 16}], "entities_global": [{"text": "h2B4 genomic clones", "type": "ENTITY", "char_start": 319322, "char_end": 319341, "token_start": 2, "token_end": 4, "note": null}, {"text": "5 ' untranslated region", "type": "ENTITY", "char_start": 319364, "char_end": 319387, "token_start": 9, "token_end": 12, "note": null}, {"text": "promoter elements", "type": "ENTITY", "char_start": 319403, "char_end": 319420, "token_start": 15, "token_end": 16, "note": null}]}
+{"sentence_id": 1941, "sentence_text": "We have identified a functional AP - 1 site that lies between ( - 106 to - 100 ) through transient transfection analysis in YT cells , a human NK cell line .", "sentence_char_start_global": 319423, "sentence_char_end_global": 319580, "entities": [{"text": "AP - 1 site", "type": "ENTITY", "char_start": 32, "char_end": 43, "token_start": 5, "token_end": 8}], "entities_global": [{"text": "AP - 1 site", "type": "ENTITY", "char_start": 319455, "char_end": 319466, "token_start": 5, "token_end": 8, "note": null}]}
+{"sentence_id": 1942, "sentence_text": "EMSAs with Abs specific for various protein factors of the AP - 1 family revealed that multiple members of the Jun family are involved in the regulation of the h2B4 gene .", "sentence_char_start_global": 319581, "sentence_char_end_global": 319752, "entities": [{"text": "Abs", "type": "ENTITY", "char_start": 11, "char_end": 14, "token_start": 2, "token_end": 2}, {"text": "protein factors", "type": "ENTITY", "char_start": 36, "char_end": 51, "token_start": 6, "token_end": 7}, {"text": "AP - 1 family", "type": "ENTITY", "char_start": 59, "char_end": 72, "token_start": 10, "token_end": 13}, {"text": "Jun family", "type": "ENTITY", "char_start": 111, "char_end": 121, "token_start": 20, "token_end": 21}, {"text": "h2B4 gene", "type": "ENTITY", "char_start": 160, "char_end": 169, "token_start": 29, "token_end": 30}], "entities_global": [{"text": "Abs", "type": "ENTITY", "char_start": 319592, "char_end": 319595, "token_start": 2, "token_end": 2, "note": null}, {"text": "protein factors", "type": "ENTITY", "char_start": 319617, "char_end": 319632, "token_start": 6, "token_end": 7, "note": null}, {"text": "AP - 1 family", "type": "ENTITY", "char_start": 319640, "char_end": 319653, "token_start": 10, "token_end": 13, "note": null}, {"text": "Jun family", "type": "ENTITY", "char_start": 319692, "char_end": 319702, "token_start": 20, "token_end": 21, "note": null}, {"text": "h2B4 gene", "type": "ENTITY", "char_start": 319741, "char_end": 319750, "token_start": 29, "token_end": 30, "note": null}]}
+{"sentence_id": 1943, "sentence_text": "Mutation of the AP - 1 site not only abolishes protein / DNA interactions but also promoter activity .", "sentence_char_start_global": 319753, "sentence_char_end_global": 319855, "entities": [{"text": "AP - 1 site", "type": "ENTITY", "char_start": 16, "char_end": 27, "token_start": 3, "token_end": 6}], "entities_global": [{"text": "AP - 1 site", "type": "ENTITY", "char_start": 319769, "char_end": 319780, "token_start": 3, "token_end": 6, "note": null}]}
+{"sentence_id": 1944, "sentence_text": "These results demonstrate a significant role for AP - 1 in the transcriptional regulation of the h2B4 gene .", "sentence_char_start_global": 319856, "sentence_char_end_global": 319964, "entities": [{"text": "AP - 1", "type": "ENTITY", "char_start": 49, "char_end": 55, "token_start": 7, "token_end": 9}, {"text": "h2B4 gene", "type": "ENTITY", "char_start": 97, "char_end": 106, "token_start": 16, "token_end": 17}], "entities_global": [{"text": "AP - 1", "type": "ENTITY", "char_start": 319905, "char_end": 319911, "token_start": 7, "token_end": 9, "note": null}, {"text": "h2B4 gene", "type": "ENTITY", "char_start": 319953, "char_end": 319962, "token_start": 16, "token_end": 17, "note": null}]}
+{"sentence_id": 1945, "sentence_text": "Functional correction of FA - C cells with FANCC suppresses the expression of interferon gamma - inducible genes .", "sentence_char_start_global": 319965, "sentence_char_end_global": 320079, "entities": [{"text": "FANCC", "type": "ENTITY", "char_start": 43, "char_end": 48, "token_start": 8, "token_end": 8}, {"text": "interferon gamma - inducible genes", "type": "ENTITY", "char_start": 78, "char_end": 112, "token_start": 13, "token_end": 17}], "entities_global": [{"text": "FANCC", "type": "ENTITY", "char_start": 320008, "char_end": 320013, "token_start": 8, "token_end": 8, "note": null}, {"text": "interferon gamma - inducible genes", "type": "ENTITY", "char_start": 320043, "char_end": 320077, "token_start": 13, "token_end": 17, "note": null}]}
+{"sentence_id": 1946, "sentence_text": "Because hematopoietic cells derived from Fanconi anemia ( FA ) patients of the C - complementation group ( FA - C ) are hypersensitive to the inhibitory effects of interferon gamma ( IFNgamma ) , the products of certain IFNgamma - inducible genes known to influence hematopoietic cell survival were quantified .", "sentence_char_start_global": 320080, "sentence_char_end_global": 320391, "entities": [{"text": "interferon gamma", "type": "ENTITY", "char_start": 164, "char_end": 180, "token_start": 29, "token_end": 30}, {"text": "IFNgamma", "type": "ENTITY", "char_start": 183, "char_end": 191, "token_start": 32, "token_end": 32}, {"text": "IFNgamma - inducible genes", "type": "ENTITY", "char_start": 220, "char_end": 246, "token_start": 39, "token_end": 42}], "entities_global": [{"text": "interferon gamma", "type": "ENTITY", "char_start": 320244, "char_end": 320260, "token_start": 29, "token_end": 30, "note": null}, {"text": "IFNgamma", "type": "ENTITY", "char_start": 320263, "char_end": 320271, "token_start": 32, "token_end": 32, "note": null}, {"text": "IFNgamma - inducible genes", "type": "ENTITY", "char_start": 320300, "char_end": 320326, "token_start": 39, "token_end": 42, "note": null}]}
+{"sentence_id": 1947, "sentence_text": "High constitutive expression of the IFNgamma - inducible genes , IFN - stimulated gene factor 3 gamma subunit ( ISGF3gamma ) , IFN regulatory factor - 1 ( IRF - 1 ) , and the cyclin - dependent kinase inhibitor p21 ( WAF1 ) was found in FANCC mutant B lymphoblasts , low - density bone marrow cells , and murine embryonic fibroblasts .", "sentence_char_start_global": 320392, "sentence_char_end_global": 320727, "entities": [{"text": "IFNgamma - inducible genes", "type": "ENTITY", "char_start": 36, "char_end": 62, "token_start": 5, "token_end": 8}, {"text": "IFN - stimulated gene factor 3 gamma subunit", "type": "ENTITY", "char_start": 65, "char_end": 109, "token_start": 10, "token_end": 17}, {"text": "ISGF3gamma", "type": "ENTITY", "char_start": 112, "char_end": 122, "token_start": 19, "token_end": 19}, {"text": "IFN regulatory factor - 1", "type": "ENTITY", "char_start": 127, "char_end": 152, "token_start": 22, "token_end": 26}, {"text": "IRF - 1", "type": "ENTITY", "char_start": 155, "char_end": 162, "token_start": 28, "token_end": 30}, {"text": "cyclin - dependent kinase inhibitor p21", "type": "ENTITY", "char_start": 175, "char_end": 214, "token_start": 35, "token_end": 40}, {"text": "WAF1", "type": "ENTITY", "char_start": 217, "char_end": 221, "token_start": 42, "token_end": 42}, {"text": "FANCC", "type": "ENTITY", "char_start": 237, "char_end": 242, "token_start": 47, "token_end": 47}], "entities_global": [{"text": "IFNgamma - inducible genes", "type": "ENTITY", "char_start": 320428, "char_end": 320454, "token_start": 5, "token_end": 8, "note": null}, {"text": "IFN - stimulated gene factor 3 gamma subunit", "type": "ENTITY", "char_start": 320457, "char_end": 320501, "token_start": 10, "token_end": 17, "note": null}, {"text": "ISGF3gamma", "type": "ENTITY", "char_start": 320504, "char_end": 320514, "token_start": 19, "token_end": 19, "note": null}, {"text": "IFN regulatory factor - 1", "type": "ENTITY", "char_start": 320519, "char_end": 320544, "token_start": 22, "token_end": 26, "note": null}, {"text": "IRF - 1", "type": "ENTITY", "char_start": 320547, "char_end": 320554, "token_start": 28, "token_end": 30, "note": null}, {"text": "cyclin - dependent kinase inhibitor p21", "type": "ENTITY", "char_start": 320567, "char_end": 320606, "token_start": 35, "token_end": 40, "note": null}, {"text": "WAF1", "type": "ENTITY", "char_start": 320609, "char_end": 320613, "token_start": 42, "token_end": 42, "note": null}, {"text": "FANCC", "type": "ENTITY", "char_start": 320629, "char_end": 320634, "token_start": 47, "token_end": 47, "note": null}]}
+{"sentence_id": 1948, "sentence_text": "Paradoxically , these cells do not activate signal transducer and activator of transcription ( STAT ) 1 properly .", "sentence_char_start_global": 320728, "sentence_char_end_global": 320842, "entities": [{"text": "activate signal transducer and activator of transcription ( STAT ) 1", "type": "ENTITY", "char_start": 35, "char_end": 103, "token_start": 6, "token_end": 16}], "entities_global": [{"text": "activate signal transducer and activator of transcription ( STAT ) 1", "type": "ENTITY", "char_start": 320763, "char_end": 320831, "token_start": 6, "token_end": 16, "note": null}]}
+{"sentence_id": 1949, "sentence_text": "In an attempt to clarify mechanisms by which FA - C cells overexpress IFNgamma - inducible genes in the face of defective STAT1 phosphorylation , it was reasoned that decreased levels of activated STAT1 might result in reduced expression of a hematopoietic IFNgamma - responsive protein that normally modulates expression of other IFNgamma - responsive genes .", "sentence_char_start_global": 320843, "sentence_char_end_global": 321203, "entities": [{"text": "IFNgamma - inducible genes", "type": "ENTITY", "char_start": 70, "char_end": 96, "token_start": 13, "token_end": 16}, {"text": "activated STAT1", "type": "ENTITY", "char_start": 187, "char_end": 202, "token_start": 32, "token_end": 33}, {"text": "hematopoietic IFNgamma - responsive protein", "type": "ENTITY", "char_start": 243, "char_end": 286, "token_start": 41, "token_end": 45}, {"text": "IFNgamma - responsive genes", "type": "ENTITY", "char_start": 331, "char_end": 358, "token_start": 52, "token_end": 55}], "entities_global": [{"text": "IFNgamma - inducible genes", "type": "ENTITY", "char_start": 320913, "char_end": 320939, "token_start": 13, "token_end": 16, "note": null}, {"text": "activated STAT1", "type": "ENTITY", "char_start": 321030, "char_end": 321045, "token_start": 32, "token_end": 33, "note": null}, {"text": "hematopoietic IFNgamma - responsive protein", "type": "ENTITY", "char_start": 321086, "char_end": 321129, "token_start": 41, "token_end": 45, "note": null}, {"text": "IFNgamma - responsive genes", "type": "ENTITY", "char_start": 321174, "char_end": 321201, "token_start": 52, "token_end": 55, "note": null}]}
+{"sentence_id": 1950, "sentence_text": "Levels of the IFNgamma - inducible factor IFN consensus sequence binding protein ( ICSBP ) , a negative trans - acting regulator of some IFNgamma - inducible genes , were quantified .", "sentence_char_start_global": 321204, "sentence_char_end_global": 321387, "entities": [{"text": "IFNgamma", "type": "ENTITY", "char_start": 14, "char_end": 22, "token_start": 3, "token_end": 3}, {"text": "IFN consensus sequence binding protein", "type": "ENTITY", "char_start": 42, "char_end": 80, "token_start": 7, "token_end": 11}, {"text": "ICSBP", "type": "ENTITY", "char_start": 83, "char_end": 88, "token_start": 13, "token_end": 13}, {"text": "negative trans - acting regulator", "type": "ENTITY", "char_start": 95, "char_end": 128, "token_start": 17, "token_end": 21}, {"text": "IFNgamma - inducible genes", "type": "ENTITY", "char_start": 137, "char_end": 163, "token_start": 24, "token_end": 27}], "entities_global": [{"text": "IFNgamma", "type": "ENTITY", "char_start": 321218, "char_end": 321226, "token_start": 3, "token_end": 3, "note": null}, {"text": "IFN consensus sequence binding protein", "type": "ENTITY", "char_start": 321246, "char_end": 321284, "token_start": 7, "token_end": 11, "note": null}, {"text": "ICSBP", "type": "ENTITY", "char_start": 321287, "char_end": 321292, "token_start": 13, "token_end": 13, "note": null}, {"text": "negative trans - acting regulator", "type": "ENTITY", "char_start": 321299, "char_end": 321332, "token_start": 17, "token_end": 21, "note": null}, {"text": "IFNgamma - inducible genes", "type": "ENTITY", "char_start": 321341, "char_end": 321367, "token_start": 24, "token_end": 27, "note": null}]}
+{"sentence_id": 1951, "sentence_text": "ICSBP levels were reduced in FA - C B lymphoblasts and MEFs .", "sentence_char_start_global": 321388, "sentence_char_end_global": 321449, "entities": [{"text": "ICSBP", "type": "ENTITY", "char_start": 0, "char_end": 5, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "ICSBP", "type": "ENTITY", "char_start": 321388, "char_end": 321393, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 1952, "sentence_text": "However , enforced expression of ICSBP failed to down - regulate IRF - 1 , ISGF3gamma , and p21 ( WAF1 ) .", "sentence_char_start_global": 321450, "sentence_char_end_global": 321556, "entities": [{"text": "ICSBP", "type": "ENTITY", "char_start": 33, "char_end": 38, "token_start": 5, "token_end": 5}, {"text": "IRF - 1", "type": "ENTITY", "char_start": 65, "char_end": 72, "token_start": 11, "token_end": 13}, {"text": "ISGF3gamma", "type": "ENTITY", "char_start": 75, "char_end": 85, "token_start": 15, "token_end": 15}, {"text": "p21 ( WAF1 )", "type": "ENTITY", "char_start": 92, "char_end": 104, "token_start": 18, "token_end": 21}], "entities_global": [{"text": "ICSBP", "type": "ENTITY", "char_start": 321483, "char_end": 321488, "token_start": 5, "token_end": 5, "note": null}, {"text": "IRF - 1", "type": "ENTITY", "char_start": 321515, "char_end": 321522, "token_start": 11, "token_end": 13, "note": null}, {"text": "ISGF3gamma", "type": "ENTITY", "char_start": 321525, "char_end": 321535, "token_start": 15, "token_end": 15, "note": null}, {"text": "p21 ( WAF1 )", "type": "ENTITY", "char_start": 321542, "char_end": 321554, "token_start": 18, "token_end": 21, "note": null}]}
+{"sentence_id": 1953, "sentence_text": "Thus , the FANCC protein functions to modulate expression of a family of genes that in normal cells are inducible only by specific environmental cues for apoptosis or mitogenic inhibition , but it does so independently of the classic IFN - STAT1 pathway and is not the direct result of reduced ICSBP expression .", "sentence_char_start_global": 321557, "sentence_char_end_global": 321869, "entities": [{"text": "FANCC protein", "type": "ENTITY", "char_start": 11, "char_end": 24, "token_start": 3, "token_end": 4}, {"text": "ICSBP", "type": "ENTITY", "char_start": 294, "char_end": 299, "token_start": 51, "token_end": 51}], "entities_global": [{"text": "FANCC protein", "type": "ENTITY", "char_start": 321568, "char_end": 321581, "token_start": 3, "token_end": 4, "note": null}, {"text": "ICSBP", "type": "ENTITY", "char_start": 321851, "char_end": 321856, "token_start": 51, "token_end": 51, "note": null}]}
+{"sentence_id": 1954, "sentence_text": "A genetic investigation of E2A function in lymphocyte development .", "sentence_char_start_global": 321870, "sentence_char_end_global": 321937, "entities": [], "entities_global": []}
+{"sentence_id": 1955, "sentence_text": "Lymphocytes are derived from hematopoietic stem cells ( HSC ) following a series of regulated differentiation events .", "sentence_char_start_global": 321938, "sentence_char_end_global": 322056, "entities": [], "entities_global": []}
+{"sentence_id": 1956, "sentence_text": "Multipotent HSCs become committed to the B cell lineage in bone marrow and the T cell lineage in the thymus after receiving appropriate signals from the corresponding microenvironment .", "sentence_char_start_global": 322057, "sentence_char_end_global": 322242, "entities": [], "entities_global": []}
+{"sentence_id": 1957, "sentence_text": "These committed lymphoid cells must then undergo V ( D ) J recombination at the immunoglobulin gene or T cell receptor gene locus resulting in clonal production of functional B or T lymphocytes , respectively .", "sentence_char_start_global": 322243, "sentence_char_end_global": 322453, "entities": [{"text": "immunoglobulin gene", "type": "ENTITY", "char_start": 80, "char_end": 99, "token_start": 15, "token_end": 16}, {"text": "T cell receptor gene locus", "type": "ENTITY", "char_start": 103, "char_end": 129, "token_start": 18, "token_end": 22}], "entities_global": [{"text": "immunoglobulin gene", "type": "ENTITY", "char_start": 322323, "char_end": 322342, "token_start": 15, "token_end": 16, "note": null}, {"text": "T cell receptor gene locus", "type": "ENTITY", "char_start": 322346, "char_end": 322372, "token_start": 18, "token_end": 22, "note": null}]}
+{"sentence_id": 1958, "sentence_text": "Lymphocyte commitment and differentiation are accompanied by programmed gene expression or repression events which are driven by lineage and stage specific transcription factors .", "sentence_char_start_global": 322454, "sentence_char_end_global": 322633, "entities": [{"text": "lineage and stage specific transcription factors", "type": "ENTITY", "char_start": 129, "char_end": 177, "token_start": 17, "token_end": 22}], "entities_global": [{"text": "lineage and stage specific transcription factors", "type": "ENTITY", "char_start": 322583, "char_end": 322631, "token_start": 17, "token_end": 22, "note": null}]}
+{"sentence_id": 1959, "sentence_text": "The basic - helix - loop - helix ( bHLH ) transcription factors encoded by the E2A gene are involved in several differentiation events during B and T cell development , including lineage commitment , initiation of V ( D ) J recombination , and antigen receptor mediated proliferation and differentiation .", "sentence_char_start_global": 322634, "sentence_char_end_global": 322939, "entities": [{"text": "basic - helix - loop - helix ( bHLH ) transcription factors", "type": "ENTITY", "char_start": 4, "char_end": 63, "token_start": 1, "token_end": 12}, {"text": "E2A gene", "type": "ENTITY", "char_start": 79, "char_end": 87, "token_start": 16, "token_end": 17}], "entities_global": [{"text": "basic - helix - loop - helix ( bHLH ) transcription factors", "type": "ENTITY", "char_start": 322638, "char_end": 322697, "token_start": 1, "token_end": 12, "note": null}, {"text": "E2A gene", "type": "ENTITY", "char_start": 322713, "char_end": 322721, "token_start": 16, "token_end": 17, "note": null}]}
+{"sentence_id": 1960, "sentence_text": "Several recent reviews have provided a comprehensive discussion of biochemical , cellular , and genetic research on E2A function in lymphocyte development ( 1 , 2 ) .", "sentence_char_start_global": 322940, "sentence_char_end_global": 323106, "entities": [], "entities_global": []}
+{"sentence_id": 1961, "sentence_text": "Here , we only discuss some of the genetic approaches our laboratory ( except where it is noted ) has undertaken to investigate the molecular pathways mediated by E2A transcription factors in lymphocyte development", "sentence_char_start_global": 323107, "sentence_char_end_global": 323321, "entities": [{"text": "E2A transcription factors", "type": "ENTITY", "char_start": 163, "char_end": 188, "token_start": 28, "token_end": 30}], "entities_global": [{"text": "E2A transcription factors", "type": "ENTITY", "char_start": 323270, "char_end": 323295, "token_start": 28, "token_end": 30, "note": null}]}
+{"sentence_id": 1962, "sentence_text": "D609 inhibits ionizing radiation - induced oxidative damage by acting as a potent antioxidant .", "sentence_char_start_global": 323322, "sentence_char_end_global": 323417, "entities": [], "entities_global": []}
+{"sentence_id": 1963, "sentence_text": "Tricyclodecan - 9 - yl - xanthogenate ( D609 ) has been extensively studied in biological systems and exhibits a variety of biological functions , including antiviral , antitumor , and anti - inflammatory activities .", "sentence_char_start_global": 323418, "sentence_char_end_global": 323635, "entities": [], "entities_global": []}
+{"sentence_id": 1964, "sentence_text": "Most of these activities have been largely attributed to the inhibitory effect of D609 on phosphatidylcholine - specific phospholipase C .", "sentence_char_start_global": 323636, "sentence_char_end_global": 323774, "entities": [{"text": "phospholipase C", "type": "ENTITY", "char_start": 121, "char_end": 136, "token_start": 18, "token_end": 19}], "entities_global": [{"text": "phospholipase C", "type": "ENTITY", "char_start": 323757, "char_end": 323772, "token_start": 18, "token_end": 19, "note": null}]}
+{"sentence_id": 1965, "sentence_text": "However , as a xanthate derivative , D609 is a strong electrolyte and readily dissociates to xanthate anions and cations of alkali metals in solution .", "sentence_char_start_global": 323775, "sentence_char_end_global": 323926, "entities": [], "entities_global": []}
+{"sentence_id": 1966, "sentence_text": "Xanthate anions and protonated xanthic acid contain a free thiol moiety and are highly reductive .", "sentence_char_start_global": 323927, "sentence_char_end_global": 324025, "entities": [], "entities_global": []}
+{"sentence_id": 1967, "sentence_text": "This implies that D609 and other xanthate derivatives may function as potent antioxidants .", "sentence_char_start_global": 324026, "sentence_char_end_global": 324117, "entities": [], "entities_global": []}
+{"sentence_id": 1968, "sentence_text": "Indeed , we found that D609 inhibited the Fenton reaction - induced oxidation of dihydrorhodamine 123 in a dose - dependent manner similar to that of pyrrolidinedithiocar , a well known antioxidant .", "sentence_char_start_global": 324118, "sentence_char_end_global": 324317, "entities": [], "entities_global": []}
+{"sentence_id": 1969, "sentence_text": "In addition , D609 inhibited the formation of the alpha - phenyl - tert - butylnitrone - free radical spin adducts and lipid peroxidation of synaptosomal membranes by the Fenton reagents .", "sentence_char_start_global": 324318, "sentence_char_end_global": 324506, "entities": [], "entities_global": []}
+{"sentence_id": 1970, "sentence_text": "Furthermore , preincubation of lymphocytes with D609 resulted in a significant diminution of ionizing radiation ( IR ) - induced 1 ) production of reactive oxygen species ; 2 ) decrease in intracellular reduced glutathione ; 3 ) oxidative damage to proteins and lipids ; and 4 ) activation of nuclear factor - kappaB .", "sentence_char_start_global": 324507, "sentence_char_end_global": 324825, "entities": [{"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 293, "char_end": 316, "token_start": 50, "token_end": 53}], "entities_global": [{"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 324800, "char_end": 324823, "token_start": 50, "token_end": 53, "note": null}]}
+{"sentence_id": 1971, "sentence_text": "Moreover , when D609 ( 50 mg / kg i . v . ) was administered to mice 10 min prior to total body IR ( 6 . 5 and 8 . 5 Gy ) , it protected the mice from IR - induced lethality .", "sentence_char_start_global": 324826, "sentence_char_end_global": 325001, "entities": [], "entities_global": []}
+{"sentence_id": 1972, "sentence_text": "Thus , these results indicate that D609 is a potent antioxidant and has the ability to inhibit IR - induced cellular oxidative stress .", "sentence_char_start_global": 325002, "sentence_char_end_global": 325137, "entities": [], "entities_global": []}
+{"sentence_id": 1973, "sentence_text": "Inhibition of AP - 1 by the glucocorticoid - inducible protein GILZ .", "sentence_char_start_global": 325138, "sentence_char_end_global": 325207, "entities": [{"text": "AP - 1", "type": "ENTITY", "char_start": 14, "char_end": 20, "token_start": 2, "token_end": 4}, {"text": "protein GILZ", "type": "ENTITY", "char_start": 55, "char_end": 67, "token_start": 10, "token_end": 11}], "entities_global": [{"text": "AP - 1", "type": "ENTITY", "char_start": 325152, "char_end": 325158, "token_start": 2, "token_end": 4, "note": null}, {"text": "protein GILZ", "type": "ENTITY", "char_start": 325193, "char_end": 325205, "token_start": 10, "token_end": 11, "note": null}]}
+{"sentence_id": 1974, "sentence_text": "The immunosuppressive effects of glucocorticoids arise largely by inhibition of cytokine gene expression , which has been ascribed to interference between the glucocorticoid receptor and transcription factors such as AP - 1 and NF - kappa B as well as by competition for common coactivators .", "sentence_char_start_global": 325208, "sentence_char_end_global": 325500, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 159, "char_end": 182, "token_start": 22, "token_end": 23}, {"text": "transcription factors", "type": "ENTITY", "char_start": 187, "char_end": 208, "token_start": 25, "token_end": 26}, {"text": "AP - 1", "type": "ENTITY", "char_start": 217, "char_end": 223, "token_start": 29, "token_end": 31}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 228, "char_end": 240, "token_start": 33, "token_end": 36}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 325367, "char_end": 325390, "token_start": 22, "token_end": 23, "note": null}, {"text": "transcription factors", "type": "ENTITY", "char_start": 325395, "char_end": 325416, "token_start": 25, "token_end": 26, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 325425, "char_end": 325431, "token_start": 29, "token_end": 31, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 325436, "char_end": 325448, "token_start": 33, "token_end": 36, "note": null}]}
+{"sentence_id": 1975, "sentence_text": "Here we show that glucocorticoid - induced inhibition of interleukin - 2 mRNA expression in activated normal T cells required new protein synthesis , suggesting that this phenomenon is secondary to expression of glucocorticoid - regulated genes .", "sentence_char_start_global": 325501, "sentence_char_end_global": 325747, "entities": [{"text": "genes", "type": "ENTITY", "char_start": 239, "char_end": 244, "token_start": 36, "token_end": 36}], "entities_global": [{"text": "genes", "type": "ENTITY", "char_start": 325740, "char_end": 325745, "token_start": 36, "token_end": 36, "note": null}]}
+{"sentence_id": 1976, "sentence_text": "One of the most prominent glucocorticoid - induced genes is glucocorticoid - induced leucine zipper ( GILZ ) , which has been reported to inhibit activation - induced up - regulation of Fas ligand ( FasL ) mRNA .", "sentence_char_start_global": 325748, "sentence_char_end_global": 325960, "entities": [{"text": "genes", "type": "ENTITY", "char_start": 51, "char_end": 56, "token_start": 8, "token_end": 8}, {"text": "glucocorticoid - induced leucine zipper", "type": "ENTITY", "char_start": 60, "char_end": 99, "token_start": 10, "token_end": 14}, {"text": "GILZ", "type": "ENTITY", "char_start": 102, "char_end": 106, "token_start": 16, "token_end": 16}, {"text": "Fas ligand ( FasL ) mRNA", "type": "ENTITY", "char_start": 186, "char_end": 210, "token_start": 32, "token_end": 37}], "entities_global": [{"text": "genes", "type": "ENTITY", "char_start": 325799, "char_end": 325804, "token_start": 8, "token_end": 8, "note": null}, {"text": "glucocorticoid - induced leucine zipper", "type": "ENTITY", "char_start": 325808, "char_end": 325847, "token_start": 10, "token_end": 14, "note": null}, {"text": "GILZ", "type": "ENTITY", "char_start": 325850, "char_end": 325854, "token_start": 16, "token_end": 16, "note": null}, {"text": "Fas ligand ( FasL ) mRNA", "type": "ENTITY", "char_start": 325934, "char_end": 325958, "token_start": 32, "token_end": 37, "note": null}]}
+{"sentence_id": 1977, "sentence_text": "Indeed , transient expression of GILZ in Jurkat T cells blocked induction of a reporter construct driven by the FasL promoter .", "sentence_char_start_global": 325961, "sentence_char_end_global": 326088, "entities": [{"text": "GILZ", "type": "ENTITY", "char_start": 33, "char_end": 37, "token_start": 5, "token_end": 5}, {"text": "reporter construct", "type": "ENTITY", "char_start": 79, "char_end": 97, "token_start": 14, "token_end": 15}, {"text": "FasL promoter", "type": "ENTITY", "char_start": 112, "char_end": 125, "token_start": 19, "token_end": 20}], "entities_global": [{"text": "GILZ", "type": "ENTITY", "char_start": 325994, "char_end": 325998, "token_start": 5, "token_end": 5, "note": null}, {"text": "reporter construct", "type": "ENTITY", "char_start": 326040, "char_end": 326058, "token_start": 14, "token_end": 15, "note": null}, {"text": "FasL promoter", "type": "ENTITY", "char_start": 326073, "char_end": 326086, "token_start": 19, "token_end": 20, "note": null}]}
+{"sentence_id": 1978, "sentence_text": "This could be accounted for by GILZ - mediated inhibition of Egr - 2 and Egr - 3 , NFAT / AP - 1 - inducible transcription factors that bind a regulatory element in the FasL promoter and up - regulate FasL expression .", "sentence_char_start_global": 326089, "sentence_char_end_global": 326307, "entities": [{"text": "GILZ", "type": "ENTITY", "char_start": 31, "char_end": 35, "token_start": 6, "token_end": 6}, {"text": "Egr - 2", "type": "ENTITY", "char_start": 61, "char_end": 68, "token_start": 11, "token_end": 13}, {"text": "Egr - 3", "type": "ENTITY", "char_start": 73, "char_end": 80, "token_start": 15, "token_end": 17}, {"text": "NFAT / AP - 1", "type": "ENTITY", "char_start": 83, "char_end": 96, "token_start": 19, "token_end": 23}, {"text": "transcription factors", "type": "ENTITY", "char_start": 109, "char_end": 130, "token_start": 26, "token_end": 27}, {"text": "regulatory element", "type": "ENTITY", "char_start": 143, "char_end": 161, "token_start": 31, "token_end": 32}, {"text": "FasL promoter", "type": "ENTITY", "char_start": 169, "char_end": 182, "token_start": 35, "token_end": 36}], "entities_global": [{"text": "GILZ", "type": "ENTITY", "char_start": 326120, "char_end": 326124, "token_start": 6, "token_end": 6, "note": null}, {"text": "Egr - 2", "type": "ENTITY", "char_start": 326150, "char_end": 326157, "token_start": 11, "token_end": 13, "note": null}, {"text": "Egr - 3", "type": "ENTITY", "char_start": 326162, "char_end": 326169, "token_start": 15, "token_end": 17, "note": null}, {"text": "NFAT / AP - 1", "type": "ENTITY", "char_start": 326172, "char_end": 326185, "token_start": 19, "token_end": 23, "note": null}, {"text": "transcription factors", "type": "ENTITY", "char_start": 326198, "char_end": 326219, "token_start": 26, "token_end": 27, "note": null}, {"text": "regulatory element", "type": "ENTITY", "char_start": 326232, "char_end": 326250, "token_start": 31, "token_end": 32, "note": null}, {"text": "FasL promoter", "type": "ENTITY", "char_start": 326258, "char_end": 326271, "token_start": 35, "token_end": 36, "note": null}]}
+{"sentence_id": 1979, "sentence_text": "GILZ also potently inhibited AP - 1 - driven and IL - 2 promoter - driven reporter constructs , and recombinant GILZ specifically interacted with c - Fos and c - Jun in vitro and inhibited the binding of active AP - 1 to its target DNA .", "sentence_char_start_global": 326308, "sentence_char_end_global": 326545, "entities": [{"text": "GILZ", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}, {"text": "AP - 1 - driven and IL - 2 promoter - driven reporter constructs", "type": "ENTITY", "char_start": 29, "char_end": 93, "token_start": 4, "token_end": 17}, {"text": "GILZ", "type": "ENTITY", "char_start": 112, "char_end": 116, "token_start": 21, "token_end": 21}, {"text": "c - Fos", "type": "ENTITY", "char_start": 146, "char_end": 153, "token_start": 25, "token_end": 27}, {"text": "c - Jun", "type": "ENTITY", "char_start": 158, "char_end": 165, "token_start": 29, "token_end": 31}, {"text": "active AP - 1", "type": "ENTITY", "char_start": 204, "char_end": 217, "token_start": 39, "token_end": 42}], "entities_global": [{"text": "GILZ", "type": "ENTITY", "char_start": 326308, "char_end": 326312, "token_start": 0, "token_end": 0, "note": null}, {"text": "AP - 1 - driven and IL - 2 promoter - driven reporter constructs", "type": "ENTITY", "char_start": 326337, "char_end": 326401, "token_start": 4, "token_end": 17, "note": null}, {"text": "GILZ", "type": "ENTITY", "char_start": 326420, "char_end": 326424, "token_start": 21, "token_end": 21, "note": null}, {"text": "c - Fos", "type": "ENTITY", "char_start": 326454, "char_end": 326461, "token_start": 25, "token_end": 27, "note": null}, {"text": "c - Jun", "type": "ENTITY", "char_start": 326466, "char_end": 326473, "token_start": 29, "token_end": 31, "note": null}, {"text": "active AP - 1", "type": "ENTITY", "char_start": 326512, "char_end": 326525, "token_start": 39, "token_end": 42, "note": null}]}
+{"sentence_id": 1980, "sentence_text": "Whereas homodimerization of GILZ required the presence of its leucine zipper , the interaction with c - Fos and c - Jun occurred through the N - terminal 60 - amino acid region of GILZ .", "sentence_char_start_global": 326546, "sentence_char_end_global": 326732, "entities": [{"text": "GILZ", "type": "ENTITY", "char_start": 28, "char_end": 32, "token_start": 3, "token_end": 3}, {"text": "leucine zipper", "type": "ENTITY", "char_start": 62, "char_end": 76, "token_start": 9, "token_end": 10}, {"text": "c - Fos", "type": "ENTITY", "char_start": 100, "char_end": 107, "token_start": 15, "token_end": 17}, {"text": "c - Jun", "type": "ENTITY", "char_start": 112, "char_end": 119, "token_start": 19, "token_end": 21}, {"text": "N - terminal", "type": "ENTITY", "char_start": 141, "char_end": 153, "token_start": 25, "token_end": 27}, {"text": "60 - amino acid region", "type": "ENTITY", "char_start": 154, "char_end": 176, "token_start": 28, "token_end": 32}, {"text": "GILZ", "type": "ENTITY", "char_start": 180, "char_end": 184, "token_start": 34, "token_end": 34}], "entities_global": [{"text": "GILZ", "type": "ENTITY", "char_start": 326574, "char_end": 326578, "token_start": 3, "token_end": 3, "note": null}, {"text": "leucine zipper", "type": "ENTITY", "char_start": 326608, "char_end": 326622, "token_start": 9, "token_end": 10, "note": null}, {"text": "c - Fos", "type": "ENTITY", "char_start": 326646, "char_end": 326653, "token_start": 15, "token_end": 17, "note": null}, {"text": "c - Jun", "type": "ENTITY", "char_start": 326658, "char_end": 326665, "token_start": 19, "token_end": 21, "note": null}, {"text": "N - terminal", "type": "ENTITY", "char_start": 326687, "char_end": 326699, "token_start": 25, "token_end": 27, "note": null}, {"text": "60 - amino acid region", "type": "ENTITY", "char_start": 326700, "char_end": 326722, "token_start": 28, "token_end": 32, "note": null}, {"text": "GILZ", "type": "ENTITY", "char_start": 326726, "char_end": 326730, "token_start": 34, "token_end": 34, "note": null}]}
+{"sentence_id": 1981, "sentence_text": "Thus , GILZ represents a glucocorticoid - induced gene product that can inhibit a variety of activation - induced events , at least in part by direct interference with AP - 1 , and is therefore a candidate for a mediator of glucocorticoid - induced immunosuppression .", "sentence_char_start_global": 326733, "sentence_char_end_global": 327001, "entities": [{"text": "GILZ", "type": "ENTITY", "char_start": 7, "char_end": 11, "token_start": 2, "token_end": 2}, {"text": "AP - 1", "type": "ENTITY", "char_start": 168, "char_end": 174, "token_start": 29, "token_end": 31}], "entities_global": [{"text": "GILZ", "type": "ENTITY", "char_start": 326740, "char_end": 326744, "token_start": 2, "token_end": 2, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 326901, "char_end": 326907, "token_start": 29, "token_end": 31, "note": null}]}
+{"sentence_id": 1982, "sentence_text": "Pharmacokinetic differences between a T cell - tolerizing and a T cell - activating peptide .", "sentence_char_start_global": 327002, "sentence_char_end_global": 327095, "entities": [], "entities_global": []}
+{"sentence_id": 1983, "sentence_text": "Vaccination with a peptide representing a CTL epitope from the human papillomavirus ( HPV ) 16 E7 protein induces a specific CTL response that prevents the outgrowth of HPV16 E7 - expressing tumors .", "sentence_char_start_global": 327096, "sentence_char_end_global": 327295, "entities": [{"text": "E7 protein", "type": "ENTITY", "char_start": 95, "char_end": 105, "token_start": 16, "token_end": 17}], "entities_global": [{"text": "E7 protein", "type": "ENTITY", "char_start": 327191, "char_end": 327201, "token_start": 16, "token_end": 17, "note": null}]}
+{"sentence_id": 1984, "sentence_text": "In contrast , vaccination with a peptide encoding an adenovirus type 5 ( Ad5 ) E1A CTL epitope results in CTL tolerance and enhanced growth of an Ad5 E1A - expressing tumor .", "sentence_char_start_global": 327296, "sentence_char_end_global": 327470, "entities": [], "entities_global": []}
+{"sentence_id": 1985, "sentence_text": "It is unclear why these peptides induce such opposite effects .", "sentence_char_start_global": 327471, "sentence_char_end_global": 327534, "entities": [], "entities_global": []}
+{"sentence_id": 1986, "sentence_text": "To determine whether a difference in pharmacokinetics can explain the functional contrasts , tritiated Ad5 E1A and HPV16 E7 peptides were injected into mice .", "sentence_char_start_global": 327535, "sentence_char_end_global": 327693, "entities": [], "entities_global": []}
+{"sentence_id": 1987, "sentence_text": "Results show that the tolerizing peptide spread through the body 16 times faster than the activating peptide and was cleared at least 2 times faster .", "sentence_char_start_global": 327694, "sentence_char_end_global": 327844, "entities": [], "entities_global": []}
+{"sentence_id": 1988, "sentence_text": "The HPV16 E7 peptide kinetics correlated with the kinetics of HPV16 E7 - specific CTL induction .", "sentence_char_start_global": 327845, "sentence_char_end_global": 327942, "entities": [{"text": "HPV16 E7", "type": "ENTITY", "char_start": 62, "char_end": 70, "token_start": 10, "token_end": 11}], "entities_global": [{"text": "HPV16 E7", "type": "ENTITY", "char_start": 327907, "char_end": 327915, "token_start": 10, "token_end": 11, "note": null}]}
+{"sentence_id": 1989, "sentence_text": "In contrast , Ad5 E1A peptide injection resulted in physical deletion of preexisting Ad5 E1A - specific CTLs within 24 h after injection .", "sentence_char_start_global": 327943, "sentence_char_end_global": 328081, "entities": [{"text": "Ad5 E1A", "type": "ENTITY", "char_start": 85, "char_end": 92, "token_start": 13, "token_end": 14}, {"text": "CTLs", "type": "ENTITY", "char_start": 104, "char_end": 108, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "Ad5 E1A", "type": "ENTITY", "char_start": 328028, "char_end": 328035, "token_start": 13, "token_end": 14, "note": null}, {"text": "CTLs", "type": "ENTITY", "char_start": 328047, "char_end": 328051, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 1990, "sentence_text": "This tolerization occurred at the time when the peptide reached its maximum peptide concentration in the organs .", "sentence_char_start_global": 328082, "sentence_char_end_global": 328195, "entities": [], "entities_global": []}
+{"sentence_id": 1991, "sentence_text": "These data suggest that ubiquitous expression of the tolerizing Ad5 E1A peptide within a short period of time causes activation - induced cell death of Ad5 E1A - specific CTLs .", "sentence_char_start_global": 328196, "sentence_char_end_global": 328373, "entities": [{"text": "Ad5 E1A", "type": "ENTITY", "char_start": 152, "char_end": 159, "token_start": 25, "token_end": 26}, {"text": "CTLs", "type": "ENTITY", "char_start": 171, "char_end": 175, "token_start": 29, "token_end": 29}], "entities_global": [{"text": "Ad5 E1A", "type": "ENTITY", "char_start": 328348, "char_end": 328355, "token_start": 25, "token_end": 26, "note": null}, {"text": "CTLs", "type": "ENTITY", "char_start": 328367, "char_end": 328371, "token_start": 29, "token_end": 29, "note": null}]}
+{"sentence_id": 1992, "sentence_text": "Therefore , information on the pharmacokinetics of peptides is vital for the safety and efficacy of peptide - based vaccines .", "sentence_char_start_global": 328374, "sentence_char_end_global": 328500, "entities": [], "entities_global": []}
+{"sentence_id": 1993, "sentence_text": "Smad3 and Smad4 mediate transforming growth factor - beta1 - induced IgA expression in murine B lymphocytes .", "sentence_char_start_global": 328501, "sentence_char_end_global": 328610, "entities": [{"text": "Smad3", "type": "ENTITY", "char_start": 0, "char_end": 5, "token_start": 0, "token_end": 0}, {"text": "Smad4", "type": "ENTITY", "char_start": 10, "char_end": 15, "token_start": 2, "token_end": 2}, {"text": "transforming growth factor - beta1", "type": "ENTITY", "char_start": 24, "char_end": 58, "token_start": 4, "token_end": 8}], "entities_global": [{"text": "Smad3", "type": "ENTITY", "char_start": 328501, "char_end": 328506, "token_start": 0, "token_end": 0, "note": null}, {"text": "Smad4", "type": "ENTITY", "char_start": 328511, "char_end": 328516, "token_start": 2, "token_end": 2, "note": null}, {"text": "transforming growth factor - beta1", "type": "ENTITY", "char_start": 328525, "char_end": 328559, "token_start": 4, "token_end": 8, "note": null}]}
+{"sentence_id": 1994, "sentence_text": "Transforming growth factor ( TGF ) - beta1 is well established as a critical IgA isotype switching factor and Smad molecules have been reported to act as transducers and transcriptional factors in the expression of TGF - beta1 - targeted genes .", "sentence_char_start_global": 328611, "sentence_char_end_global": 328856, "entities": [{"text": "Transforming growth factor ( TGF ) - beta1", "type": "ENTITY", "char_start": 0, "char_end": 42, "token_start": 0, "token_end": 7}, {"text": "IgA isotype switching factor", "type": "ENTITY", "char_start": 77, "char_end": 105, "token_start": 14, "token_end": 17}, {"text": "Smad molecules", "type": "ENTITY", "char_start": 110, "char_end": 124, "token_start": 19, "token_end": 20}, {"text": "transducers", "type": "ENTITY", "char_start": 154, "char_end": 165, "token_start": 27, "token_end": 27}, {"text": "transcriptional factors", "type": "ENTITY", "char_start": 170, "char_end": 193, "token_start": 29, "token_end": 30}, {"text": "TGF - beta1", "type": "ENTITY", "char_start": 215, "char_end": 226, "token_start": 35, "token_end": 37}, {"text": "genes", "type": "ENTITY", "char_start": 238, "char_end": 243, "token_start": 40, "token_end": 40}], "entities_global": [{"text": "Transforming growth factor ( TGF ) - beta1", "type": "ENTITY", "char_start": 328611, "char_end": 328653, "token_start": 0, "token_end": 7, "note": null}, {"text": "IgA isotype switching factor", "type": "ENTITY", "char_start": 328688, "char_end": 328716, "token_start": 14, "token_end": 17, "note": null}, {"text": "Smad molecules", "type": "ENTITY", "char_start": 328721, "char_end": 328735, "token_start": 19, "token_end": 20, "note": null}, {"text": "transducers", "type": "ENTITY", "char_start": 328765, "char_end": 328776, "token_start": 27, "token_end": 27, "note": null}, {"text": "transcriptional factors", "type": "ENTITY", "char_start": 328781, "char_end": 328804, "token_start": 29, "token_end": 30, "note": null}, {"text": "TGF - beta1", "type": "ENTITY", "char_start": 328826, "char_end": 328837, "token_start": 35, "token_end": 37, "note": null}, {"text": "genes", "type": "ENTITY", "char_start": 328849, "char_end": 328854, "token_start": 40, "token_end": 40, "note": null}]}
+{"sentence_id": 1995, "sentence_text": "We examined the involvement of Smad proteins in TGF - beta1 - induced IgA expression .", "sentence_char_start_global": 328857, "sentence_char_end_global": 328943, "entities": [{"text": "Smad proteins", "type": "ENTITY", "char_start": 31, "char_end": 44, "token_start": 5, "token_end": 6}, {"text": "TGF - beta1", "type": "ENTITY", "char_start": 48, "char_end": 59, "token_start": 8, "token_end": 10}], "entities_global": [{"text": "Smad proteins", "type": "ENTITY", "char_start": 328888, "char_end": 328901, "token_start": 5, "token_end": 6, "note": null}, {"text": "TGF - beta1", "type": "ENTITY", "char_start": 328905, "char_end": 328916, "token_start": 8, "token_end": 10, "note": null}]}
+{"sentence_id": 1996, "sentence_text": "First , we found that TGF - beta1 significantly increases endogenous germ - line ( GL ) alpha transcripts by LPS - stimulated CH12 . LX . 4933 ( mu ( + ) ) B lymphoma cells .", "sentence_char_start_global": 328944, "sentence_char_end_global": 329118, "entities": [{"text": "TGF - beta1", "type": "ENTITY", "char_start": 22, "char_end": 33, "token_start": 5, "token_end": 7}, {"text": "endogenous germ - line ( GL ) alpha transcripts", "type": "ENTITY", "char_start": 58, "char_end": 105, "token_start": 10, "token_end": 18}], "entities_global": [{"text": "TGF - beta1", "type": "ENTITY", "char_start": 328966, "char_end": 328977, "token_start": 5, "token_end": 7, "note": null}, {"text": "endogenous germ - line ( GL ) alpha transcripts", "type": "ENTITY", "char_start": 329002, "char_end": 329049, "token_start": 10, "token_end": 18, "note": null}]}
+{"sentence_id": 1997, "sentence_text": "To investigate its signaling mechanisms , the lymphoma cell line was transfected with pFL3 that contains the TGF - beta - responsive element of the GLalpha promoter , and stimulated with TGF - beta1 .", "sentence_char_start_global": 329119, "sentence_char_end_global": 329319, "entities": [{"text": "pFL3", "type": "ENTITY", "char_start": 86, "char_end": 90, "token_start": 13, "token_end": 13}, {"text": "TGF - beta - responsive element", "type": "ENTITY", "char_start": 109, "char_end": 140, "token_start": 17, "token_end": 22}, {"text": "GLalpha promoter", "type": "ENTITY", "char_start": 148, "char_end": 164, "token_start": 25, "token_end": 26}, {"text": "TGF - beta1", "type": "ENTITY", "char_start": 187, "char_end": 198, "token_start": 31, "token_end": 33}], "entities_global": [{"text": "pFL3", "type": "ENTITY", "char_start": 329205, "char_end": 329209, "token_start": 13, "token_end": 13, "note": null}, {"text": "TGF - beta - responsive element", "type": "ENTITY", "char_start": 329228, "char_end": 329259, "token_start": 17, "token_end": 22, "note": null}, {"text": "GLalpha promoter", "type": "ENTITY", "char_start": 329267, "char_end": 329283, "token_start": 25, "token_end": 26, "note": null}, {"text": "TGF - beta1", "type": "ENTITY", "char_start": 329306, "char_end": 329317, "token_start": 31, "token_end": 33, "note": null}]}
+{"sentence_id": 1998, "sentence_text": "Similar to endogenous GLalpha transcripts , TGF - beta1 induces GLalpha promoter activity and overexpression of Smad3 markedly enhances the promoter activity .", "sentence_char_start_global": 329320, "sentence_char_end_global": 329479, "entities": [{"text": "endogenous GLalpha transcripts", "type": "ENTITY", "char_start": 11, "char_end": 41, "token_start": 2, "token_end": 4}, {"text": "TGF - beta1", "type": "ENTITY", "char_start": 44, "char_end": 55, "token_start": 6, "token_end": 8}, {"text": "GLalpha promoter", "type": "ENTITY", "char_start": 64, "char_end": 80, "token_start": 10, "token_end": 11}, {"text": "Smad3", "type": "ENTITY", "char_start": 112, "char_end": 117, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "endogenous GLalpha transcripts", "type": "ENTITY", "char_start": 329331, "char_end": 329361, "token_start": 2, "token_end": 4, "note": null}, {"text": "TGF - beta1", "type": "ENTITY", "char_start": 329364, "char_end": 329375, "token_start": 6, "token_end": 8, "note": null}, {"text": "GLalpha promoter", "type": "ENTITY", "char_start": 329384, "char_end": 329400, "token_start": 10, "token_end": 11, "note": null}, {"text": "Smad3", "type": "ENTITY", "char_start": 329432, "char_end": 329437, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 1999, "sentence_text": "This activity is further augmented by cotransfected Smad4 .", "sentence_char_start_global": 329480, "sentence_char_end_global": 329539, "entities": [{"text": "cotransfected Smad4", "type": "ENTITY", "char_start": 38, "char_end": 57, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "cotransfected Smad4", "type": "ENTITY", "char_start": 329518, "char_end": 329537, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 2000, "sentence_text": "On the other hand , Smad7 substantially abrogates the synergistic effect of Smad3 / 4 on GLalpha promoter activity .", "sentence_char_start_global": 329540, "sentence_char_end_global": 329656, "entities": [{"text": "Smad7", "type": "ENTITY", "char_start": 20, "char_end": 25, "token_start": 5, "token_end": 5}, {"text": "Smad3 / 4", "type": "ENTITY", "char_start": 76, "char_end": 85, "token_start": 12, "token_end": 14}, {"text": "GLalpha promoter", "type": "ENTITY", "char_start": 89, "char_end": 105, "token_start": 16, "token_end": 17}], "entities_global": [{"text": "Smad7", "type": "ENTITY", "char_start": 329560, "char_end": 329565, "token_start": 5, "token_end": 5, "note": null}, {"text": "Smad3 / 4", "type": "ENTITY", "char_start": 329616, "char_end": 329625, "token_start": 12, "token_end": 14, "note": null}, {"text": "GLalpha promoter", "type": "ENTITY", "char_start": 329629, "char_end": 329645, "token_start": 16, "token_end": 17, "note": null}]}
+{"sentence_id": 2001, "sentence_text": "In addition , overexpression of Smad3 / 4 enhances TGF - beta1 - induced endogenous GLalpha transcripts in normal spleen B cell s .", "sentence_char_start_global": 329657, "sentence_char_end_global": 329788, "entities": [{"text": "Smad3 / 4", "type": "ENTITY", "char_start": 32, "char_end": 41, "token_start": 5, "token_end": 7}, {"text": "TGF - beta1", "type": "ENTITY", "char_start": 51, "char_end": 62, "token_start": 9, "token_end": 11}, {"text": "endogenous GLalpha transcripts", "type": "ENTITY", "char_start": 73, "char_end": 103, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "Smad3 / 4", "type": "ENTITY", "char_start": 329689, "char_end": 329698, "token_start": 5, "token_end": 7, "note": null}, {"text": "TGF - beta1", "type": "ENTITY", "char_start": 329708, "char_end": 329719, "token_start": 9, "token_end": 11, "note": null}, {"text": "endogenous GLalpha transcripts", "type": "ENTITY", "char_start": 329730, "char_end": 329760, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 2002, "sentence_text": "Finally , in the presence of TGF - beta1 , overexpression of Smad3 / 4 selectively increases both surface IgA expression and IgA production .", "sentence_char_start_global": 329789, "sentence_char_end_global": 329930, "entities": [{"text": "TGF - beta1", "type": "ENTITY", "char_start": 29, "char_end": 40, "token_start": 6, "token_end": 8}, {"text": "Smad3 / 4", "type": "ENTITY", "char_start": 61, "char_end": 70, "token_start": 12, "token_end": 14}], "entities_global": [{"text": "TGF - beta1", "type": "ENTITY", "char_start": 329818, "char_end": 329829, "token_start": 6, "token_end": 8, "note": null}, {"text": "Smad3 / 4", "type": "ENTITY", "char_start": 329850, "char_end": 329859, "token_start": 12, "token_end": 14, "note": null}]}
+{"sentence_id": 2003, "sentence_text": "The results from the present study indicate that Smad3 , Smad4 , and Smad7 , at least in part , serve as mediators linking TGF - beta1 to transcriptional regulation of IgA switching related gene and regulation of IgA class switching .", "sentence_char_start_global": 329931, "sentence_char_end_global": 330165, "entities": [{"text": "Smad3", "type": "ENTITY", "char_start": 49, "char_end": 54, "token_start": 8, "token_end": 8}, {"text": "Smad4", "type": "ENTITY", "char_start": 57, "char_end": 62, "token_start": 10, "token_end": 10}, {"text": "Smad7", "type": "ENTITY", "char_start": 69, "char_end": 74, "token_start": 13, "token_end": 13}, {"text": "TGF - beta1", "type": "ENTITY", "char_start": 123, "char_end": 134, "token_start": 24, "token_end": 26}, {"text": "IgA switching related gene", "type": "ENTITY", "char_start": 168, "char_end": 194, "token_start": 31, "token_end": 34}], "entities_global": [{"text": "Smad3", "type": "ENTITY", "char_start": 329980, "char_end": 329985, "token_start": 8, "token_end": 8, "note": null}, {"text": "Smad4", "type": "ENTITY", "char_start": 329988, "char_end": 329993, "token_start": 10, "token_end": 10, "note": null}, {"text": "Smad7", "type": "ENTITY", "char_start": 330000, "char_end": 330005, "token_start": 13, "token_end": 13, "note": null}, {"text": "TGF - beta1", "type": "ENTITY", "char_start": 330054, "char_end": 330065, "token_start": 24, "token_end": 26, "note": null}, {"text": "IgA switching related gene", "type": "ENTITY", "char_start": 330099, "char_end": 330125, "token_start": 31, "token_end": 34, "note": null}]}
+{"sentence_id": 2004, "sentence_text": "The translesion DNA polymerase zeta plays a major role in Ig and bcl - 6 somatic hypermutation .", "sentence_char_start_global": 330166, "sentence_char_end_global": 330262, "entities": [{"text": "translesion DNA polymerase zeta", "type": "ENTITY", "char_start": 4, "char_end": 35, "token_start": 1, "token_end": 4}], "entities_global": [{"text": "translesion DNA polymerase zeta", "type": "ENTITY", "char_start": 330170, "char_end": 330201, "token_start": 1, "token_end": 4, "note": null}]}
+{"sentence_id": 2005, "sentence_text": "Ig somatic mutations would be introduced by a polymerase ( pol ) while repairing DNA outside main DNA replication .", "sentence_char_start_global": 330263, "sentence_char_end_global": 330378, "entities": [{"text": "polymerase", "type": "ENTITY", "char_start": 46, "char_end": 56, "token_start": 8, "token_end": 8}, {"text": "pol", "type": "ENTITY", "char_start": 59, "char_end": 62, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "polymerase", "type": "ENTITY", "char_start": 330309, "char_end": 330319, "token_start": 8, "token_end": 8, "note": null}, {"text": "pol", "type": "ENTITY", "char_start": 330322, "char_end": 330325, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 2006, "sentence_text": "We show that human B cells constitutively express the translesion pol zeta , which effectively extends DNA past mismatched bases ( mispair extender ) , and pol eta , which bypasses DNA lesions in an error - free fashion .", "sentence_char_start_global": 330379, "sentence_char_end_global": 330600, "entities": [{"text": "translesion pol zeta", "type": "ENTITY", "char_start": 54, "char_end": 74, "token_start": 9, "token_end": 11}, {"text": "pol eta", "type": "ENTITY", "char_start": 156, "char_end": 163, "token_start": 26, "token_end": 27}], "entities_global": [{"text": "translesion pol zeta", "type": "ENTITY", "char_start": 330433, "char_end": 330453, "token_start": 9, "token_end": 11, "note": null}, {"text": "pol eta", "type": "ENTITY", "char_start": 330535, "char_end": 330542, "token_start": 26, "token_end": 27, "note": null}]}
+{"sentence_id": 2007, "sentence_text": "Upon B cell receptor ( BCR ) engagement and coculture with activated CD4 + T cells , these lymphocytes upregulated pol zeta , downregulated pol eta , and mutated the Ig and bcl - 6 genes .", "sentence_char_start_global": 330601, "sentence_char_end_global": 330789, "entities": [{"text": "B cell receptor", "type": "ENTITY", "char_start": 5, "char_end": 20, "token_start": 1, "token_end": 3}, {"text": "BCR", "type": "ENTITY", "char_start": 23, "char_end": 26, "token_start": 5, "token_end": 5}, {"text": "pol zeta", "type": "ENTITY", "char_start": 115, "char_end": 123, "token_start": 20, "token_end": 21}, {"text": "pol eta", "type": "ENTITY", "char_start": 140, "char_end": 147, "token_start": 24, "token_end": 25}, {"text": "Ig and bcl - 6 genes", "type": "ENTITY", "char_start": 166, "char_end": 186, "token_start": 30, "token_end": 35}], "entities_global": [{"text": "B cell receptor", "type": "ENTITY", "char_start": 330606, "char_end": 330621, "token_start": 1, "token_end": 3, "note": null}, {"text": "BCR", "type": "ENTITY", "char_start": 330624, "char_end": 330627, "token_start": 5, "token_end": 5, "note": null}, {"text": "pol zeta", "type": "ENTITY", "char_start": 330716, "char_end": 330724, "token_start": 20, "token_end": 21, "note": null}, {"text": "pol eta", "type": "ENTITY", "char_start": 330741, "char_end": 330748, "token_start": 24, "token_end": 25, "note": null}, {"text": "Ig and bcl - 6 genes", "type": "ENTITY", "char_start": 330767, "char_end": 330787, "token_start": 30, "token_end": 35, "note": null}]}
+{"sentence_id": 2008, "sentence_text": "Inhibition of the pol zeta REV3 catalytic subunit by specific phosphorothioate - modified oligonucleotides impaired Ig and bcl - 6 hypermutation and UV damage - induced DNA mutagenesis , without affecting cell cycle or viability .", "sentence_char_start_global": 330790, "sentence_char_end_global": 331020, "entities": [{"text": "pol zeta", "type": "ENTITY", "char_start": 18, "char_end": 26, "token_start": 3, "token_end": 4}, {"text": "REV3 catalytic subunit", "type": "ENTITY", "char_start": 27, "char_end": 49, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "pol zeta", "type": "ENTITY", "char_start": 330808, "char_end": 330816, "token_start": 3, "token_end": 4, "note": null}, {"text": "REV3 catalytic subunit", "type": "ENTITY", "char_start": 330817, "char_end": 330839, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 2009, "sentence_text": "Thus , pol zeta plays a critical role in Ig and bcl - 6 hypermutation , perhaps facilitated by the downregulation of pol eta .", "sentence_char_start_global": 331021, "sentence_char_end_global": 331147, "entities": [{"text": "pol zeta", "type": "ENTITY", "char_start": 7, "char_end": 15, "token_start": 2, "token_end": 3}, {"text": "pol eta", "type": "ENTITY", "char_start": 117, "char_end": 124, "token_start": 22, "token_end": 23}], "entities_global": [{"text": "pol zeta", "type": "ENTITY", "char_start": 331028, "char_end": 331036, "token_start": 2, "token_end": 3, "note": null}, {"text": "pol eta", "type": "ENTITY", "char_start": 331138, "char_end": 331145, "token_start": 22, "token_end": 23, "note": null}]}
+{"sentence_id": 2010, "sentence_text": "Molecular mechanism of cell cycle progression induced by the oncogene product Tax of human T - cell leukemia virus type I .", "sentence_char_start_global": 331148, "sentence_char_end_global": 331271, "entities": [{"text": "oncogene product Tax", "type": "ENTITY", "char_start": 61, "char_end": 81, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "oncogene product Tax", "type": "ENTITY", "char_start": 331209, "char_end": 331229, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 2011, "sentence_text": "The trans - activator protein Tax of human T - cell leukemia virus type I ( HTLV - I ) plays an important role in the development of adult T - cell leukemia through , at least in part , its ability to stimulate cell growth .", "sentence_char_start_global": 331272, "sentence_char_end_global": 331496, "entities": [{"text": "trans - activator protein Tax", "type": "ENTITY", "char_start": 4, "char_end": 33, "token_start": 1, "token_end": 5}], "entities_global": [{"text": "trans - activator protein Tax", "type": "ENTITY", "char_start": 331276, "char_end": 331305, "token_start": 1, "token_end": 5, "note": null}]}
+{"sentence_id": 2012, "sentence_text": "We previously reported that Tax induced cell cycle progression from G0 / G1 phase to S and G2 / M phases in human T - cell line Kit 225 cells .", "sentence_char_start_global": 331497, "sentence_char_end_global": 331640, "entities": [{"text": "Tax", "type": "ENTITY", "char_start": 28, "char_end": 31, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "Tax", "type": "ENTITY", "char_start": 331525, "char_end": 331528, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 2013, "sentence_text": "To elucidate molecular mechanism of Tax - induced cell cycle progression , we systematically examined the effects of Tax on biochemical events associated with cell cycle progression .", "sentence_char_start_global": 331641, "sentence_char_end_global": 331824, "entities": [{"text": "Tax", "type": "ENTITY", "char_start": 36, "char_end": 39, "token_start": 5, "token_end": 5}, {"text": "Tax", "type": "ENTITY", "char_start": 117, "char_end": 120, "token_start": 18, "token_end": 18}], "entities_global": [{"text": "Tax", "type": "ENTITY", "char_start": 331677, "char_end": 331680, "token_start": 5, "token_end": 5, "note": null}, {"text": "Tax", "type": "ENTITY", "char_start": 331758, "char_end": 331761, "token_start": 18, "token_end": 18, "note": null}]}
+{"sentence_id": 2014, "sentence_text": "Introduction of Tax into resting Kit 225 cells induced activation of the G1 / S transition regulation cascade consisting of activation of cyclin dependent kinase 2 ( CDK2 ) and CDK4 , phosphorylation of the Rb family proteins and an increase in free E2F .", "sentence_char_start_global": 331825, "sentence_char_end_global": 332080, "entities": [{"text": "Tax", "type": "ENTITY", "char_start": 16, "char_end": 19, "token_start": 2, "token_end": 2}, {"text": "cyclin dependent kinase 2", "type": "ENTITY", "char_start": 138, "char_end": 163, "token_start": 22, "token_end": 25}, {"text": "CDK2", "type": "ENTITY", "char_start": 166, "char_end": 170, "token_start": 27, "token_end": 27}, {"text": "CDK4", "type": "ENTITY", "char_start": 177, "char_end": 181, "token_start": 30, "token_end": 30}, {"text": "Rb family proteins", "type": "ENTITY", "char_start": 207, "char_end": 225, "token_start": 35, "token_end": 37}, {"text": "E2F", "type": "ENTITY", "char_start": 250, "char_end": 253, "token_start": 43, "token_end": 43}], "entities_global": [{"text": "Tax", "type": "ENTITY", "char_start": 331841, "char_end": 331844, "token_start": 2, "token_end": 2, "note": null}, {"text": "cyclin dependent kinase 2", "type": "ENTITY", "char_start": 331963, "char_end": 331988, "token_start": 22, "token_end": 25, "note": null}, {"text": "CDK2", "type": "ENTITY", "char_start": 331991, "char_end": 331995, "token_start": 27, "token_end": 27, "note": null}, {"text": "CDK4", "type": "ENTITY", "char_start": 332002, "char_end": 332006, "token_start": 30, "token_end": 30, "note": null}, {"text": "Rb family proteins", "type": "ENTITY", "char_start": 332032, "char_end": 332050, "token_start": 35, "token_end": 37, "note": null}, {"text": "E2F", "type": "ENTITY", "char_start": 332075, "char_end": 332078, "token_start": 43, "token_end": 43, "note": null}]}
+{"sentence_id": 2015, "sentence_text": "The kinase activation was found to result from Tax - induced expression of genes for cell cycle regulatory molecules including cyclin D2 , cyclin E , E2F1 , CDK2 , CDK4 and CDK6 , and Tax - induced reduction of CDK inhibitors p19 ( INK4d ) and p27 ( Kip1 ) .", "sentence_char_start_global": 332081, "sentence_char_end_global": 332339, "entities": [{"text": "Tax", "type": "ENTITY", "char_start": 47, "char_end": 50, "token_start": 8, "token_end": 8}, {"text": "cell cycle regulatory molecules", "type": "ENTITY", "char_start": 85, "char_end": 116, "token_start": 15, "token_end": 18}, {"text": "cyclin D2", "type": "ENTITY", "char_start": 127, "char_end": 136, "token_start": 20, "token_end": 21}, {"text": "cyclin E", "type": "ENTITY", "char_start": 139, "char_end": 147, "token_start": 23, "token_end": 24}, {"text": "E2F1", "type": "ENTITY", "char_start": 150, "char_end": 154, "token_start": 26, "token_end": 26}, {"text": "CDK2", "type": "ENTITY", "char_start": 157, "char_end": 161, "token_start": 28, "token_end": 28}, {"text": "CDK4", "type": "ENTITY", "char_start": 164, "char_end": 168, "token_start": 30, "token_end": 30}, {"text": "CDK6", "type": "ENTITY", "char_start": 173, "char_end": 177, "token_start": 32, "token_end": 32}, {"text": "Tax", "type": "ENTITY", "char_start": 184, "char_end": 187, "token_start": 35, "token_end": 35}, {"text": "CDK inhibitors p19", "type": "ENTITY", "char_start": 211, "char_end": 229, "token_start": 40, "token_end": 42}, {"text": "INK4d", "type": "ENTITY", "char_start": 232, "char_end": 237, "token_start": 44, "token_end": 44}, {"text": "p27 ( Kip1 )", "type": "ENTITY", "char_start": 244, "char_end": 256, "token_start": 47, "token_end": 50}], "entities_global": [{"text": "Tax", "type": "ENTITY", "char_start": 332128, "char_end": 332131, "token_start": 8, "token_end": 8, "note": null}, {"text": "cell cycle regulatory molecules", "type": "ENTITY", "char_start": 332166, "char_end": 332197, "token_start": 15, "token_end": 18, "note": null}, {"text": "cyclin D2", "type": "ENTITY", "char_start": 332208, "char_end": 332217, "token_start": 20, "token_end": 21, "note": null}, {"text": "cyclin E", "type": "ENTITY", "char_start": 332220, "char_end": 332228, "token_start": 23, "token_end": 24, "note": null}, {"text": "E2F1", "type": "ENTITY", "char_start": 332231, "char_end": 332235, "token_start": 26, "token_end": 26, "note": null}, {"text": "CDK2", "type": "ENTITY", "char_start": 332238, "char_end": 332242, "token_start": 28, "token_end": 28, "note": null}, {"text": "CDK4", "type": "ENTITY", "char_start": 332245, "char_end": 332249, "token_start": 30, "token_end": 30, "note": null}, {"text": "CDK6", "type": "ENTITY", "char_start": 332254, "char_end": 332258, "token_start": 32, "token_end": 32, "note": null}, {"text": "Tax", "type": "ENTITY", "char_start": 332265, "char_end": 332268, "token_start": 35, "token_end": 35, "note": null}, {"text": "CDK inhibitors p19", "type": "ENTITY", "char_start": 332292, "char_end": 332310, "token_start": 40, "token_end": 42, "note": null}, {"text": "INK4d", "type": "ENTITY", "char_start": 332313, "char_end": 332318, "token_start": 44, "token_end": 44, "note": null}, {"text": "p27 ( Kip1 )", "type": "ENTITY", "char_start": 332325, "char_end": 332337, "token_start": 47, "token_end": 50, "note": null}]}
+{"sentence_id": 2016, "sentence_text": "These modulations by Tax always paralleled the ability of Tax to activate the NF - kappaB transcription pathway .", "sentence_char_start_global": 332340, "sentence_char_end_global": 332453, "entities": [{"text": "Tax", "type": "ENTITY", "char_start": 21, "char_end": 24, "token_start": 3, "token_end": 3}, {"text": "Tax", "type": "ENTITY", "char_start": 58, "char_end": 61, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "Tax", "type": "ENTITY", "char_start": 332361, "char_end": 332364, "token_start": 3, "token_end": 3, "note": null}, {"text": "Tax", "type": "ENTITY", "char_start": 332398, "char_end": 332401, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 2017, "sentence_text": "These results indicate the important role of Tax - mediated trans - activation of the genes for cell cycle regulatory molecules in Tax - induced cell cycle progression .", "sentence_char_start_global": 332454, "sentence_char_end_global": 332623, "entities": [{"text": "Tax", "type": "ENTITY", "char_start": 45, "char_end": 48, "token_start": 7, "token_end": 7}, {"text": "cell cycle regulatory molecules", "type": "ENTITY", "char_start": 96, "char_end": 127, "token_start": 17, "token_end": 20}, {"text": "Tax", "type": "ENTITY", "char_start": 131, "char_end": 134, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "Tax", "type": "ENTITY", "char_start": 332499, "char_end": 332502, "token_start": 7, "token_end": 7, "note": null}, {"text": "cell cycle regulatory molecules", "type": "ENTITY", "char_start": 332550, "char_end": 332581, "token_start": 17, "token_end": 20, "note": null}, {"text": "Tax", "type": "ENTITY", "char_start": 332585, "char_end": 332588, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 2018, "sentence_text": "Cot kinase induces cyclooxygenase - 2 expression in T cells through activation of the nuclear factor of activated T cells .", "sentence_char_start_global": 332624, "sentence_char_end_global": 332747, "entities": [{"text": "Cot kinase", "type": "ENTITY", "char_start": 0, "char_end": 10, "token_start": 0, "token_end": 1}, {"text": "nuclear factor of activated T cells", "type": "ENTITY", "char_start": 86, "char_end": 121, "token_start": 14, "token_end": 19}], "entities_global": [{"text": "Cot kinase", "type": "ENTITY", "char_start": 332624, "char_end": 332634, "token_start": 0, "token_end": 1, "note": null}, {"text": "nuclear factor of activated T cells", "type": "ENTITY", "char_start": 332710, "char_end": 332745, "token_start": 14, "token_end": 19, "note": null}]}
+{"sentence_id": 2019, "sentence_text": "Cyclooxygenase - 2 ( COX - 2 ) is induced in human T lymphocytes upon T cell receptor triggering .", "sentence_char_start_global": 332748, "sentence_char_end_global": 332846, "entities": [{"text": "Cyclooxygenase - 2", "type": "ENTITY", "char_start": 0, "char_end": 18, "token_start": 0, "token_end": 2}, {"text": "COX - 2", "type": "ENTITY", "char_start": 21, "char_end": 28, "token_start": 4, "token_end": 6}, {"text": "T cell receptor", "type": "ENTITY", "char_start": 70, "char_end": 85, "token_start": 15, "token_end": 17}], "entities_global": [{"text": "Cyclooxygenase - 2", "type": "ENTITY", "char_start": 332748, "char_end": 332766, "token_start": 0, "token_end": 2, "note": null}, {"text": "COX - 2", "type": "ENTITY", "char_start": 332769, "char_end": 332776, "token_start": 4, "token_end": 6, "note": null}, {"text": "T cell receptor", "type": "ENTITY", "char_start": 332818, "char_end": 332833, "token_start": 15, "token_end": 17, "note": null}]}
+{"sentence_id": 2020, "sentence_text": "Here we report that Cot kinase , a mitogen - activated protein kinase kinase kinase involved in T cell activation , up - regulates COX - 2 gene expression in Jurkat T cells .", "sentence_char_start_global": 332847, "sentence_char_end_global": 333021, "entities": [{"text": "Cot kinase", "type": "ENTITY", "char_start": 20, "char_end": 30, "token_start": 4, "token_end": 5}, {"text": "mitogen - activated protein kinase kinase kinase", "type": "ENTITY", "char_start": 35, "char_end": 83, "token_start": 8, "token_end": 14}, {"text": "COX - 2 gene", "type": "ENTITY", "char_start": 131, "char_end": 143, "token_start": 24, "token_end": 27}], "entities_global": [{"text": "Cot kinase", "type": "ENTITY", "char_start": 332867, "char_end": 332877, "token_start": 4, "token_end": 5, "note": null}, {"text": "mitogen - activated protein kinase kinase kinase", "type": "ENTITY", "char_start": 332882, "char_end": 332930, "token_start": 8, "token_end": 14, "note": null}, {"text": "COX - 2 gene", "type": "ENTITY", "char_start": 332978, "char_end": 332990, "token_start": 24, "token_end": 27, "note": null}]}
+{"sentence_id": 2021, "sentence_text": "Induction of COX - 2 promoter activity by Cot kinase occurred mainly through activation of the nuclear factor of activated T cells ( NFAT ) .", "sentence_char_start_global": 333022, "sentence_char_end_global": 333163, "entities": [{"text": "Cot kinase", "type": "ENTITY", "char_start": 42, "char_end": 52, "token_start": 8, "token_end": 9}, {"text": "nuclear factor of activated T cells", "type": "ENTITY", "char_start": 95, "char_end": 130, "token_start": 16, "token_end": 21}, {"text": "NFAT", "type": "ENTITY", "char_start": 133, "char_end": 137, "token_start": 23, "token_end": 23}], "entities_global": [{"text": "Cot kinase", "type": "ENTITY", "char_start": 333064, "char_end": 333074, "token_start": 8, "token_end": 9, "note": null}, {"text": "nuclear factor of activated T cells", "type": "ENTITY", "char_start": 333117, "char_end": 333152, "token_start": 16, "token_end": 21, "note": null}, {"text": "NFAT", "type": "ENTITY", "char_start": 333155, "char_end": 333159, "token_start": 23, "token_end": 23, "note": null}]}
+{"sentence_id": 2022, "sentence_text": "Mutation of the distal ( - 105 / - 97 ) and proximal ( - 76 / - 61 ) NFAT response elements in the COX - 2 promoter abolished the activation induced by Cot kinase .", "sentence_char_start_global": 333164, "sentence_char_end_global": 333328, "entities": [{"text": "distal ( - 105 / - 97 )", "type": "ENTITY", "char_start": 16, "char_end": 39, "token_start": 3, "token_end": 10}, {"text": "proximal ( - 76 / - 61 )", "type": "ENTITY", "char_start": 44, "char_end": 68, "token_start": 12, "token_end": 19}, {"text": "NFAT response elements", "type": "ENTITY", "char_start": 69, "char_end": 91, "token_start": 20, "token_end": 22}, {"text": "COX - 2 promoter", "type": "ENTITY", "char_start": 99, "char_end": 115, "token_start": 25, "token_end": 28}, {"text": "Cot kinase", "type": "ENTITY", "char_start": 152, "char_end": 162, "token_start": 34, "token_end": 35}], "entities_global": [{"text": "distal ( - 105 / - 97 )", "type": "ENTITY", "char_start": 333180, "char_end": 333203, "token_start": 3, "token_end": 10, "note": null}, {"text": "proximal ( - 76 / - 61 )", "type": "ENTITY", "char_start": 333208, "char_end": 333232, "token_start": 12, "token_end": 19, "note": null}, {"text": "NFAT response elements", "type": "ENTITY", "char_start": 333233, "char_end": 333255, "token_start": 20, "token_end": 22, "note": null}, {"text": "COX - 2 promoter", "type": "ENTITY", "char_start": 333263, "char_end": 333279, "token_start": 25, "token_end": 28, "note": null}, {"text": "Cot kinase", "type": "ENTITY", "char_start": 333316, "char_end": 333326, "token_start": 34, "token_end": 35, "note": null}]}
+{"sentence_id": 2023, "sentence_text": "Even more , coexpression of a dominant negative version of NFAT inhibited Cot kinase - mediated COX - 2 promoter activation , whereas cotransfection of a constitutively active version of the calcium - dependent phosphatase calcineurin synergizes with Cot kinase in the up - regulation of COX - 2 promoter - driven transcription .", "sentence_char_start_global": 333329, "sentence_char_end_global": 333658, "entities": [{"text": "NFAT", "type": "ENTITY", "char_start": 59, "char_end": 63, "token_start": 10, "token_end": 10}, {"text": "Cot kinase", "type": "ENTITY", "char_start": 74, "char_end": 84, "token_start": 12, "token_end": 13}, {"text": "COX - 2 promoter", "type": "ENTITY", "char_start": 96, "char_end": 112, "token_start": 16, "token_end": 19}, {"text": "calcium - dependent phosphatase calcineurin", "type": "ENTITY", "char_start": 191, "char_end": 234, "token_start": 31, "token_end": 35}, {"text": "Cot kinase", "type": "ENTITY", "char_start": 251, "char_end": 261, "token_start": 38, "token_end": 39}, {"text": "COX - 2 promoter", "type": "ENTITY", "char_start": 288, "char_end": 304, "token_start": 46, "token_end": 49}], "entities_global": [{"text": "NFAT", "type": "ENTITY", "char_start": 333388, "char_end": 333392, "token_start": 10, "token_end": 10, "note": null}, {"text": "Cot kinase", "type": "ENTITY", "char_start": 333403, "char_end": 333413, "token_start": 12, "token_end": 13, "note": null}, {"text": "COX - 2 promoter", "type": "ENTITY", "char_start": 333425, "char_end": 333441, "token_start": 16, "token_end": 19, "note": null}, {"text": "calcium - dependent phosphatase calcineurin", "type": "ENTITY", "char_start": 333520, "char_end": 333563, "token_start": 31, "token_end": 35, "note": null}, {"text": "Cot kinase", "type": "ENTITY", "char_start": 333580, "char_end": 333590, "token_start": 38, "token_end": 39, "note": null}, {"text": "COX - 2 promoter", "type": "ENTITY", "char_start": 333617, "char_end": 333633, "token_start": 46, "token_end": 49, "note": null}]}
+{"sentence_id": 2024, "sentence_text": "Strikingly , Cot kinase increased transactivation mediated by a GAL4 - NFAT fusion protein containing the N - terminal transactivation domain of NFATp .", "sentence_char_start_global": 333659, "sentence_char_end_global": 333811, "entities": [{"text": "Cot kinase", "type": "ENTITY", "char_start": 13, "char_end": 23, "token_start": 2, "token_end": 3}, {"text": "GAL4 - NFAT fusion protein", "type": "ENTITY", "char_start": 64, "char_end": 90, "token_start": 9, "token_end": 13}, {"text": "N - terminal transactivation domain", "type": "ENTITY", "char_start": 106, "char_end": 141, "token_start": 16, "token_end": 20}, {"text": "NFATp", "type": "ENTITY", "char_start": 145, "char_end": 150, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "Cot kinase", "type": "ENTITY", "char_start": 333672, "char_end": 333682, "token_start": 2, "token_end": 3, "note": null}, {"text": "GAL4 - NFAT fusion protein", "type": "ENTITY", "char_start": 333723, "char_end": 333749, "token_start": 9, "token_end": 13, "note": null}, {"text": "N - terminal transactivation domain", "type": "ENTITY", "char_start": 333765, "char_end": 333800, "token_start": 16, "token_end": 20, "note": null}, {"text": "NFATp", "type": "ENTITY", "char_start": 333804, "char_end": 333809, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 2025, "sentence_text": "In contrast to phorbol ester plus calcium ionophore A23187 , Cot kinase increases both COX - 2 promoter activity and NFAT - mediated transactivation in a cyclosporin A - independent manner .", "sentence_char_start_global": 333812, "sentence_char_end_global": 334002, "entities": [{"text": "Cot kinase", "type": "ENTITY", "char_start": 61, "char_end": 71, "token_start": 10, "token_end": 11}, {"text": "COX - 2 promoter", "type": "ENTITY", "char_start": 87, "char_end": 103, "token_start": 14, "token_end": 17}, {"text": "NFAT", "type": "ENTITY", "char_start": 117, "char_end": 121, "token_start": 20, "token_end": 20}], "entities_global": [{"text": "Cot kinase", "type": "ENTITY", "char_start": 333873, "char_end": 333883, "token_start": 10, "token_end": 11, "note": null}, {"text": "COX - 2 promoter", "type": "ENTITY", "char_start": 333899, "char_end": 333915, "token_start": 14, "token_end": 17, "note": null}, {"text": "NFAT", "type": "ENTITY", "char_start": 333929, "char_end": 333933, "token_start": 20, "token_end": 20, "note": null}]}
+{"sentence_id": 2026, "sentence_text": "These data indicate that Cot kinase up - regulates COX - 2 promoter - driven transcription through the NFAT response elements , being the Cot kinase - induced NFAT - dependent transactivation presumably implicated in this up - regulation .", "sentence_char_start_global": 334003, "sentence_char_end_global": 334242, "entities": [{"text": "Cot kinase", "type": "ENTITY", "char_start": 25, "char_end": 35, "token_start": 4, "token_end": 5}, {"text": "COX - 2 promoter", "type": "ENTITY", "char_start": 51, "char_end": 67, "token_start": 9, "token_end": 12}, {"text": "NFAT response elements", "type": "ENTITY", "char_start": 103, "char_end": 125, "token_start": 18, "token_end": 20}, {"text": "Cot kinase", "type": "ENTITY", "char_start": 138, "char_end": 148, "token_start": 24, "token_end": 25}, {"text": "NFAT", "type": "ENTITY", "char_start": 159, "char_end": 163, "token_start": 28, "token_end": 28}], "entities_global": [{"text": "Cot kinase", "type": "ENTITY", "char_start": 334028, "char_end": 334038, "token_start": 4, "token_end": 5, "note": null}, {"text": "COX - 2 promoter", "type": "ENTITY", "char_start": 334054, "char_end": 334070, "token_start": 9, "token_end": 12, "note": null}, {"text": "NFAT response elements", "type": "ENTITY", "char_start": 334106, "char_end": 334128, "token_start": 18, "token_end": 20, "note": null}, {"text": "Cot kinase", "type": "ENTITY", "char_start": 334141, "char_end": 334151, "token_start": 24, "token_end": 25, "note": null}, {"text": "NFAT", "type": "ENTITY", "char_start": 334162, "char_end": 334166, "token_start": 28, "token_end": 28, "note": null}]}
+{"sentence_id": 2027, "sentence_text": "Positive and negative roles of the trans - acting T cell factor - 1 for the acquisition of distinct Ly - 49 MHC class I receptors by NK cells .", "sentence_char_start_global": 334243, "sentence_char_end_global": 334386, "entities": [{"text": "trans - acting T cell factor - 1", "type": "ENTITY", "char_start": 35, "char_end": 67, "token_start": 6, "token_end": 13}, {"text": "Ly - 49 MHC class I receptors", "type": "ENTITY", "char_start": 100, "char_end": 129, "token_start": 19, "token_end": 25}], "entities_global": [{"text": "trans - acting T cell factor - 1", "type": "ENTITY", "char_start": 334278, "char_end": 334310, "token_start": 6, "token_end": 13, "note": null}, {"text": "Ly - 49 MHC class I receptors", "type": "ENTITY", "char_start": 334343, "char_end": 334372, "token_start": 19, "token_end": 25, "note": null}]}
+{"sentence_id": 2028, "sentence_text": "Members of the Ly - 49 gene family code for class I MHC - specific receptors that regulate NK cell function .", "sentence_char_start_global": 334387, "sentence_char_end_global": 334496, "entities": [{"text": "Ly - 49 gene family", "type": "ENTITY", "char_start": 15, "char_end": 34, "token_start": 3, "token_end": 7}, {"text": "class I MHC - specific receptors", "type": "ENTITY", "char_start": 44, "char_end": 76, "token_start": 10, "token_end": 15}], "entities_global": [{"text": "Ly - 49 gene family", "type": "ENTITY", "char_start": 334402, "char_end": 334421, "token_start": 3, "token_end": 7, "note": null}, {"text": "class I MHC - specific receptors", "type": "ENTITY", "char_start": 334431, "char_end": 334463, "token_start": 10, "token_end": 15, "note": null}]}
+{"sentence_id": 2029, "sentence_text": "Due to a combinatorial distribution of Ly - 49 receptors , NK cells display considerable clonal heterogeneity .", "sentence_char_start_global": 334497, "sentence_char_end_global": 334608, "entities": [{"text": "Ly - 49 receptors", "type": "ENTITY", "char_start": 39, "char_end": 56, "token_start": 6, "token_end": 9}], "entities_global": [{"text": "Ly - 49 receptors", "type": "ENTITY", "char_start": 334536, "char_end": 334553, "token_start": 6, "token_end": 9, "note": null}]}
+{"sentence_id": 2030, "sentence_text": "The acquisition of one Ly - 49 receptor , Ly - 49A is strictly dependent on the transcriptional trans - acting factor T cell - specific factor - 1 ( TCF - 1 ) .", "sentence_char_start_global": 334609, "sentence_char_end_global": 334769, "entities": [{"text": "Ly - 49 receptor", "type": "ENTITY", "char_start": 23, "char_end": 39, "token_start": 4, "token_end": 7}, {"text": "Ly - 49A", "type": "ENTITY", "char_start": 42, "char_end": 50, "token_start": 9, "token_end": 11}, {"text": "transcriptional trans - acting factor", "type": "ENTITY", "char_start": 80, "char_end": 117, "token_start": 17, "token_end": 21}, {"text": "T cell - specific factor - 1", "type": "ENTITY", "char_start": 118, "char_end": 146, "token_start": 22, "token_end": 28}, {"text": "TCF - 1", "type": "ENTITY", "char_start": 149, "char_end": 156, "token_start": 30, "token_end": 32}], "entities_global": [{"text": "Ly - 49 receptor", "type": "ENTITY", "char_start": 334632, "char_end": 334648, "token_start": 4, "token_end": 7, "note": null}, {"text": "Ly - 49A", "type": "ENTITY", "char_start": 334651, "char_end": 334659, "token_start": 9, "token_end": 11, "note": null}, {"text": "transcriptional trans - acting factor", "type": "ENTITY", "char_start": 334689, "char_end": 334726, "token_start": 17, "token_end": 21, "note": null}, {"text": "T cell - specific factor - 1", "type": "ENTITY", "char_start": 334727, "char_end": 334755, "token_start": 22, "token_end": 28, "note": null}, {"text": "TCF - 1", "type": "ENTITY", "char_start": 334758, "char_end": 334765, "token_start": 30, "token_end": 32, "note": null}]}
+{"sentence_id": 2031, "sentence_text": "Indeed , TCF - 1 binds to two sites in the Ly - 49a promoter and regulates its activity , suggesting that the Ly - 49a gene is a direct TCF - 1 target .", "sentence_char_start_global": 334770, "sentence_char_end_global": 334922, "entities": [{"text": "TCF - 1", "type": "ENTITY", "char_start": 9, "char_end": 16, "token_start": 2, "token_end": 4}, {"text": "Ly - 49a promoter", "type": "ENTITY", "char_start": 43, "char_end": 60, "token_start": 11, "token_end": 14}, {"text": "Ly - 49a gene", "type": "ENTITY", "char_start": 110, "char_end": 123, "token_start": 23, "token_end": 26}, {"text": "TCF - 1", "type": "ENTITY", "char_start": 136, "char_end": 143, "token_start": 30, "token_end": 32}], "entities_global": [{"text": "TCF - 1", "type": "ENTITY", "char_start": 334779, "char_end": 334786, "token_start": 2, "token_end": 4, "note": null}, {"text": "Ly - 49a promoter", "type": "ENTITY", "char_start": 334813, "char_end": 334830, "token_start": 11, "token_end": 14, "note": null}, {"text": "Ly - 49a gene", "type": "ENTITY", "char_start": 334880, "char_end": 334893, "token_start": 23, "token_end": 26, "note": null}, {"text": "TCF - 1", "type": "ENTITY", "char_start": 334906, "char_end": 334913, "token_start": 30, "token_end": 32, "note": null}]}
+{"sentence_id": 2032, "sentence_text": "TCF - 1 deficiency resulted in the altered usage of additional Ly - 49 receptors .", "sentence_char_start_global": 334923, "sentence_char_end_global": 335005, "entities": [{"text": "TCF - 1", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 2}, {"text": "Ly - 49 receptors", "type": "ENTITY", "char_start": 63, "char_end": 80, "token_start": 11, "token_end": 14}], "entities_global": [{"text": "TCF - 1", "type": "ENTITY", "char_start": 334923, "char_end": 334930, "token_start": 0, "token_end": 2, "note": null}, {"text": "Ly - 49 receptors", "type": "ENTITY", "char_start": 334986, "char_end": 335003, "token_start": 11, "token_end": 14, "note": null}]}
+{"sentence_id": 2033, "sentence_text": "We show in this study , using TCF - 1 beta ( 2 ) - microglobulin double - deficient mice , that these repertoire alterations are not due to Ly - 49 / MHC class I interactions .", "sentence_char_start_global": 335006, "sentence_char_end_global": 335182, "entities": [{"text": "TCF - 1 beta ( 2 ) - microglobulin", "type": "ENTITY", "char_start": 30, "char_end": 64, "token_start": 7, "token_end": 15}], "entities_global": [{"text": "TCF - 1 beta ( 2 ) - microglobulin", "type": "ENTITY", "char_start": 335036, "char_end": 335070, "token_start": 7, "token_end": 15, "note": null}]}
+{"sentence_id": 2034, "sentence_text": "Our findings rather suggest a TCF - 1 - dependent , cell autonomous effect on the acquisition of multiple Ly - 49 receptors .", "sentence_char_start_global": 335183, "sentence_char_end_global": 335308, "entities": [{"text": "TCF - 1", "type": "ENTITY", "char_start": 30, "char_end": 37, "token_start": 5, "token_end": 7}, {"text": "Ly - 49 receptors", "type": "ENTITY", "char_start": 106, "char_end": 123, "token_start": 19, "token_end": 22}], "entities_global": [{"text": "TCF - 1", "type": "ENTITY", "char_start": 335213, "char_end": 335220, "token_start": 5, "token_end": 7, "note": null}, {"text": "Ly - 49 receptors", "type": "ENTITY", "char_start": 335289, "char_end": 335306, "token_start": 19, "token_end": 22, "note": null}]}
+{"sentence_id": 2035, "sentence_text": "Besides reduced receptor usage ( Ly - 49A and D ) , we also observed no effect ( Ly - 49C ) and significantly expanded ( Ly - 49G and I ) receptor usage in the absence of TCF - 1 .", "sentence_char_start_global": 335309, "sentence_char_end_global": 335489, "entities": [{"text": "Ly - 49A and D", "type": "ENTITY", "char_start": 33, "char_end": 47, "token_start": 5, "token_end": 9}, {"text": "Ly - 49C", "type": "ENTITY", "char_start": 81, "char_end": 89, "token_start": 18, "token_end": 20}, {"text": "Ly - 49G and I", "type": "ENTITY", "char_start": 121, "char_end": 135, "token_start": 26, "token_end": 30}, {"text": "TCF - 1", "type": "ENTITY", "char_start": 171, "char_end": 178, "token_start": 38, "token_end": 40}], "entities_global": [{"text": "Ly - 49A and D", "type": "ENTITY", "char_start": 335342, "char_end": 335356, "token_start": 5, "token_end": 9, "note": null}, {"text": "Ly - 49C", "type": "ENTITY", "char_start": 335390, "char_end": 335398, "token_start": 18, "token_end": 20, "note": null}, {"text": "Ly - 49G and I", "type": "ENTITY", "char_start": 335430, "char_end": 335444, "token_start": 26, "token_end": 30, "note": null}, {"text": "TCF - 1", "type": "ENTITY", "char_start": 335480, "char_end": 335487, "token_start": 38, "token_end": 40, "note": null}]}
+{"sentence_id": 2036, "sentence_text": "These effects did not in all cases correlate with the presence of TCF binding sites in the respective proximal promoter .", "sentence_char_start_global": 335490, "sentence_char_end_global": 335611, "entities": [{"text": "TCF binding sites", "type": "ENTITY", "char_start": 66, "char_end": 83, "token_start": 12, "token_end": 14}, {"text": "proximal promoter", "type": "ENTITY", "char_start": 102, "char_end": 119, "token_start": 18, "token_end": 19}], "entities_global": [{"text": "TCF binding sites", "type": "ENTITY", "char_start": 335556, "char_end": 335573, "token_start": 12, "token_end": 14, "note": null}, {"text": "proximal promoter", "type": "ENTITY", "char_start": 335592, "char_end": 335609, "token_start": 18, "token_end": 19, "note": null}]}
+{"sentence_id": 2037, "sentence_text": "Therefore , besides TCF - 1 binding to the proximal promoter , Ly - 49 acquisition may also be regulated by TCF - 1 binding to more distant cis - acting elements and / or by regulating the expression of additional trans - acting factors .", "sentence_char_start_global": 335612, "sentence_char_end_global": 335850, "entities": [{"text": "TCF - 1", "type": "ENTITY", "char_start": 20, "char_end": 27, "token_start": 3, "token_end": 5}, {"text": "proximal promoter", "type": "ENTITY", "char_start": 43, "char_end": 60, "token_start": 9, "token_end": 10}, {"text": "TCF - 1", "type": "ENTITY", "char_start": 108, "char_end": 115, "token_start": 21, "token_end": 23}, {"text": "cis - acting elements", "type": "ENTITY", "char_start": 140, "char_end": 161, "token_start": 28, "token_end": 31}, {"text": "trans - acting factors", "type": "ENTITY", "char_start": 214, "char_end": 236, "token_start": 41, "token_end": 44}], "entities_global": [{"text": "TCF - 1", "type": "ENTITY", "char_start": 335632, "char_end": 335639, "token_start": 3, "token_end": 5, "note": null}, {"text": "proximal promoter", "type": "ENTITY", "char_start": 335655, "char_end": 335672, "token_start": 9, "token_end": 10, "note": null}, {"text": "TCF - 1", "type": "ENTITY", "char_start": 335720, "char_end": 335727, "token_start": 21, "token_end": 23, "note": null}, {"text": "cis - acting elements", "type": "ENTITY", "char_start": 335752, "char_end": 335773, "token_start": 28, "token_end": 31, "note": null}, {"text": "trans - acting factors", "type": "ENTITY", "char_start": 335826, "char_end": 335848, "token_start": 41, "token_end": 44, "note": null}]}
+{"sentence_id": 2038, "sentence_text": "Consistent with the observed differential , positive or negative role of TCF - 1 for Ly - 49 receptor acquisition , reporter gene assays revealed the presence of an inducing as well as a repressing TCF site in certain proximal Ly - 49 promoters .", "sentence_char_start_global": 335851, "sentence_char_end_global": 336097, "entities": [{"text": "TCF - 1", "type": "ENTITY", "char_start": 73, "char_end": 80, "token_start": 11, "token_end": 13}, {"text": "Ly - 49 receptor", "type": "ENTITY", "char_start": 85, "char_end": 101, "token_start": 15, "token_end": 18}, {"text": "TCF site", "type": "ENTITY", "char_start": 198, "char_end": 206, "token_start": 35, "token_end": 36}, {"text": "Ly - 49 promoters", "type": "ENTITY", "char_start": 227, "char_end": 244, "token_start": 40, "token_end": 43}], "entities_global": [{"text": "TCF - 1", "type": "ENTITY", "char_start": 335924, "char_end": 335931, "token_start": 11, "token_end": 13, "note": null}, {"text": "Ly - 49 receptor", "type": "ENTITY", "char_start": 335936, "char_end": 335952, "token_start": 15, "token_end": 18, "note": null}, {"text": "TCF site", "type": "ENTITY", "char_start": 336049, "char_end": 336057, "token_start": 35, "token_end": 36, "note": null}, {"text": "Ly - 49 promoters", "type": "ENTITY", "char_start": 336078, "char_end": 336095, "token_start": 40, "token_end": 43, "note": null}]}
+{"sentence_id": 2039, "sentence_text": "These findings reveal an important role of TCF - 1 for the formation of the NK cell receptor repertoire .", "sentence_char_start_global": 336098, "sentence_char_end_global": 336203, "entities": [{"text": "TCF - 1", "type": "ENTITY", "char_start": 43, "char_end": 50, "token_start": 7, "token_end": 9}, {"text": "NK cell receptor", "type": "ENTITY", "char_start": 76, "char_end": 92, "token_start": 15, "token_end": 17}], "entities_global": [{"text": "TCF - 1", "type": "ENTITY", "char_start": 336141, "char_end": 336148, "token_start": 7, "token_end": 9, "note": null}, {"text": "NK cell receptor", "type": "ENTITY", "char_start": 336174, "char_end": 336190, "token_start": 15, "token_end": 17, "note": null}]}
+{"sentence_id": 2040, "sentence_text": "Ligation of CD11b and CD11c beta ( 2 ) integrins by antibodies or soluble CD23 induces macrophage inflammatory protein 1alpha ( MIP - 1alpha ) and MIP - 1beta production in primary human monocytes through a pathway dependent on nuclear factor - kappaB .", "sentence_char_start_global": 336204, "sentence_char_end_global": 336457, "entities": [{"text": "CD11b", "type": "ENTITY", "char_start": 12, "char_end": 17, "token_start": 2, "token_end": 2}, {"text": "CD11c beta ( 2 )", "type": "ENTITY", "char_start": 22, "char_end": 38, "token_start": 4, "token_end": 8}, {"text": "integrins", "type": "ENTITY", "char_start": 39, "char_end": 48, "token_start": 9, "token_end": 9}, {"text": "antibodies", "type": "ENTITY", "char_start": 52, "char_end": 62, "token_start": 11, "token_end": 11}, {"text": "soluble CD23", "type": "ENTITY", "char_start": 66, "char_end": 78, "token_start": 13, "token_end": 14}, {"text": "macrophage inflammatory protein 1alpha", "type": "ENTITY", "char_start": 87, "char_end": 125, "token_start": 16, "token_end": 19}, {"text": "MIP - 1alpha", "type": "ENTITY", "char_start": 128, "char_end": 140, "token_start": 21, "token_end": 23}, {"text": "MIP - 1beta", "type": "ENTITY", "char_start": 147, "char_end": 158, "token_start": 26, "token_end": 28}, {"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 228, "char_end": 251, "token_start": 39, "token_end": 42}], "entities_global": [{"text": "CD11b", "type": "ENTITY", "char_start": 336216, "char_end": 336221, "token_start": 2, "token_end": 2, "note": null}, {"text": "CD11c beta ( 2 )", "type": "ENTITY", "char_start": 336226, "char_end": 336242, "token_start": 4, "token_end": 8, "note": null}, {"text": "integrins", "type": "ENTITY", "char_start": 336243, "char_end": 336252, "token_start": 9, "token_end": 9, "note": null}, {"text": "antibodies", "type": "ENTITY", "char_start": 336256, "char_end": 336266, "token_start": 11, "token_end": 11, "note": null}, {"text": "soluble CD23", "type": "ENTITY", "char_start": 336270, "char_end": 336282, "token_start": 13, "token_end": 14, "note": null}, {"text": "macrophage inflammatory protein 1alpha", "type": "ENTITY", "char_start": 336291, "char_end": 336329, "token_start": 16, "token_end": 19, "note": null}, {"text": "MIP - 1alpha", "type": "ENTITY", "char_start": 336332, "char_end": 336344, "token_start": 21, "token_end": 23, "note": null}, {"text": "MIP - 1beta", "type": "ENTITY", "char_start": 336351, "char_end": 336362, "token_start": 26, "token_end": 28, "note": null}, {"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 336432, "char_end": 336455, "token_start": 39, "token_end": 42, "note": null}]}
+{"sentence_id": 2041, "sentence_text": "Chemokines and adhesion molecules such as integrins play a major part in the trafficking , extravasation , and recruitment of leukocytes to inflammatory sites .", "sentence_char_start_global": 336458, "sentence_char_end_global": 336618, "entities": [{"text": "Chemokines", "type": "ENTITY", "char_start": 0, "char_end": 10, "token_start": 0, "token_end": 0}, {"text": "adhesion molecules", "type": "ENTITY", "char_start": 15, "char_end": 33, "token_start": 2, "token_end": 3}, {"text": "integrins", "type": "ENTITY", "char_start": 42, "char_end": 51, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "Chemokines", "type": "ENTITY", "char_start": 336458, "char_end": 336468, "token_start": 0, "token_end": 0, "note": null}, {"text": "adhesion molecules", "type": "ENTITY", "char_start": 336473, "char_end": 336491, "token_start": 2, "token_end": 3, "note": null}, {"text": "integrins", "type": "ENTITY", "char_start": 336500, "char_end": 336509, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 2042, "sentence_text": "This study investigated the effects of beta ( 2 ) integrin engagement on chemokine production by freshly isolated human monocytes .", "sentence_char_start_global": 336619, "sentence_char_end_global": 336750, "entities": [], "entities_global": []}
+{"sentence_id": 2043, "sentence_text": "We found that ligation of CD11b or CD11c but not CD11a alpha chains of beta ( 2 ) integrins by antibodies or soluble CD23 ( sCD23 ) fusion proteins rapidly induced transcription and secretion of interleukin 8 , macrophage inflammatory protein ( MIP ) 1alpha , and MIP - 1beta .", "sentence_char_start_global": 336751, "sentence_char_end_global": 337028, "entities": [{"text": "CD11b", "type": "ENTITY", "char_start": 26, "char_end": 31, "token_start": 5, "token_end": 5}, {"text": "CD11c", "type": "ENTITY", "char_start": 35, "char_end": 40, "token_start": 7, "token_end": 7}, {"text": "CD11a alpha chains", "type": "ENTITY", "char_start": 49, "char_end": 67, "token_start": 10, "token_end": 12}, {"text": "beta ( 2 ) integrins", "type": "ENTITY", "char_start": 71, "char_end": 91, "token_start": 14, "token_end": 18}, {"text": "antibodies", "type": "ENTITY", "char_start": 95, "char_end": 105, "token_start": 20, "token_end": 20}, {"text": "soluble CD23 ( sCD23 ) fusion proteins", "type": "ENTITY", "char_start": 109, "char_end": 147, "token_start": 22, "token_end": 28}, {"text": "interleukin 8", "type": "ENTITY", "char_start": 195, "char_end": 208, "token_start": 35, "token_end": 36}, {"text": "macrophage inflammatory protein ( MIP ) 1alpha", "type": "ENTITY", "char_start": 211, "char_end": 257, "token_start": 38, "token_end": 44}, {"text": "MIP - 1beta", "type": "ENTITY", "char_start": 264, "char_end": 275, "token_start": 47, "token_end": 49}], "entities_global": [{"text": "CD11b", "type": "ENTITY", "char_start": 336777, "char_end": 336782, "token_start": 5, "token_end": 5, "note": null}, {"text": "CD11c", "type": "ENTITY", "char_start": 336786, "char_end": 336791, "token_start": 7, "token_end": 7, "note": null}, {"text": "CD11a alpha chains", "type": "ENTITY", "char_start": 336800, "char_end": 336818, "token_start": 10, "token_end": 12, "note": null}, {"text": "beta ( 2 ) integrins", "type": "ENTITY", "char_start": 336822, "char_end": 336842, "token_start": 14, "token_end": 18, "note": null}, {"text": "antibodies", "type": "ENTITY", "char_start": 336846, "char_end": 336856, "token_start": 20, "token_end": 20, "note": null}, {"text": "soluble CD23 ( sCD23 ) fusion proteins", "type": "ENTITY", "char_start": 336860, "char_end": 336898, "token_start": 22, "token_end": 28, "note": null}, {"text": "interleukin 8", "type": "ENTITY", "char_start": 336946, "char_end": 336959, "token_start": 35, "token_end": 36, "note": null}, {"text": "macrophage inflammatory protein ( MIP ) 1alpha", "type": "ENTITY", "char_start": 336962, "char_end": 337008, "token_start": 38, "token_end": 44, "note": null}, {"text": "MIP - 1beta", "type": "ENTITY", "char_start": 337015, "char_end": 337026, "token_start": 47, "token_end": 49, "note": null}]}
+{"sentence_id": 2044, "sentence_text": "Because the promoters of these chemokine genes contain kappaB binding sites , we assessed the possible role of nuclear factor - kappaB ( NF - kappaB ) in controlling induction of the genes through beta ( 2 ) integrin engagement .", "sentence_char_start_global": 337029, "sentence_char_end_global": 337258, "entities": [{"text": "promoters", "type": "ENTITY", "char_start": 12, "char_end": 21, "token_start": 2, "token_end": 2}, {"text": "chemokine genes", "type": "ENTITY", "char_start": 31, "char_end": 46, "token_start": 5, "token_end": 6}, {"text": "kappaB binding sites", "type": "ENTITY", "char_start": 55, "char_end": 75, "token_start": 8, "token_end": 10}, {"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 111, "char_end": 134, "token_start": 18, "token_end": 21}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 137, "char_end": 148, "token_start": 23, "token_end": 25}], "entities_global": [{"text": "promoters", "type": "ENTITY", "char_start": 337041, "char_end": 337050, "token_start": 2, "token_end": 2, "note": null}, {"text": "chemokine genes", "type": "ENTITY", "char_start": 337060, "char_end": 337075, "token_start": 5, "token_end": 6, "note": null}, {"text": "kappaB binding sites", "type": "ENTITY", "char_start": 337084, "char_end": 337104, "token_start": 8, "token_end": 10, "note": null}, {"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 337140, "char_end": 337163, "token_start": 18, "token_end": 21, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 337166, "char_end": 337177, "token_start": 23, "token_end": 25, "note": null}]}
+{"sentence_id": 2045, "sentence_text": "Electrophoretic mobility shift assays showed that sCD23 or antibodies to CD11b or to CD11c up - regulated DNA - binding activity of NF - kappaB .", "sentence_char_start_global": 337259, "sentence_char_end_global": 337404, "entities": [{"text": "sCD23", "type": "ENTITY", "char_start": 50, "char_end": 55, "token_start": 6, "token_end": 6}, {"text": "antibodies", "type": "ENTITY", "char_start": 59, "char_end": 69, "token_start": 8, "token_end": 8}, {"text": "CD11b", "type": "ENTITY", "char_start": 73, "char_end": 78, "token_start": 10, "token_end": 10}, {"text": "CD11c", "type": "ENTITY", "char_start": 85, "char_end": 90, "token_start": 13, "token_end": 13}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 132, "char_end": 143, "token_start": 22, "token_end": 24}], "entities_global": [{"text": "sCD23", "type": "ENTITY", "char_start": 337309, "char_end": 337314, "token_start": 6, "token_end": 6, "note": null}, {"text": "antibodies", "type": "ENTITY", "char_start": 337318, "char_end": 337328, "token_start": 8, "token_end": 8, "note": null}, {"text": "CD11b", "type": "ENTITY", "char_start": 337332, "char_end": 337337, "token_start": 10, "token_end": 10, "note": null}, {"text": "CD11c", "type": "ENTITY", "char_start": 337344, "char_end": 337349, "token_start": 13, "token_end": 13, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 337391, "char_end": 337402, "token_start": 22, "token_end": 24, "note": null}]}
+{"sentence_id": 2046, "sentence_text": "Activation of NF - kappaB was accompanied by degradation of its cytosolic inhibitor IkappaB - alpha .", "sentence_char_start_global": 337405, "sentence_char_end_global": 337506, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 14, "char_end": 25, "token_start": 2, "token_end": 4}, {"text": "cytosolic inhibitor IkappaB - alpha", "type": "ENTITY", "char_start": 64, "char_end": 99, "token_start": 11, "token_end": 15}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 337419, "char_end": 337430, "token_start": 2, "token_end": 4, "note": null}, {"text": "cytosolic inhibitor IkappaB - alpha", "type": "ENTITY", "char_start": 337469, "char_end": 337504, "token_start": 11, "token_end": 15, "note": null}]}
+{"sentence_id": 2047, "sentence_text": "Blockade of depletion of IkappaB - alpha by proteasome inhibitors ( proteasome inhibitor I or acetyl - leucinyl - leucinyl - norleucinal ) led to concomitant inhibition of NF - kappaB DNA - binding activity and expression of MIP - 1alpha and MIP - 1beta messenger RNA induced by beta ( 2 ) integrin ligation .", "sentence_char_start_global": 337507, "sentence_char_end_global": 337816, "entities": [{"text": "IkappaB - alpha", "type": "ENTITY", "char_start": 25, "char_end": 40, "token_start": 4, "token_end": 6}, {"text": "MIP - 1alpha and MIP - 1beta messenger RNA", "type": "ENTITY", "char_start": 225, "char_end": 267, "token_start": 38, "token_end": 46}], "entities_global": [{"text": "IkappaB - alpha", "type": "ENTITY", "char_start": 337532, "char_end": 337547, "token_start": 4, "token_end": 6, "note": null}, {"text": "MIP - 1alpha and MIP - 1beta messenger RNA", "type": "ENTITY", "char_start": 337732, "char_end": 337774, "token_start": 38, "token_end": 46, "note": null}]}
+{"sentence_id": 2048, "sentence_text": "These results suggest that triggering of CD11b or CD11c beta ( 2 ) integrin on primary human monocytes provides activation signals leading to nuclear translocation of NF - kappaB and subsequent secretion of MIP - 1alpha and MIP - 1beta that may have an important role in recruitment of other inflammatory cells during initiation of an inflammatory response", "sentence_char_start_global": 337817, "sentence_char_end_global": 338173, "entities": [{"text": "CD11b", "type": "ENTITY", "char_start": 41, "char_end": 46, "token_start": 6, "token_end": 6}, {"text": "CD11c beta ( 2 )", "type": "ENTITY", "char_start": 50, "char_end": 66, "token_start": 8, "token_end": 12}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 167, "char_end": 178, "token_start": 26, "token_end": 28}, {"text": "MIP - 1alpha", "type": "ENTITY", "char_start": 207, "char_end": 219, "token_start": 33, "token_end": 35}, {"text": "MIP - 1beta", "type": "ENTITY", "char_start": 224, "char_end": 235, "token_start": 37, "token_end": 39}], "entities_global": [{"text": "CD11b", "type": "ENTITY", "char_start": 337858, "char_end": 337863, "token_start": 6, "token_end": 6, "note": null}, {"text": "CD11c beta ( 2 )", "type": "ENTITY", "char_start": 337867, "char_end": 337883, "token_start": 8, "token_end": 12, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 337984, "char_end": 337995, "token_start": 26, "token_end": 28, "note": null}, {"text": "MIP - 1alpha", "type": "ENTITY", "char_start": 338024, "char_end": 338036, "token_start": 33, "token_end": 35, "note": null}, {"text": "MIP - 1beta", "type": "ENTITY", "char_start": 338041, "char_end": 338052, "token_start": 37, "token_end": 39, "note": null}]}
+{"sentence_id": 2049, "sentence_text": "Synergistic transcriptional activation of human Acyl - coenzyme A : cholesterol acyltransterase - 1 gene by interferon - gamma and all - trans - retinoic acid THP - 1 cells .", "sentence_char_start_global": 338174, "sentence_char_end_global": 338348, "entities": [{"text": "human Acyl - coenzyme A : cholesterol acyltransterase - 1 gene", "type": "ENTITY", "char_start": 42, "char_end": 104, "token_start": 4, "token_end": 14}, {"text": "interferon - gamma", "type": "ENTITY", "char_start": 108, "char_end": 126, "token_start": 16, "token_end": 18}], "entities_global": [{"text": "human Acyl - coenzyme A : cholesterol acyltransterase - 1 gene", "type": "ENTITY", "char_start": 338216, "char_end": 338278, "token_start": 4, "token_end": 14, "note": null}, {"text": "interferon - gamma", "type": "ENTITY", "char_start": 338282, "char_end": 338300, "token_start": 16, "token_end": 18, "note": null}]}
+{"sentence_id": 2050, "sentence_text": "Acyl - coenzyme A : cholesterol acyltransferase ( ACAT ) is an intracellular enzyme involved in cellular cholesterol homeostasis and in atherosclerotic foam cell formation .", "sentence_char_start_global": 338349, "sentence_char_end_global": 338522, "entities": [{"text": "Acyl - coenzyme A : cholesterol acyltransferase", "type": "ENTITY", "char_start": 0, "char_end": 47, "token_start": 0, "token_end": 6}, {"text": "ACAT", "type": "ENTITY", "char_start": 50, "char_end": 54, "token_start": 8, "token_end": 8}, {"text": "intracellular enzyme", "type": "ENTITY", "char_start": 63, "char_end": 83, "token_start": 12, "token_end": 13}], "entities_global": [{"text": "Acyl - coenzyme A : cholesterol acyltransferase", "type": "ENTITY", "char_start": 338349, "char_end": 338396, "token_start": 0, "token_end": 6, "note": null}, {"text": "ACAT", "type": "ENTITY", "char_start": 338399, "char_end": 338403, "token_start": 8, "token_end": 8, "note": null}, {"text": "intracellular enzyme", "type": "ENTITY", "char_start": 338412, "char_end": 338432, "token_start": 12, "token_end": 13, "note": null}]}
+{"sentence_id": 2051, "sentence_text": "Human ACAT - 1 gene contains two promoters ( P1 and P7 ) , each located in a different chromosome ( 1 and 7 ) ( Li , B . L . , Li , X . L . , Duan , Z . J . , Lee , O . , Lin , S . , Ma , Z . M . , Chang , C . C . , Yang , X . Y . , Park , J . P . , Mohandas , T . K . , Noll , W . , Chan , L . , and Chang , T . Y . ( 1999 ) J . Biol Chem . 274 , 11060 - 11071 ) .", "sentence_char_start_global": 338523, "sentence_char_end_global": 338888, "entities": [{"text": "Human ACAT - 1 gene", "type": "ENTITY", "char_start": 0, "char_end": 19, "token_start": 0, "token_end": 4}, {"text": "promoters", "type": "ENTITY", "char_start": 33, "char_end": 42, "token_start": 7, "token_end": 7}, {"text": "P1", "type": "ENTITY", "char_start": 45, "char_end": 47, "token_start": 9, "token_end": 9}, {"text": "P7", "type": "ENTITY", "char_start": 52, "char_end": 54, "token_start": 11, "token_end": 11}, {"text": "chromosome ( 1 and 7 )", "type": "ENTITY", "char_start": 87, "char_end": 109, "token_start": 19, "token_end": 24}], "entities_global": [{"text": "Human ACAT - 1 gene", "type": "ENTITY", "char_start": 338523, "char_end": 338542, "token_start": 0, "token_end": 4, "note": null}, {"text": "promoters", "type": "ENTITY", "char_start": 338556, "char_end": 338565, "token_start": 7, "token_end": 7, "note": null}, {"text": "P1", "type": "ENTITY", "char_start": 338568, "char_end": 338570, "token_start": 9, "token_end": 9, "note": null}, {"text": "P7", "type": "ENTITY", "char_start": 338575, "char_end": 338577, "token_start": 11, "token_end": 11, "note": null}, {"text": "chromosome ( 1 and 7 )", "type": "ENTITY", "char_start": 338610, "char_end": 338632, "token_start": 19, "token_end": 24, "note": null}]}
+{"sentence_id": 2052, "sentence_text": "Interferon - gamma ( IFN - gamma ) , a cytokine that exerts many pro - atherosclerotic effects in vivo , causes up - regulation of ACAT - 1 mRNA in human blood monocyte - derived macrophages and macrophage - like cells but not in other cell types .", "sentence_char_start_global": 338889, "sentence_char_end_global": 339137, "entities": [{"text": "Interferon - gamma", "type": "ENTITY", "char_start": 0, "char_end": 18, "token_start": 0, "token_end": 2}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 21, "char_end": 32, "token_start": 4, "token_end": 6}, {"text": "cytokine", "type": "ENTITY", "char_start": 39, "char_end": 47, "token_start": 10, "token_end": 10}, {"text": "ACAT - 1 mRNA", "type": "ENTITY", "char_start": 131, "char_end": 144, "token_start": 26, "token_end": 29}], "entities_global": [{"text": "Interferon - gamma", "type": "ENTITY", "char_start": 338889, "char_end": 338907, "token_start": 0, "token_end": 2, "note": null}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 338910, "char_end": 338921, "token_start": 4, "token_end": 6, "note": null}, {"text": "cytokine", "type": "ENTITY", "char_start": 338928, "char_end": 338936, "token_start": 10, "token_end": 10, "note": null}, {"text": "ACAT - 1 mRNA", "type": "ENTITY", "char_start": 339020, "char_end": 339033, "token_start": 26, "token_end": 29, "note": null}]}
+{"sentence_id": 2053, "sentence_text": "To examine the molecular nature of this observation , we identified within the ACAT - 1 P1 promoter a 159 - base pair core region .", "sentence_char_start_global": 339138, "sentence_char_end_global": 339269, "entities": [{"text": "ACAT - 1 P1 promoter", "type": "ENTITY", "char_start": 79, "char_end": 99, "token_start": 13, "token_end": 17}, {"text": "159 - base pair core region", "type": "ENTITY", "char_start": 102, "char_end": 129, "token_start": 19, "token_end": 24}], "entities_global": [{"text": "ACAT - 1 P1 promoter", "type": "ENTITY", "char_start": 339217, "char_end": 339237, "token_start": 13, "token_end": 17, "note": null}, {"text": "159 - base pair core region", "type": "ENTITY", "char_start": 339240, "char_end": 339267, "token_start": 19, "token_end": 24, "note": null}]}
+{"sentence_id": 2054, "sentence_text": "This region contains 4 Sp1 elements and an IFN - gamma activated sequence ( GAS ) that overlaps with the second Sp1 element .", "sentence_char_start_global": 339270, "sentence_char_end_global": 339395, "entities": [{"text": "Sp1 elements", "type": "ENTITY", "char_start": 23, "char_end": 35, "token_start": 4, "token_end": 5}, {"text": "IFN - gamma activated sequence", "type": "ENTITY", "char_start": 43, "char_end": 73, "token_start": 8, "token_end": 12}, {"text": "GAS", "type": "ENTITY", "char_start": 76, "char_end": 79, "token_start": 14, "token_end": 14}, {"text": "Sp1 element", "type": "ENTITY", "char_start": 112, "char_end": 123, "token_start": 21, "token_end": 22}], "entities_global": [{"text": "Sp1 elements", "type": "ENTITY", "char_start": 339293, "char_end": 339305, "token_start": 4, "token_end": 5, "note": null}, {"text": "IFN - gamma activated sequence", "type": "ENTITY", "char_start": 339313, "char_end": 339343, "token_start": 8, "token_end": 12, "note": null}, {"text": "GAS", "type": "ENTITY", "char_start": 339346, "char_end": 339349, "token_start": 14, "token_end": 14, "note": null}, {"text": "Sp1 element", "type": "ENTITY", "char_start": 339382, "char_end": 339393, "token_start": 21, "token_end": 22, "note": null}]}
+{"sentence_id": 2055, "sentence_text": "In the monocytic cell line THP - 1 cell , the combination of IFN - gamma and all - trans - retinoic acid ( a known differentiation agent ) enhances the ACAT - 1 P1 promoter but not the P7 promoter .", "sentence_char_start_global": 339396, "sentence_char_end_global": 339594, "entities": [{"text": "IFN - gamma", "type": "ENTITY", "char_start": 61, "char_end": 72, "token_start": 13, "token_end": 15}, {"text": "ACAT - 1 P1 promoter", "type": "ENTITY", "char_start": 152, "char_end": 172, "token_start": 31, "token_end": 35}, {"text": "P7 promoter", "type": "ENTITY", "char_start": 185, "char_end": 196, "token_start": 39, "token_end": 40}], "entities_global": [{"text": "IFN - gamma", "type": "ENTITY", "char_start": 339457, "char_end": 339468, "token_start": 13, "token_end": 15, "note": null}, {"text": "ACAT - 1 P1 promoter", "type": "ENTITY", "char_start": 339548, "char_end": 339568, "token_start": 31, "token_end": 35, "note": null}, {"text": "P7 promoter", "type": "ENTITY", "char_start": 339581, "char_end": 339592, "token_start": 39, "token_end": 40, "note": null}]}
+{"sentence_id": 2056, "sentence_text": "Additional experiments showed that all - trans - retinoic acid causes large induction of the transcription factor STAT1 , while IFN - gamma causes activation of STAT1 such that it binds to the GAS / Sp1 site in the ACAT - 1 P1 promoter .", "sentence_char_start_global": 339595, "sentence_char_end_global": 339832, "entities": [{"text": "transcription factor STAT1", "type": "ENTITY", "char_start": 93, "char_end": 119, "token_start": 15, "token_end": 17}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 128, "char_end": 139, "token_start": 20, "token_end": 22}, {"text": "STAT1", "type": "ENTITY", "char_start": 161, "char_end": 166, "token_start": 26, "token_end": 26}, {"text": "GAS / Sp1 site", "type": "ENTITY", "char_start": 193, "char_end": 207, "token_start": 33, "token_end": 36}, {"text": "ACAT - 1 P1 promoter", "type": "ENTITY", "char_start": 215, "char_end": 235, "token_start": 39, "token_end": 43}], "entities_global": [{"text": "transcription factor STAT1", "type": "ENTITY", "char_start": 339688, "char_end": 339714, "token_start": 15, "token_end": 17, "note": null}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 339723, "char_end": 339734, "token_start": 20, "token_end": 22, "note": null}, {"text": "STAT1", "type": "ENTITY", "char_start": 339756, "char_end": 339761, "token_start": 26, "token_end": 26, "note": null}, {"text": "GAS / Sp1 site", "type": "ENTITY", "char_start": 339788, "char_end": 339802, "token_start": 33, "token_end": 36, "note": null}, {"text": "ACAT - 1 P1 promoter", "type": "ENTITY", "char_start": 339810, "char_end": 339830, "token_start": 39, "token_end": 43, "note": null}]}
+{"sentence_id": 2057, "sentence_text": "Our work provides a molecular mechanism to account for the effect of IFN - gamma in causing transcriptional activation of ACAT - 1 in macrophage - like cells .", "sentence_char_start_global": 339833, "sentence_char_end_global": 339992, "entities": [{"text": "IFN - gamma", "type": "ENTITY", "char_start": 69, "char_end": 80, "token_start": 12, "token_end": 14}, {"text": "ACAT - 1", "type": "ENTITY", "char_start": 122, "char_end": 130, "token_start": 20, "token_end": 22}], "entities_global": [{"text": "IFN - gamma", "type": "ENTITY", "char_start": 339902, "char_end": 339913, "token_start": 12, "token_end": 14, "note": null}, {"text": "ACAT - 1", "type": "ENTITY", "char_start": 339955, "char_end": 339963, "token_start": 20, "token_end": 22, "note": null}]}
+{"sentence_id": 2058, "sentence_text": "Inhaled nitric oxide down - regulates intrapulmonary nitric oxide production in lipopolysaccharide - induced acute lung injury .", "sentence_char_start_global": 339993, "sentence_char_end_global": 340121, "entities": [], "entities_global": []}
+{"sentence_id": 2059, "sentence_text": "OBJECTIVE : To examine whether inhaled nitric oxide ( NO ) affected the intrapulmonary production of NO , reactive oxygen species , and nuclear factor - kappaB in a lipopolysaccharide ( LPS ) - induced model of acute lung injury .", "sentence_char_start_global": 340122, "sentence_char_end_global": 340352, "entities": [{"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 136, "char_end": 159, "token_start": 23, "token_end": 26}], "entities_global": [{"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 340258, "char_end": 340281, "token_start": 23, "token_end": 26, "note": null}]}
+{"sentence_id": 2060, "sentence_text": "DESIGN : Prospective , randomized , laboratory study .", "sentence_char_start_global": 340353, "sentence_char_end_global": 340407, "entities": [], "entities_global": []}
+{"sentence_id": 2061, "sentence_text": "SETTING : Experimental laboratory at a biomedical institute .", "sentence_char_start_global": 340408, "sentence_char_end_global": 340469, "entities": [], "entities_global": []}
+{"sentence_id": 2062, "sentence_text": "SUBJECTS : Twenty male rabbits weighing 2 . 5 - 3 . 5 kg .", "sentence_char_start_global": 340470, "sentence_char_end_global": 340528, "entities": [], "entities_global": []}
+{"sentence_id": 2063, "sentence_text": "INTERVENTIONS : Saline or LPS ( 5 mg / kg of body weight ) was administered intravenously with or without NO inhalation ( 10 ppm ) in each group of five rabbits .", "sentence_char_start_global": 340529, "sentence_char_end_global": 340691, "entities": [], "entities_global": []}
+{"sentence_id": 2064, "sentence_text": "MEASUREMENTS AND MAIN RESULTS : LPS increased the lung leak index , the neutrophils and NO levels in bronchoalveolar lavage fluid , and NO levels produced by resting and stimulated alveolar macrophages .", "sentence_char_start_global": 340692, "sentence_char_end_global": 340895, "entities": [], "entities_global": []}
+{"sentence_id": 2065, "sentence_text": "Inhaled NO decreased the lung leak index , the neutrophils and NO levels as measured by nitrite levels in the lavage fluid , and NO produced by the resting and stimulated alveolar macrophages .", "sentence_char_start_global": 340896, "sentence_char_end_global": 341089, "entities": [], "entities_global": []}
+{"sentence_id": 2066, "sentence_text": "Inhaled NO also blocked the activities of reactive oxygen species and nuclear factor - kappaB binding to DNA in lavage cells and in alveolar macrophages .", "sentence_char_start_global": 341090, "sentence_char_end_global": 341244, "entities": [{"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 70, "char_end": 93, "token_start": 11, "token_end": 14}], "entities_global": [{"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 341160, "char_end": 341183, "token_start": 11, "token_end": 14, "note": null}]}
+{"sentence_id": 2067, "sentence_text": "CONCLUSION : Inhaled NO attenuates LPS - induced acute lung injury , possibly by decreasing NO production in the lungs .", "sentence_char_start_global": 341245, "sentence_char_end_global": 341365, "entities": [], "entities_global": []}
+{"sentence_id": 2068, "sentence_text": "The mechanism of reducing NO production resulting from inhaled NO may involve , in part , the activities of reactive oxygen species and / or nuclear factor - kappaB .", "sentence_char_start_global": 341366, "sentence_char_end_global": 341532, "entities": [{"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 141, "char_end": 164, "token_start": 25, "token_end": 28}], "entities_global": [{"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 341507, "char_end": 341530, "token_start": 25, "token_end": 28, "note": null}]}
+{"sentence_id": 2069, "sentence_text": "Treatment of allergic airway inflammation and hyperresponsiveness by antisense - induced local blockade of GATA - 3 expression .", "sentence_char_start_global": 341533, "sentence_char_end_global": 341661, "entities": [{"text": "GATA - 3", "type": "ENTITY", "char_start": 107, "char_end": 115, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "GATA - 3", "type": "ENTITY", "char_start": 341640, "char_end": 341648, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 2070, "sentence_text": "Recent studies in transgenic mice have revealed that expression of a dominant negative form of the transcription factor GATA - 3 in T cells can prevent T helper cell type 2 ( Th2 ) - mediated allergic airway inflammation in mice .", "sentence_char_start_global": 341662, "sentence_char_end_global": 341892, "entities": [{"text": "transcription factor GATA - 3", "type": "ENTITY", "char_start": 99, "char_end": 128, "token_start": 16, "token_end": 20}], "entities_global": [{"text": "transcription factor GATA - 3", "type": "ENTITY", "char_start": 341761, "char_end": 341790, "token_start": 16, "token_end": 20, "note": null}]}
+{"sentence_id": 2071, "sentence_text": "However , it remains unclear whether GATA - 3 plays a role in the effector phase of allergic airway inflammation and whether antagonizing the expression and / or function of GATA - 3 can be used for the therapy of allergic airway inflammation and hyperresponsiveness .", "sentence_char_start_global": 341893, "sentence_char_end_global": 342161, "entities": [{"text": "GATA - 3", "type": "ENTITY", "char_start": 37, "char_end": 45, "token_start": 6, "token_end": 8}, {"text": "GATA - 3", "type": "ENTITY", "char_start": 174, "char_end": 182, "token_start": 30, "token_end": 32}], "entities_global": [{"text": "GATA - 3", "type": "ENTITY", "char_start": 341930, "char_end": 341938, "token_start": 6, "token_end": 8, "note": null}, {"text": "GATA - 3", "type": "ENTITY", "char_start": 342067, "char_end": 342075, "token_start": 30, "token_end": 32, "note": null}]}
+{"sentence_id": 2072, "sentence_text": "Here , we analyzed the effects of locally antagonizing GATA - 3 function in a murine model of asthma .", "sentence_char_start_global": 342162, "sentence_char_end_global": 342264, "entities": [{"text": "GATA - 3", "type": "ENTITY", "char_start": 55, "char_end": 63, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "GATA - 3", "type": "ENTITY", "char_start": 342217, "char_end": 342225, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 2073, "sentence_text": "We could suppress GATA - 3 expression in interleukin ( IL ) - 4 - producing T cells in vitro and in vivo by an antisense phosphorothioate oligonucleotide overlapping the translation start site of GATA - 3 , whereas nonsense control oligonucleotides were virtually inactive .", "sentence_char_start_global": 342265, "sentence_char_end_global": 342539, "entities": [{"text": "interleukin ( IL ) - 4", "type": "ENTITY", "char_start": 41, "char_end": 63, "token_start": 8, "token_end": 13}, {"text": "translation start site", "type": "ENTITY", "char_start": 170, "char_end": 192, "token_start": 30, "token_end": 32}, {"text": "GATA - 3", "type": "ENTITY", "char_start": 196, "char_end": 204, "token_start": 34, "token_end": 36}], "entities_global": [{"text": "interleukin ( IL ) - 4", "type": "ENTITY", "char_start": 342306, "char_end": 342328, "token_start": 8, "token_end": 13, "note": null}, {"text": "translation start site", "type": "ENTITY", "char_start": 342435, "char_end": 342457, "token_start": 30, "token_end": 32, "note": null}, {"text": "GATA - 3", "type": "ENTITY", "char_start": 342461, "char_end": 342469, "token_start": 34, "token_end": 36, "note": null}]}
+{"sentence_id": 2074, "sentence_text": "In a murine model of asthma associated with allergic pulmonary inflammation and hyperresponsiveness in ovalbumin ( OVA ) - sensitized mice , local intranasal administration of fluorescein isothiocyanate - labeled GATA - 3 antisense oligonucleotides led to DNA uptake in lung cells associated with a reduction of intracellular GATA - 3 expression .", "sentence_char_start_global": 342540, "sentence_char_end_global": 342887, "entities": [], "entities_global": []}
+{"sentence_id": 2075, "sentence_text": "Such intrapulmonary blockade of GATA - 3 expression caused an abrogation of signs of lung inflammation including infiltration of eosinophils and Th2 cytokine production .", "sentence_char_start_global": 342888, "sentence_char_end_global": 343058, "entities": [], "entities_global": []}
+{"sentence_id": 2076, "sentence_text": "Furthermore , treatment with antisense but not nonsense oligonucleotides induced a significant reduction of airway hyperresponsiveness in OVA - sensitized mice to levels comparable to saline - treated control mice , as assessed by both enhanced pause ( PenH ) responses and pulmonary resistance determined by body plethysmography .", "sentence_char_start_global": 343059, "sentence_char_end_global": 343390, "entities": [], "entities_global": []}
+{"sentence_id": 2077, "sentence_text": "These data indicate a critical role for GATA - 3 in the effector phase of a murine asthma model and suggest that local delivery of GATA - 3 antisense oligonucleotides may be a novel approach for the treatment of airway hyperresponsiveness such as in asthma .", "sentence_char_start_global": 343391, "sentence_char_end_global": 343649, "entities": [{"text": "GATA - 3", "type": "ENTITY", "char_start": 40, "char_end": 48, "token_start": 7, "token_end": 9}], "entities_global": [{"text": "GATA - 3", "type": "ENTITY", "char_start": 343431, "char_end": 343439, "token_start": 7, "token_end": 9, "note": null}]}
+{"sentence_id": 2078, "sentence_text": "This approach has the potential advantage of suppressing the expression of various proinflammatory Th2 cytokines simultaneously rather than suppressing the activity of a single cytokine .", "sentence_char_start_global": 343650, "sentence_char_end_global": 343837, "entities": [{"text": "proinflammatory Th2 cytokines", "type": "ENTITY", "char_start": 83, "char_end": 112, "token_start": 12, "token_end": 14}, {"text": "cytokine", "type": "ENTITY", "char_start": 177, "char_end": 185, "token_start": 24, "token_end": 24}], "entities_global": [{"text": "proinflammatory Th2 cytokines", "type": "ENTITY", "char_start": 343733, "char_end": 343762, "token_start": 12, "token_end": 14, "note": null}, {"text": "cytokine", "type": "ENTITY", "char_start": 343827, "char_end": 343835, "token_start": 24, "token_end": 24, "note": null}]}
+{"sentence_id": 2079, "sentence_text": "T helper - cell phenotype regulates atherosclerosis in mice under conditions of mild hypercholesterolemia .", "sentence_char_start_global": 343838, "sentence_char_end_global": 343945, "entities": [], "entities_global": []}
+{"sentence_id": 2080, "sentence_text": "BACKGROUND : T cells are implicated in atherosclerosis , but little is known about the genetic control or molecular pathways , especially under conditions of mild hypercholesterolemia .", "sentence_char_start_global": 343946, "sentence_char_end_global": 344131, "entities": [], "entities_global": []}
+{"sentence_id": 2081, "sentence_text": "METHODS AND RESULTS : BALB / c mice , making a CD4 + Th2 ( IL - 4 + ) cell response , express both MHC class II antigens ( IA ( d ) , IE ( d ) ) and are atherosclerosis - resistant .", "sentence_char_start_global": 344132, "sentence_char_end_global": 344314, "entities": [{"text": "MHC class II antigens", "type": "ENTITY", "char_start": 99, "char_end": 120, "token_start": 25, "token_end": 28}, {"text": "IA ( d )", "type": "ENTITY", "char_start": 123, "char_end": 131, "token_start": 30, "token_end": 33}, {"text": "IE ( d )", "type": "ENTITY", "char_start": 134, "char_end": 142, "token_start": 35, "token_end": 38}], "entities_global": [{"text": "MHC class II antigens", "type": "ENTITY", "char_start": 344231, "char_end": 344252, "token_start": 25, "token_end": 28, "note": null}, {"text": "IA ( d )", "type": "ENTITY", "char_start": 344255, "char_end": 344263, "token_start": 30, "token_end": 33, "note": null}, {"text": "IE ( d )", "type": "ENTITY", "char_start": 344266, "char_end": 344274, "token_start": 35, "token_end": 38, "note": null}]}
+{"sentence_id": 2082, "sentence_text": "C57Bl / 6 mice produce a CD4 + Th1 ( interferon [ IFN ] gamma + ) response , express IA ( b ) but no IE , and are atherosclerosis - prone .", "sentence_char_start_global": 344315, "sentence_char_end_global": 344454, "entities": [{"text": "IA ( b )", "type": "ENTITY", "char_start": 85, "char_end": 93, "token_start": 20, "token_end": 23}, {"text": "IE", "type": "ENTITY", "char_start": 101, "char_end": 103, "token_start": 26, "token_end": 26}], "entities_global": [{"text": "IA ( b )", "type": "ENTITY", "char_start": 344400, "char_end": 344408, "token_start": 20, "token_end": 23, "note": null}, {"text": "IE", "type": "ENTITY", "char_start": 344416, "char_end": 344418, "token_start": 26, "token_end": 26, "note": null}]}
+{"sentence_id": 2083, "sentence_text": "To evaluate T helper - cell phenotype in fatty streak formation , wild - type C57Bl / 6 mice ( IA ( b ) + IE - ) and transgenic mice , either AB ( o ) , IA ( b ) - IE - ; ABEalpha , IA - IE ( k ) + ; or BL : TG : Ealpha , IA ( b ) + IE ( k ) + , were fed a high - cholesterol diet for 16 weeks and evaluated histomorphometricall for aortic lesions .", "sentence_char_start_global": 344455, "sentence_char_end_global": 344804, "entities": [], "entities_global": []}
+{"sentence_id": 2084, "sentence_text": "Lesion size in AB ( o ) , ABEalpha , and BL : TG : Ealpha strains was decreased by 54 % , 79 % , and 82 % , respectively , compared with wild - type , correlating with decreased Th1 and increased Th2 expression and suggesting that T helper - cell phenotype is important in fatty lesion development .", "sentence_char_start_global": 344805, "sentence_char_end_global": 345104, "entities": [], "entities_global": []}
+{"sentence_id": 2085, "sentence_text": "Decreasing Th1 cells by antibodies ( alpha - CD4 ) or cytokines ( IL - 4 ) also caused > / = 80 % reductions in lesion size .", "sentence_char_start_global": 345105, "sentence_char_end_global": 345230, "entities": [{"text": "antibodies", "type": "ENTITY", "char_start": 24, "char_end": 34, "token_start": 4, "token_end": 4}, {"text": "alpha - CD4", "type": "ENTITY", "char_start": 37, "char_end": 48, "token_start": 6, "token_end": 8}, {"text": "cytokines", "type": "ENTITY", "char_start": 54, "char_end": 63, "token_start": 11, "token_end": 11}, {"text": "IL - 4", "type": "ENTITY", "char_start": 66, "char_end": 72, "token_start": 13, "token_end": 15}], "entities_global": [{"text": "antibodies", "type": "ENTITY", "char_start": 345129, "char_end": 345139, "token_start": 4, "token_end": 4, "note": null}, {"text": "alpha - CD4", "type": "ENTITY", "char_start": 345142, "char_end": 345153, "token_start": 6, "token_end": 8, "note": null}, {"text": "cytokines", "type": "ENTITY", "char_start": 345159, "char_end": 345168, "token_start": 11, "token_end": 11, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 345171, "char_end": 345177, "token_start": 13, "token_end": 15, "note": null}]}
+{"sentence_id": 2086, "sentence_text": "Immunohistology revealed IFN - gamma , but not IL - 4 , colocalized with activated macrophages .", "sentence_char_start_global": 345231, "sentence_char_end_global": 345327, "entities": [{"text": "IFN - gamma", "type": "ENTITY", "char_start": 25, "char_end": 36, "token_start": 2, "token_end": 4}, {"text": "IL - 4", "type": "ENTITY", "char_start": 47, "char_end": 53, "token_start": 8, "token_end": 10}], "entities_global": [{"text": "IFN - gamma", "type": "ENTITY", "char_start": 345256, "char_end": 345267, "token_start": 2, "token_end": 4, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 345278, "char_end": 345284, "token_start": 8, "token_end": 10, "note": null}]}
+{"sentence_id": 2087, "sentence_text": "Confirming these findings in a different mouse strain , BALB / c Stat 6 knockout mice ( Th2 cell - deficient ) developed aortic lesions comparable to C57Bl / 6 mice on the same diet .", "sentence_char_start_global": 345328, "sentence_char_end_global": 345511, "entities": [], "entities_global": []}
+{"sentence_id": 2088, "sentence_text": "CONCLUSIONS : In mildly hypercholesterolemic C57Bl / 6 mice , presence of IA ( b ) and absence of IE regulated CD4 + T helper - cell phenotype ; fatty lesions were proportional to IFNgamma + Th1 cells in both C57Bl / 6 and BALB / c strains .", "sentence_char_start_global": 345512, "sentence_char_end_global": 345753, "entities": [{"text": "IA ( b )", "type": "ENTITY", "char_start": 74, "char_end": 82, "token_start": 12, "token_end": 15}, {"text": "IE", "type": "ENTITY", "char_start": 98, "char_end": 100, "token_start": 19, "token_end": 19}], "entities_global": [{"text": "IA ( b )", "type": "ENTITY", "char_start": 345586, "char_end": 345594, "token_start": 12, "token_end": 15, "note": null}, {"text": "IE", "type": "ENTITY", "char_start": 345610, "char_end": 345612, "token_start": 19, "token_end": 19, "note": null}]}
+{"sentence_id": 2089, "sentence_text": "IFN - gamma may participate through macrophage activation , whereas IL - 4 may act to limit Th1 - cell response .", "sentence_char_start_global": 345754, "sentence_char_end_global": 345867, "entities": [{"text": "IFN - gamma", "type": "ENTITY", "char_start": 0, "char_end": 11, "token_start": 0, "token_end": 2}, {"text": "IL - 4", "type": "ENTITY", "char_start": 68, "char_end": 74, "token_start": 10, "token_end": 12}], "entities_global": [{"text": "IFN - gamma", "type": "ENTITY", "char_start": 345754, "char_end": 345765, "token_start": 0, "token_end": 2, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 345822, "char_end": 345828, "token_start": 10, "token_end": 12, "note": null}]}
+{"sentence_id": 2090, "sentence_text": "Requirement for p38 and p44 / p42 mitogen - activated protein kinases in RAGE - mediated nuclear factor - kappaB transcriptional activation and cytokine secretion .", "sentence_char_start_global": 345868, "sentence_char_end_global": 346032, "entities": [{"text": "p38", "type": "ENTITY", "char_start": 16, "char_end": 19, "token_start": 2, "token_end": 2}, {"text": "p44 / p42", "type": "ENTITY", "char_start": 24, "char_end": 33, "token_start": 4, "token_end": 6}, {"text": "mitogen - activated protein kinases", "type": "ENTITY", "char_start": 34, "char_end": 69, "token_start": 7, "token_end": 11}, {"text": "RAGE", "type": "ENTITY", "char_start": 73, "char_end": 77, "token_start": 13, "token_end": 13}, {"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 89, "char_end": 112, "token_start": 16, "token_end": 19}], "entities_global": [{"text": "p38", "type": "ENTITY", "char_start": 345884, "char_end": 345887, "token_start": 2, "token_end": 2, "note": null}, {"text": "p44 / p42", "type": "ENTITY", "char_start": 345892, "char_end": 345901, "token_start": 4, "token_end": 6, "note": null}, {"text": "mitogen - activated protein kinases", "type": "ENTITY", "char_start": 345902, "char_end": 345937, "token_start": 7, "token_end": 11, "note": null}, {"text": "RAGE", "type": "ENTITY", "char_start": 345941, "char_end": 345945, "token_start": 13, "token_end": 13, "note": null}, {"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 345957, "char_end": 345980, "token_start": 16, "token_end": 19, "note": null}]}
+{"sentence_id": 2091, "sentence_text": "Advanced glycation end product ( AGE ) activation of the signal - transducing receptor for AGE ( RAGE ) has been linked to a proinflammatory phenotypic change within cells .", "sentence_char_start_global": 346033, "sentence_char_end_global": 346206, "entities": [{"text": "signal - transducing receptor for AGE", "type": "ENTITY", "char_start": 57, "char_end": 94, "token_start": 10, "token_end": 15}, {"text": "RAGE", "type": "ENTITY", "char_start": 97, "char_end": 101, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "signal - transducing receptor for AGE", "type": "ENTITY", "char_start": 346090, "char_end": 346127, "token_start": 10, "token_end": 15, "note": null}, {"text": "RAGE", "type": "ENTITY", "char_start": 346130, "char_end": 346134, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 2092, "sentence_text": "However , the precise intracellular signaling pathways involved have not been elucidated .", "sentence_char_start_global": 346207, "sentence_char_end_global": 346297, "entities": [], "entities_global": []}
+{"sentence_id": 2093, "sentence_text": "We demonstrate here that human serum albumin modified with N ( varepsilon ) - ( carboxymethyl ) lysine ( CML ) , a major AGE adduct that progressively accumulates with aging , diabetes , and renal failure , induced nuclear factor ( NF ) - kappaB - driven reporter gene expression in human monocytic THP - 1 cells .", "sentence_char_start_global": 346298, "sentence_char_end_global": 346612, "entities": [{"text": "nuclear factor ( NF ) - kappaB", "type": "ENTITY", "char_start": 215, "char_end": 245, "token_start": 39, "token_end": 45}], "entities_global": [{"text": "nuclear factor ( NF ) - kappaB", "type": "ENTITY", "char_start": 346513, "char_end": 346543, "token_start": 39, "token_end": 45, "note": null}]}
+{"sentence_id": 2094, "sentence_text": "The NF - kappaB response was blocked with a synthetic peptide corresponding to the putative ligand - binding domain of RAGE , with anti - RAGE antiserum , and by coexpression of truncated receptors lacking the intracellular domain .", "sentence_char_start_global": 346613, "sentence_char_end_global": 346845, "entities": [{"text": "putative ligand - binding domain", "type": "ENTITY", "char_start": 83, "char_end": 115, "token_start": 14, "token_end": 18}, {"text": "RAGE", "type": "ENTITY", "char_start": 119, "char_end": 123, "token_start": 20, "token_end": 20}, {"text": "RAGE", "type": "ENTITY", "char_start": 138, "char_end": 142, "token_start": 25, "token_end": 25}, {"text": "truncated receptors", "type": "ENTITY", "char_start": 178, "char_end": 197, "token_start": 32, "token_end": 33}, {"text": "intracellular domain", "type": "ENTITY", "char_start": 210, "char_end": 230, "token_start": 36, "token_end": 37}], "entities_global": [{"text": "putative ligand - binding domain", "type": "ENTITY", "char_start": 346696, "char_end": 346728, "token_start": 14, "token_end": 18, "note": null}, {"text": "RAGE", "type": "ENTITY", "char_start": 346732, "char_end": 346736, "token_start": 20, "token_end": 20, "note": null}, {"text": "RAGE", "type": "ENTITY", "char_start": 346751, "char_end": 346755, "token_start": 25, "token_end": 25, "note": null}, {"text": "truncated receptors", "type": "ENTITY", "char_start": 346791, "char_end": 346810, "token_start": 32, "token_end": 33, "note": null}, {"text": "intracellular domain", "type": "ENTITY", "char_start": 346823, "char_end": 346843, "token_start": 36, "token_end": 37, "note": null}]}
+{"sentence_id": 2095, "sentence_text": "Signal transduction from RAGE to NF - kappaB involved the generation of reactive oxygen species , since reporter gene expression was blocked with the antioxidant N - acetyl - L - cysteine .", "sentence_char_start_global": 346846, "sentence_char_end_global": 347035, "entities": [{"text": "RAGE", "type": "ENTITY", "char_start": 25, "char_end": 29, "token_start": 3, "token_end": 3}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 33, "char_end": 44, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "RAGE", "type": "ENTITY", "char_start": 346871, "char_end": 346875, "token_start": 3, "token_end": 3, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 346879, "char_end": 346890, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 2096, "sentence_text": "CML - modified albumin produced rapid transient activation of tyrosine phosphorylation , extracellular signal - regulated kinase 1 and 2 , and p38 mitogen - activated protein kinase ( MAPK ) , but not c - Jun NH ( 2 ) - terminal kinase .", "sentence_char_start_global": 347036, "sentence_char_end_global": 347273, "entities": [{"text": "CML - modified albumin", "type": "ENTITY", "char_start": 0, "char_end": 22, "token_start": 0, "token_end": 3}, {"text": "extracellular signal - regulated kinase 1 and 2", "type": "ENTITY", "char_start": 89, "char_end": 136, "token_start": 12, "token_end": 19}, {"text": "p38 mitogen - activated protein kinase", "type": "ENTITY", "char_start": 143, "char_end": 181, "token_start": 22, "token_end": 27}, {"text": "MAPK", "type": "ENTITY", "char_start": 184, "char_end": 188, "token_start": 29, "token_end": 29}, {"text": "c - Jun NH ( 2 ) - terminal kinase", "type": "ENTITY", "char_start": 201, "char_end": 235, "token_start": 34, "token_end": 43}], "entities_global": [{"text": "CML - modified albumin", "type": "ENTITY", "char_start": 347036, "char_end": 347058, "token_start": 0, "token_end": 3, "note": null}, {"text": "extracellular signal - regulated kinase 1 and 2", "type": "ENTITY", "char_start": 347125, "char_end": 347172, "token_start": 12, "token_end": 19, "note": null}, {"text": "p38 mitogen - activated protein kinase", "type": "ENTITY", "char_start": 347179, "char_end": 347217, "token_start": 22, "token_end": 27, "note": null}, {"text": "MAPK", "type": "ENTITY", "char_start": 347220, "char_end": 347224, "token_start": 29, "token_end": 29, "note": null}, {"text": "c - Jun NH ( 2 ) - terminal kinase", "type": "ENTITY", "char_start": 347237, "char_end": 347271, "token_start": 34, "token_end": 43, "note": null}]}
+{"sentence_id": 2097, "sentence_text": "RAGE - mediated NF - kappaB activation was suppressed by the selective p38 MAPK inhibitor SB203580 and by coexpression of a kinase - dead p38 dominant - negative mutant .", "sentence_char_start_global": 347274, "sentence_char_end_global": 347444, "entities": [{"text": "RAGE", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}, {"text": "p38 MAPK", "type": "ENTITY", "char_start": 71, "char_end": 79, "token_start": 12, "token_end": 13}], "entities_global": [{"text": "RAGE", "type": "ENTITY", "char_start": 347274, "char_end": 347278, "token_start": 0, "token_end": 0, "note": null}, {"text": "p38 MAPK", "type": "ENTITY", "char_start": 347345, "char_end": 347353, "token_start": 12, "token_end": 13, "note": null}]}
+{"sentence_id": 2098, "sentence_text": "Activation of NF - kappaB by CML - modified albumin increased secretion of proinflammatory cytokines ( tumor necrosis factor - alpha , interleukin - 1beta , and monocyte chemoattractant protein - 1 ) severalfold , and inhibition of p38 MAPK blocked these increases .", "sentence_char_start_global": 347445, "sentence_char_end_global": 347711, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 14, "char_end": 25, "token_start": 2, "token_end": 4}, {"text": "CML - modified albumin", "type": "ENTITY", "char_start": 29, "char_end": 51, "token_start": 6, "token_end": 9}, {"text": "proinflammatory cytokines", "type": "ENTITY", "char_start": 75, "char_end": 100, "token_start": 13, "token_end": 14}, {"text": "tumor necrosis factor - alpha", "type": "ENTITY", "char_start": 103, "char_end": 132, "token_start": 16, "token_end": 20}, {"text": "interleukin - 1beta", "type": "ENTITY", "char_start": 135, "char_end": 154, "token_start": 22, "token_end": 24}, {"text": "monocyte chemoattractant protein - 1", "type": "ENTITY", "char_start": 161, "char_end": 197, "token_start": 27, "token_end": 31}, {"text": "p38 MAPK", "type": "ENTITY", "char_start": 232, "char_end": 240, "token_start": 38, "token_end": 39}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 347459, "char_end": 347470, "token_start": 2, "token_end": 4, "note": null}, {"text": "CML - modified albumin", "type": "ENTITY", "char_start": 347474, "char_end": 347496, "token_start": 6, "token_end": 9, "note": null}, {"text": "proinflammatory cytokines", "type": "ENTITY", "char_start": 347520, "char_end": 347545, "token_start": 13, "token_end": 14, "note": null}, {"text": "tumor necrosis factor - alpha", "type": "ENTITY", "char_start": 347548, "char_end": 347577, "token_start": 16, "token_end": 20, "note": null}, {"text": "interleukin - 1beta", "type": "ENTITY", "char_start": 347580, "char_end": 347599, "token_start": 22, "token_end": 24, "note": null}, {"text": "monocyte chemoattractant protein - 1", "type": "ENTITY", "char_start": 347606, "char_end": 347642, "token_start": 27, "token_end": 31, "note": null}, {"text": "p38 MAPK", "type": "ENTITY", "char_start": 347677, "char_end": 347685, "token_start": 38, "token_end": 39, "note": null}]}
+{"sentence_id": 2099, "sentence_text": "These results indicate that p38 MAPK activation mediates RAGE - induced NF - kappaB - dependent secretion of proinflammatory cytokines and suggest that accelerated inflammation may be a consequence of cellular activation induced by this receptor .", "sentence_char_start_global": 347712, "sentence_char_end_global": 347959, "entities": [{"text": "p38 MAPK", "type": "ENTITY", "char_start": 28, "char_end": 36, "token_start": 4, "token_end": 5}, {"text": "RAGE", "type": "ENTITY", "char_start": 57, "char_end": 61, "token_start": 8, "token_end": 8}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 72, "char_end": 83, "token_start": 11, "token_end": 13}, {"text": "proinflammatory cytokines", "type": "ENTITY", "char_start": 109, "char_end": 134, "token_start": 18, "token_end": 19}], "entities_global": [{"text": "p38 MAPK", "type": "ENTITY", "char_start": 347740, "char_end": 347748, "token_start": 4, "token_end": 5, "note": null}, {"text": "RAGE", "type": "ENTITY", "char_start": 347769, "char_end": 347773, "token_start": 8, "token_end": 8, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 347784, "char_end": 347795, "token_start": 11, "token_end": 13, "note": null}, {"text": "proinflammatory cytokines", "type": "ENTITY", "char_start": 347821, "char_end": 347846, "token_start": 18, "token_end": 19, "note": null}]}
+{"sentence_id": 2100, "sentence_text": "Antigen - receptor cross - linking and lipopolysaccharide trigger distinct phosphoinositide 3 - kinase - dependent pathways to NF - kappa B activation in primary B cells .", "sentence_char_start_global": 347960, "sentence_char_end_global": 348131, "entities": [{"text": "phosphoinositide 3 - kinase", "type": "ENTITY", "char_start": 75, "char_end": 102, "token_start": 10, "token_end": 13}], "entities_global": [{"text": "phosphoinositide 3 - kinase", "type": "ENTITY", "char_start": 348035, "char_end": 348062, "token_start": 10, "token_end": 13, "note": null}]}
+{"sentence_id": 2101, "sentence_text": "The NF - kappaB / Rel transcription factors play an important role in the expression of genes involved in B cell development , differentiation and function .", "sentence_char_start_global": 348132, "sentence_char_end_global": 348289, "entities": [{"text": "NF - kappaB / Rel transcription factors", "type": "ENTITY", "char_start": 4, "char_end": 43, "token_start": 1, "token_end": 7}], "entities_global": [{"text": "NF - kappaB / Rel transcription factors", "type": "ENTITY", "char_start": 348136, "char_end": 348175, "token_start": 1, "token_end": 7, "note": null}]}
+{"sentence_id": 2102, "sentence_text": "Nuclear NF - kappaB is induced in B cells by engagement of either the BCR or CD40 or by stimulation with lipopolysaccharide ( LPS ) .", "sentence_char_start_global": 348290, "sentence_char_end_global": 348423, "entities": [{"text": "Nuclear NF - kappaB", "type": "ENTITY", "char_start": 0, "char_end": 19, "token_start": 0, "token_end": 3}, {"text": "BCR", "type": "ENTITY", "char_start": 70, "char_end": 73, "token_start": 14, "token_end": 14}, {"text": "CD40", "type": "ENTITY", "char_start": 77, "char_end": 81, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "Nuclear NF - kappaB", "type": "ENTITY", "char_start": 348290, "char_end": 348309, "token_start": 0, "token_end": 3, "note": null}, {"text": "BCR", "type": "ENTITY", "char_start": 348360, "char_end": 348363, "token_start": 14, "token_end": 14, "note": null}, {"text": "CD40", "type": "ENTITY", "char_start": 348367, "char_end": 348371, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 2103, "sentence_text": "Despite the importance of NF - kappaB to B cell function , little is known about the signaling pathways leading to NF - kappaB activation .", "sentence_char_start_global": 348424, "sentence_char_end_global": 348563, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 26, "char_end": 37, "token_start": 4, "token_end": 6}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 348450, "char_end": 348461, "token_start": 4, "token_end": 6, "note": null}]}
+{"sentence_id": 2104, "sentence_text": "In this report we address the role of phosphoinositide 3 ' - kinase ( PI 3 - kinase ) in BCR - and LPS - induced NF - kappaB activation using populations of primary murine resting B cells .", "sentence_char_start_global": 348564, "sentence_char_end_global": 348753, "entities": [{"text": "phosphoinositide 3 ' - kinase", "type": "ENTITY", "char_start": 38, "char_end": 67, "token_start": 8, "token_end": 12}, {"text": "PI 3 - kinase", "type": "ENTITY", "char_start": 70, "char_end": 83, "token_start": 14, "token_end": 17}, {"text": "BCR", "type": "ENTITY", "char_start": 89, "char_end": 92, "token_start": 20, "token_end": 20}], "entities_global": [{"text": "phosphoinositide 3 ' - kinase", "type": "ENTITY", "char_start": 348602, "char_end": 348631, "token_start": 8, "token_end": 12, "note": null}, {"text": "PI 3 - kinase", "type": "ENTITY", "char_start": 348634, "char_end": 348647, "token_start": 14, "token_end": 17, "note": null}, {"text": "BCR", "type": "ENTITY", "char_start": 348653, "char_end": 348656, "token_start": 20, "token_end": 20, "note": null}]}
+{"sentence_id": 2105, "sentence_text": "Using the specific pharmacological inhibitors of PI 3 - kinase , Wortmannin and LY294002 , we demonstrate that PI 3 - kinase activity is vital for BCR - induced NF - kappaB DNA - binding activity .", "sentence_char_start_global": 348754, "sentence_char_end_global": 348951, "entities": [{"text": "PI 3 - kinase", "type": "ENTITY", "char_start": 49, "char_end": 62, "token_start": 6, "token_end": 9}, {"text": "PI 3 - kinase", "type": "ENTITY", "char_start": 111, "char_end": 124, "token_start": 18, "token_end": 21}, {"text": "BCR", "type": "ENTITY", "char_start": 147, "char_end": 150, "token_start": 26, "token_end": 26}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 161, "char_end": 172, "token_start": 29, "token_end": 31}], "entities_global": [{"text": "PI 3 - kinase", "type": "ENTITY", "char_start": 348803, "char_end": 348816, "token_start": 6, "token_end": 9, "note": null}, {"text": "PI 3 - kinase", "type": "ENTITY", "char_start": 348865, "char_end": 348878, "token_start": 18, "token_end": 21, "note": null}, {"text": "BCR", "type": "ENTITY", "char_start": 348901, "char_end": 348904, "token_start": 26, "token_end": 26, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 348915, "char_end": 348926, "token_start": 29, "token_end": 31, "note": null}]}
+{"sentence_id": 2106, "sentence_text": "Furthermore , we show that this is achieved via protein kinase C - dependent degradation of IkappaBalpha .", "sentence_char_start_global": 348952, "sentence_char_end_global": 349058, "entities": [{"text": "protein kinase C", "type": "ENTITY", "char_start": 48, "char_end": 64, "token_start": 9, "token_end": 11}, {"text": "IkappaBalpha", "type": "ENTITY", "char_start": 92, "char_end": 104, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "protein kinase C", "type": "ENTITY", "char_start": 349000, "char_end": 349016, "token_start": 9, "token_end": 11, "note": null}, {"text": "IkappaBalpha", "type": "ENTITY", "char_start": 349044, "char_end": 349056, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 2107, "sentence_text": "Similar analyses reveal that PI 3 - kinase is also critical in triggering NF - kappaB DNA - binding activity and IkappaBalpha degradation following LPS stimulation .", "sentence_char_start_global": 349059, "sentence_char_end_global": 349224, "entities": [{"text": "PI 3 - kinase", "type": "ENTITY", "char_start": 29, "char_end": 42, "token_start": 4, "token_end": 7}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 74, "char_end": 85, "token_start": 13, "token_end": 15}, {"text": "IkappaBalpha", "type": "ENTITY", "char_start": 113, "char_end": 125, "token_start": 21, "token_end": 21}], "entities_global": [{"text": "PI 3 - kinase", "type": "ENTITY", "char_start": 349088, "char_end": 349101, "token_start": 4, "token_end": 7, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 349133, "char_end": 349144, "token_start": 13, "token_end": 15, "note": null}, {"text": "IkappaBalpha", "type": "ENTITY", "char_start": 349172, "char_end": 349184, "token_start": 21, "token_end": 21, "note": null}]}
+{"sentence_id": 2108, "sentence_text": "Interestingly , a PKC inhibitor which blocked the BCR - induced IkappaBalpha degradation had no effect on the degradation of IkappaBalpha after LPS stimulation .", "sentence_char_start_global": 349225, "sentence_char_end_global": 349386, "entities": [{"text": "BCR", "type": "ENTITY", "char_start": 50, "char_end": 53, "token_start": 8, "token_end": 8}, {"text": "IkappaBalpha", "type": "ENTITY", "char_start": 64, "char_end": 76, "token_start": 11, "token_end": 11}, {"text": "IkappaBalpha", "type": "ENTITY", "char_start": 125, "char_end": 137, "token_start": 20, "token_end": 20}], "entities_global": [{"text": "BCR", "type": "ENTITY", "char_start": 349275, "char_end": 349278, "token_start": 8, "token_end": 8, "note": null}, {"text": "IkappaBalpha", "type": "ENTITY", "char_start": 349289, "char_end": 349301, "token_start": 11, "token_end": 11, "note": null}, {"text": "IkappaBalpha", "type": "ENTITY", "char_start": 349350, "char_end": 349362, "token_start": 20, "token_end": 20, "note": null}]}
+{"sentence_id": 2109, "sentence_text": "Taken together , our results indicate the involvement of PI 3 - kinase in at least two distinct signaling pathways leading to activation of NF - kappaB in B cells .", "sentence_char_start_global": 349387, "sentence_char_end_global": 349551, "entities": [{"text": "PI 3 - kinase", "type": "ENTITY", "char_start": 57, "char_end": 70, "token_start": 9, "token_end": 12}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 140, "char_end": 151, "token_start": 24, "token_end": 26}], "entities_global": [{"text": "PI 3 - kinase", "type": "ENTITY", "char_start": 349444, "char_end": 349457, "token_start": 9, "token_end": 12, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 349527, "char_end": 349538, "token_start": 24, "token_end": 26, "note": null}]}
+{"sentence_id": 2110, "sentence_text": "Tetramer - guided epitope mapping : rapid identification and characterization of immunodominant CD4 + T cell epitopes from complex antigens .", "sentence_char_start_global": 349552, "sentence_char_end_global": 349693, "entities": [{"text": "antigens", "type": "ENTITY", "char_start": 131, "char_end": 139, "token_start": 19, "token_end": 19}], "entities_global": [{"text": "antigens", "type": "ENTITY", "char_start": 349683, "char_end": 349691, "token_start": 19, "token_end": 19, "note": null}]}
+{"sentence_id": 2111, "sentence_text": "T cell responses to Ags involve recognition of selected peptide epitopes contained within the antigenic protein .", "sentence_char_start_global": 349694, "sentence_char_end_global": 349807, "entities": [{"text": "Ags", "type": "ENTITY", "char_start": 20, "char_end": 23, "token_start": 4, "token_end": 4}, {"text": "peptide epitopes", "type": "ENTITY", "char_start": 56, "char_end": 72, "token_start": 9, "token_end": 10}, {"text": "antigenic protein", "type": "ENTITY", "char_start": 94, "char_end": 111, "token_start": 14, "token_end": 15}], "entities_global": [{"text": "Ags", "type": "ENTITY", "char_start": 349714, "char_end": 349717, "token_start": 4, "token_end": 4, "note": null}, {"text": "peptide epitopes", "type": "ENTITY", "char_start": 349750, "char_end": 349766, "token_start": 9, "token_end": 10, "note": null}, {"text": "antigenic protein", "type": "ENTITY", "char_start": 349788, "char_end": 349805, "token_start": 14, "token_end": 15, "note": null}]}
+{"sentence_id": 2112, "sentence_text": "In this report , we describe a new approach for direct identification of CD4 + T cell epitopes of complex Ags that uses human class II tetramers to identify reactive cells .", "sentence_char_start_global": 349808, "sentence_char_end_global": 349981, "entities": [{"text": "Ags", "type": "ENTITY", "char_start": 106, "char_end": 109, "token_start": 20, "token_end": 20}, {"text": "human class II tetramers", "type": "ENTITY", "char_start": 120, "char_end": 144, "token_start": 23, "token_end": 26}], "entities_global": [{"text": "Ags", "type": "ENTITY", "char_start": 349914, "char_end": 349917, "token_start": 20, "token_end": 20, "note": null}, {"text": "human class II tetramers", "type": "ENTITY", "char_start": 349928, "char_end": 349952, "token_start": 23, "token_end": 26, "note": null}]}
+{"sentence_id": 2113, "sentence_text": "With a panel of 60 overlapping peptides covering the entire sequence of the VP16 protein , a major Ag for HSV - 2 , we generated a panel of class II MHC tetramers loaded with peptide pools that were used to stain peripheral lymphocytes of an HSV - 2 infected individual .", "sentence_char_start_global": 349982, "sentence_char_end_global": 350253, "entities": [{"text": "VP16 protein", "type": "ENTITY", "char_start": 76, "char_end": 88, "token_start": 13, "token_end": 14}, {"text": "Ag", "type": "ENTITY", "char_start": 99, "char_end": 101, "token_start": 18, "token_end": 18}, {"text": "class II MHC tetramers", "type": "ENTITY", "char_start": 140, "char_end": 162, "token_start": 29, "token_end": 32}], "entities_global": [{"text": "VP16 protein", "type": "ENTITY", "char_start": 350058, "char_end": 350070, "token_start": 13, "token_end": 14, "note": null}, {"text": "Ag", "type": "ENTITY", "char_start": 350081, "char_end": 350083, "token_start": 18, "token_end": 18, "note": null}, {"text": "class II MHC tetramers", "type": "ENTITY", "char_start": 350122, "char_end": 350144, "token_start": 29, "token_end": 32, "note": null}]}
+{"sentence_id": 2114, "sentence_text": "With this approach , we identified four new DRA1 * 0101 / DRB1 * 0401 - and two DRA1 * 0101 / DRB1 * 0404 - restricted , VP16 - specific epitopes .", "sentence_char_start_global": 350254, "sentence_char_end_global": 350401, "entities": [{"text": "VP16 - specific epitopes", "type": "ENTITY", "char_start": 121, "char_end": 145, "token_start": 28, "token_end": 31}], "entities_global": [{"text": "VP16 - specific epitopes", "type": "ENTITY", "char_start": 350375, "char_end": 350399, "token_start": 28, "token_end": 31, "note": null}]}
+{"sentence_id": 2115, "sentence_text": "By using tetramers to sort individual cells , we easily obtained a large number of clones specific to these epitopes .", "sentence_char_start_global": 350402, "sentence_char_end_global": 350520, "entities": [{"text": "tetramers", "type": "ENTITY", "char_start": 9, "char_end": 18, "token_start": 2, "token_end": 2}, {"text": "epitopes", "type": "ENTITY", "char_start": 108, "char_end": 116, "token_start": 19, "token_end": 19}], "entities_global": [{"text": "tetramers", "type": "ENTITY", "char_start": 350411, "char_end": 350420, "token_start": 2, "token_end": 2, "note": null}, {"text": "epitopes", "type": "ENTITY", "char_start": 350510, "char_end": 350518, "token_start": 19, "token_end": 19, "note": null}]}
+{"sentence_id": 2116, "sentence_text": "Although DRA1 * 0101 / DRB1 * 0401 and DRA1 * 0101 / DRB1 * 0404 are structurally very similar , nonoverlapping VP16 epitopes were identified , illustrating high selectivity of individual allele polymorphisms within common MHC variants .", "sentence_char_start_global": 350521, "sentence_char_end_global": 350758, "entities": [{"text": "VP16 epitopes", "type": "ENTITY", "char_start": 112, "char_end": 125, "token_start": 22, "token_end": 23}], "entities_global": [{"text": "VP16 epitopes", "type": "ENTITY", "char_start": 350633, "char_end": 350646, "token_start": 22, "token_end": 23, "note": null}]}
+{"sentence_id": 2117, "sentence_text": "This rapid approach to detecting CD4 + T cell epitopes from complex Ags can be applied to any known Ag that gives a T cell response .", "sentence_char_start_global": 350759, "sentence_char_end_global": 350892, "entities": [{"text": "Ags", "type": "ENTITY", "char_start": 68, "char_end": 71, "token_start": 12, "token_end": 12}, {"text": "Ag", "type": "ENTITY", "char_start": 100, "char_end": 102, "token_start": 19, "token_end": 19}], "entities_global": [{"text": "Ags", "type": "ENTITY", "char_start": 350827, "char_end": 350830, "token_start": 12, "token_end": 12, "note": null}, {"text": "Ag", "type": "ENTITY", "char_start": 350859, "char_end": 350861, "token_start": 19, "token_end": 19, "note": null}]}
+{"sentence_id": 2118, "sentence_text": "Localized pancreatic NF - kappaB activation and inflammatory response in taurocholate - induced pancreatitis .", "sentence_char_start_global": 350893, "sentence_char_end_global": 351003, "entities": [], "entities_global": []}
+{"sentence_id": 2119, "sentence_text": "Transcription factor nuclear factor - kappaB ( NF - kappaB ) is activated in cerulein pancreatitis and mediates cytokine expression .", "sentence_char_start_global": 351004, "sentence_char_end_global": 351137, "entities": [{"text": "Transcription factor nuclear factor - kappaB", "type": "ENTITY", "char_start": 0, "char_end": 44, "token_start": 0, "token_end": 5}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 47, "char_end": 58, "token_start": 7, "token_end": 9}], "entities_global": [{"text": "Transcription factor nuclear factor - kappaB", "type": "ENTITY", "char_start": 351004, "char_end": 351048, "token_start": 0, "token_end": 5, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 351051, "char_end": 351062, "token_start": 7, "token_end": 9, "note": null}]}
+{"sentence_id": 2120, "sentence_text": "The role of transcription factor activation in other models of pancreatitis has not been established .", "sentence_char_start_global": 351138, "sentence_char_end_global": 351240, "entities": [], "entities_global": []}
+{"sentence_id": 2121, "sentence_text": "Here we report upregulation of NF - kappaB and inflammatory molecules , and their correlation with local pancreatic injury , in a model of severe pancreatitis .", "sentence_char_start_global": 351241, "sentence_char_end_global": 351401, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 31, "char_end": 42, "token_start": 5, "token_end": 7}, {"text": "inflammatory molecules", "type": "ENTITY", "char_start": 47, "char_end": 69, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 351272, "char_end": 351283, "token_start": 5, "token_end": 7, "note": null}, {"text": "inflammatory molecules", "type": "ENTITY", "char_start": 351288, "char_end": 351310, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 2122, "sentence_text": "Rats received intraductal infusion of taurocholate or saline , and the pancreatic head and tail were analyzed separately .", "sentence_char_start_global": 351402, "sentence_char_end_global": 351524, "entities": [], "entities_global": []}
+{"sentence_id": 2123, "sentence_text": "NF - kappaB and activator protein - 1 ( AP - 1 ) activation were assessed by gel shift assay , and mRNA expression of interleukin - 6 , tumor necrosis factor - alpha , KC , monocyte chemoattractant protein - 1 , and inducible nitric oxide synthase was assessed by semiquantitative RT - PCR .", "sentence_char_start_global": 351525, "sentence_char_end_global": 351816, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 0, "char_end": 11, "token_start": 0, "token_end": 2}, {"text": "activator protein - 1", "type": "ENTITY", "char_start": 16, "char_end": 37, "token_start": 4, "token_end": 7}, {"text": "AP - 1", "type": "ENTITY", "char_start": 40, "char_end": 46, "token_start": 9, "token_end": 11}, {"text": "interleukin - 6", "type": "ENTITY", "char_start": 118, "char_end": 133, "token_start": 25, "token_end": 27}, {"text": "tumor necrosis factor - alpha", "type": "ENTITY", "char_start": 136, "char_end": 165, "token_start": 29, "token_end": 33}, {"text": "monocyte chemoattractant protein - 1", "type": "ENTITY", "char_start": 173, "char_end": 209, "token_start": 37, "token_end": 41}, {"text": "inducible nitric oxide synthase", "type": "ENTITY", "char_start": 216, "char_end": 247, "token_start": 44, "token_end": 47}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 351525, "char_end": 351536, "token_start": 0, "token_end": 2, "note": null}, {"text": "activator protein - 1", "type": "ENTITY", "char_start": 351541, "char_end": 351562, "token_start": 4, "token_end": 7, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 351565, "char_end": 351571, "token_start": 9, "token_end": 11, "note": null}, {"text": "interleukin - 6", "type": "ENTITY", "char_start": 351643, "char_end": 351658, "token_start": 25, "token_end": 27, "note": null}, {"text": "tumor necrosis factor - alpha", "type": "ENTITY", "char_start": 351661, "char_end": 351690, "token_start": 29, "token_end": 33, "note": null}, {"text": "monocyte chemoattractant protein - 1", "type": "ENTITY", "char_start": 351698, "char_end": 351734, "token_start": 37, "token_end": 41, "note": null}, {"text": "inducible nitric oxide synthase", "type": "ENTITY", "char_start": 351741, "char_end": 351772, "token_start": 44, "token_end": 47, "note": null}]}
+{"sentence_id": 2124, "sentence_text": "Morphological damage and trypsin activation were much greater in the pancreatic head than tail , in parallel with a stronger activation of NF - kappaB and cytokine mRNA .", "sentence_char_start_global": 351817, "sentence_char_end_global": 351987, "entities": [{"text": "NF - kappaB and cytokine mRNA", "type": "ENTITY", "char_start": 139, "char_end": 168, "token_start": 22, "token_end": 27}], "entities_global": [{"text": "NF - kappaB and cytokine mRNA", "type": "ENTITY", "char_start": 351956, "char_end": 351985, "token_start": 22, "token_end": 27, "note": null}]}
+{"sentence_id": 2125, "sentence_text": "Saline infusion mildly affected these parameters .", "sentence_char_start_global": 351988, "sentence_char_end_global": 352038, "entities": [], "entities_global": []}
+{"sentence_id": 2126, "sentence_text": "AP - 1 was strongly activated in both pancreatic segments after either taurocholate or saline infusion .", "sentence_char_start_global": 352039, "sentence_char_end_global": 352143, "entities": [{"text": "AP - 1", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "AP - 1", "type": "ENTITY", "char_start": 352039, "char_end": 352045, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 2127, "sentence_text": "NF - kappaB inhibition with N - acetylcysteine ameliorated the local inflammatory response .", "sentence_char_start_global": 352144, "sentence_char_end_global": 352236, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 0, "char_end": 11, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 352144, "char_end": 352155, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 2128, "sentence_text": "Correlation between localized NF - kappaB activation , cytokine upregulation , and tissue damage suggests a key role for NF - kappaB in the development of the inflammatory response of acute pancreatitis .", "sentence_char_start_global": 352237, "sentence_char_end_global": 352441, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 30, "char_end": 41, "token_start": 3, "token_end": 5}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 121, "char_end": 132, "token_start": 19, "token_end": 21}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 352267, "char_end": 352278, "token_start": 3, "token_end": 5, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 352358, "char_end": 352369, "token_start": 19, "token_end": 21, "note": null}]}
+{"sentence_id": 2129, "sentence_text": "CD45 tyrosine phosphatase controls common gamma - chain cytokine - mediated STAT and extracellular signal - related kinase phosphorylation in activated human lymphoblasts : inhibition of proliferation without induction of apoptosis .", "sentence_char_start_global": 352442, "sentence_char_end_global": 352675, "entities": [{"text": "CD45 tyrosine phosphatase", "type": "ENTITY", "char_start": 0, "char_end": 25, "token_start": 0, "token_end": 2}, {"text": "gamma - chain cytokine", "type": "ENTITY", "char_start": 42, "char_end": 64, "token_start": 5, "token_end": 8}, {"text": "STAT", "type": "ENTITY", "char_start": 76, "char_end": 80, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "CD45 tyrosine phosphatase", "type": "ENTITY", "char_start": 352442, "char_end": 352467, "token_start": 0, "token_end": 2, "note": null}, {"text": "gamma - chain cytokine", "type": "ENTITY", "char_start": 352484, "char_end": 352506, "token_start": 5, "token_end": 8, "note": null}, {"text": "STAT", "type": "ENTITY", "char_start": 352518, "char_end": 352522, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 2130, "sentence_text": "The objective of this study was to test whether CD45 signals can influence signaling processes in activated human lymphoblasts .", "sentence_char_start_global": 352676, "sentence_char_end_global": 352804, "entities": [], "entities_global": []}
+{"sentence_id": 2131, "sentence_text": "To this end , we generated lymphoblasts which proliferate in response to common gamma - chain cytokines , but readily undergo apoptosis after cytokine withdrawal .", "sentence_char_start_global": 352805, "sentence_char_end_global": 352968, "entities": [{"text": "gamma - chain cytokines", "type": "ENTITY", "char_start": 80, "char_end": 103, "token_start": 13, "token_end": 16}], "entities_global": [{"text": "gamma - chain cytokines", "type": "ENTITY", "char_start": 352885, "char_end": 352908, "token_start": 13, "token_end": 16, "note": null}]}
+{"sentence_id": 2132, "sentence_text": "In experiments with the CD45R0 mAb UCHL - 1 , but not control CD45 mAbs , we found significant inhibition of proliferation .", "sentence_char_start_global": 352969, "sentence_char_end_global": 353093, "entities": [{"text": "CD45R0 mAb UCHL - 1", "type": "ENTITY", "char_start": 24, "char_end": 43, "token_start": 4, "token_end": 8}, {"text": "control CD45 mAbs", "type": "ENTITY", "char_start": 54, "char_end": 71, "token_start": 12, "token_end": 14}], "entities_global": [{"text": "CD45R0 mAb UCHL - 1", "type": "ENTITY", "char_start": 352993, "char_end": 353012, "token_start": 4, "token_end": 8, "note": null}, {"text": "control CD45 mAbs", "type": "ENTITY", "char_start": 353023, "char_end": 353040, "token_start": 12, "token_end": 14, "note": null}]}
+{"sentence_id": 2133, "sentence_text": "Interestingly , the pan - CD45 mAb GAP8 . 3 , which is most effective in inhibition of OKT - 3 - mediated proliferation in quiescent lymphocytes , was ineffective in lymphoblasts .", "sentence_char_start_global": 353094, "sentence_char_end_global": 353274, "entities": [{"text": "pan - CD45 mAb GAP8 . 3", "type": "ENTITY", "char_start": 20, "char_end": 43, "token_start": 3, "token_end": 9}], "entities_global": [{"text": "pan - CD45 mAb GAP8 . 3", "type": "ENTITY", "char_start": 353114, "char_end": 353137, "token_start": 3, "token_end": 9, "note": null}]}
+{"sentence_id": 2134, "sentence_text": "Addition of CD3 mAb OKT - 3 had no influence on IL - 2 - mediated proliferation ( with or without UCHL - 1 ) .", "sentence_char_start_global": 353275, "sentence_char_end_global": 353385, "entities": [{"text": "CD3 mAb OKT - 3", "type": "ENTITY", "char_start": 12, "char_end": 27, "token_start": 2, "token_end": 6}, {"text": "UCHL - 1", "type": "ENTITY", "char_start": 98, "char_end": 106, "token_start": 21, "token_end": 23}], "entities_global": [{"text": "CD3 mAb OKT - 3", "type": "ENTITY", "char_start": 353287, "char_end": 353302, "token_start": 2, "token_end": 6, "note": null}, {"text": "UCHL - 1", "type": "ENTITY", "char_start": 353373, "char_end": 353381, "token_start": 21, "token_end": 23, "note": null}]}
+{"sentence_id": 2135, "sentence_text": "In contrast , after addition of OKT - 3 to IL - 4 - and IL - 7 - stimulated proliferation assays , UCHL - 1 signals could not significantly alter cellular proliferation .", "sentence_char_start_global": 353386, "sentence_char_end_global": 353556, "entities": [{"text": "OKT - 3", "type": "ENTITY", "char_start": 32, "char_end": 39, "token_start": 6, "token_end": 8}, {"text": "IL - 4", "type": "ENTITY", "char_start": 43, "char_end": 49, "token_start": 10, "token_end": 12}, {"text": "IL - 7", "type": "ENTITY", "char_start": 56, "char_end": 62, "token_start": 15, "token_end": 17}, {"text": "UCHL - 1", "type": "ENTITY", "char_start": 99, "char_end": 107, "token_start": 23, "token_end": 25}], "entities_global": [{"text": "OKT - 3", "type": "ENTITY", "char_start": 353418, "char_end": 353425, "token_start": 6, "token_end": 8, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 353429, "char_end": 353435, "token_start": 10, "token_end": 12, "note": null}, {"text": "IL - 7", "type": "ENTITY", "char_start": 353442, "char_end": 353448, "token_start": 15, "token_end": 17, "note": null}, {"text": "UCHL - 1", "type": "ENTITY", "char_start": 353485, "char_end": 353493, "token_start": 23, "token_end": 25, "note": null}]}
+{"sentence_id": 2136, "sentence_text": "We did not find induction of apoptosis following CD45R0 signaling .", "sentence_char_start_global": 353557, "sentence_char_end_global": 353624, "entities": [], "entities_global": []}
+{"sentence_id": 2137, "sentence_text": "In Western blots using mAbs detecting phosphorylated STAT - 3 , STAT - 5 , STAT - 6 , or extracellular signal - related kinase 1 / 2 , we found that CD45R0 signaling could effectively diminish phosphorylation of these intracellular signaling components .", "sentence_char_start_global": 353625, "sentence_char_end_global": 353879, "entities": [{"text": "mAbs", "type": "ENTITY", "char_start": 23, "char_end": 27, "token_start": 4, "token_end": 4}, {"text": "phosphorylated STAT - 3 , STAT - 5 , STAT - 6", "type": "ENTITY", "char_start": 38, "char_end": 83, "token_start": 6, "token_end": 17}, {"text": "extracellular signal - related kinase 1 / 2", "type": "ENTITY", "char_start": 89, "char_end": 132, "token_start": 20, "token_end": 27}], "entities_global": [{"text": "mAbs", "type": "ENTITY", "char_start": 353648, "char_end": 353652, "token_start": 4, "token_end": 4, "note": null}, {"text": "phosphorylated STAT - 3 , STAT - 5 , STAT - 6", "type": "ENTITY", "char_start": 353663, "char_end": 353708, "token_start": 6, "token_end": 17, "note": null}, {"text": "extracellular signal - related kinase 1 / 2", "type": "ENTITY", "char_start": 353714, "char_end": 353757, "token_start": 20, "token_end": 27, "note": null}]}
+{"sentence_id": 2138, "sentence_text": "Using RT - PCR , we found that CD45R0 signaling inhibited IL - 2 mRNA production without major influence on IL - 13 , IL - 5 , or IFN - gamma mRNA levels .", "sentence_char_start_global": 353880, "sentence_char_end_global": 354035, "entities": [{"text": "IL - 13", "type": "ENTITY", "char_start": 108, "char_end": 115, "token_start": 20, "token_end": 22}, {"text": "IL - 5", "type": "ENTITY", "char_start": 118, "char_end": 124, "token_start": 24, "token_end": 26}, {"text": "IFN - gamma mRNA", "type": "ENTITY", "char_start": 130, "char_end": 146, "token_start": 29, "token_end": 32}], "entities_global": [{"text": "IL - 13", "type": "ENTITY", "char_start": 353988, "char_end": 353995, "token_start": 20, "token_end": 22, "note": null}, {"text": "IL - 5", "type": "ENTITY", "char_start": 353998, "char_end": 354004, "token_start": 24, "token_end": 26, "note": null}, {"text": "IFN - gamma mRNA", "type": "ENTITY", "char_start": 354010, "char_end": 354026, "token_start": 29, "token_end": 32, "note": null}]}
+{"sentence_id": 2139, "sentence_text": "Costimulation with OKT - 3 and IL - 2 optimally induced secretion of IFN - gamma , TNF - alpha , and IL - 5 , which was not decreased by CD45 signals .", "sentence_char_start_global": 354036, "sentence_char_end_global": 354187, "entities": [{"text": "OKT - 3", "type": "ENTITY", "char_start": 19, "char_end": 26, "token_start": 2, "token_end": 4}, {"text": "IL - 2", "type": "ENTITY", "char_start": 31, "char_end": 37, "token_start": 6, "token_end": 8}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 69, "char_end": 80, "token_start": 13, "token_end": 15}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 83, "char_end": 94, "token_start": 17, "token_end": 19}, {"text": "IL - 5", "type": "ENTITY", "char_start": 101, "char_end": 107, "token_start": 22, "token_end": 24}], "entities_global": [{"text": "OKT - 3", "type": "ENTITY", "char_start": 354055, "char_end": 354062, "token_start": 2, "token_end": 4, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 354067, "char_end": 354073, "token_start": 6, "token_end": 8, "note": null}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 354105, "char_end": 354116, "token_start": 13, "token_end": 15, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 354119, "char_end": 354130, "token_start": 17, "token_end": 19, "note": null}, {"text": "IL - 5", "type": "ENTITY", "char_start": 354137, "char_end": 354143, "token_start": 22, "token_end": 24, "note": null}]}
+{"sentence_id": 2140, "sentence_text": "In conclusion , we illustrate that CD45R0 signals control early cytokine receptor - associated signaling processes and mRNA and DNA synthesis in activated human lymphoblasts .", "sentence_char_start_global": 354188, "sentence_char_end_global": 354363, "entities": [], "entities_global": []}
+{"sentence_id": 2141, "sentence_text": "Furthermore , we show the existence of CD45 epitopes ( GAP8 . 3 ) , which are active and critical for signaling in quiescent lymphocytes , but are nonfunctional in activated human lymphoblasts .", "sentence_char_start_global": 354364, "sentence_char_end_global": 354558, "entities": [{"text": "CD45 epitopes", "type": "ENTITY", "char_start": 39, "char_end": 52, "token_start": 7, "token_end": 8}, {"text": "GAP8 . 3", "type": "ENTITY", "char_start": 55, "char_end": 63, "token_start": 10, "token_end": 12}], "entities_global": [{"text": "CD45 epitopes", "type": "ENTITY", "char_start": 354403, "char_end": 354416, "token_start": 7, "token_end": 8, "note": null}, {"text": "GAP8 . 3", "type": "ENTITY", "char_start": 354419, "char_end": 354427, "token_start": 10, "token_end": 12, "note": null}]}
+{"sentence_id": 2142, "sentence_text": "Pax5 determines the identity of B cells from the beginning to the end of B - lymphopoiesis .", "sentence_char_start_global": 354559, "sentence_char_end_global": 354651, "entities": [{"text": "Pax5", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "Pax5", "type": "ENTITY", "char_start": 354559, "char_end": 354563, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 2143, "sentence_text": "Despite being one of the most intensively studied cell types , the molecular basis of B cell specification is largely unknown .", "sentence_char_start_global": 354652, "sentence_char_end_global": 354779, "entities": [], "entities_global": []}
+{"sentence_id": 2144, "sentence_text": "The Pax5 gene encoding the transcription factor BSAP is required for progression of B - lymphopoiesis beyond the pro - B cell stage .", "sentence_char_start_global": 354780, "sentence_char_end_global": 354913, "entities": [{"text": "Pax5 gene", "type": "ENTITY", "char_start": 4, "char_end": 13, "token_start": 1, "token_end": 2}, {"text": "transcription factor BSAP", "type": "ENTITY", "char_start": 27, "char_end": 52, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "Pax5 gene", "type": "ENTITY", "char_start": 354784, "char_end": 354793, "token_start": 1, "token_end": 2, "note": null}, {"text": "transcription factor BSAP", "type": "ENTITY", "char_start": 354807, "char_end": 354832, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 2145, "sentence_text": "Pax5 - deficient pro - B cells are , however , not yet committed to the B - lymphoid lineage , but instead have a broad lymphomyeloid developmental potential .", "sentence_char_start_global": 354914, "sentence_char_end_global": 355073, "entities": [], "entities_global": []}
+{"sentence_id": 2146, "sentence_text": "Pax5 appears to mediate B - lineage commitment by repressing the transcription of non - B - lymphoid genes and by simultaneously activating the expression of B - lineage - specific genes .", "sentence_char_start_global": 355074, "sentence_char_end_global": 355262, "entities": [{"text": "Pax5", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}, {"text": "non - B - lymphoid genes", "type": "ENTITY", "char_start": 82, "char_end": 106, "token_start": 13, "token_end": 18}, {"text": "B - lineage - specific genes", "type": "ENTITY", "char_start": 158, "char_end": 186, "token_start": 26, "token_end": 31}], "entities_global": [{"text": "Pax5", "type": "ENTITY", "char_start": 355074, "char_end": 355078, "token_start": 0, "token_end": 0, "note": null}, {"text": "non - B - lymphoid genes", "type": "ENTITY", "char_start": 355156, "char_end": 355180, "token_start": 13, "token_end": 18, "note": null}, {"text": "B - lineage - specific genes", "type": "ENTITY", "char_start": 355232, "char_end": 355260, "token_start": 26, "token_end": 31, "note": null}]}
+{"sentence_id": 2147, "sentence_text": "Pax5 thus functions both as a transcriptional repressor and activator , depending on its interactions with corepressors of the Groucho protein family or with positive regulators such as the TATA - binding protein .", "sentence_char_start_global": 355263, "sentence_char_end_global": 355477, "entities": [{"text": "Pax5", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}, {"text": "corepressors", "type": "ENTITY", "char_start": 107, "char_end": 119, "token_start": 16, "token_end": 16}, {"text": "Groucho protein family", "type": "ENTITY", "char_start": 127, "char_end": 149, "token_start": 19, "token_end": 21}, {"text": "TATA - binding protein", "type": "ENTITY", "char_start": 190, "char_end": 212, "token_start": 29, "token_end": 32}], "entities_global": [{"text": "Pax5", "type": "ENTITY", "char_start": 355263, "char_end": 355267, "token_start": 0, "token_end": 0, "note": null}, {"text": "corepressors", "type": "ENTITY", "char_start": 355370, "char_end": 355382, "token_start": 16, "token_end": 16, "note": null}, {"text": "Groucho protein family", "type": "ENTITY", "char_start": 355390, "char_end": 355412, "token_start": 19, "token_end": 21, "note": null}, {"text": "TATA - binding protein", "type": "ENTITY", "char_start": 355453, "char_end": 355475, "token_start": 29, "token_end": 32, "note": null}]}
+{"sentence_id": 2148, "sentence_text": "Once committed to the B - lineage , B cells require Pax5 function to maintain their B - lymphoid identity throughout B cell development", "sentence_char_start_global": 355478, "sentence_char_end_global": 355613, "entities": [{"text": "Pax5", "type": "ENTITY", "char_start": 52, "char_end": 56, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "Pax5", "type": "ENTITY", "char_start": 355530, "char_end": 355534, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 2149, "sentence_text": "Partners in transcription : NFAT and AP - 1 .", "sentence_char_start_global": 355614, "sentence_char_end_global": 355659, "entities": [{"text": "NFAT", "type": "ENTITY", "char_start": 28, "char_end": 32, "token_start": 4, "token_end": 4}, {"text": "AP - 1", "type": "ENTITY", "char_start": 37, "char_end": 43, "token_start": 6, "token_end": 8}], "entities_global": [{"text": "NFAT", "type": "ENTITY", "char_start": 355642, "char_end": 355646, "token_start": 4, "token_end": 4, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 355651, "char_end": 355657, "token_start": 6, "token_end": 8, "note": null}]}
+{"sentence_id": 2150, "sentence_text": "Combinatorial regulation is a powerful mechanism that enables tight control of gene expression , via integration of multiple signaling pathways that induce different transcription factors required for enhanceosome assembly .", "sentence_char_start_global": 355660, "sentence_char_end_global": 355884, "entities": [{"text": "transcription factors", "type": "ENTITY", "char_start": 166, "char_end": 187, "token_start": 23, "token_end": 24}], "entities_global": [{"text": "transcription factors", "type": "ENTITY", "char_start": 355826, "char_end": 355847, "token_start": 23, "token_end": 24, "note": null}]}
+{"sentence_id": 2151, "sentence_text": "The four calcium - regulated transcription factors of the NFAT family act synergistically with AP - 1 ( Fos / Jun ) proteins on composite DNA elements which contain adjacent NFAT and AP - 1 binding sites , where they form highly stable ternary complexes to regulate the expression of diverse inducible genes .", "sentence_char_start_global": 355885, "sentence_char_end_global": 356194, "entities": [{"text": "transcription factors", "type": "ENTITY", "char_start": 29, "char_end": 50, "token_start": 5, "token_end": 6}, {"text": "NFAT family", "type": "ENTITY", "char_start": 58, "char_end": 69, "token_start": 9, "token_end": 10}, {"text": "AP - 1 ( Fos / Jun ) proteins", "type": "ENTITY", "char_start": 95, "char_end": 124, "token_start": 14, "token_end": 22}, {"text": "NFAT and AP - 1 binding sites", "type": "ENTITY", "char_start": 174, "char_end": 203, "token_start": 30, "token_end": 36}], "entities_global": [{"text": "transcription factors", "type": "ENTITY", "char_start": 355914, "char_end": 355935, "token_start": 5, "token_end": 6, "note": null}, {"text": "NFAT family", "type": "ENTITY", "char_start": 355943, "char_end": 355954, "token_start": 9, "token_end": 10, "note": null}, {"text": "AP - 1 ( Fos / Jun ) proteins", "type": "ENTITY", "char_start": 355980, "char_end": 356009, "token_start": 14, "token_end": 22, "note": null}, {"text": "NFAT and AP - 1 binding sites", "type": "ENTITY", "char_start": 356059, "char_end": 356088, "token_start": 30, "token_end": 36, "note": null}]}
+{"sentence_id": 2152, "sentence_text": "Concomitant induction of NFAT and AP - 1 requires concerted activation of two different signaling pathways : calcium / calcineurin , which promotes NFAT dephosphorylation , nuclear translocation and activation ; and protein kinase C ( PKC ) / Ras , which promotes the synthesis , phosphorylation and activation of members of the Fos and Jun families of transcription factors .", "sentence_char_start_global": 356195, "sentence_char_end_global": 356571, "entities": [{"text": "NFAT", "type": "ENTITY", "char_start": 25, "char_end": 29, "token_start": 3, "token_end": 3}, {"text": "AP - 1", "type": "ENTITY", "char_start": 34, "char_end": 40, "token_start": 5, "token_end": 7}, {"text": "protein kinase C ( PKC ) / Ras", "type": "ENTITY", "char_start": 216, "char_end": 246, "token_start": 32, "token_end": 39}, {"text": "Fos and Jun families", "type": "ENTITY", "char_start": 329, "char_end": 349, "token_start": 53, "token_end": 56}, {"text": "transcription factors", "type": "ENTITY", "char_start": 353, "char_end": 374, "token_start": 58, "token_end": 59}], "entities_global": [{"text": "NFAT", "type": "ENTITY", "char_start": 356220, "char_end": 356224, "token_start": 3, "token_end": 3, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 356229, "char_end": 356235, "token_start": 5, "token_end": 7, "note": null}, {"text": "protein kinase C ( PKC ) / Ras", "type": "ENTITY", "char_start": 356411, "char_end": 356441, "token_start": 32, "token_end": 39, "note": null}, {"text": "Fos and Jun families", "type": "ENTITY", "char_start": 356524, "char_end": 356544, "token_start": 53, "token_end": 56, "note": null}, {"text": "transcription factors", "type": "ENTITY", "char_start": 356548, "char_end": 356569, "token_start": 58, "token_end": 59, "note": null}]}
+{"sentence_id": 2153, "sentence_text": "A fifth member of the NFAT family , NFAT5 , controls the cellular response to osmotic stress , by a mechanism that requires dimer formation and is independent of calcineurin or of interaction with AP - 1 .", "sentence_char_start_global": 356572, "sentence_char_end_global": 356777, "entities": [{"text": "NFAT family", "type": "ENTITY", "char_start": 22, "char_end": 33, "token_start": 5, "token_end": 6}, {"text": "NFAT5", "type": "ENTITY", "char_start": 36, "char_end": 41, "token_start": 8, "token_end": 8}, {"text": "calcineurin", "type": "ENTITY", "char_start": 162, "char_end": 173, "token_start": 29, "token_end": 29}, {"text": "AP - 1", "type": "ENTITY", "char_start": 197, "char_end": 203, "token_start": 34, "token_end": 36}], "entities_global": [{"text": "NFAT family", "type": "ENTITY", "char_start": 356594, "char_end": 356605, "token_start": 5, "token_end": 6, "note": null}, {"text": "NFAT5", "type": "ENTITY", "char_start": 356608, "char_end": 356613, "token_start": 8, "token_end": 8, "note": null}, {"text": "calcineurin", "type": "ENTITY", "char_start": 356734, "char_end": 356745, "token_start": 29, "token_end": 29, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 356769, "char_end": 356775, "token_start": 34, "token_end": 36, "note": null}]}
+{"sentence_id": 2154, "sentence_text": "Pharmacological interference with theNFAT : AP - 1 interaction may be useful in selective manipulation of the immune response .", "sentence_char_start_global": 356778, "sentence_char_end_global": 356905, "entities": [], "entities_global": []}
+{"sentence_id": 2155, "sentence_text": "Balanced activation of NFAT and AP - 1 is known to be required for productive immune responses , but the role of NFAT : AP - 1 interactions in other cell types and biological processes remains to be understood .", "sentence_char_start_global": 356906, "sentence_char_end_global": 357117, "entities": [{"text": "NFAT", "type": "ENTITY", "char_start": 23, "char_end": 27, "token_start": 3, "token_end": 3}, {"text": "AP - 1", "type": "ENTITY", "char_start": 32, "char_end": 38, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "NFAT", "type": "ENTITY", "char_start": 356929, "char_end": 356933, "token_start": 3, "token_end": 3, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 356938, "char_end": 356944, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 2156, "sentence_text": "Cytokine production by Vgamma ( + ) - T - cell subsets is an important factor determining CD4 ( + ) - Th - cell phenotype and susceptibility of BALB / c mice to coxsackievirus B3 - induced myocarditis .", "sentence_char_start_global": 357118, "sentence_char_end_global": 357320, "entities": [], "entities_global": []}
+{"sentence_id": 2157, "sentence_text": "Two coxsackievirus B3 ( CVB3 ) variants ( H3 and H310A1 ) differ by a single amino acid mutation in the VP2 capsid protein .", "sentence_char_start_global": 357321, "sentence_char_end_global": 357445, "entities": [{"text": "VP2 capsid protein", "type": "ENTITY", "char_start": 104, "char_end": 122, "token_start": 21, "token_end": 23}], "entities_global": [{"text": "VP2 capsid protein", "type": "ENTITY", "char_start": 357425, "char_end": 357443, "token_start": 21, "token_end": 23, "note": null}]}
+{"sentence_id": 2158, "sentence_text": "H3 induces severe myocarditis in BALB / c mice , but H310A1 is amyocarditic .", "sentence_char_start_global": 357446, "sentence_char_end_global": 357523, "entities": [], "entities_global": []}
+{"sentence_id": 2159, "sentence_text": "Infection with H3 , but not H310A1 , preferentially activates Vgamma4 Vdelta4 cells , which are strongly positive for gamma interferon ( IFN - gamma ) , whereas Vgamma1 Vdelta4 cells are increased in both H3 and H310A1 virus - infected animals .", "sentence_char_start_global": 357524, "sentence_char_end_global": 357769, "entities": [{"text": "gamma interferon", "type": "ENTITY", "char_start": 118, "char_end": 134, "token_start": 19, "token_end": 20}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 137, "char_end": 148, "token_start": 22, "token_end": 24}], "entities_global": [{"text": "gamma interferon", "type": "ENTITY", "char_start": 357642, "char_end": 357658, "token_start": 19, "token_end": 20, "note": null}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 357661, "char_end": 357672, "token_start": 22, "token_end": 24, "note": null}]}
+{"sentence_id": 2160, "sentence_text": "Depletion of Vgamma1 ( + ) cells using monoclonal anti - Vgamma1 antibody enhanced myocarditis and CD4 ( + ) - , IFN - gamma ( + ) - cell responses in both H3 - and H310A1 - infected mice yet decreased the CD4 ( + ) - , IL - 4 ( + ) - cell response .", "sentence_char_start_global": 357770, "sentence_char_end_global": 358020, "entities": [{"text": "monoclonal anti - Vgamma1 antibody", "type": "ENTITY", "char_start": 39, "char_end": 73, "token_start": 8, "token_end": 12}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 113, "char_end": 124, "token_start": 22, "token_end": 24}], "entities_global": [{"text": "monoclonal anti - Vgamma1 antibody", "type": "ENTITY", "char_start": 357809, "char_end": 357843, "token_start": 8, "token_end": 12, "note": null}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 357883, "char_end": 357894, "token_start": 22, "token_end": 24, "note": null}]}
+{"sentence_id": 2161, "sentence_text": "Depleting Vgamma4 ( + ) cells suppressed myocarditis and reduced CD4 ( + ) IFN - gamma ( + ) cells but increased CD4 ( + ) IL - 4 ( + ) T cells .", "sentence_char_start_global": 358021, "sentence_char_end_global": 358166, "entities": [], "entities_global": []}
+{"sentence_id": 2162, "sentence_text": "The role of cytokine production by Vgamma1 ( + ) and Vgamma4 ( + ) T cells was investigated by adoptively transferring these cells isolated from H3 - infected BALB / c Stat4 knockout ( Stat4ko ) ( defective in IFN - gamma expression ) or BALB / c Stat6ko ( defective in IL - 4 expression ) mice into H3 virus - infected wild - type BALB / c recipients .", "sentence_char_start_global": 358167, "sentence_char_end_global": 358520, "entities": [{"text": "IFN - gamma", "type": "ENTITY", "char_start": 210, "char_end": 221, "token_start": 40, "token_end": 42}], "entities_global": [{"text": "IFN - gamma", "type": "ENTITY", "char_start": 358377, "char_end": 358388, "token_start": 40, "token_end": 42, "note": null}]}
+{"sentence_id": 2163, "sentence_text": "Vgamma4 and Vgamma1 ( + ) T cells from Stat4ko mice expressed IL - 4 but no or minimal IFN - gamma , whereas these cell populations derived from Stat6ko mice expressed IFN - gamma but no IL - 4 .", "sentence_char_start_global": 358521, "sentence_char_end_global": 358716, "entities": [{"text": "IL - 4", "type": "ENTITY", "char_start": 62, "char_end": 68, "token_start": 12, "token_end": 14}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 87, "char_end": 98, "token_start": 19, "token_end": 21}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 168, "char_end": 179, "token_start": 32, "token_end": 34}, {"text": "IL - 4", "type": "ENTITY", "char_start": 187, "char_end": 193, "token_start": 37, "token_end": 39}], "entities_global": [{"text": "IL - 4", "type": "ENTITY", "char_start": 358583, "char_end": 358589, "token_start": 12, "token_end": 14, "note": null}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 358608, "char_end": 358619, "token_start": 19, "token_end": 21, "note": null}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 358689, "char_end": 358700, "token_start": 32, "token_end": 34, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 358708, "char_end": 358714, "token_start": 37, "token_end": 39, "note": null}]}
+{"sentence_id": 2164, "sentence_text": "Stat4ko Vgamma1 ( + ) cells ( IL - 4 ( + ) ) suppress myocarditis .", "sentence_char_start_global": 358717, "sentence_char_end_global": 358784, "entities": [], "entities_global": []}
+{"sentence_id": 2165, "sentence_text": "Stat6ko Vgamma1 ( + ) cells ( IFN - gamma ( + ) ) were not inhibitory .", "sentence_char_start_global": 358785, "sentence_char_end_global": 358856, "entities": [], "entities_global": []}
+{"sentence_id": 2166, "sentence_text": "Stat6ko Vgamma4 ( + ) cells ( IFN - gamma ( + ) ) significantly enhanced myocarditis .", "sentence_char_start_global": 358857, "sentence_char_end_global": 358943, "entities": [], "entities_global": []}
+{"sentence_id": 2167, "sentence_text": "Stat4ko Vgamma4 ( + ) cells ( IL - 4 ( + ) ) neither inhibited nor enhanced disease .", "sentence_char_start_global": 358944, "sentence_char_end_global": 359029, "entities": [], "entities_global": []}
+{"sentence_id": 2168, "sentence_text": "These results show that distinct gammadelta - T - cell subsets control myocarditis susceptibility and bias the CD4 ( + ) - Th - cell response .", "sentence_char_start_global": 359030, "sentence_char_end_global": 359173, "entities": [], "entities_global": []}
+{"sentence_id": 2169, "sentence_text": "The cytokines produced by the Vgamma subpopulation have a significant influence on the CD4 ( + ) - Th - cell phenotype .", "sentence_char_start_global": 359174, "sentence_char_end_global": 359294, "entities": [{"text": "cytokines", "type": "ENTITY", "char_start": 4, "char_end": 13, "token_start": 1, "token_end": 1}, {"text": "CD4", "type": "ENTITY", "char_start": 87, "char_end": 90, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "cytokines", "type": "ENTITY", "char_start": 359178, "char_end": 359187, "token_start": 1, "token_end": 1, "note": null}, {"text": "CD4", "type": "ENTITY", "char_start": 359261, "char_end": 359264, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 2170, "sentence_text": "Plasmin - induced expression of cytokines and tissue factor in human monocytes involves AP - 1 and IKKbeta - mediated NF - kappaB activation .", "sentence_char_start_global": 359295, "sentence_char_end_global": 359437, "entities": [{"text": "Plasmin", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 0}, {"text": "cytokines", "type": "ENTITY", "char_start": 32, "char_end": 41, "token_start": 5, "token_end": 5}, {"text": "tissue factor", "type": "ENTITY", "char_start": 46, "char_end": 59, "token_start": 7, "token_end": 8}, {"text": "AP - 1", "type": "ENTITY", "char_start": 88, "char_end": 94, "token_start": 13, "token_end": 15}, {"text": "IKKbeta", "type": "ENTITY", "char_start": 99, "char_end": 106, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "Plasmin", "type": "ENTITY", "char_start": 359295, "char_end": 359302, "token_start": 0, "token_end": 0, "note": null}, {"text": "cytokines", "type": "ENTITY", "char_start": 359327, "char_end": 359336, "token_start": 5, "token_end": 5, "note": null}, {"text": "tissue factor", "type": "ENTITY", "char_start": 359341, "char_end": 359354, "token_start": 7, "token_end": 8, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 359383, "char_end": 359389, "token_start": 13, "token_end": 15, "note": null}, {"text": "IKKbeta", "type": "ENTITY", "char_start": 359394, "char_end": 359401, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 2171, "sentence_text": "It was previously shown that plasmin activates human peripheral monocytes in terms of lipid mediator release and chemotactic migration .", "sentence_char_start_global": 359438, "sentence_char_end_global": 359574, "entities": [{"text": "plasmin", "type": "ENTITY", "char_start": 29, "char_end": 36, "token_start": 5, "token_end": 5}], "entities_global": [{"text": "plasmin", "type": "ENTITY", "char_start": 359467, "char_end": 359474, "token_start": 5, "token_end": 5, "note": null}]}
+{"sentence_id": 2172, "sentence_text": "Here it is demonstrated that plasmin induces proinflammatory cytokine release and tissue factor ( TF ) expression by monocytes .", "sentence_char_start_global": 359575, "sentence_char_end_global": 359703, "entities": [{"text": "plasmin", "type": "ENTITY", "char_start": 29, "char_end": 36, "token_start": 5, "token_end": 5}, {"text": "proinflammatory cytokine", "type": "ENTITY", "char_start": 45, "char_end": 69, "token_start": 7, "token_end": 8}, {"text": "tissue factor", "type": "ENTITY", "char_start": 82, "char_end": 95, "token_start": 11, "token_end": 12}, {"text": "TF", "type": "ENTITY", "char_start": 98, "char_end": 100, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "plasmin", "type": "ENTITY", "char_start": 359604, "char_end": 359611, "token_start": 5, "token_end": 5, "note": null}, {"text": "proinflammatory cytokine", "type": "ENTITY", "char_start": 359620, "char_end": 359644, "token_start": 7, "token_end": 8, "note": null}, {"text": "tissue factor", "type": "ENTITY", "char_start": 359657, "char_end": 359670, "token_start": 11, "token_end": 12, "note": null}, {"text": "TF", "type": "ENTITY", "char_start": 359673, "char_end": 359675, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 2173, "sentence_text": "Plasmin 0 . 043 to 1 . 43 CTA U / mL , but not active site - blocked plasmin , triggered concentration - dependent expression of mRNA for interleukin - 1alpha ( IL - 1alpha ) , IL - 1beta , tumor necrosis factor - alpha ( TNF - alpha ) , and TF with maximum responses after 4 hours .", "sentence_char_start_global": 359704, "sentence_char_end_global": 359987, "entities": [{"text": "Plasmin", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 0}, {"text": "active site - blocked plasmin", "type": "ENTITY", "char_start": 47, "char_end": 76, "token_start": 15, "token_end": 19}, {"text": "interleukin - 1alpha", "type": "ENTITY", "char_start": 138, "char_end": 158, "token_start": 29, "token_end": 31}, {"text": "IL - 1alpha", "type": "ENTITY", "char_start": 161, "char_end": 172, "token_start": 33, "token_end": 35}, {"text": "IL - 1beta", "type": "ENTITY", "char_start": 177, "char_end": 187, "token_start": 38, "token_end": 40}, {"text": "tumor necrosis factor - alpha", "type": "ENTITY", "char_start": 190, "char_end": 219, "token_start": 42, "token_end": 46}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 222, "char_end": 233, "token_start": 48, "token_end": 50}, {"text": "TF", "type": "ENTITY", "char_start": 242, "char_end": 244, "token_start": 54, "token_end": 54}], "entities_global": [{"text": "Plasmin", "type": "ENTITY", "char_start": 359704, "char_end": 359711, "token_start": 0, "token_end": 0, "note": null}, {"text": "active site - blocked plasmin", "type": "ENTITY", "char_start": 359751, "char_end": 359780, "token_start": 15, "token_end": 19, "note": null}, {"text": "interleukin - 1alpha", "type": "ENTITY", "char_start": 359842, "char_end": 359862, "token_start": 29, "token_end": 31, "note": null}, {"text": "IL - 1alpha", "type": "ENTITY", "char_start": 359865, "char_end": 359876, "token_start": 33, "token_end": 35, "note": null}, {"text": "IL - 1beta", "type": "ENTITY", "char_start": 359881, "char_end": 359891, "token_start": 38, "token_end": 40, "note": null}, {"text": "tumor necrosis factor - alpha", "type": "ENTITY", "char_start": 359894, "char_end": 359923, "token_start": 42, "token_end": 46, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 359926, "char_end": 359937, "token_start": 48, "token_end": 50, "note": null}, {"text": "TF", "type": "ENTITY", "char_start": 359946, "char_end": 359948, "token_start": 54, "token_end": 54, "note": null}]}
+{"sentence_id": 2174, "sentence_text": "Plasmin - mediated mRNA expression was inhibited in a concentration - dependent manner by the lysine analogue trans - 4 - ( aminomethyl ) cyclohexane - 1 - carboxylic acid ( t - AMCA ) .", "sentence_char_start_global": 359988, "sentence_char_end_global": 360174, "entities": [{"text": "Plasmin", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "Plasmin", "type": "ENTITY", "char_start": 359988, "char_end": 359995, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 2175, "sentence_text": "Increases in mRNA levels were followed by concentration - and time - dependent release of IL - 1alpha , IL - 1beta and TNF - alpha and by TF expression on monocyte surfaces .", "sentence_char_start_global": 360175, "sentence_char_end_global": 360349, "entities": [{"text": "IL - 1alpha", "type": "ENTITY", "char_start": 90, "char_end": 101, "token_start": 15, "token_end": 17}, {"text": "IL - 1beta", "type": "ENTITY", "char_start": 104, "char_end": 114, "token_start": 19, "token_end": 21}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 119, "char_end": 130, "token_start": 23, "token_end": 25}, {"text": "TF", "type": "ENTITY", "char_start": 138, "char_end": 140, "token_start": 28, "token_end": 28}], "entities_global": [{"text": "IL - 1alpha", "type": "ENTITY", "char_start": 360265, "char_end": 360276, "token_start": 15, "token_end": 17, "note": null}, {"text": "IL - 1beta", "type": "ENTITY", "char_start": 360279, "char_end": 360289, "token_start": 19, "token_end": 21, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 360294, "char_end": 360305, "token_start": 23, "token_end": 25, "note": null}, {"text": "TF", "type": "ENTITY", "char_start": 360313, "char_end": 360315, "token_start": 28, "token_end": 28, "note": null}]}
+{"sentence_id": 2176, "sentence_text": "Neither cytokines nor TF could be detected when monocytes were preincubated with actinomycin D or cycloheximide .", "sentence_char_start_global": 360350, "sentence_char_end_global": 360463, "entities": [{"text": "cytokines", "type": "ENTITY", "char_start": 8, "char_end": 17, "token_start": 1, "token_end": 1}, {"text": "TF", "type": "ENTITY", "char_start": 22, "char_end": 24, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "cytokines", "type": "ENTITY", "char_start": 360358, "char_end": 360367, "token_start": 1, "token_end": 1, "note": null}, {"text": "TF", "type": "ENTITY", "char_start": 360372, "char_end": 360374, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 2177, "sentence_text": "Electrophoretic mobility shift assays indicated plasmin - induced activation of NF - kappaB ; DNA - binding complexes were composed of p50 , p65 , and c - Rel , as shown by supershift experiments .", "sentence_char_start_global": 360464, "sentence_char_end_global": 360661, "entities": [{"text": "plasmin", "type": "ENTITY", "char_start": 48, "char_end": 55, "token_start": 5, "token_end": 5}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 80, "char_end": 91, "token_start": 10, "token_end": 12}, {"text": "DNA - binding complexes", "type": "ENTITY", "char_start": 94, "char_end": 117, "token_start": 14, "token_end": 17}, {"text": "p50", "type": "ENTITY", "char_start": 135, "char_end": 138, "token_start": 21, "token_end": 21}, {"text": "p65", "type": "ENTITY", "char_start": 141, "char_end": 144, "token_start": 23, "token_end": 23}, {"text": "c - Rel", "type": "ENTITY", "char_start": 151, "char_end": 158, "token_start": 26, "token_end": 28}], "entities_global": [{"text": "plasmin", "type": "ENTITY", "char_start": 360512, "char_end": 360519, "token_start": 5, "token_end": 5, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 360544, "char_end": 360555, "token_start": 10, "token_end": 12, "note": null}, {"text": "DNA - binding complexes", "type": "ENTITY", "char_start": 360558, "char_end": 360581, "token_start": 14, "token_end": 17, "note": null}, {"text": "p50", "type": "ENTITY", "char_start": 360599, "char_end": 360602, "token_start": 21, "token_end": 21, "note": null}, {"text": "p65", "type": "ENTITY", "char_start": 360605, "char_end": 360608, "token_start": 23, "token_end": 23, "note": null}, {"text": "c - Rel", "type": "ENTITY", "char_start": 360615, "char_end": 360622, "token_start": 26, "token_end": 28, "note": null}]}
+{"sentence_id": 2178, "sentence_text": "Nuclear translocation of NF - kappaB / Rel proteins coincided with IkappaBalpha degradation .", "sentence_char_start_global": 360662, "sentence_char_end_global": 360755, "entities": [{"text": "NF - kappaB / Rel proteins", "type": "ENTITY", "char_start": 25, "char_end": 51, "token_start": 3, "token_end": 8}], "entities_global": [{"text": "NF - kappaB / Rel proteins", "type": "ENTITY", "char_start": 360687, "char_end": 360713, "token_start": 3, "token_end": 8, "note": null}]}
+{"sentence_id": 2179, "sentence_text": "At variance with endotoxic lipopolysaccharide , plasmin elicited the rapid degradation of another cytoplasmic NF - kappaB inhibitor , p105 .", "sentence_char_start_global": 360756, "sentence_char_end_global": 360896, "entities": [{"text": "plasmin", "type": "ENTITY", "char_start": 48, "char_end": 55, "token_start": 6, "token_end": 6}, {"text": "cytoplasmic NF - kappaB inhibitor , p105", "type": "ENTITY", "char_start": 98, "char_end": 138, "token_start": 13, "token_end": 19}], "entities_global": [{"text": "plasmin", "type": "ENTITY", "char_start": 360804, "char_end": 360811, "token_start": 6, "token_end": 6, "note": null}, {"text": "cytoplasmic NF - kappaB inhibitor , p105", "type": "ENTITY", "char_start": 360854, "char_end": 360894, "token_start": 13, "token_end": 19, "note": null}]}
+{"sentence_id": 2180, "sentence_text": "Proteolysis of NF - kappaB inhibitors was apparently due to transient activation of IkappaB kinase ( IKK ) beta that reached maximum activity at 1 hour after plasmin stimulation .", "sentence_char_start_global": 360897, "sentence_char_end_global": 361076, "entities": [{"text": "IkappaB kinase ( IKK ) beta", "type": "ENTITY", "char_start": 84, "char_end": 111, "token_start": 13, "token_end": 18}, {"text": "plasmin", "type": "ENTITY", "char_start": 158, "char_end": 165, "token_start": 27, "token_end": 27}], "entities_global": [{"text": "IkappaB kinase ( IKK ) beta", "type": "ENTITY", "char_start": 360981, "char_end": 361008, "token_start": 13, "token_end": 18, "note": null}, {"text": "plasmin", "type": "ENTITY", "char_start": 361055, "char_end": 361062, "token_start": 27, "token_end": 27, "note": null}]}
+{"sentence_id": 2181, "sentence_text": "In addition , AP - 1 binding was increased in plasmin - treated monocytes , with most complexes composed of JunD , c - Fos , and FosB .", "sentence_char_start_global": 361077, "sentence_char_end_global": 361212, "entities": [{"text": "plasmin", "type": "ENTITY", "char_start": 46, "char_end": 53, "token_start": 10, "token_end": 10}, {"text": "JunD", "type": "ENTITY", "char_start": 108, "char_end": 112, "token_start": 20, "token_end": 20}, {"text": "c - Fos", "type": "ENTITY", "char_start": 115, "char_end": 122, "token_start": 22, "token_end": 24}, {"text": "FosB", "type": "ENTITY", "char_start": 129, "char_end": 133, "token_start": 27, "token_end": 27}], "entities_global": [{"text": "plasmin", "type": "ENTITY", "char_start": 361123, "char_end": 361130, "token_start": 10, "token_end": 10, "note": null}, {"text": "JunD", "type": "ENTITY", "char_start": 361185, "char_end": 361189, "token_start": 20, "token_end": 20, "note": null}, {"text": "c - Fos", "type": "ENTITY", "char_start": 361192, "char_end": 361199, "token_start": 22, "token_end": 24, "note": null}, {"text": "FosB", "type": "ENTITY", "char_start": 361206, "char_end": 361210, "token_start": 27, "token_end": 27, "note": null}]}
+{"sentence_id": 2182, "sentence_text": "These findings further substantiate the role of plasmin as a proinflammatory activator of human monocytes and reveal an important new link between the plasminogen - plasmin system and inflammation .", "sentence_char_start_global": 361213, "sentence_char_end_global": 361411, "entities": [{"text": "plasmin", "type": "ENTITY", "char_start": 48, "char_end": 55, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "plasmin", "type": "ENTITY", "char_start": 361261, "char_end": 361268, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 2183, "sentence_text": "( Blood . 2001 ; 97 : 3941 - 3950 )", "sentence_char_start_global": 361412, "sentence_char_end_global": 361447, "entities": [], "entities_global": []}
+{"sentence_id": 2184, "sentence_text": "STAT3 is constitutively active in some patients with Polycythemia rubra vera .", "sentence_char_start_global": 361448, "sentence_char_end_global": 361526, "entities": [{"text": "STAT3", "type": "ENTITY", "char_start": 0, "char_end": 5, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "STAT3", "type": "ENTITY", "char_start": 361448, "char_end": 361453, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 2185, "sentence_text": "OBJECTIVE : Polycythemia vera is a clonal stem cell disorder characterized by hyperproliferation of the erythroid , myeloid , and megakaryocytic lineages .", "sentence_char_start_global": 361527, "sentence_char_end_global": 361682, "entities": [], "entities_global": []}
+{"sentence_id": 2186, "sentence_text": "While it has been shown that progenitor cells of P . vera patients are hypersensitive to several growth factors including erythropoietin , insulin - like growth factor - 1 , thrombopoietin , interleukin - 3 , and granulocyte / monocyte colony - stimulating factor , the molecular pathogenesis of this disease remains unknown .", "sentence_char_start_global": 361683, "sentence_char_end_global": 362009, "entities": [{"text": "erythropoietin", "type": "ENTITY", "char_start": 122, "char_end": 136, "token_start": 20, "token_end": 20}, {"text": "insulin - like growth factor - 1", "type": "ENTITY", "char_start": 139, "char_end": 171, "token_start": 22, "token_end": 28}, {"text": "thrombopoietin", "type": "ENTITY", "char_start": 174, "char_end": 188, "token_start": 30, "token_end": 30}, {"text": "interleukin - 3", "type": "ENTITY", "char_start": 191, "char_end": 206, "token_start": 32, "token_end": 34}, {"text": "granulocyte / monocyte colony - stimulating factor", "type": "ENTITY", "char_start": 213, "char_end": 263, "token_start": 37, "token_end": 43}], "entities_global": [{"text": "erythropoietin", "type": "ENTITY", "char_start": 361805, "char_end": 361819, "token_start": 20, "token_end": 20, "note": null}, {"text": "insulin - like growth factor - 1", "type": "ENTITY", "char_start": 361822, "char_end": 361854, "token_start": 22, "token_end": 28, "note": null}, {"text": "thrombopoietin", "type": "ENTITY", "char_start": 361857, "char_end": 361871, "token_start": 30, "token_end": 30, "note": null}, {"text": "interleukin - 3", "type": "ENTITY", "char_start": 361874, "char_end": 361889, "token_start": 32, "token_end": 34, "note": null}, {"text": "granulocyte / monocyte colony - stimulating factor", "type": "ENTITY", "char_start": 361896, "char_end": 361946, "token_start": 37, "token_end": 43, "note": null}]}
+{"sentence_id": 2187, "sentence_text": "Growth factor hypersensitivity could be mediated by changes in signal transduction pathways .", "sentence_char_start_global": 362010, "sentence_char_end_global": 362103, "entities": [], "entities_global": []}
+{"sentence_id": 2188, "sentence_text": "We therefore investigated a common downstream effector of cytokines , the signal transducers and activators of transcription ( STATs ) .", "sentence_char_start_global": 362104, "sentence_char_end_global": 362240, "entities": [{"text": "cytokines", "type": "ENTITY", "char_start": 58, "char_end": 67, "token_start": 8, "token_end": 8}, {"text": "signal transducers and activators of transcription", "type": "ENTITY", "char_start": 74, "char_end": 124, "token_start": 11, "token_end": 16}, {"text": "STATs", "type": "ENTITY", "char_start": 127, "char_end": 132, "token_start": 18, "token_end": 18}], "entities_global": [{"text": "cytokines", "type": "ENTITY", "char_start": 362162, "char_end": 362171, "token_start": 8, "token_end": 8, "note": null}, {"text": "signal transducers and activators of transcription", "type": "ENTITY", "char_start": 362178, "char_end": 362228, "token_start": 11, "token_end": 16, "note": null}, {"text": "STATs", "type": "ENTITY", "char_start": 362231, "char_end": 362236, "token_start": 18, "token_end": 18, "note": null}]}
+{"sentence_id": 2189, "sentence_text": "A constitutive activation of STAT factors could explain the increased proliferation of P . vera cells even in the absence of growth factor stimulation .", "sentence_char_start_global": 362241, "sentence_char_end_global": 362393, "entities": [{"text": "STAT factors", "type": "ENTITY", "char_start": 29, "char_end": 41, "token_start": 4, "token_end": 5}], "entities_global": [{"text": "STAT factors", "type": "ENTITY", "char_start": 362270, "char_end": 362282, "token_start": 4, "token_end": 5, "note": null}]}
+{"sentence_id": 2190, "sentence_text": "METHODS : Peripheral granulocytes from patients with P . vera and from healthy volunteers were assayed for STAT1 , 3 , and 5 DNA binding by electrophoretic mobility shift assay .", "sentence_char_start_global": 362394, "sentence_char_end_global": 362572, "entities": [{"text": "STAT1 , 3 , and 5", "type": "ENTITY", "char_start": 107, "char_end": 124, "token_start": 17, "token_end": 22}], "entities_global": [{"text": "STAT1 , 3 , and 5", "type": "ENTITY", "char_start": 362501, "char_end": 362518, "token_start": 17, "token_end": 22, "note": null}]}
+{"sentence_id": 2191, "sentence_text": "RESULTS : Four of 14 P . vera patients analyzed showed constitutive STAT3 DNA binding in unstimulated peripheral granulocytes , while none of the 17 healthy volunteers tested did .", "sentence_char_start_global": 362573, "sentence_char_end_global": 362753, "entities": [], "entities_global": []}
+{"sentence_id": 2192, "sentence_text": "None of the subjects showed constitutive STAT1 or STAT5 activity .", "sentence_char_start_global": 362754, "sentence_char_end_global": 362820, "entities": [{"text": "STAT1", "type": "ENTITY", "char_start": 41, "char_end": 46, "token_start": 6, "token_end": 6}, {"text": "STAT5", "type": "ENTITY", "char_start": 50, "char_end": 55, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "STAT1", "type": "ENTITY", "char_start": 362795, "char_end": 362800, "token_start": 6, "token_end": 6, "note": null}, {"text": "STAT5", "type": "ENTITY", "char_start": 362804, "char_end": 362809, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 2193, "sentence_text": "Western blotting demonstrated that , in the three patients , STAT3 is constitutively phosphorylated on Tyr 705 , whereas it is unphosphorylated in the other patients and in controls .", "sentence_char_start_global": 362821, "sentence_char_end_global": 363004, "entities": [{"text": "STAT3", "type": "ENTITY", "char_start": 61, "char_end": 66, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "STAT3", "type": "ENTITY", "char_start": 362882, "char_end": 362887, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 2194, "sentence_text": "Interestingly , constitutive STAT3 activity did not correlate with the duration of disease or the treatment regimen .", "sentence_char_start_global": 363005, "sentence_char_end_global": 363122, "entities": [{"text": "STAT3", "type": "ENTITY", "char_start": 29, "char_end": 34, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "STAT3", "type": "ENTITY", "char_start": 363034, "char_end": 363039, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 2195, "sentence_text": "It was observed in a recently diagnosed patient and in two patients treated only with phlebotomy .", "sentence_char_start_global": 363123, "sentence_char_end_global": 363221, "entities": [], "entities_global": []}
+{"sentence_id": 2196, "sentence_text": "CONCLUSION : Our data suggest that constitutive phosphorylation and activation of STAT3 is not a secondary event induced by mutagenizing agents or by prolonged hyperproliferation of hematopoietic cells , but rather represents a primary molecular aberration .", "sentence_char_start_global": 363222, "sentence_char_end_global": 363480, "entities": [{"text": "STAT3", "type": "ENTITY", "char_start": 82, "char_end": 87, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "STAT3", "type": "ENTITY", "char_start": 363304, "char_end": 363309, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 2197, "sentence_text": "Constitutively active STAT3 may contribute to the growth factor hypersensitivity of P . vera cells .", "sentence_char_start_global": 363481, "sentence_char_end_global": 363581, "entities": [{"text": "Constitutively active STAT3", "type": "ENTITY", "char_start": 0, "char_end": 27, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "Constitutively active STAT3", "type": "ENTITY", "char_start": 363481, "char_end": 363508, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 2198, "sentence_text": "Identification of phosphorylation sites for Bruton ' s tyrosine kinase within the transcriptional regulator BAP / TFII - I .", "sentence_char_start_global": 363582, "sentence_char_end_global": 363706, "entities": [{"text": "phosphorylation sites", "type": "ENTITY", "char_start": 18, "char_end": 39, "token_start": 2, "token_end": 3}, {"text": "Bruton ' s tyrosine kinase", "type": "ENTITY", "char_start": 44, "char_end": 70, "token_start": 5, "token_end": 9}, {"text": "transcriptional regulator BAP / TFII - I", "type": "ENTITY", "char_start": 82, "char_end": 122, "token_start": 12, "token_end": 18}], "entities_global": [{"text": "phosphorylation sites", "type": "ENTITY", "char_start": 363600, "char_end": 363621, "token_start": 2, "token_end": 3, "note": null}, {"text": "Bruton ' s tyrosine kinase", "type": "ENTITY", "char_start": 363626, "char_end": 363652, "token_start": 5, "token_end": 9, "note": null}, {"text": "transcriptional regulator BAP / TFII - I", "type": "ENTITY", "char_start": 363664, "char_end": 363704, "token_start": 12, "token_end": 18, "note": null}]}
+{"sentence_id": 2199, "sentence_text": "Bruton ' s tyrosine kinase ( Btk ) , a member of the Tec family of cytosolic kinases , is essential for B cell development and function .", "sentence_char_start_global": 363707, "sentence_char_end_global": 363844, "entities": [{"text": "Bruton ' s tyrosine kinase", "type": "ENTITY", "char_start": 0, "char_end": 26, "token_start": 0, "token_end": 4}, {"text": "Btk", "type": "ENTITY", "char_start": 29, "char_end": 32, "token_start": 6, "token_end": 6}, {"text": "Tec family of cytosolic kinases", "type": "ENTITY", "char_start": 53, "char_end": 84, "token_start": 13, "token_end": 17}], "entities_global": [{"text": "Bruton ' s tyrosine kinase", "type": "ENTITY", "char_start": 363707, "char_end": 363733, "token_start": 0, "token_end": 4, "note": null}, {"text": "Btk", "type": "ENTITY", "char_start": 363736, "char_end": 363739, "token_start": 6, "token_end": 6, "note": null}, {"text": "Tec family of cytosolic kinases", "type": "ENTITY", "char_start": 363760, "char_end": 363791, "token_start": 13, "token_end": 17, "note": null}]}
+{"sentence_id": 2200, "sentence_text": "BAP / TFII - I , a protein implicated in transcriptional regulation , is associated with Btk in B cells and is transiently phosphorylated on tyrosine following B cell receptor engagement .", "sentence_char_start_global": 363845, "sentence_char_end_global": 364033, "entities": [{"text": "BAP / TFII - I", "type": "ENTITY", "char_start": 0, "char_end": 14, "token_start": 0, "token_end": 4}, {"text": "Btk", "type": "ENTITY", "char_start": 89, "char_end": 92, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "BAP / TFII - I", "type": "ENTITY", "char_start": 363845, "char_end": 363859, "token_start": 0, "token_end": 4, "note": null}, {"text": "Btk", "type": "ENTITY", "char_start": 363934, "char_end": 363937, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 2201, "sentence_text": "BAP / TFII - I is a substrate for Btk in vitro and is hyperphosphorylated on tyrosine upon coexpression with Btk in mammalian cells .", "sentence_char_start_global": 364034, "sentence_char_end_global": 364167, "entities": [{"text": "BAP / TFII - I", "type": "ENTITY", "char_start": 0, "char_end": 14, "token_start": 0, "token_end": 4}, {"text": "Btk", "type": "ENTITY", "char_start": 34, "char_end": 37, "token_start": 9, "token_end": 9}, {"text": "Btk", "type": "ENTITY", "char_start": 109, "char_end": 112, "token_start": 20, "token_end": 20}], "entities_global": [{"text": "BAP / TFII - I", "type": "ENTITY", "char_start": 364034, "char_end": 364048, "token_start": 0, "token_end": 4, "note": null}, {"text": "Btk", "type": "ENTITY", "char_start": 364068, "char_end": 364071, "token_start": 9, "token_end": 9, "note": null}, {"text": "Btk", "type": "ENTITY", "char_start": 364143, "char_end": 364146, "token_start": 20, "token_end": 20, "note": null}]}
+{"sentence_id": 2202, "sentence_text": "In an effort to understand the physiologic consequences of BAP / TFII - I tyrosine phosphorylation following B cell receptor stimulation , site - directed mutagenesis and phosphopeptide mapping were used to locate the predominant sites of BAP / TFII - I phosphorylation by Btk in vitro .", "sentence_char_start_global": 364168, "sentence_char_end_global": 364455, "entities": [{"text": "BAP / TFII - I", "type": "ENTITY", "char_start": 59, "char_end": 73, "token_start": 9, "token_end": 13}, {"text": "BAP / TFII - I", "type": "ENTITY", "char_start": 239, "char_end": 253, "token_start": 37, "token_end": 41}, {"text": "Btk", "type": "ENTITY", "char_start": 273, "char_end": 276, "token_start": 44, "token_end": 44}], "entities_global": [{"text": "BAP / TFII - I", "type": "ENTITY", "char_start": 364227, "char_end": 364241, "token_start": 9, "token_end": 13, "note": null}, {"text": "BAP / TFII - I", "type": "ENTITY", "char_start": 364407, "char_end": 364421, "token_start": 37, "token_end": 41, "note": null}, {"text": "Btk", "type": "ENTITY", "char_start": 364441, "char_end": 364444, "token_start": 44, "token_end": 44, "note": null}]}
+{"sentence_id": 2203, "sentence_text": "These residues , Tyr248 , Tyr357 , and Tyr462 , were also found to be the major sites for Btk - dependent phosphorylation of BAP / TFII - I in vivo .", "sentence_char_start_global": 364456, "sentence_char_end_global": 364605, "entities": [{"text": "Btk", "type": "ENTITY", "char_start": 90, "char_end": 93, "token_start": 19, "token_end": 19}, {"text": "BAP / TFII - I", "type": "ENTITY", "char_start": 125, "char_end": 139, "token_start": 24, "token_end": 28}], "entities_global": [{"text": "Btk", "type": "ENTITY", "char_start": 364546, "char_end": 364549, "token_start": 19, "token_end": 19, "note": null}, {"text": "BAP / TFII - I", "type": "ENTITY", "char_start": 364581, "char_end": 364595, "token_start": 24, "token_end": 28, "note": null}]}
+{"sentence_id": 2204, "sentence_text": "Residues Tyr357 and Tyr462 are contained within the loop regions of adjacent helix - loop - helix - like repeats within BAP / TFII - I .", "sentence_char_start_global": 364606, "sentence_char_end_global": 364742, "entities": [{"text": "loop regions", "type": "ENTITY", "char_start": 52, "char_end": 64, "token_start": 8, "token_end": 9}, {"text": "helix - loop - helix - like repeats", "type": "ENTITY", "char_start": 77, "char_end": 112, "token_start": 12, "token_end": 19}, {"text": "BAP / TFII - I", "type": "ENTITY", "char_start": 120, "char_end": 134, "token_start": 21, "token_end": 25}], "entities_global": [{"text": "loop regions", "type": "ENTITY", "char_start": 364658, "char_end": 364670, "token_start": 8, "token_end": 9, "note": null}, {"text": "helix - loop - helix - like repeats", "type": "ENTITY", "char_start": 364683, "char_end": 364718, "token_start": 12, "token_end": 19, "note": null}, {"text": "BAP / TFII - I", "type": "ENTITY", "char_start": 364726, "char_end": 364740, "token_start": 21, "token_end": 25, "note": null}]}
+{"sentence_id": 2205, "sentence_text": "Mutation of either Tyr248 , Tyr357 , or Tyr462 to phenylalanine reduced transcription from a c - fos promoter relative to wild - type BAP / TFII - I in transfected COS - 7 cells , consistent with the interpretation that phosphorylation at these sites contributes to transcriptional activation .", "sentence_char_start_global": 364743, "sentence_char_end_global": 365037, "entities": [{"text": "c - fos promoter", "type": "ENTITY", "char_start": 93, "char_end": 109, "token_start": 15, "token_end": 18}, {"text": "wild - type BAP / TFII - I", "type": "ENTITY", "char_start": 122, "char_end": 148, "token_start": 21, "token_end": 28}], "entities_global": [{"text": "c - fos promoter", "type": "ENTITY", "char_start": 364836, "char_end": 364852, "token_start": 15, "token_end": 18, "note": null}, {"text": "wild - type BAP / TFII - I", "type": "ENTITY", "char_start": 364865, "char_end": 364891, "token_start": 21, "token_end": 28, "note": null}]}
+{"sentence_id": 2206, "sentence_text": "Phosphorylation of BAP / TFII - I by Btk may link engagement of receptors such as surface immunoglobulin to modulation of gene expression .", "sentence_char_start_global": 365038, "sentence_char_end_global": 365177, "entities": [{"text": "BAP / TFII - I", "type": "ENTITY", "char_start": 19, "char_end": 33, "token_start": 2, "token_end": 6}, {"text": "Btk", "type": "ENTITY", "char_start": 37, "char_end": 40, "token_start": 8, "token_end": 8}, {"text": "immunoglobulin", "type": "ENTITY", "char_start": 90, "char_end": 104, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "BAP / TFII - I", "type": "ENTITY", "char_start": 365057, "char_end": 365071, "token_start": 2, "token_end": 6, "note": null}, {"text": "Btk", "type": "ENTITY", "char_start": 365075, "char_end": 365078, "token_start": 8, "token_end": 8, "note": null}, {"text": "immunoglobulin", "type": "ENTITY", "char_start": 365128, "char_end": 365142, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 2207, "sentence_text": "Expression of interferon consensus sequence binding protein induces potent immunity against BCR / ABL - induced leukemia .", "sentence_char_start_global": 365178, "sentence_char_end_global": 365300, "entities": [{"text": "interferon consensus sequence binding protein", "type": "ENTITY", "char_start": 14, "char_end": 59, "token_start": 2, "token_end": 6}], "entities_global": [{"text": "interferon consensus sequence binding protein", "type": "ENTITY", "char_start": 365192, "char_end": 365237, "token_start": 2, "token_end": 6, "note": null}]}
+{"sentence_id": 2208, "sentence_text": "Mice deficient in the interferon consensus sequence binding protein ( ICSBP ) develop a disease resembling chronic myeloid leukemia ( CML ) , which in humans is caused by the BCR / ABL oncoprotein .", "sentence_char_start_global": 365301, "sentence_char_end_global": 365499, "entities": [{"text": "interferon consensus sequence binding protein", "type": "ENTITY", "char_start": 22, "char_end": 67, "token_start": 4, "token_end": 8}, {"text": "ICSBP", "type": "ENTITY", "char_start": 70, "char_end": 75, "token_start": 10, "token_end": 10}, {"text": "BCR / ABL oncoprotein", "type": "ENTITY", "char_start": 175, "char_end": 196, "token_start": 30, "token_end": 33}], "entities_global": [{"text": "interferon consensus sequence binding protein", "type": "ENTITY", "char_start": 365323, "char_end": 365368, "token_start": 4, "token_end": 8, "note": null}, {"text": "ICSBP", "type": "ENTITY", "char_start": 365371, "char_end": 365376, "token_start": 10, "token_end": 10, "note": null}, {"text": "BCR / ABL oncoprotein", "type": "ENTITY", "char_start": 365476, "char_end": 365497, "token_start": 30, "token_end": 33, "note": null}]}
+{"sentence_id": 2209, "sentence_text": "Interferon - alpha ( IFN - alpha ) induces ICSBP expression and is an effective therapy for CML .", "sentence_char_start_global": 365500, "sentence_char_end_global": 365597, "entities": [{"text": "Interferon - alpha", "type": "ENTITY", "char_start": 0, "char_end": 18, "token_start": 0, "token_end": 2}, {"text": "IFN - alpha", "type": "ENTITY", "char_start": 21, "char_end": 32, "token_start": 4, "token_end": 6}, {"text": "ICSBP", "type": "ENTITY", "char_start": 43, "char_end": 48, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "Interferon - alpha", "type": "ENTITY", "char_start": 365500, "char_end": 365518, "token_start": 0, "token_end": 2, "note": null}, {"text": "IFN - alpha", "type": "ENTITY", "char_start": 365521, "char_end": 365532, "token_start": 4, "token_end": 6, "note": null}, {"text": "ICSBP", "type": "ENTITY", "char_start": 365543, "char_end": 365548, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 2210, "sentence_text": "This study examined whether enforced expression of ICSBP might antagonize BCR / ABL - induced leukemia ; results demonstrated that ICSBP - modified cells generated a protective CD8 ( + ) cytotoxic T - cell response against BCR / ABL - transformed BaF3 cells in a murine leukemia model .", "sentence_char_start_global": 365598, "sentence_char_end_global": 365884, "entities": [{"text": "ICSBP", "type": "ENTITY", "char_start": 51, "char_end": 56, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "ICSBP", "type": "ENTITY", "char_start": 365649, "char_end": 365654, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 2211, "sentence_text": "ICSBP expression represents a novel means of stimulating a host immune response to BCR / ABL ( + ) leukemia cells and a potential strategy for immunotherapy of CML .", "sentence_char_start_global": 365885, "sentence_char_end_global": 366050, "entities": [{"text": "ICSBP", "type": "ENTITY", "char_start": 0, "char_end": 5, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "ICSBP", "type": "ENTITY", "char_start": 365885, "char_end": 365890, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 2212, "sentence_text": "( Blood . 2001 ; 97 : 3491 - 3497 )", "sentence_char_start_global": 366051, "sentence_char_end_global": 366086, "entities": [], "entities_global": []}
+{"sentence_id": 2213, "sentence_text": "A transcriptional block in the IL - 2 promoter at the - 150 AP - 1 site in effector CD8 + T cells .", "sentence_char_start_global": 366087, "sentence_char_end_global": 366186, "entities": [{"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 31, "char_end": 46, "token_start": 5, "token_end": 8}, {"text": "- 150 AP - 1 site", "type": "ENTITY", "char_start": 54, "char_end": 71, "token_start": 11, "token_end": 16}], "entities_global": [{"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 366118, "char_end": 366133, "token_start": 5, "token_end": 8, "note": null}, {"text": "- 150 AP - 1 site", "type": "ENTITY", "char_start": 366141, "char_end": 366158, "token_start": 11, "token_end": 16, "note": null}]}
+{"sentence_id": 2214, "sentence_text": "Both CD4 + and CD8 + T cells that produce IL - 2 in response to Ag recognition have been isolated .", "sentence_char_start_global": 366187, "sentence_char_end_global": 366286, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 42, "char_end": 48, "token_start": 10, "token_end": 12}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 366229, "char_end": 366235, "token_start": 10, "token_end": 12, "note": null}]}
+{"sentence_id": 2215, "sentence_text": "However , most effector CD8 + T cells recovered after exposure to Ag do not produce sufficient IL - 2 to sustain growth , and depend on CD4 + T helper cells for this obligate growth factor .", "sentence_char_start_global": 366287, "sentence_char_end_global": 366477, "entities": [{"text": "Ag", "type": "ENTITY", "char_start": 66, "char_end": 68, "token_start": 12, "token_end": 12}, {"text": "IL - 2", "type": "ENTITY", "char_start": 95, "char_end": 101, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "Ag", "type": "ENTITY", "char_start": 366353, "char_end": 366355, "token_start": 12, "token_end": 12, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 366382, "char_end": 366388, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 2216, "sentence_text": "IL - 2 expression in CD4 + T cells is primarily controlled at the level of transcription , but mechanisms restricting IL - 2 production in CD8 + T cells have not been elucidated .", "sentence_char_start_global": 366478, "sentence_char_end_global": 366657, "entities": [], "entities_global": []}
+{"sentence_id": 2217, "sentence_text": "To evaluate transcriptional regulation of the IL - 2 gene in CD8 + T cells , we stably transfected reporter genes into Ag - specific CD8 + T cell clones .", "sentence_char_start_global": 366658, "sentence_char_end_global": 366812, "entities": [{"text": "IL - 2 gene", "type": "ENTITY", "char_start": 46, "char_end": 57, "token_start": 6, "token_end": 9}, {"text": "reporter genes", "type": "ENTITY", "char_start": 99, "char_end": 113, "token_start": 19, "token_end": 20}, {"text": "Ag", "type": "ENTITY", "char_start": 119, "char_end": 121, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "IL - 2 gene", "type": "ENTITY", "char_start": 366704, "char_end": 366715, "token_start": 6, "token_end": 9, "note": null}, {"text": "reporter genes", "type": "ENTITY", "char_start": 366757, "char_end": 366771, "token_start": 19, "token_end": 20, "note": null}, {"text": "Ag", "type": "ENTITY", "char_start": 366777, "char_end": 366779, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 2218, "sentence_text": "CD28 + CD8 ( + ) T cells unable to transcribe the IL - 2 gene in response to antigenic stimulation had a block in transactivation of the - 150 CD28 response element ( CD28RE ) / AP - 1 site of the IL - 2 promoter , but did transactivate the composite NFAT / AP - 1 and OCT / AP - 1 sites , and a consensus AP - 1 motif .", "sentence_char_start_global": 366813, "sentence_char_end_global": 367133, "entities": [{"text": "IL - 2 gene", "type": "ENTITY", "char_start": 50, "char_end": 61, "token_start": 12, "token_end": 15}, {"text": "- 150 CD28 response element ( CD28RE ) / AP - 1 site", "type": "ENTITY", "char_start": 137, "char_end": 189, "token_start": 28, "token_end": 40}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 197, "char_end": 212, "token_start": 43, "token_end": 46}, {"text": "NFAT / AP - 1 and OCT / AP - 1 sites", "type": "ENTITY", "char_start": 251, "char_end": 287, "token_start": 53, "token_end": 64}, {"text": "consensus AP - 1 motif", "type": "ENTITY", "char_start": 296, "char_end": 318, "token_start": 68, "token_end": 72}], "entities_global": [{"text": "IL - 2 gene", "type": "ENTITY", "char_start": 366863, "char_end": 366874, "token_start": 12, "token_end": 15, "note": null}, {"text": "- 150 CD28 response element ( CD28RE ) / AP - 1 site", "type": "ENTITY", "char_start": 366950, "char_end": 367002, "token_start": 28, "token_end": 40, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 367010, "char_end": 367025, "token_start": 43, "token_end": 46, "note": null}, {"text": "NFAT / AP - 1 and OCT / AP - 1 sites", "type": "ENTITY", "char_start": 367064, "char_end": 367100, "token_start": 53, "token_end": 64, "note": null}, {"text": "consensus AP - 1 motif", "type": "ENTITY", "char_start": 367109, "char_end": 367131, "token_start": 68, "token_end": 72, "note": null}]}
+{"sentence_id": 2219, "sentence_text": "Mutation of the nonconsensus - 150 AP - 1 site to a consensus AP - 1 site , or insertion of a CD28RE / AP - 1 consensus site upstream of the native - 150 CD28RE / AP - 1 site restored transactivation of the altered promoter .", "sentence_char_start_global": 367134, "sentence_char_end_global": 367359, "entities": [{"text": "nonconsensus - 150 AP - 1 site", "type": "ENTITY", "char_start": 16, "char_end": 46, "token_start": 3, "token_end": 9}, {"text": "consensus AP - 1 site", "type": "ENTITY", "char_start": 52, "char_end": 73, "token_start": 12, "token_end": 16}, {"text": "CD28RE / AP - 1 consensus site", "type": "ENTITY", "char_start": 94, "char_end": 124, "token_start": 22, "token_end": 28}, {"text": "- 150 CD28RE / AP - 1 site", "type": "ENTITY", "char_start": 148, "char_end": 174, "token_start": 33, "token_end": 40}, {"text": "promoter", "type": "ENTITY", "char_start": 215, "char_end": 223, "token_start": 46, "token_end": 46}], "entities_global": [{"text": "nonconsensus - 150 AP - 1 site", "type": "ENTITY", "char_start": 367150, "char_end": 367180, "token_start": 3, "token_end": 9, "note": null}, {"text": "consensus AP - 1 site", "type": "ENTITY", "char_start": 367186, "char_end": 367207, "token_start": 12, "token_end": 16, "note": null}, {"text": "CD28RE / AP - 1 consensus site", "type": "ENTITY", "char_start": 367228, "char_end": 367258, "token_start": 22, "token_end": 28, "note": null}, {"text": "- 150 CD28RE / AP - 1 site", "type": "ENTITY", "char_start": 367282, "char_end": 367308, "token_start": 33, "token_end": 40, "note": null}, {"text": "promoter", "type": "ENTITY", "char_start": 367349, "char_end": 367357, "token_start": 46, "token_end": 46, "note": null}]}
+{"sentence_id": 2220, "sentence_text": "These results suggest that the defect at the - 150 site may reflect the absence or inactivity of a required factor rather than repression of the IL - 2 promoter .", "sentence_char_start_global": 367360, "sentence_char_end_global": 367522, "entities": [{"text": "- 150 site", "type": "ENTITY", "char_start": 45, "char_end": 55, "token_start": 8, "token_end": 10}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 145, "char_end": 160, "token_start": 26, "token_end": 29}], "entities_global": [{"text": "- 150 site", "type": "ENTITY", "char_start": 367405, "char_end": 367415, "token_start": 8, "token_end": 10, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 367505, "char_end": 367520, "token_start": 26, "token_end": 29, "note": null}]}
+{"sentence_id": 2221, "sentence_text": "Stem cell factor and interleukin - 3 induce stepwise generation of erythroid precursor cells from a basic fibroblast growth factor - dependent hematopoietic stem cell line , A - 6 .", "sentence_char_start_global": 367523, "sentence_char_end_global": 367704, "entities": [{"text": "Stem cell factor", "type": "ENTITY", "char_start": 0, "char_end": 16, "token_start": 0, "token_end": 2}, {"text": "interleukin - 3", "type": "ENTITY", "char_start": 21, "char_end": 36, "token_start": 4, "token_end": 6}, {"text": "fibroblast growth factor", "type": "ENTITY", "char_start": 106, "char_end": 130, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "Stem cell factor", "type": "ENTITY", "char_start": 367523, "char_end": 367539, "token_start": 0, "token_end": 2, "note": null}, {"text": "interleukin - 3", "type": "ENTITY", "char_start": 367544, "char_end": 367559, "token_start": 4, "token_end": 6, "note": null}, {"text": "fibroblast growth factor", "type": "ENTITY", "char_start": 367629, "char_end": 367653, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 2222, "sentence_text": "A m ultipotent immature myeloid cell population was produced from a basic fibroblast growth factor ( bFGF ) - dependent hematopoietic stem cell line , A - 6 , when cultured with stem cell factor ( SCF ) replacing bFGF .", "sentence_char_start_global": 367705, "sentence_char_end_global": 367924, "entities": [{"text": "basic fibroblast growth factor", "type": "ENTITY", "char_start": 68, "char_end": 98, "token_start": 11, "token_end": 14}, {"text": "bFGF", "type": "ENTITY", "char_start": 101, "char_end": 105, "token_start": 16, "token_end": 16}, {"text": "stem cell factor", "type": "ENTITY", "char_start": 178, "char_end": 194, "token_start": 32, "token_end": 34}, {"text": "SCF", "type": "ENTITY", "char_start": 197, "char_end": 200, "token_start": 36, "token_end": 36}, {"text": "bFGF", "type": "ENTITY", "char_start": 213, "char_end": 217, "token_start": 39, "token_end": 39}], "entities_global": [{"text": "basic fibroblast growth factor", "type": "ENTITY", "char_start": 367773, "char_end": 367803, "token_start": 11, "token_end": 14, "note": null}, {"text": "bFGF", "type": "ENTITY", "char_start": 367806, "char_end": 367810, "token_start": 16, "token_end": 16, "note": null}, {"text": "stem cell factor", "type": "ENTITY", "char_start": 367883, "char_end": 367899, "token_start": 32, "token_end": 34, "note": null}, {"text": "SCF", "type": "ENTITY", "char_start": 367902, "char_end": 367905, "token_start": 36, "token_end": 36, "note": null}, {"text": "bFGF", "type": "ENTITY", "char_start": 367918, "char_end": 367922, "token_start": 39, "token_end": 39, "note": null}]}
+{"sentence_id": 2223, "sentence_text": "Those cells were positive for stem cell markers , c - kit and CD34 , and a myeloid cell marker , F4 / 80 .", "sentence_char_start_global": 367925, "sentence_char_end_global": 368031, "entities": [{"text": "stem cell markers", "type": "ENTITY", "char_start": 30, "char_end": 47, "token_start": 5, "token_end": 7}, {"text": "c - kit", "type": "ENTITY", "char_start": 50, "char_end": 57, "token_start": 9, "token_end": 11}, {"text": "CD34", "type": "ENTITY", "char_start": 62, "char_end": 66, "token_start": 13, "token_end": 13}, {"text": "myeloid cell marker , F4 / 80", "type": "ENTITY", "char_start": 75, "char_end": 104, "token_start": 17, "token_end": 23}], "entities_global": [{"text": "stem cell markers", "type": "ENTITY", "char_start": 367955, "char_end": 367972, "token_start": 5, "token_end": 7, "note": null}, {"text": "c - kit", "type": "ENTITY", "char_start": 367975, "char_end": 367982, "token_start": 9, "token_end": 11, "note": null}, {"text": "CD34", "type": "ENTITY", "char_start": 367987, "char_end": 367991, "token_start": 13, "token_end": 13, "note": null}, {"text": "myeloid cell marker , F4 / 80", "type": "ENTITY", "char_start": 368000, "char_end": 368029, "token_start": 17, "token_end": 23, "note": null}]}
+{"sentence_id": 2224, "sentence_text": "Some cell fractions were also positive for Mac - 1 , a macrophage marker or Gr - 1 , a granulocytic maker , but negative for an erythroid marker TER119 .", "sentence_char_start_global": 368032, "sentence_char_end_global": 368185, "entities": [{"text": "Mac - 1 , a macrophage marker", "type": "ENTITY", "char_start": 43, "char_end": 72, "token_start": 7, "token_end": 13}, {"text": "Gr - 1 , a granulocytic maker", "type": "ENTITY", "char_start": 76, "char_end": 105, "token_start": 15, "token_end": 21}, {"text": "erythroid marker TER119", "type": "ENTITY", "char_start": 128, "char_end": 151, "token_start": 27, "token_end": 29}], "entities_global": [{"text": "Mac - 1 , a macrophage marker", "type": "ENTITY", "char_start": 368075, "char_end": 368104, "token_start": 7, "token_end": 13, "note": null}, {"text": "Gr - 1 , a granulocytic maker", "type": "ENTITY", "char_start": 368108, "char_end": 368137, "token_start": 15, "token_end": 21, "note": null}, {"text": "erythroid marker TER119", "type": "ENTITY", "char_start": 368160, "char_end": 368183, "token_start": 27, "token_end": 29, "note": null}]}
+{"sentence_id": 2225, "sentence_text": "They also showed the expression of mRNA for the myeloid - specific PU . 1 but did not that for the erythroid - specific GATA - 1 .", "sentence_char_start_global": 368186, "sentence_char_end_global": 368316, "entities": [{"text": "myeloid - specific PU . 1", "type": "ENTITY", "char_start": 48, "char_end": 73, "token_start": 9, "token_end": 14}, {"text": "erythroid - specific GATA - 1", "type": "ENTITY", "char_start": 99, "char_end": 128, "token_start": 21, "token_end": 26}], "entities_global": [{"text": "myeloid - specific PU . 1", "type": "ENTITY", "char_start": 368234, "char_end": 368259, "token_start": 9, "token_end": 14, "note": null}, {"text": "erythroid - specific GATA - 1", "type": "ENTITY", "char_start": 368285, "char_end": 368314, "token_start": 21, "token_end": 26, "note": null}]}
+{"sentence_id": 2226, "sentence_text": "Among various cytokines , interleukin - 3 ( IL - 3 ) induced erythroid precursor cells that expressed the erythroid - specific GATA - 1 and beta - major globin .", "sentence_char_start_global": 368317, "sentence_char_end_global": 368478, "entities": [{"text": "cytokines", "type": "ENTITY", "char_start": 14, "char_end": 23, "token_start": 2, "token_end": 2}, {"text": "interleukin - 3", "type": "ENTITY", "char_start": 26, "char_end": 41, "token_start": 4, "token_end": 6}, {"text": "IL - 3", "type": "ENTITY", "char_start": 44, "char_end": 50, "token_start": 8, "token_end": 10}, {"text": "erythroid - specific GATA - 1", "type": "ENTITY", "char_start": 106, "char_end": 135, "token_start": 19, "token_end": 24}, {"text": "beta - major globin", "type": "ENTITY", "char_start": 140, "char_end": 159, "token_start": 26, "token_end": 29}], "entities_global": [{"text": "cytokines", "type": "ENTITY", "char_start": 368331, "char_end": 368340, "token_start": 2, "token_end": 2, "note": null}, {"text": "interleukin - 3", "type": "ENTITY", "char_start": 368343, "char_end": 368358, "token_start": 4, "token_end": 6, "note": null}, {"text": "IL - 3", "type": "ENTITY", "char_start": 368361, "char_end": 368367, "token_start": 8, "token_end": 10, "note": null}, {"text": "erythroid - specific GATA - 1", "type": "ENTITY", "char_start": 368423, "char_end": 368452, "token_start": 19, "token_end": 24, "note": null}, {"text": "beta - major globin", "type": "ENTITY", "char_start": 368457, "char_end": 368476, "token_start": 26, "token_end": 29, "note": null}]}
+{"sentence_id": 2227, "sentence_text": "The quantitative analysis showed that erythroid precursor cells were newly produced from the immature myeloid cells by cultivation with IL - 3 .", "sentence_char_start_global": 368479, "sentence_char_end_global": 368623, "entities": [{"text": "IL - 3", "type": "ENTITY", "char_start": 136, "char_end": 142, "token_start": 19, "token_end": 21}], "entities_global": [{"text": "IL - 3", "type": "ENTITY", "char_start": 368615, "char_end": 368621, "token_start": 19, "token_end": 21, "note": null}]}
+{"sentence_id": 2228, "sentence_text": "SCF and IL - 3 induced stepwise generation of erythroid precursor cells from an A - 6 hematopoietic stem cell line .", "sentence_char_start_global": 368624, "sentence_char_end_global": 368740, "entities": [{"text": "SCF", "type": "ENTITY", "char_start": 0, "char_end": 3, "token_start": 0, "token_end": 0}, {"text": "IL - 3", "type": "ENTITY", "char_start": 8, "char_end": 14, "token_start": 2, "token_end": 4}], "entities_global": [{"text": "SCF", "type": "ENTITY", "char_start": 368624, "char_end": 368627, "token_start": 0, "token_end": 0, "note": null}, {"text": "IL - 3", "type": "ENTITY", "char_start": 368632, "char_end": 368638, "token_start": 2, "token_end": 4, "note": null}]}
+{"sentence_id": 2229, "sentence_text": "Copyright 2001 Academic Press .", "sentence_char_start_global": 368741, "sentence_char_end_global": 368772, "entities": [], "entities_global": []}
+{"sentence_id": 2230, "sentence_text": "Distinct BMI - 1 and EZH2 expression patterns in thymocytes and mature T cells suggest a role for Polycomb genes in human T cell differentiation .", "sentence_char_start_global": 368773, "sentence_char_end_global": 368919, "entities": [{"text": "BMI - 1", "type": "ENTITY", "char_start": 9, "char_end": 16, "token_start": 1, "token_end": 3}, {"text": "EZH2", "type": "ENTITY", "char_start": 21, "char_end": 25, "token_start": 5, "token_end": 5}, {"text": "Polycomb genes", "type": "ENTITY", "char_start": 98, "char_end": 112, "token_start": 18, "token_end": 19}], "entities_global": [{"text": "BMI - 1", "type": "ENTITY", "char_start": 368782, "char_end": 368789, "token_start": 1, "token_end": 3, "note": null}, {"text": "EZH2", "type": "ENTITY", "char_start": 368794, "char_end": 368798, "token_start": 5, "token_end": 5, "note": null}, {"text": "Polycomb genes", "type": "ENTITY", "char_start": 368871, "char_end": 368885, "token_start": 18, "token_end": 19, "note": null}]}
+{"sentence_id": 2231, "sentence_text": "BMI - 1 and EZH2 Polycomb - group ( PcG ) proteins belong to two distinct protein complexes involved in the regulation of hematopoiesis .", "sentence_char_start_global": 368920, "sentence_char_end_global": 369057, "entities": [{"text": "BMI - 1", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 2}, {"text": "EZH2", "type": "ENTITY", "char_start": 12, "char_end": 16, "token_start": 4, "token_end": 4}, {"text": "Polycomb - group ( PcG ) proteins", "type": "ENTITY", "char_start": 17, "char_end": 50, "token_start": 5, "token_end": 11}], "entities_global": [{"text": "BMI - 1", "type": "ENTITY", "char_start": 368920, "char_end": 368927, "token_start": 0, "token_end": 2, "note": null}, {"text": "EZH2", "type": "ENTITY", "char_start": 368932, "char_end": 368936, "token_start": 4, "token_end": 4, "note": null}, {"text": "Polycomb - group ( PcG ) proteins", "type": "ENTITY", "char_start": 368937, "char_end": 368970, "token_start": 5, "token_end": 11, "note": null}]}
+{"sentence_id": 2232, "sentence_text": "Using unique PcG - specific antisera and triple immunofluorescence , we found that mature resting peripheral T cells expressed BMI - 1 , whereas dividing blasts were EZH2 ( + ) .", "sentence_char_start_global": 369058, "sentence_char_end_global": 369236, "entities": [{"text": "BMI - 1", "type": "ENTITY", "char_start": 127, "char_end": 134, "token_start": 19, "token_end": 21}], "entities_global": [{"text": "BMI - 1", "type": "ENTITY", "char_start": 369185, "char_end": 369192, "token_start": 19, "token_end": 21, "note": null}]}
+{"sentence_id": 2233, "sentence_text": "By contrast , subcapsular immature double - negative ( DN ) ( CD4 ( - ) / CD8 ( - ) ) T cells in the thymus coexpressed BMI - 1 and EZH2 or were BMI - 1 single positive .", "sentence_char_start_global": 369237, "sentence_char_end_global": 369407, "entities": [{"text": "BMI - 1", "type": "ENTITY", "char_start": 120, "char_end": 127, "token_start": 28, "token_end": 30}, {"text": "EZH2", "type": "ENTITY", "char_start": 132, "char_end": 136, "token_start": 32, "token_end": 32}], "entities_global": [{"text": "BMI - 1", "type": "ENTITY", "char_start": 369357, "char_end": 369364, "token_start": 28, "token_end": 30, "note": null}, {"text": "EZH2", "type": "ENTITY", "char_start": 369369, "char_end": 369373, "token_start": 32, "token_end": 32, "note": null}]}
+{"sentence_id": 2234, "sentence_text": "Their descendants , double - positive ( DP ; CD4 ( + ) / CD8 ( + ) ) cortical thymocytes , expressed EZH2 without BMI - 1 .", "sentence_char_start_global": 369408, "sentence_char_end_global": 369531, "entities": [{"text": "EZH2", "type": "ENTITY", "char_start": 101, "char_end": 105, "token_start": 23, "token_end": 23}, {"text": "BMI - 1", "type": "ENTITY", "char_start": 114, "char_end": 121, "token_start": 25, "token_end": 27}], "entities_global": [{"text": "EZH2", "type": "ENTITY", "char_start": 369509, "char_end": 369513, "token_start": 23, "token_end": 23, "note": null}, {"text": "BMI - 1", "type": "ENTITY", "char_start": 369522, "char_end": 369529, "token_start": 25, "token_end": 27, "note": null}]}
+{"sentence_id": 2235, "sentence_text": "Most EZH2 ( + ) DN and DP thymocytes were dividing , while DN BMI - 1 ( + ) / EZH2 ( - ) thymocytes were resting and proliferation was occasionally noted in DN BMI - 1 ( + ) / EZH2 ( + ) cells .", "sentence_char_start_global": 369532, "sentence_char_end_global": 369726, "entities": [], "entities_global": []}
+{"sentence_id": 2236, "sentence_text": "Maturation of DP cortical thymocytes to single - positive ( CD4 ( + ) / CD8 ( - ) or CD8 ( + ) / CD4 ( - ) ) medullar thymocytes correlated with decreased detectability of EZH2 and continued relative absence of BMI - 1 .", "sentence_char_start_global": 369727, "sentence_char_end_global": 369947, "entities": [{"text": "EZH2", "type": "ENTITY", "char_start": 172, "char_end": 176, "token_start": 37, "token_end": 37}, {"text": "BMI - 1", "type": "ENTITY", "char_start": 211, "char_end": 218, "token_start": 43, "token_end": 45}], "entities_global": [{"text": "EZH2", "type": "ENTITY", "char_start": 369899, "char_end": 369903, "token_start": 37, "token_end": 37, "note": null}, {"text": "BMI - 1", "type": "ENTITY", "char_start": 369938, "char_end": 369945, "token_start": 43, "token_end": 45, "note": null}]}
+{"sentence_id": 2237, "sentence_text": "Our data show that BMI - 1 and EZH2 expression in mature peripheral T cells is mutually exclusive and linked to proliferation status , and that this pattern is not yet established in thymocytes of the cortex and medulla .", "sentence_char_start_global": 369948, "sentence_char_end_global": 370169, "entities": [{"text": "BMI - 1", "type": "ENTITY", "char_start": 19, "char_end": 26, "token_start": 4, "token_end": 6}, {"text": "EZH2", "type": "ENTITY", "char_start": 31, "char_end": 35, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "BMI - 1", "type": "ENTITY", "char_start": 369967, "char_end": 369974, "token_start": 4, "token_end": 6, "note": null}, {"text": "EZH2", "type": "ENTITY", "char_start": 369979, "char_end": 369983, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 2238, "sentence_text": "T cell stage - specific PcG expression profiles suggest that PcG genes contribute to regulation of T cell differentiation .", "sentence_char_start_global": 370170, "sentence_char_end_global": 370293, "entities": [{"text": "PcG genes", "type": "ENTITY", "char_start": 61, "char_end": 70, "token_start": 10, "token_end": 11}], "entities_global": [{"text": "PcG genes", "type": "ENTITY", "char_start": 370231, "char_end": 370240, "token_start": 10, "token_end": 11, "note": null}]}
+{"sentence_id": 2239, "sentence_text": "They probably reflect stabilization of cell type - specific gene expression and irreversibility of lineage choice .", "sentence_char_start_global": 370294, "sentence_char_end_global": 370409, "entities": [], "entities_global": []}
+{"sentence_id": 2240, "sentence_text": "The difference in PcG expression between medullar thymocytes and mature interfollicular T cells indicates that additional maturation processes occur after thymocyte transportation from the thymus .", "sentence_char_start_global": 370410, "sentence_char_end_global": 370607, "entities": [], "entities_global": []}
+{"sentence_id": 2241, "sentence_text": "Stepwise lineage restriction of progenitors in lympho - myelopoiesis .", "sentence_char_start_global": 370608, "sentence_char_end_global": 370678, "entities": [], "entities_global": []}
+{"sentence_id": 2242, "sentence_text": "It has long been controversial whether hematopoiesis progresses through ordered stages of determination as in embryonic development .", "sentence_char_start_global": 370679, "sentence_char_end_global": 370812, "entities": [], "entities_global": []}
+{"sentence_id": 2243, "sentence_text": "This is due to the absence of a methodology capable of exactly determining the developmental potential of hematopoietic stem / progenitor cells .", "sentence_char_start_global": 370813, "sentence_char_end_global": 370958, "entities": [], "entities_global": []}
+{"sentence_id": 2244, "sentence_text": "The multilineage progenitor ( MLP ) assay enabled us to discriminate among seven types of hematopoietic progenitors , which are multipotent progenitor p - MTB ( capable of generating myeloid , T and B cells ) , bipotent progenitors p - MT , p - MB and p - TB , and unipotent progenitors p - M , p - T and p - B .", "sentence_char_start_global": 370959, "sentence_char_end_global": 371271, "entities": [], "entities_global": []}
+{"sentence_id": 2245, "sentence_text": "Among these seven types , the p - TB type progenitor was found to be absent .", "sentence_char_start_global": 371272, "sentence_char_end_global": 371349, "entities": [], "entities_global": []}
+{"sentence_id": 2246, "sentence_text": "These findings indicate that the process of lineage commitment proceeds through an ordered but not random process .", "sentence_char_start_global": 371350, "sentence_char_end_global": 371465, "entities": [], "entities_global": []}
+{"sentence_id": 2247, "sentence_text": "By extending the area of investigation to include the erythroid lineage , more convincing evidence for the ordered process was obtained .", "sentence_char_start_global": 371466, "sentence_char_end_global": 371603, "entities": [], "entities_global": []}
+{"sentence_id": 2248, "sentence_text": "Detailed and exact illustration of the process of hematopoiesis will provide an opportunity to revive hematopoiesis as one of the most fascinating targets of research in developmental biology", "sentence_char_start_global": 371604, "sentence_char_end_global": 371795, "entities": [], "entities_global": []}
+{"sentence_id": 2249, "sentence_text": "Epstein - Barr Virus and its glycoprotein - 350 upregulate IL - 6 in human B - lymphocytes via CD21 , involving activation of NF - kappaB and different signaling pathways .", "sentence_char_start_global": 371796, "sentence_char_end_global": 371968, "entities": [{"text": "glycoprotein - 350", "type": "ENTITY", "char_start": 29, "char_end": 47, "token_start": 6, "token_end": 8}, {"text": "IL - 6", "type": "ENTITY", "char_start": 59, "char_end": 65, "token_start": 10, "token_end": 12}, {"text": "CD21", "type": "ENTITY", "char_start": 95, "char_end": 99, "token_start": 19, "token_end": 19}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 126, "char_end": 137, "token_start": 24, "token_end": 26}], "entities_global": [{"text": "glycoprotein - 350", "type": "ENTITY", "char_start": 371825, "char_end": 371843, "token_start": 6, "token_end": 8, "note": null}, {"text": "IL - 6", "type": "ENTITY", "char_start": 371855, "char_end": 371861, "token_start": 10, "token_end": 12, "note": null}, {"text": "CD21", "type": "ENTITY", "char_start": 371891, "char_end": 371895, "token_start": 19, "token_end": 19, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 371922, "char_end": 371933, "token_start": 24, "token_end": 26, "note": null}]}
+{"sentence_id": 2250, "sentence_text": "Epstein - Barr virus ( EBV ) is a ubiquitous and highly immunotropic gamma herpesvirus that infects more than 90 % of humans worldwide .", "sentence_char_start_global": 371969, "sentence_char_end_global": 372105, "entities": [], "entities_global": []}
+{"sentence_id": 2251, "sentence_text": "Its pathogenicity leads to a number of diseases including tumors that result from EBV ' s ability to readily transform B - lymphocytes and , to a lesser extent , epithelial cells .", "sentence_char_start_global": 372106, "sentence_char_end_global": 372286, "entities": [], "entities_global": []}
+{"sentence_id": 2252, "sentence_text": "EBV utilizes CD21 / CR2 as its receptor on B cells to initiate the infection process .", "sentence_char_start_global": 372287, "sentence_char_end_global": 372373, "entities": [{"text": "CD21 / CR2", "type": "ENTITY", "char_start": 13, "char_end": 23, "token_start": 2, "token_end": 4}], "entities_global": [{"text": "CD21 / CR2", "type": "ENTITY", "char_start": 372300, "char_end": 372310, "token_start": 2, "token_end": 4, "note": null}]}
+{"sentence_id": 2253, "sentence_text": "EBV binds to CR2 through its major envelope glycoprotein - 350 ( gp350 ) and is also a remarkable immunomodulating agent .", "sentence_char_start_global": 372374, "sentence_char_end_global": 372496, "entities": [{"text": "CR2", "type": "ENTITY", "char_start": 13, "char_end": 16, "token_start": 3, "token_end": 3}, {"text": "major envelope glycoprotein - 350", "type": "ENTITY", "char_start": 29, "char_end": 62, "token_start": 6, "token_end": 10}, {"text": "gp350", "type": "ENTITY", "char_start": 65, "char_end": 70, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "CR2", "type": "ENTITY", "char_start": 372387, "char_end": 372390, "token_start": 3, "token_end": 3, "note": null}, {"text": "major envelope glycoprotein - 350", "type": "ENTITY", "char_start": 372403, "char_end": 372436, "token_start": 6, "token_end": 10, "note": null}, {"text": "gp350", "type": "ENTITY", "char_start": 372439, "char_end": 372444, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 2254, "sentence_text": "We had previously shown that EBV is capable of modulating the synthesis of a number of cytokines .", "sentence_char_start_global": 372497, "sentence_char_end_global": 372595, "entities": [{"text": "cytokines", "type": "ENTITY", "char_start": 87, "char_end": 96, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "cytokines", "type": "ENTITY", "char_start": 372584, "char_end": 372593, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 2255, "sentence_text": "We now show that while both purified recombinant gp350 ( rgp350 ) and EBV upregulate IL - 6 mRNA synthesis in B cells , EBV - induced IL - 6 gene activation occurs for a significantly longer period of time ( i . e . 12 hours for EBV as compared to 6 hours for rgp350 ) .", "sentence_char_start_global": 372596, "sentence_char_end_global": 372866, "entities": [{"text": "recombinant gp350", "type": "ENTITY", "char_start": 37, "char_end": 54, "token_start": 7, "token_end": 8}, {"text": "rgp350", "type": "ENTITY", "char_start": 57, "char_end": 63, "token_start": 10, "token_end": 10}, {"text": "IL - 6 mRNA", "type": "ENTITY", "char_start": 85, "char_end": 96, "token_start": 15, "token_end": 18}, {"text": "rgp350", "type": "ENTITY", "char_start": 260, "char_end": 266, "token_start": 55, "token_end": 55}], "entities_global": [{"text": "recombinant gp350", "type": "ENTITY", "char_start": 372633, "char_end": 372650, "token_start": 7, "token_end": 8, "note": null}, {"text": "rgp350", "type": "ENTITY", "char_start": 372653, "char_end": 372659, "token_start": 10, "token_end": 10, "note": null}, {"text": "IL - 6 mRNA", "type": "ENTITY", "char_start": 372681, "char_end": 372692, "token_start": 15, "token_end": 18, "note": null}, {"text": "rgp350", "type": "ENTITY", "char_start": 372856, "char_end": 372862, "token_start": 55, "token_end": 55, "note": null}]}
+{"sentence_id": 2256, "sentence_text": "Moreover , the half - life of EBV - induced IL - 6 mRNA was also significantly longer ( 10 hours ) than that of mRNA induced by rgp350 ( about 6 hours ) .", "sentence_char_start_global": 372867, "sentence_char_end_global": 373021, "entities": [{"text": "IL - 6 mRNA", "type": "ENTITY", "char_start": 44, "char_end": 55, "token_start": 10, "token_end": 13}, {"text": "rgp350", "type": "ENTITY", "char_start": 128, "char_end": 134, "token_start": 28, "token_end": 28}], "entities_global": [{"text": "IL - 6 mRNA", "type": "ENTITY", "char_start": 372911, "char_end": 372922, "token_start": 10, "token_end": 13, "note": null}, {"text": "rgp350", "type": "ENTITY", "char_start": 372995, "char_end": 373001, "token_start": 28, "token_end": 28, "note": null}]}
+{"sentence_id": 2257, "sentence_text": "Both EBV and gp350 enhance the binding of the NF - kappaB transcription factor , as determined by band - shift and augment NF - kappaB - mediated activation of a CAT reporter plasmid .", "sentence_char_start_global": 373022, "sentence_char_end_global": 373206, "entities": [{"text": "gp350", "type": "ENTITY", "char_start": 13, "char_end": 18, "token_start": 3, "token_end": 3}, {"text": "NF - kappaB transcription factor", "type": "ENTITY", "char_start": 46, "char_end": 78, "token_start": 9, "token_end": 13}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 123, "char_end": 134, "token_start": 23, "token_end": 25}, {"text": "CAT reporter plasmid", "type": "ENTITY", "char_start": 162, "char_end": 182, "token_start": 31, "token_end": 33}], "entities_global": [{"text": "gp350", "type": "ENTITY", "char_start": 373035, "char_end": 373040, "token_start": 3, "token_end": 3, "note": null}, {"text": "NF - kappaB transcription factor", "type": "ENTITY", "char_start": 373068, "char_end": 373100, "token_start": 9, "token_end": 13, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 373145, "char_end": 373156, "token_start": 23, "token_end": 25, "note": null}, {"text": "CAT reporter plasmid", "type": "ENTITY", "char_start": 373184, "char_end": 373204, "token_start": 31, "token_end": 33, "note": null}]}
+{"sentence_id": 2258, "sentence_text": "Furthermore , we demonstrate that while the activation of IL - 6 gene expression by gp350 is mediated primarily by the protein kinase C pathway , EBV can mediate its effects through multiple signaling pathways .", "sentence_char_start_global": 373207, "sentence_char_end_global": 373418, "entities": [{"text": "gp350", "type": "ENTITY", "char_start": 84, "char_end": 89, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "gp350", "type": "ENTITY", "char_start": 373291, "char_end": 373296, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 2259, "sentence_text": "To our knowledge this is the first report showing that the binding of a herpesvirus envelope glycoprotein to CR2 on human B cells results in the activation of the NF - kappaB transcription factor leading to the upregulation of IL - 6 gene expression in these lymphocytes .", "sentence_char_start_global": 373419, "sentence_char_end_global": 373691, "entities": [{"text": "herpesvirus envelope glycoprotein", "type": "ENTITY", "char_start": 72, "char_end": 105, "token_start": 14, "token_end": 16}, {"text": "CR2", "type": "ENTITY", "char_start": 109, "char_end": 112, "token_start": 18, "token_end": 18}, {"text": "NF - kappaB transcription factor", "type": "ENTITY", "char_start": 163, "char_end": 195, "token_start": 29, "token_end": 33}], "entities_global": [{"text": "herpesvirus envelope glycoprotein", "type": "ENTITY", "char_start": 373491, "char_end": 373524, "token_start": 14, "token_end": 16, "note": null}, {"text": "CR2", "type": "ENTITY", "char_start": 373528, "char_end": 373531, "token_start": 18, "token_end": 18, "note": null}, {"text": "NF - kappaB transcription factor", "type": "ENTITY", "char_start": 373582, "char_end": 373614, "token_start": 29, "token_end": 33, "note": null}]}
+{"sentence_id": 2260, "sentence_text": "Copyright 2001 Academic Press .", "sentence_char_start_global": 373692, "sentence_char_end_global": 373723, "entities": [], "entities_global": []}
+{"sentence_id": 2261, "sentence_text": "Gene - and tissue - specificity of mutation in Big Blue rats treated with the hepatocarcinogen N - hydroxy - 2 - acetylaminofluorene .", "sentence_char_start_global": 373724, "sentence_char_end_global": 373858, "entities": [], "entities_global": []}
+{"sentence_id": 2262, "sentence_text": "In a previous study , we found that treating transgenic Big Blue rats with the hepatocarcinogen N - hydroxy - 2 - acetylaminofluorene ( N - OH - AAF ) produced the same major DNA adduct in the target liver and the nontarget spleen lymphocytes and bone marrow cells , induced lacI mutants in the liver , and induced much lower frequencies of l acI and hprt mutants in spleen lymphocytes .", "sentence_char_start_global": 373859, "sentence_char_end_global": 374246, "entities": [], "entities_global": []}
+{"sentence_id": 2263, "sentence_text": "In the present study , sequence analysis was conducted on lacI DNA and hprt cDNA from the mutants , to determine the mutational specificity of N - OH - AAF in the rat .", "sentence_char_start_global": 374247, "sentence_char_end_global": 374415, "entities": [{"text": "lacI DNA", "type": "ENTITY", "char_start": 58, "char_end": 66, "token_start": 10, "token_end": 11}, {"text": "hprt cDNA", "type": "ENTITY", "char_start": 71, "char_end": 80, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "lacI DNA", "type": "ENTITY", "char_start": 374305, "char_end": 374313, "token_start": 10, "token_end": 11, "note": null}, {"text": "hprt cDNA", "type": "ENTITY", "char_start": 374318, "char_end": 374327, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 2264, "sentence_text": "All the mutation spectra from N - OH - AAF - treated rats differed significantly from corresponding mutation profiles from untreated animals ( P = 0 . 02 to P < 0 . 0001 ) .", "sentence_char_start_global": 374416, "sentence_char_end_global": 374589, "entities": [], "entities_global": []}
+{"sentence_id": 2265, "sentence_text": "Although there were similarities among the mutational patterns derived from N - OH - AAF - treated rats ( e . g . , G : C - - > T : A transversion was the most common mutation in all mutation sets ) , there were significant differences in the patterns of basepair substitution and frameshift mutation between the liver and spleen lymphocyte lacI mutants ( P = 0 . 02 ) and between the spleen lymphocyte lacI and hprt mutants ( P = 0 . 04 ) .", "sentence_char_start_global": 374590, "sentence_char_end_global": 375031, "entities": [], "entities_global": []}
+{"sentence_id": 2266, "sentence_text": "Also , multiplex PCR analysis of genomic DNA from the hprt mutants indicated that 12 % of mutants from treated rats had major deletions in the hprt gene ; no corresponding incidence of large deletions was evident among lacI mutations .", "sentence_char_start_global": 375032, "sentence_char_end_global": 375267, "entities": [{"text": "genomic DNA", "type": "ENTITY", "char_start": 33, "char_end": 44, "token_start": 6, "token_end": 7}, {"text": "hprt gene", "type": "ENTITY", "char_start": 143, "char_end": 152, "token_start": 26, "token_end": 27}], "entities_global": [{"text": "genomic DNA", "type": "ENTITY", "char_start": 375065, "char_end": 375076, "token_start": 6, "token_end": 7, "note": null}, {"text": "hprt gene", "type": "ENTITY", "char_start": 375175, "char_end": 375184, "token_start": 26, "token_end": 27, "note": null}]}
+{"sentence_id": 2267, "sentence_text": "All the mutation profiles reflect the general mutational specificity of the major DNA adduct formed by N - OH - AAF .", "sentence_char_start_global": 375268, "sentence_char_end_global": 375385, "entities": [], "entities_global": []}
+{"sentence_id": 2268, "sentence_text": "The differences between N - OH - AAF mutation in the endogenous gene and transgene can be partially explained by the structures of the two genes .", "sentence_char_start_global": 375386, "sentence_char_end_global": 375532, "entities": [{"text": "endogenous gene", "type": "ENTITY", "char_start": 53, "char_end": 68, "token_start": 11, "token_end": 12}, {"text": "transgene", "type": "ENTITY", "char_start": 73, "char_end": 82, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "endogenous gene", "type": "ENTITY", "char_start": 375439, "char_end": 375454, "token_start": 11, "token_end": 12, "note": null}, {"text": "transgene", "type": "ENTITY", "char_start": 375459, "char_end": 375468, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 2269, "sentence_text": "The tissue - specificity of the mutation spectra may contribute to targeting tumor formation to the liver .", "sentence_char_start_global": 375533, "sentence_char_end_global": 375640, "entities": [], "entities_global": []}
+{"sentence_id": 2270, "sentence_text": "Environ . Mol . Mutagen . 37 : 203 - 214 , 2001 .", "sentence_char_start_global": 375641, "sentence_char_end_global": 375690, "entities": [], "entities_global": []}
+{"sentence_id": 2271, "sentence_text": "Published 2001 Wiley - Liss , Inc .", "sentence_char_start_global": 375691, "sentence_char_end_global": 375726, "entities": [], "entities_global": []}
+{"sentence_id": 2272, "sentence_text": "Caspase - dependent cleavage of the hematopoietic specific adaptor protein Gads alters signalling from the T cell receptor .", "sentence_char_start_global": 375727, "sentence_char_end_global": 375851, "entities": [{"text": "Caspase", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 0}, {"text": "hematopoietic specific adaptor protein Gads", "type": "ENTITY", "char_start": 36, "char_end": 79, "token_start": 6, "token_end": 10}, {"text": "T cell receptor", "type": "ENTITY", "char_start": 107, "char_end": 122, "token_start": 15, "token_end": 17}], "entities_global": [{"text": "Caspase", "type": "ENTITY", "char_start": 375727, "char_end": 375734, "token_start": 0, "token_end": 0, "note": null}, {"text": "hematopoietic specific adaptor protein Gads", "type": "ENTITY", "char_start": 375763, "char_end": 375806, "token_start": 6, "token_end": 10, "note": null}, {"text": "T cell receptor", "type": "ENTITY", "char_start": 375834, "char_end": 375849, "token_start": 15, "token_end": 17, "note": null}]}
+{"sentence_id": 2273, "sentence_text": "Gads is a SH2 and SH3 domain - containing , hematopoietic - specific adaptor protein that functions in signalling from the T cell receptor .", "sentence_char_start_global": 375852, "sentence_char_end_global": 375992, "entities": [{"text": "Gads", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}, {"text": "SH2 and SH3 domain", "type": "ENTITY", "char_start": 10, "char_end": 28, "token_start": 3, "token_end": 6}, {"text": "hematopoietic - specific adaptor protein", "type": "ENTITY", "char_start": 44, "char_end": 84, "token_start": 10, "token_end": 14}, {"text": "T cell receptor", "type": "ENTITY", "char_start": 123, "char_end": 138, "token_start": 21, "token_end": 23}], "entities_global": [{"text": "Gads", "type": "ENTITY", "char_start": 375852, "char_end": 375856, "token_start": 0, "token_end": 0, "note": null}, {"text": "SH2 and SH3 domain", "type": "ENTITY", "char_start": 375862, "char_end": 375880, "token_start": 3, "token_end": 6, "note": null}, {"text": "hematopoietic - specific adaptor protein", "type": "ENTITY", "char_start": 375896, "char_end": 375936, "token_start": 10, "token_end": 14, "note": null}, {"text": "T cell receptor", "type": "ENTITY", "char_start": 375975, "char_end": 375990, "token_start": 21, "token_end": 23, "note": null}]}
+{"sentence_id": 2274, "sentence_text": "Gads acts by linking SLP - 76 , bound by the carboxy - terminal Gads SH3 domain , to tyrosine phosphorylated LAT which contains binding sites for the Gads SH2 domain .", "sentence_char_start_global": 375993, "sentence_char_end_global": 376160, "entities": [{"text": "Gads", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}, {"text": "SLP - 76", "type": "ENTITY", "char_start": 21, "char_end": 29, "token_start": 4, "token_end": 6}, {"text": "carboxy - terminal Gads SH3 domain", "type": "ENTITY", "char_start": 45, "char_end": 79, "token_start": 11, "token_end": 16}, {"text": "tyrosine phosphorylated LAT", "type": "ENTITY", "char_start": 85, "char_end": 112, "token_start": 19, "token_end": 21}, {"text": "Gads SH2 domain", "type": "ENTITY", "char_start": 150, "char_end": 165, "token_start": 28, "token_end": 30}], "entities_global": [{"text": "Gads", "type": "ENTITY", "char_start": 375993, "char_end": 375997, "token_start": 0, "token_end": 0, "note": null}, {"text": "SLP - 76", "type": "ENTITY", "char_start": 376014, "char_end": 376022, "token_start": 4, "token_end": 6, "note": null}, {"text": "carboxy - terminal Gads SH3 domain", "type": "ENTITY", "char_start": 376038, "char_end": 376072, "token_start": 11, "token_end": 16, "note": null}, {"text": "tyrosine phosphorylated LAT", "type": "ENTITY", "char_start": 376078, "char_end": 376105, "token_start": 19, "token_end": 21, "note": null}, {"text": "Gads SH2 domain", "type": "ENTITY", "char_start": 376143, "char_end": 376158, "token_start": 28, "token_end": 30, "note": null}]}
+{"sentence_id": 2275, "sentence_text": "Gads is distinguished from Grb2 and the closely related Grap protein by the presence of a 120 amino acid unique region between the SH2 domain and the carboxy terminal SH3 domain .", "sentence_char_start_global": 376161, "sentence_char_end_global": 376340, "entities": [{"text": "Gads", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}, {"text": "Grb2", "type": "ENTITY", "char_start": 27, "char_end": 31, "token_start": 4, "token_end": 4}, {"text": "Grap protein", "type": "ENTITY", "char_start": 56, "char_end": 68, "token_start": 9, "token_end": 10}, {"text": "120 amino acid unique region", "type": "ENTITY", "char_start": 90, "char_end": 118, "token_start": 16, "token_end": 20}, {"text": "SH2 domain", "type": "ENTITY", "char_start": 131, "char_end": 141, "token_start": 23, "token_end": 24}, {"text": "carboxy terminal SH3 domain", "type": "ENTITY", "char_start": 150, "char_end": 177, "token_start": 27, "token_end": 30}], "entities_global": [{"text": "Gads", "type": "ENTITY", "char_start": 376161, "char_end": 376165, "token_start": 0, "token_end": 0, "note": null}, {"text": "Grb2", "type": "ENTITY", "char_start": 376188, "char_end": 376192, "token_start": 4, "token_end": 4, "note": null}, {"text": "Grap protein", "type": "ENTITY", "char_start": 376217, "char_end": 376229, "token_start": 9, "token_end": 10, "note": null}, {"text": "120 amino acid unique region", "type": "ENTITY", "char_start": 376251, "char_end": 376279, "token_start": 16, "token_end": 20, "note": null}, {"text": "SH2 domain", "type": "ENTITY", "char_start": 376292, "char_end": 376302, "token_start": 23, "token_end": 24, "note": null}, {"text": "carboxy terminal SH3 domain", "type": "ENTITY", "char_start": 376311, "char_end": 376338, "token_start": 27, "token_end": 30, "note": null}]}
+{"sentence_id": 2276, "sentence_text": "Here we demonstrate that the unique region of Gads contains a capase cleavage site .", "sentence_char_start_global": 376341, "sentence_char_end_global": 376425, "entities": [{"text": "Gads", "type": "ENTITY", "char_start": 46, "char_end": 50, "token_start": 8, "token_end": 8}, {"text": "capase cleavage site", "type": "ENTITY", "char_start": 62, "char_end": 82, "token_start": 11, "token_end": 13}], "entities_global": [{"text": "Gads", "type": "ENTITY", "char_start": 376387, "char_end": 376391, "token_start": 8, "token_end": 8, "note": null}, {"text": "capase cleavage site", "type": "ENTITY", "char_start": 376403, "char_end": 376423, "token_start": 11, "token_end": 13, "note": null}]}
+{"sentence_id": 2277, "sentence_text": "Induction of apoptosis in lymphocytes results in detectable Gads cleavage by 60 min .", "sentence_char_start_global": 376426, "sentence_char_end_global": 376511, "entities": [{"text": "Gads", "type": "ENTITY", "char_start": 60, "char_end": 64, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "Gads", "type": "ENTITY", "char_start": 376486, "char_end": 376490, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 2278, "sentence_text": "Gads cleavage is blocked in vivo by treating cells with a caspase 3 inhibitor .", "sentence_char_start_global": 376512, "sentence_char_end_global": 376591, "entities": [{"text": "Gads", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "Gads", "type": "ENTITY", "char_start": 376512, "char_end": 376516, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 2279, "sentence_text": "A putative caspase 3 cleavage site was identified within the unique region and mutation of this site prevented Gads cleavage in vitro , and in vivo .", "sentence_char_start_global": 376592, "sentence_char_end_global": 376741, "entities": [{"text": "putative caspase 3 cleavage site", "type": "ENTITY", "char_start": 2, "char_end": 34, "token_start": 1, "token_end": 5}, {"text": "Gads", "type": "ENTITY", "char_start": 111, "char_end": 115, "token_start": 18, "token_end": 18}], "entities_global": [{"text": "putative caspase 3 cleavage site", "type": "ENTITY", "char_start": 376594, "char_end": 376626, "token_start": 1, "token_end": 5, "note": null}, {"text": "Gads", "type": "ENTITY", "char_start": 376703, "char_end": 376707, "token_start": 18, "token_end": 18, "note": null}]}
+{"sentence_id": 2280, "sentence_text": "The Gads cleavage products retained the predicted binding specificity for SLP - 76 and LAT .", "sentence_char_start_global": 376742, "sentence_char_end_global": 376834, "entities": [{"text": "Gads", "type": "ENTITY", "char_start": 4, "char_end": 8, "token_start": 1, "token_end": 1}, {"text": "SLP - 76", "type": "ENTITY", "char_start": 74, "char_end": 82, "token_start": 10, "token_end": 12}, {"text": "LAT", "type": "ENTITY", "char_start": 87, "char_end": 90, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "Gads", "type": "ENTITY", "char_start": 376746, "char_end": 376750, "token_start": 1, "token_end": 1, "note": null}, {"text": "SLP - 76", "type": "ENTITY", "char_start": 376816, "char_end": 376824, "token_start": 10, "token_end": 12, "note": null}, {"text": "LAT", "type": "ENTITY", "char_start": 376829, "char_end": 376832, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 2281, "sentence_text": "Expression of the Gads cleavage products in Jurkat T cells inhibited NFAT activation following TCR cross linking .", "sentence_char_start_global": 376835, "sentence_char_end_global": 376949, "entities": [{"text": "Gads", "type": "ENTITY", "char_start": 18, "char_end": 22, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "Gads", "type": "ENTITY", "char_start": 376853, "char_end": 376857, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 2282, "sentence_text": "These findings indicate that cleavage of Gads in vivo could function to alter signalling downstream of the T cell receptor by disrupting cross talk between SLP - 76 and LAT .", "sentence_char_start_global": 376950, "sentence_char_end_global": 377124, "entities": [{"text": "Gads", "type": "ENTITY", "char_start": 41, "char_end": 45, "token_start": 6, "token_end": 6}, {"text": "T cell receptor", "type": "ENTITY", "char_start": 107, "char_end": 122, "token_start": 17, "token_end": 19}, {"text": "SLP - 76", "type": "ENTITY", "char_start": 156, "char_end": 164, "token_start": 25, "token_end": 27}, {"text": "LAT", "type": "ENTITY", "char_start": 169, "char_end": 172, "token_start": 29, "token_end": 29}], "entities_global": [{"text": "Gads", "type": "ENTITY", "char_start": 376991, "char_end": 376995, "token_start": 6, "token_end": 6, "note": null}, {"text": "T cell receptor", "type": "ENTITY", "char_start": 377057, "char_end": 377072, "token_start": 17, "token_end": 19, "note": null}, {"text": "SLP - 76", "type": "ENTITY", "char_start": 377106, "char_end": 377114, "token_start": 25, "token_end": 27, "note": null}, {"text": "LAT", "type": "ENTITY", "char_start": 377119, "char_end": 377122, "token_start": 29, "token_end": 29, "note": null}]}
+{"sentence_id": 2283, "sentence_text": "Targeting of p300 to the interleukin - 2 promoter via CREB - Rel cross - talk during mitogen and oncogenic molecular signaling in activated T - cells .", "sentence_char_start_global": 377125, "sentence_char_end_global": 377276, "entities": [{"text": "p300", "type": "ENTITY", "char_start": 13, "char_end": 17, "token_start": 2, "token_end": 2}, {"text": "interleukin - 2 promoter", "type": "ENTITY", "char_start": 25, "char_end": 49, "token_start": 5, "token_end": 8}, {"text": "mitogen", "type": "ENTITY", "char_start": 85, "char_end": 92, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "p300", "type": "ENTITY", "char_start": 377138, "char_end": 377142, "token_start": 2, "token_end": 2, "note": null}, {"text": "interleukin - 2 promoter", "type": "ENTITY", "char_start": 377150, "char_end": 377174, "token_start": 5, "token_end": 8, "note": null}, {"text": "mitogen", "type": "ENTITY", "char_start": 377210, "char_end": 377217, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 2284, "sentence_text": "In this report , we explore the mechanisms of targeting of p300 to the interleukin - 2 ( IL - 2 ) promoter in response to mitogenic and oncogenic molecular signals .", "sentence_char_start_global": 377277, "sentence_char_end_global": 377442, "entities": [{"text": "p300", "type": "ENTITY", "char_start": 59, "char_end": 63, "token_start": 11, "token_end": 11}, {"text": "interleukin - 2 ( IL - 2 ) promoter", "type": "ENTITY", "char_start": 71, "char_end": 106, "token_start": 14, "token_end": 22}], "entities_global": [{"text": "p300", "type": "ENTITY", "char_start": 377336, "char_end": 377340, "token_start": 11, "token_end": 11, "note": null}, {"text": "interleukin - 2 ( IL - 2 ) promoter", "type": "ENTITY", "char_start": 377348, "char_end": 377383, "token_start": 14, "token_end": 22, "note": null}]}
+{"sentence_id": 2285, "sentence_text": "Recruitment of p300 by cAMP - responsive element - binding protein - Rel cross - talk at the composite CD28 response element ( CD28RE ) - TRE element of the IL - 2 promoter is essential for promoter inducibility during T - cell activation , and CD28RE - TRE is the exclusive target of the human T - cell lymphotropic virus type I oncoprotein Tax .", "sentence_char_start_global": 377443, "sentence_char_end_global": 377790, "entities": [{"text": "p300", "type": "ENTITY", "char_start": 15, "char_end": 19, "token_start": 2, "token_end": 2}, {"text": "cAMP - responsive element - binding protein - Rel", "type": "ENTITY", "char_start": 23, "char_end": 72, "token_start": 4, "token_end": 12}, {"text": "composite CD28 response element", "type": "ENTITY", "char_start": 93, "char_end": 124, "token_start": 18, "token_end": 21}, {"text": "CD28RE", "type": "ENTITY", "char_start": 127, "char_end": 133, "token_start": 23, "token_end": 23}, {"text": "TRE element", "type": "ENTITY", "char_start": 138, "char_end": 149, "token_start": 26, "token_end": 27}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 157, "char_end": 172, "token_start": 30, "token_end": 33}, {"text": "CD28RE - TRE", "type": "ENTITY", "char_start": 245, "char_end": 257, "token_start": 46, "token_end": 48}, {"text": "oncoprotein Tax", "type": "ENTITY", "char_start": 330, "char_end": 345, "token_start": 63, "token_end": 64}], "entities_global": [{"text": "p300", "type": "ENTITY", "char_start": 377458, "char_end": 377462, "token_start": 2, "token_end": 2, "note": null}, {"text": "cAMP - responsive element - binding protein - Rel", "type": "ENTITY", "char_start": 377466, "char_end": 377515, "token_start": 4, "token_end": 12, "note": null}, {"text": "composite CD28 response element", "type": "ENTITY", "char_start": 377536, "char_end": 377567, "token_start": 18, "token_end": 21, "note": null}, {"text": "CD28RE", "type": "ENTITY", "char_start": 377570, "char_end": 377576, "token_start": 23, "token_end": 23, "note": null}, {"text": "TRE element", "type": "ENTITY", "char_start": 377581, "char_end": 377592, "token_start": 26, "token_end": 27, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 377600, "char_end": 377615, "token_start": 30, "token_end": 33, "note": null}, {"text": "CD28RE - TRE", "type": "ENTITY", "char_start": 377688, "char_end": 377700, "token_start": 46, "token_end": 48, "note": null}, {"text": "oncoprotein Tax", "type": "ENTITY", "char_start": 377773, "char_end": 377788, "token_start": 63, "token_end": 64, "note": null}]}
+{"sentence_id": 2286, "sentence_text": "The intrinsic histone acetyltransferase activity of p300 is dispensable for activation of the IL - 2 promoter , and the N - terminal 743 residues contain the minimal structural requirements for synergistic transactivation of the CD28RE - TRE , the IL - 2 promoter , and endogenous IL - 2 gene expression .", "sentence_char_start_global": 377791, "sentence_char_end_global": 378096, "entities": [{"text": "p300", "type": "ENTITY", "char_start": 52, "char_end": 56, "token_start": 6, "token_end": 6}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 94, "char_end": 109, "token_start": 13, "token_end": 16}, {"text": "N - terminal 743 residues", "type": "ENTITY", "char_start": 120, "char_end": 145, "token_start": 20, "token_end": 24}, {"text": "CD28RE - TRE", "type": "ENTITY", "char_start": 229, "char_end": 241, "token_start": 35, "token_end": 37}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 248, "char_end": 263, "token_start": 40, "token_end": 43}, {"text": "IL - 2 gene", "type": "ENTITY", "char_start": 281, "char_end": 292, "token_start": 47, "token_end": 50}], "entities_global": [{"text": "p300", "type": "ENTITY", "char_start": 377843, "char_end": 377847, "token_start": 6, "token_end": 6, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 377885, "char_end": 377900, "token_start": 13, "token_end": 16, "note": null}, {"text": "N - terminal 743 residues", "type": "ENTITY", "char_start": 377911, "char_end": 377936, "token_start": 20, "token_end": 24, "note": null}, {"text": "CD28RE - TRE", "type": "ENTITY", "char_start": 378020, "char_end": 378032, "token_start": 35, "token_end": 37, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 378039, "char_end": 378054, "token_start": 40, "token_end": 43, "note": null}, {"text": "IL - 2 gene", "type": "ENTITY", "char_start": 378072, "char_end": 378083, "token_start": 47, "token_end": 50, "note": null}]}
+{"sentence_id": 2287, "sentence_text": "Mutational analysis of p300 reveals differential structural requirements for the N - terminal p300 module by individual cis - elements within the IL - 2 promoter .", "sentence_char_start_global": 378097, "sentence_char_end_global": 378260, "entities": [{"text": "p300", "type": "ENTITY", "char_start": 23, "char_end": 27, "token_start": 3, "token_end": 3}, {"text": "cis - elements", "type": "ENTITY", "char_start": 120, "char_end": 134, "token_start": 17, "token_end": 19}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 146, "char_end": 161, "token_start": 22, "token_end": 25}], "entities_global": [{"text": "p300", "type": "ENTITY", "char_start": 378120, "char_end": 378124, "token_start": 3, "token_end": 3, "note": null}, {"text": "cis - elements", "type": "ENTITY", "char_start": 378217, "char_end": 378231, "token_start": 17, "token_end": 19, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 378243, "char_end": 378258, "token_start": 22, "token_end": 25, "note": null}]}
+{"sentence_id": 2288, "sentence_text": "These findings provide evidence that p300 assembles at the IL - 2 promoter to form an enhanceosome - like signal transduction target that is centrally integrated at the CD28RE - TRE element of the IL - 2 promoter through specific protein module - targeted associations in activated T - cells .", "sentence_char_start_global": 378261, "sentence_char_end_global": 378554, "entities": [{"text": "p300", "type": "ENTITY", "char_start": 37, "char_end": 41, "token_start": 5, "token_end": 5}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 59, "char_end": 74, "token_start": 9, "token_end": 12}, {"text": "CD28RE - TRE element", "type": "ENTITY", "char_start": 169, "char_end": 189, "token_start": 28, "token_end": 31}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 197, "char_end": 212, "token_start": 34, "token_end": 37}], "entities_global": [{"text": "p300", "type": "ENTITY", "char_start": 378298, "char_end": 378302, "token_start": 5, "token_end": 5, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 378320, "char_end": 378335, "token_start": 9, "token_end": 12, "note": null}, {"text": "CD28RE - TRE element", "type": "ENTITY", "char_start": 378430, "char_end": 378450, "token_start": 28, "token_end": 31, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 378458, "char_end": 378473, "token_start": 34, "token_end": 37, "note": null}]}
+{"sentence_id": 2289, "sentence_text": "Regulation of cytokine production in T - cell responses to inhalant allergen : GATA - 3 expression distinguishes between Th1 - and Th2 - polarized immunity .", "sentence_char_start_global": 378555, "sentence_char_end_global": 378712, "entities": [{"text": "GATA - 3", "type": "ENTITY", "char_start": 79, "char_end": 87, "token_start": 13, "token_end": 15}], "entities_global": [{"text": "GATA - 3", "type": "ENTITY", "char_start": 378634, "char_end": 378642, "token_start": 13, "token_end": 15, "note": null}]}
+{"sentence_id": 2290, "sentence_text": "BACKGROUND : The precise nature of allergen - specific cytokine responses in atopics versus non - atopics , in particular the ' Th1 polarity ' of responses in non - atopics , remains controversial .", "sentence_char_start_global": 378713, "sentence_char_end_global": 378911, "entities": [], "entities_global": []}
+{"sentence_id": 2291, "sentence_text": "This is due in part to the relative insensitivity of cytokine detection systems , and associated variations in kinetics of cytokine production and catabolism in in vitro culture systems .", "sentence_char_start_global": 378912, "sentence_char_end_global": 379099, "entities": [], "entities_global": []}
+{"sentence_id": 2292, "sentence_text": "As an alternative to cytokine measurement , this study focuses on expression of the transcription factor GATA - 3 for analysis of allergen - specific Th cell responses .", "sentence_char_start_global": 379100, "sentence_char_end_global": 379269, "entities": [{"text": "transcription factor GATA - 3", "type": "ENTITY", "char_start": 84, "char_end": 113, "token_start": 14, "token_end": 18}], "entities_global": [{"text": "transcription factor GATA - 3", "type": "ENTITY", "char_start": 379184, "char_end": 379213, "token_start": 14, "token_end": 18, "note": null}]}
+{"sentence_id": 2293, "sentence_text": "METHODS : Cord blood mononuclear cells were Th1 - or Th2 - polarized by culture in IL - 12 - or IL - 4 - employing established methods ; PBMC from house dust mite ( HDM ) - sensitive atopics and controls were stimulated overnight with HDM ; cytokine production was measured by ELISA and GATA - 3 mRNA expression by PCR .", "sentence_char_start_global": 379270, "sentence_char_end_global": 379590, "entities": [{"text": "GATA - 3 mRNA", "type": "ENTITY", "char_start": 287, "char_end": 300, "token_start": 55, "token_end": 58}], "entities_global": [{"text": "GATA - 3 mRNA", "type": "ENTITY", "char_start": 379557, "char_end": 379570, "token_start": 55, "token_end": 58, "note": null}]}
+{"sentence_id": 2294, "sentence_text": "RESULTS : Cytokine - driven Th2 polarization of naive T cells is associated with marked upregulation of GATA - 3 expression , whereas a reciprocal expression pattern accompanies differentiation towards the Th1 cytokine phenotype .", "sentence_char_start_global": 379591, "sentence_char_end_global": 379821, "entities": [{"text": "Cytokine", "type": "ENTITY", "char_start": 10, "char_end": 18, "token_start": 2, "token_end": 2}, {"text": "GATA - 3", "type": "ENTITY", "char_start": 104, "char_end": 112, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "Cytokine", "type": "ENTITY", "char_start": 379601, "char_end": 379609, "token_start": 2, "token_end": 2, "note": null}, {"text": "GATA - 3", "type": "ENTITY", "char_start": 379695, "char_end": 379703, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 2295, "sentence_text": "In T cells from HDM skin prick test - positive ( HDM - SPT + / HDM - IgE + ) volunteers , overnight stimulation results in marked upregulation of GATA - 3 expression , compared to an equally marked downregulation of expression in T cells from SPT - / IgE - subjects .", "sentence_char_start_global": 379822, "sentence_char_end_global": 380089, "entities": [{"text": "GATA - 3", "type": "ENTITY", "char_start": 146, "char_end": 154, "token_start": 30, "token_end": 32}], "entities_global": [{"text": "GATA - 3", "type": "ENTITY", "char_start": 379968, "char_end": 379976, "token_start": 30, "token_end": 32, "note": null}]}
+{"sentence_id": 2296, "sentence_text": "In subjects who are HDM - SPT + but IgE - , GATA - 3 expression levels remained relatively stable during culture with HDM .", "sentence_char_start_global": 380090, "sentence_char_end_global": 380213, "entities": [{"text": "GATA - 3", "type": "ENTITY", "char_start": 44, "char_end": 52, "token_start": 12, "token_end": 14}], "entities_global": [{"text": "GATA - 3", "type": "ENTITY", "char_start": 380134, "char_end": 380142, "token_start": 12, "token_end": 14, "note": null}]}
+{"sentence_id": 2297, "sentence_text": "CONCLUSIONS : Upregulation of GATA - 3 expression in PBMC is a hallmark of the early phase of Th2 recall responses to specific allergen in atopics .", "sentence_char_start_global": 380214, "sentence_char_end_global": 380362, "entities": [{"text": "GATA - 3", "type": "ENTITY", "char_start": 30, "char_end": 38, "token_start": 4, "token_end": 6}], "entities_global": [{"text": "GATA - 3", "type": "ENTITY", "char_start": 380244, "char_end": 380252, "token_start": 4, "token_end": 6, "note": null}]}
+{"sentence_id": 2298, "sentence_text": "The reciprocal expression pattern observed in HDM - specific recall responses of non - atopics provides independent confirmation of the presence of underlying Th1 - like immunity in these subjects .", "sentence_char_start_global": 380363, "sentence_char_end_global": 380561, "entities": [], "entities_global": []}
+{"sentence_id": 2299, "sentence_text": "The parallel findings in neonatal T cells suggest that the same approach may be utilized for monitoring the progress of allergen - specific Th1 / Th2 memory development during early childhood , and hence in assessment of risk for future allergic disease .", "sentence_char_start_global": 380562, "sentence_char_end_global": 380817, "entities": [], "entities_global": []}
+{"sentence_id": 2300, "sentence_text": "Copyright 2001 S . Karger AG , Basel", "sentence_char_start_global": 380818, "sentence_char_end_global": 380854, "entities": [], "entities_global": []}
+{"sentence_id": 2301, "sentence_text": "The heat shock response reduces myelin oligodendrocyte glycoprotein - induced experimental autoimmune encephalomyelitis in mice .", "sentence_char_start_global": 380855, "sentence_char_end_global": 380984, "entities": [{"text": "myelin oligodendrocyte glycoprotein", "type": "ENTITY", "char_start": 32, "char_end": 67, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "myelin oligodendrocyte glycoprotein", "type": "ENTITY", "char_start": 380887, "char_end": 380922, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 2302, "sentence_text": "The stress response ( SR ) can block inflammatory gene expression by preventing activation of transcription factor nuclear factor - kappa B ( NF - kappaB ) .", "sentence_char_start_global": 380985, "sentence_char_end_global": 381142, "entities": [{"text": "transcription factor", "type": "ENTITY", "char_start": 94, "char_end": 114, "token_start": 15, "token_end": 16}, {"text": "nuclear factor - kappa B", "type": "ENTITY", "char_start": 115, "char_end": 139, "token_start": 17, "token_end": 21}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 142, "char_end": 153, "token_start": 23, "token_end": 25}], "entities_global": [{"text": "transcription factor", "type": "ENTITY", "char_start": 381079, "char_end": 381099, "token_start": 15, "token_end": 16, "note": null}, {"text": "nuclear factor - kappa B", "type": "ENTITY", "char_start": 381100, "char_end": 381124, "token_start": 17, "token_end": 21, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 381127, "char_end": 381138, "token_start": 23, "token_end": 25, "note": null}]}
+{"sentence_id": 2303, "sentence_text": "As inflammatory gene expression contributes to the pathogenesis of demyelinating diseases , we tested the effects of the SR on the progression of the demyelinating disease experimental autoimmune encephalomyelitis ( EAE ) .", "sentence_char_start_global": 381143, "sentence_char_end_global": 381366, "entities": [], "entities_global": []}
+{"sentence_id": 2304, "sentence_text": "EAE was actively induced in C57BL / 6 mice using an encephalitogenic myelin oligodendrocyte glycoprotein ( MOG ( 35 - 55 ) ) peptide .", "sentence_char_start_global": 381367, "sentence_char_end_global": 381501, "entities": [{"text": "myelin oligodendrocyte glycoprotein", "type": "ENTITY", "char_start": 69, "char_end": 104, "token_start": 12, "token_end": 14}, {"text": "MOG ( 35 - 55 )", "type": "ENTITY", "char_start": 107, "char_end": 122, "token_start": 16, "token_end": 21}], "entities_global": [{"text": "myelin oligodendrocyte glycoprotein", "type": "ENTITY", "char_start": 381436, "char_end": 381471, "token_start": 12, "token_end": 14, "note": null}, {"text": "MOG ( 35 - 55 )", "type": "ENTITY", "char_start": 381474, "char_end": 381489, "token_start": 16, "token_end": 21, "note": null}]}
+{"sentence_id": 2305, "sentence_text": "Whole body hyperthermia was used to induce a heat shock response ( HSR ) in immunized mice 2 days after the booster MOG ( 35 - 55 ) peptide injection .", "sentence_char_start_global": 381502, "sentence_char_end_global": 381653, "entities": [], "entities_global": []}
+{"sentence_id": 2306, "sentence_text": "The HSR reduced the incidence of EAE by 70 % , delayed disease onset by 6 days , and attenuated disease severity .", "sentence_char_start_global": 381654, "sentence_char_end_global": 381768, "entities": [], "entities_global": []}
+{"sentence_id": 2307, "sentence_text": "The HSR attenuated leukocyte infiltration into CNS assessed by quantitation of perivascular infiltrates , and by reduced staining for CD4 and CD25 immunopositive T - cells .", "sentence_char_start_global": 381769, "sentence_char_end_global": 381942, "entities": [{"text": "CD4", "type": "ENTITY", "char_start": 134, "char_end": 137, "token_start": 19, "token_end": 19}, {"text": "CD25", "type": "ENTITY", "char_start": 142, "char_end": 146, "token_start": 21, "token_end": 21}], "entities_global": [{"text": "CD4", "type": "ENTITY", "char_start": 381903, "char_end": 381906, "token_start": 19, "token_end": 19, "note": null}, {"text": "CD25", "type": "ENTITY", "char_start": 381911, "char_end": 381915, "token_start": 21, "token_end": 21, "note": null}]}
+{"sentence_id": 2308, "sentence_text": "T - cell activation , assessed by the production of interferon gamma ( IFNgamma ) in response to MOG ( 35 - 55 ) , was also decreased by the HSR .", "sentence_char_start_global": 381943, "sentence_char_end_global": 382089, "entities": [{"text": "interferon gamma", "type": "ENTITY", "char_start": 52, "char_end": 68, "token_start": 10, "token_end": 11}, {"text": "IFNgamma", "type": "ENTITY", "char_start": 71, "char_end": 79, "token_start": 13, "token_end": 13}, {"text": "MOG ( 35 - 55 )", "type": "ENTITY", "char_start": 97, "char_end": 112, "token_start": 18, "token_end": 23}], "entities_global": [{"text": "interferon gamma", "type": "ENTITY", "char_start": 381995, "char_end": 382011, "token_start": 10, "token_end": 11, "note": null}, {"text": "IFNgamma", "type": "ENTITY", "char_start": 382014, "char_end": 382022, "token_start": 13, "token_end": 13, "note": null}, {"text": "MOG ( 35 - 55 )", "type": "ENTITY", "char_start": 382040, "char_end": 382055, "token_start": 18, "token_end": 23, "note": null}]}
+{"sentence_id": 2309, "sentence_text": "The HSR reduced inflammatory gene expression in the brain that normally occurs during EAE , including the early increase in RANTES ( regulated on activation of normal T - cell expressed and secreted ) expression , and the later expression of the inducible form of nitric oxide synthase .", "sentence_char_start_global": 382090, "sentence_char_end_global": 382377, "entities": [{"text": "RANTES", "type": "ENTITY", "char_start": 124, "char_end": 130, "token_start": 20, "token_end": 20}, {"text": "regulated on activation of normal T - cell expressed and secreted", "type": "ENTITY", "char_start": 133, "char_end": 198, "token_start": 22, "token_end": 32}, {"text": "nitric oxide synthase", "type": "ENTITY", "char_start": 264, "char_end": 285, "token_start": 45, "token_end": 47}], "entities_global": [{"text": "RANTES", "type": "ENTITY", "char_start": 382214, "char_end": 382220, "token_start": 20, "token_end": 20, "note": null}, {"text": "regulated on activation of normal T - cell expressed and secreted", "type": "ENTITY", "char_start": 382223, "char_end": 382288, "token_start": 22, "token_end": 32, "note": null}, {"text": "nitric oxide synthase", "type": "ENTITY", "char_start": 382354, "char_end": 382375, "token_start": 45, "token_end": 47, "note": null}]}
+{"sentence_id": 2310, "sentence_text": "The early activation of transcription factor NF - kappaB was also blocked by the HSR .", "sentence_char_start_global": 382378, "sentence_char_end_global": 382464, "entities": [{"text": "transcription factor", "type": "ENTITY", "char_start": 24, "char_end": 44, "token_start": 4, "token_end": 5}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 45, "char_end": 56, "token_start": 6, "token_end": 8}], "entities_global": [{"text": "transcription factor", "type": "ENTITY", "char_start": 382402, "char_end": 382422, "token_start": 4, "token_end": 5, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 382423, "char_end": 382434, "token_start": 6, "token_end": 8, "note": null}]}
+{"sentence_id": 2311, "sentence_text": "The finding that the SR reduces inflammation in the brain and the clinical severity of EAE opens a novel therapeutic approach for prevention of autoimmune diseases .", "sentence_char_start_global": 382465, "sentence_char_end_global": 382630, "entities": [], "entities_global": []}
+{"sentence_id": 2312, "sentence_text": "In vivo detection of intracellular signaling pathways in developing thymocytes .", "sentence_char_start_global": 382631, "sentence_char_end_global": 382711, "entities": [], "entities_global": []}
+{"sentence_id": 2313, "sentence_text": "Information regarding the intracellular signaling processes that occur during the development of T cells has largely been obtained with the use of transgenic mouse models , which although providing invaluable information are time consuming and costly .", "sentence_char_start_global": 382712, "sentence_char_end_global": 382964, "entities": [], "entities_global": []}
+{"sentence_id": 2314, "sentence_text": "To this end , we have developed a novel system that facilitates the in vivo analysis of signal transduction pathways during T - lymphocyte development .", "sentence_char_start_global": 382965, "sentence_char_end_global": 383117, "entities": [], "entities_global": []}
+{"sentence_id": 2315, "sentence_text": "This approach uses reporter - plasmids for the detection of intracellular signals mediated by the mitogen - activated protein kinase or cyclic AMP - dependent protein kinase .", "sentence_char_start_global": 383118, "sentence_char_end_global": 383293, "entities": [{"text": "reporter - plasmids", "type": "ENTITY", "char_start": 19, "char_end": 38, "token_start": 3, "token_end": 5}, {"text": "mitogen - activated protein kinase", "type": "ENTITY", "char_start": 98, "char_end": 132, "token_start": 15, "token_end": 19}, {"text": "cyclic AMP - dependent protein kinase", "type": "ENTITY", "char_start": 136, "char_end": 173, "token_start": 21, "token_end": 26}], "entities_global": [{"text": "reporter - plasmids", "type": "ENTITY", "char_start": 383137, "char_end": 383156, "token_start": 3, "token_end": 5, "note": null}, {"text": "mitogen - activated protein kinase", "type": "ENTITY", "char_start": 383216, "char_end": 383250, "token_start": 15, "token_end": 19, "note": null}, {"text": "cyclic AMP - dependent protein kinase", "type": "ENTITY", "char_start": 383254, "char_end": 383291, "token_start": 21, "token_end": 26, "note": null}]}
+{"sentence_id": 2316, "sentence_text": "Reporter - plasmids are transfected into thymocytes in fetal thymic organ culture by accelerated DNA / particle bombardment ( gene gun ) , and the activation of a signaling pathway is determined in the form of a standard luciferase assay .", "sentence_char_start_global": 383294, "sentence_char_end_global": 383533, "entities": [{"text": "Reporter - plasmids", "type": "ENTITY", "char_start": 0, "char_end": 19, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "Reporter - plasmids", "type": "ENTITY", "char_start": 383294, "char_end": 383313, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 2317, "sentence_text": "Importantly , this powerful technique preserves the structural integrity of the thymus , and will provide an invaluable tool to study how thymocytes respond to normal environmental stimuli encountered during differentiation within the thymic milieu .", "sentence_char_start_global": 383534, "sentence_char_end_global": 383784, "entities": [], "entities_global": []}
+{"sentence_id": 2318, "sentence_text": "Thus , this method allows for the monitoring of signals that occur in a biological time frame , such as during differentiation , and within the natural environment of differentiating cells .", "sentence_char_start_global": 383785, "sentence_char_end_global": 383975, "entities": [], "entities_global": []}
+{"sentence_id": 2319, "sentence_text": "Core - binding factor beta ( CBFbeta ) , but not CBFbeta - smooth muscle myosin heavy chain , rescues definitive hematopoiesis in CBFbeta - deficient embryonic stem cells .", "sentence_char_start_global": 383976, "sentence_char_end_global": 384148, "entities": [{"text": "Core - binding factor beta", "type": "ENTITY", "char_start": 0, "char_end": 26, "token_start": 0, "token_end": 4}, {"text": "CBFbeta", "type": "ENTITY", "char_start": 29, "char_end": 36, "token_start": 6, "token_end": 6}, {"text": "CBFbeta - smooth muscle myosin heavy chain", "type": "ENTITY", "char_start": 49, "char_end": 91, "token_start": 11, "token_end": 17}, {"text": "CBFbeta", "type": "ENTITY", "char_start": 130, "char_end": 137, "token_start": 23, "token_end": 23}], "entities_global": [{"text": "Core - binding factor beta", "type": "ENTITY", "char_start": 383976, "char_end": 384002, "token_start": 0, "token_end": 4, "note": null}, {"text": "CBFbeta", "type": "ENTITY", "char_start": 384005, "char_end": 384012, "token_start": 6, "token_end": 6, "note": null}, {"text": "CBFbeta - smooth muscle myosin heavy chain", "type": "ENTITY", "char_start": 384025, "char_end": 384067, "token_start": 11, "token_end": 17, "note": null}, {"text": "CBFbeta", "type": "ENTITY", "char_start": 384106, "char_end": 384113, "token_start": 23, "token_end": 23, "note": null}]}
+{"sentence_id": 2320, "sentence_text": "Core - binding factor beta ( CBFbeta ) is the non - DNA - binding subunit of the heterodimeric CBFs .", "sentence_char_start_global": 384149, "sentence_char_end_global": 384250, "entities": [{"text": "Core - binding factor beta", "type": "ENTITY", "char_start": 0, "char_end": 26, "token_start": 0, "token_end": 4}, {"text": "CBFbeta", "type": "ENTITY", "char_start": 29, "char_end": 36, "token_start": 6, "token_end": 6}, {"text": "non - DNA - binding subunit", "type": "ENTITY", "char_start": 46, "char_end": 73, "token_start": 10, "token_end": 15}, {"text": "heterodimeric CBFs", "type": "ENTITY", "char_start": 81, "char_end": 99, "token_start": 18, "token_end": 19}], "entities_global": [{"text": "Core - binding factor beta", "type": "ENTITY", "char_start": 384149, "char_end": 384175, "token_start": 0, "token_end": 4, "note": null}, {"text": "CBFbeta", "type": "ENTITY", "char_start": 384178, "char_end": 384185, "token_start": 6, "token_end": 6, "note": null}, {"text": "non - DNA - binding subunit", "type": "ENTITY", "char_start": 384195, "char_end": 384222, "token_start": 10, "token_end": 15, "note": null}, {"text": "heterodimeric CBFs", "type": "ENTITY", "char_start": 384230, "char_end": 384248, "token_start": 18, "token_end": 19, "note": null}]}
+{"sentence_id": 2321, "sentence_text": "Genes encoding CBFbeta ( CBFB ) , and one of the DNA - binding CBFalpha subunits , Runx1 ( also known as CBFalpha2 , AML1 , and PEBP2alphaB ) , are required for normal hematopoiesis and are also frequent targets of chromosomal translocations in acute leukemias in humans .", "sentence_char_start_global": 384251, "sentence_char_end_global": 384523, "entities": [{"text": "Genes encoding CBFbeta", "type": "ENTITY", "char_start": 0, "char_end": 22, "token_start": 0, "token_end": 2}, {"text": "CBFB", "type": "ENTITY", "char_start": 25, "char_end": 29, "token_start": 4, "token_end": 4}, {"text": "DNA - binding CBFalpha subunits , Runx1", "type": "ENTITY", "char_start": 49, "char_end": 88, "token_start": 11, "token_end": 17}, {"text": "CBFalpha2", "type": "ENTITY", "char_start": 105, "char_end": 114, "token_start": 22, "token_end": 22}, {"text": "AML1", "type": "ENTITY", "char_start": 117, "char_end": 121, "token_start": 24, "token_end": 24}, {"text": "PEBP2alphaB", "type": "ENTITY", "char_start": 128, "char_end": 139, "token_start": 27, "token_end": 27}], "entities_global": [{"text": "Genes encoding CBFbeta", "type": "ENTITY", "char_start": 384251, "char_end": 384273, "token_start": 0, "token_end": 2, "note": null}, {"text": "CBFB", "type": "ENTITY", "char_start": 384276, "char_end": 384280, "token_start": 4, "token_end": 4, "note": null}, {"text": "DNA - binding CBFalpha subunits , Runx1", "type": "ENTITY", "char_start": 384300, "char_end": 384339, "token_start": 11, "token_end": 17, "note": null}, {"text": "CBFalpha2", "type": "ENTITY", "char_start": 384356, "char_end": 384365, "token_start": 22, "token_end": 22, "note": null}, {"text": "AML1", "type": "ENTITY", "char_start": 384368, "char_end": 384372, "token_start": 24, "token_end": 24, "note": null}, {"text": "PEBP2alphaB", "type": "ENTITY", "char_start": 384379, "char_end": 384390, "token_start": 27, "token_end": 27, "note": null}]}
+{"sentence_id": 2322, "sentence_text": "Homozygous disruption of either the Runx1 or Cbfb gene in mice results in embryonic lethality at midgestation due to hemorrhaging in the central nervous system , and severely impairs fetal liver hematopoiesis .", "sentence_char_start_global": 384524, "sentence_char_end_global": 384734, "entities": [{"text": "Runx1 or Cbfb gene", "type": "ENTITY", "char_start": 36, "char_end": 54, "token_start": 5, "token_end": 8}], "entities_global": [{"text": "Runx1 or Cbfb gene", "type": "ENTITY", "char_start": 384560, "char_end": 384578, "token_start": 5, "token_end": 8, "note": null}]}
+{"sentence_id": 2323, "sentence_text": "Results of this study show that Cbfb - deficient mouse embryonic stem ( ES ) cells can differentiate into primitive erythroid colonies in vitro , but are impaired in their ability to produce definitive erythroid and myeloid colonies , mimicking the in vivo defect .", "sentence_char_start_global": 384735, "sentence_char_end_global": 385000, "entities": [], "entities_global": []}
+{"sentence_id": 2324, "sentence_text": "Definitive hematopoiesis is restored by ectopic expression of full - length Cbfb transgenes , as well as by a transgene encoding only the heterodimerization domain of CBFbeta .", "sentence_char_start_global": 385001, "sentence_char_end_global": 385177, "entities": [{"text": "full - length Cbfb transgenes", "type": "ENTITY", "char_start": 62, "char_end": 91, "token_start": 8, "token_end": 12}, {"text": "heterodimerization domain", "type": "ENTITY", "char_start": 138, "char_end": 163, "token_start": 23, "token_end": 24}, {"text": "CBFbeta", "type": "ENTITY", "char_start": 167, "char_end": 174, "token_start": 26, "token_end": 26}], "entities_global": [{"text": "full - length Cbfb transgenes", "type": "ENTITY", "char_start": 385063, "char_end": 385092, "token_start": 8, "token_end": 12, "note": null}, {"text": "heterodimerization domain", "type": "ENTITY", "char_start": 385139, "char_end": 385164, "token_start": 23, "token_end": 24, "note": null}, {"text": "CBFbeta", "type": "ENTITY", "char_start": 385168, "char_end": 385175, "token_start": 26, "token_end": 26, "note": null}]}
+{"sentence_id": 2325, "sentence_text": "In contrast , the CBFbeta - smooth muscle myosin heavy chain ( SMMHC ) fusion protein generated by the inv ( 16 ) associated with acute myeloid leukemias ( M4Eo ) can not rescue definitive hematopoiesis by Cbfb - deficient ES cells .", "sentence_char_start_global": 385178, "sentence_char_end_global": 385411, "entities": [{"text": "CBFbeta", "type": "ENTITY", "char_start": 18, "char_end": 25, "token_start": 4, "token_end": 4}, {"text": "smooth muscle myosin heavy chain ( SMMHC ) fusion protein", "type": "ENTITY", "char_start": 28, "char_end": 85, "token_start": 6, "token_end": 15}, {"text": "inv ( 16 )", "type": "ENTITY", "char_start": 103, "char_end": 113, "token_start": 19, "token_end": 22}], "entities_global": [{"text": "CBFbeta", "type": "ENTITY", "char_start": 385196, "char_end": 385203, "token_start": 4, "token_end": 4, "note": null}, {"text": "smooth muscle myosin heavy chain ( SMMHC ) fusion protein", "type": "ENTITY", "char_start": 385206, "char_end": 385263, "token_start": 6, "token_end": 15, "note": null}, {"text": "inv ( 16 )", "type": "ENTITY", "char_start": 385281, "char_end": 385291, "token_start": 19, "token_end": 22, "note": null}]}
+{"sentence_id": 2326, "sentence_text": "Sequences responsible for the inability of CBFbeta - SMMHC to rescue definitive hematopoiesis reside in the SMMHC portion of the fusion protein .", "sentence_char_start_global": 385412, "sentence_char_end_global": 385557, "entities": [{"text": "CBFbeta", "type": "ENTITY", "char_start": 43, "char_end": 50, "token_start": 6, "token_end": 6}, {"text": "SMMHC portion", "type": "ENTITY", "char_start": 108, "char_end": 121, "token_start": 16, "token_end": 17}, {"text": "fusion protein", "type": "ENTITY", "char_start": 129, "char_end": 143, "token_start": 20, "token_end": 21}], "entities_global": [{"text": "CBFbeta", "type": "ENTITY", "char_start": 385455, "char_end": 385462, "token_start": 6, "token_end": 6, "note": null}, {"text": "SMMHC portion", "type": "ENTITY", "char_start": 385520, "char_end": 385533, "token_start": 16, "token_end": 17, "note": null}, {"text": "fusion protein", "type": "ENTITY", "char_start": 385541, "char_end": 385555, "token_start": 20, "token_end": 21, "note": null}]}
+{"sentence_id": 2327, "sentence_text": "Results also show that the CBFbeta - SMMHC fusion protein transdominantly inhibits definitive hematopoiesis , but not to the same extent as homozygous loss of Runx1 or Cbfb .", "sentence_char_start_global": 385558, "sentence_char_end_global": 385732, "entities": [{"text": "CBFbeta - SMMHC fusion protein", "type": "ENTITY", "char_start": 27, "char_end": 57, "token_start": 5, "token_end": 9}, {"text": "Runx1", "type": "ENTITY", "char_start": 159, "char_end": 164, "token_start": 25, "token_end": 25}, {"text": "Cbfb", "type": "ENTITY", "char_start": 168, "char_end": 172, "token_start": 27, "token_end": 27}], "entities_global": [{"text": "CBFbeta - SMMHC fusion protein", "type": "ENTITY", "char_start": 385585, "char_end": 385615, "token_start": 5, "token_end": 9, "note": null}, {"text": "Runx1", "type": "ENTITY", "char_start": 385717, "char_end": 385722, "token_start": 25, "token_end": 25, "note": null}, {"text": "Cbfb", "type": "ENTITY", "char_start": 385726, "char_end": 385730, "token_start": 27, "token_end": 27, "note": null}]}
+{"sentence_id": 2328, "sentence_text": "CBFbeta - SMMHC preferentially inhibits the differentiation of myeloid lineage cells , while increasing the number of blastlike cells in culture .", "sentence_char_start_global": 385733, "sentence_char_end_global": 385879, "entities": [{"text": "CBFbeta - SMMHC", "type": "ENTITY", "char_start": 0, "char_end": 15, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "CBFbeta - SMMHC", "type": "ENTITY", "char_start": 385733, "char_end": 385748, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 2329, "sentence_text": "The latency pattern of Epstein - Barr virus infection and viral IL - 10 expression in cutaneous natural killer / T - cell lymphomas .", "sentence_char_start_global": 385880, "sentence_char_end_global": 386013, "entities": [{"text": "IL - 10", "type": "ENTITY", "char_start": 64, "char_end": 71, "token_start": 11, "token_end": 13}], "entities_global": [{"text": "IL - 10", "type": "ENTITY", "char_start": 385944, "char_end": 385951, "token_start": 11, "token_end": 13, "note": null}]}
+{"sentence_id": 2330, "sentence_text": "The nasal type , extranodal natural killer or T ( NK / T ) - cell lymphoma is usually associated with latent Epstein - Barr virus ( EBV ) infection .", "sentence_char_start_global": 386014, "sentence_char_end_global": 386163, "entities": [], "entities_global": []}
+{"sentence_id": 2331, "sentence_text": "In order to elucidate the EBV gene expression patterns in vivo , we examined eight patients with cutaneous EBV - related NK / T - cell lymphomas , including six patients with a NK - cell phenotype and two patients with a T - cell phenotype .", "sentence_char_start_global": 386164, "sentence_char_end_global": 386405, "entities": [], "entities_global": []}
+{"sentence_id": 2332, "sentence_text": "The implication of EBV in the skin lesions was determined by the presence of EBV - DNA , EBV - encoded nuclear RNA ( EBER ) and a clonality of EBV - DNA fragments containing the terminal repeats .", "sentence_char_start_global": 386406, "sentence_char_end_global": 386602, "entities": [{"text": "EBV - DNA", "type": "ENTITY", "char_start": 77, "char_end": 86, "token_start": 14, "token_end": 16}, {"text": "EBV - encoded nuclear RNA", "type": "ENTITY", "char_start": 89, "char_end": 114, "token_start": 18, "token_end": 22}, {"text": "EBER", "type": "ENTITY", "char_start": 117, "char_end": 121, "token_start": 24, "token_end": 24}, {"text": "EBV - DNA fragments", "type": "ENTITY", "char_start": 143, "char_end": 162, "token_start": 30, "token_end": 33}, {"text": "terminal repeats", "type": "ENTITY", "char_start": 178, "char_end": 194, "token_start": 36, "token_end": 37}], "entities_global": [{"text": "EBV - DNA", "type": "ENTITY", "char_start": 386483, "char_end": 386492, "token_start": 14, "token_end": 16, "note": null}, {"text": "EBV - encoded nuclear RNA", "type": "ENTITY", "char_start": 386495, "char_end": 386520, "token_start": 18, "token_end": 22, "note": null}, {"text": "EBER", "type": "ENTITY", "char_start": 386523, "char_end": 386527, "token_start": 24, "token_end": 24, "note": null}, {"text": "EBV - DNA fragments", "type": "ENTITY", "char_start": 386549, "char_end": 386568, "token_start": 30, "token_end": 33, "note": null}, {"text": "terminal repeats", "type": "ENTITY", "char_start": 386584, "char_end": 386600, "token_start": 36, "token_end": 37, "note": null}]}
+{"sentence_id": 2333, "sentence_text": "Transcripts of EBV - encoded genes were screened by reverse transcription - polymerase chain reaction ( RT - PCR ) , and confirmed by Southern blot hybridization .", "sentence_char_start_global": 386603, "sentence_char_end_global": 386766, "entities": [{"text": "EBV - encoded genes", "type": "ENTITY", "char_start": 15, "char_end": 34, "token_start": 2, "token_end": 5}], "entities_global": [{"text": "EBV - encoded genes", "type": "ENTITY", "char_start": 386618, "char_end": 386637, "token_start": 2, "token_end": 5, "note": null}]}
+{"sentence_id": 2334, "sentence_text": "The expression of EBV - related antigens was examined by immunostaining using paraffin - embedded tissue sections and cell pellets of EBV - positive cell lines .", "sentence_char_start_global": 386767, "sentence_char_end_global": 386928, "entities": [{"text": "EBV - related antigens", "type": "ENTITY", "char_start": 18, "char_end": 40, "token_start": 3, "token_end": 6}], "entities_global": [{"text": "EBV - related antigens", "type": "ENTITY", "char_start": 386785, "char_end": 386807, "token_start": 3, "token_end": 6, "note": null}]}
+{"sentence_id": 2335, "sentence_text": "Our study demonstrated that all samples from the patients contained EBV nuclear antigen ( EBNA ) - 1 mRNA which was transcribed using the Q promoter , whereas both the Q promoter and another upstream promoter ( Cp / Wp ) were used in EBV - positive cell lines , B95 . 8 , Raji and Jiyoye .", "sentence_char_start_global": 386929, "sentence_char_end_global": 387218, "entities": [{"text": "EBV nuclear antigen ( EBNA ) - 1 mRNA", "type": "ENTITY", "char_start": 68, "char_end": 105, "token_start": 10, "token_end": 18}, {"text": "Q promoter", "type": "ENTITY", "char_start": 138, "char_end": 148, "token_start": 24, "token_end": 25}, {"text": "Q promoter", "type": "ENTITY", "char_start": 168, "char_end": 178, "token_start": 30, "token_end": 31}, {"text": "upstream promoter", "type": "ENTITY", "char_start": 191, "char_end": 208, "token_start": 34, "token_end": 35}, {"text": "Cp / Wp", "type": "ENTITY", "char_start": 211, "char_end": 218, "token_start": 37, "token_end": 39}], "entities_global": [{"text": "EBV nuclear antigen ( EBNA ) - 1 mRNA", "type": "ENTITY", "char_start": 386997, "char_end": 387034, "token_start": 10, "token_end": 18, "note": null}, {"text": "Q promoter", "type": "ENTITY", "char_start": 387067, "char_end": 387077, "token_start": 24, "token_end": 25, "note": null}, {"text": "Q promoter", "type": "ENTITY", "char_start": 387097, "char_end": 387107, "token_start": 30, "token_end": 31, "note": null}, {"text": "upstream promoter", "type": "ENTITY", "char_start": 387120, "char_end": 387137, "token_start": 34, "token_end": 35, "note": null}, {"text": "Cp / Wp", "type": "ENTITY", "char_start": 387140, "char_end": 387147, "token_start": 37, "token_end": 39, "note": null}]}
+{"sentence_id": 2336, "sentence_text": "Latent membrane protein - 1 ( LMP - 1 ) mRNA was detected in seven of eight patients and all cell lines , whereas EBNA - 2 transcripts were found only in the cell lines .", "sentence_char_start_global": 387219, "sentence_char_end_global": 387389, "entities": [{"text": "Latent membrane protein - 1 ( LMP - 1 ) mRNA", "type": "ENTITY", "char_start": 0, "char_end": 44, "token_start": 0, "token_end": 10}, {"text": "EBNA - 2 transcripts", "type": "ENTITY", "char_start": 114, "char_end": 134, "token_start": 24, "token_end": 27}], "entities_global": [{"text": "Latent membrane protein - 1 ( LMP - 1 ) mRNA", "type": "ENTITY", "char_start": 387219, "char_end": 387263, "token_start": 0, "token_end": 10, "note": null}, {"text": "EBNA - 2 transcripts", "type": "ENTITY", "char_start": 387333, "char_end": 387353, "token_start": 24, "token_end": 27, "note": null}]}
+{"sentence_id": 2337, "sentence_text": "Immunostaining showed no LMP - 1 , EBNA - 2 or ZEBRA antigens in the paraffin - embedded tissue sections , although they were positive in the cell line cells .", "sentence_char_start_global": 387390, "sentence_char_end_global": 387549, "entities": [{"text": "LMP - 1 , EBNA - 2 or ZEBRA antigens", "type": "ENTITY", "char_start": 25, "char_end": 61, "token_start": 3, "token_end": 12}], "entities_global": [{"text": "LMP - 1 , EBNA - 2 or ZEBRA antigens", "type": "ENTITY", "char_start": 387415, "char_end": 387451, "token_start": 3, "token_end": 12, "note": null}]}
+{"sentence_id": 2338, "sentence_text": "Latent BHRF1 transcripts encoding bcl - 2 homologue and BCRF1 transcripts encoding viral interleukin ( vIL ) - 10 were detected in one and two of eight patients , respectively .", "sentence_char_start_global": 387550, "sentence_char_end_global": 387727, "entities": [{"text": "Latent BHRF1 transcripts", "type": "ENTITY", "char_start": 0, "char_end": 24, "token_start": 0, "token_end": 2}, {"text": "bcl - 2 homologue", "type": "ENTITY", "char_start": 34, "char_end": 51, "token_start": 4, "token_end": 7}, {"text": "BCRF1 transcripts", "type": "ENTITY", "char_start": 56, "char_end": 73, "token_start": 9, "token_end": 10}, {"text": "viral interleukin ( vIL ) - 10", "type": "ENTITY", "char_start": 83, "char_end": 113, "token_start": 12, "token_end": 18}], "entities_global": [{"text": "Latent BHRF1 transcripts", "type": "ENTITY", "char_start": 387550, "char_end": 387574, "token_start": 0, "token_end": 2, "note": null}, {"text": "bcl - 2 homologue", "type": "ENTITY", "char_start": 387584, "char_end": 387601, "token_start": 4, "token_end": 7, "note": null}, {"text": "BCRF1 transcripts", "type": "ENTITY", "char_start": 387606, "char_end": 387623, "token_start": 9, "token_end": 10, "note": null}, {"text": "viral interleukin ( vIL ) - 10", "type": "ENTITY", "char_start": 387633, "char_end": 387663, "token_start": 12, "token_end": 18, "note": null}]}
+{"sentence_id": 2339, "sentence_text": "A patient with NK - cell lymphoma expressing both transcripts died of rapid progression of the illness .", "sentence_char_start_global": 387728, "sentence_char_end_global": 387832, "entities": [], "entities_global": []}
+{"sentence_id": 2340, "sentence_text": "Our results indicate that the restricted expression of the latency - associated EBV genes and the production of vIL - 10 and bcl - 2 homologue may favour tumour growth , evading the host immune surveillance .", "sentence_char_start_global": 387833, "sentence_char_end_global": 388041, "entities": [{"text": "latency - associated EBV genes", "type": "ENTITY", "char_start": 59, "char_end": 89, "token_start": 9, "token_end": 13}, {"text": "vIL - 10 and bcl - 2 homologue", "type": "ENTITY", "char_start": 112, "char_end": 142, "token_start": 18, "token_end": 25}], "entities_global": [{"text": "latency - associated EBV genes", "type": "ENTITY", "char_start": 387892, "char_end": 387922, "token_start": 9, "token_end": 13, "note": null}, {"text": "vIL - 10 and bcl - 2 homologue", "type": "ENTITY", "char_start": 387945, "char_end": 387975, "token_start": 18, "token_end": 25, "note": null}]}
+{"sentence_id": 2341, "sentence_text": "Copyright 2001 Cancer Research Campaign .", "sentence_char_start_global": 388042, "sentence_char_end_global": 388083, "entities": [], "entities_global": []}
+{"sentence_id": 2342, "sentence_text": "Oxidized alkyl phospholipids are specific , high affinity peroxisome proliferator - activated receptor gamma ligands and agonists .", "sentence_char_start_global": 388084, "sentence_char_end_global": 388215, "entities": [], "entities_global": []}
+{"sentence_id": 2343, "sentence_text": "Synthetic high affinity peroxisome proliferator - activated receptor ( PPAR ) agonists are known , but biologic ligands are of low affinity .", "sentence_char_start_global": 388216, "sentence_char_end_global": 388357, "entities": [], "entities_global": []}
+{"sentence_id": 2344, "sentence_text": "Oxidized low density lipoprotein ( oxLDL ) is inflammatory and signals through PPARs .", "sentence_char_start_global": 388358, "sentence_char_end_global": 388444, "entities": [{"text": "Oxidized low density lipoprotein", "type": "ENTITY", "char_start": 0, "char_end": 32, "token_start": 0, "token_end": 3}, {"text": "oxLDL", "type": "ENTITY", "char_start": 35, "char_end": 40, "token_start": 5, "token_end": 5}, {"text": "PPARs", "type": "ENTITY", "char_start": 79, "char_end": 84, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "Oxidized low density lipoprotein", "type": "ENTITY", "char_start": 388358, "char_end": 388390, "token_start": 0, "token_end": 3, "note": null}, {"text": "oxLDL", "type": "ENTITY", "char_start": 388393, "char_end": 388398, "token_start": 5, "token_end": 5, "note": null}, {"text": "PPARs", "type": "ENTITY", "char_start": 388437, "char_end": 388442, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 2345, "sentence_text": "We showed , by phospholipase A ( 1 ) digestion , that PPARgamma agonists in oxLDL arise from the small pool of alkyl phosphatidylcholines in LDL .", "sentence_char_start_global": 388445, "sentence_char_end_global": 388591, "entities": [{"text": "oxLDL", "type": "ENTITY", "char_start": 76, "char_end": 81, "token_start": 15, "token_end": 15}, {"text": "LDL", "type": "ENTITY", "char_start": 141, "char_end": 144, "token_start": 25, "token_end": 25}], "entities_global": [{"text": "oxLDL", "type": "ENTITY", "char_start": 388521, "char_end": 388526, "token_start": 15, "token_end": 15, "note": null}, {"text": "LDL", "type": "ENTITY", "char_start": 388586, "char_end": 388589, "token_start": 25, "token_end": 25, "note": null}]}
+{"sentence_id": 2346, "sentence_text": "We identified an abundant oxidatively fragmented alkyl phospholipid in oxLDL , hexadecyl azelaoyl phosphatidylcholine ( azPC ) , as a high affinity ligand and agonist for PPARgamma .", "sentence_char_start_global": 388592, "sentence_char_end_global": 388774, "entities": [{"text": "oxLDL", "type": "ENTITY", "char_start": 71, "char_end": 76, "token_start": 9, "token_end": 9}, {"text": "PPARgamma", "type": "ENTITY", "char_start": 171, "char_end": 180, "token_start": 26, "token_end": 26}], "entities_global": [{"text": "oxLDL", "type": "ENTITY", "char_start": 388663, "char_end": 388668, "token_start": 9, "token_end": 9, "note": null}, {"text": "PPARgamma", "type": "ENTITY", "char_start": 388763, "char_end": 388772, "token_start": 26, "token_end": 26, "note": null}]}
+{"sentence_id": 2347, "sentence_text": "[ ( 3 ) H ] azPC bound recombinant PPARgamma with an affinity ( K ( d ) ( ( app ) ) approximately 40 nm ) that was equivalent to rosiglitazone ( BRL49653 ) , and competition with rosiglitazone showed that binding occurred in the ligand - binding pocket .", "sentence_char_start_global": 388775, "sentence_char_end_global": 389029, "entities": [{"text": "recombinant PPARgamma", "type": "ENTITY", "char_start": 23, "char_end": 44, "token_start": 8, "token_end": 9}, {"text": "ligand - binding pocket", "type": "ENTITY", "char_start": 229, "char_end": 252, "token_start": 46, "token_end": 49}], "entities_global": [{"text": "recombinant PPARgamma", "type": "ENTITY", "char_start": 388798, "char_end": 388819, "token_start": 8, "token_end": 9, "note": null}, {"text": "ligand - binding pocket", "type": "ENTITY", "char_start": 389004, "char_end": 389027, "token_start": 46, "token_end": 49, "note": null}]}
+{"sentence_id": 2348, "sentence_text": "azPC induced PPRE reporter gene expression , as did rosiglitazone , with a half - maximal effect at 100 nm .", "sentence_char_start_global": 389030, "sentence_char_end_global": 389138, "entities": [], "entities_global": []}
+{"sentence_id": 2349, "sentence_text": "Overexpression of PPARalpha or PPARgamma revealed that azPC was a specific PPARgamma agonist .", "sentence_char_start_global": 389139, "sentence_char_end_global": 389233, "entities": [{"text": "PPARalpha", "type": "ENTITY", "char_start": 18, "char_end": 27, "token_start": 2, "token_end": 2}, {"text": "PPARgamma", "type": "ENTITY", "char_start": 31, "char_end": 40, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "PPARalpha", "type": "ENTITY", "char_start": 389157, "char_end": 389166, "token_start": 2, "token_end": 2, "note": null}, {"text": "PPARgamma", "type": "ENTITY", "char_start": 389170, "char_end": 389179, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 2350, "sentence_text": "The scavenger receptor CD36 is encoded by a PPRE - responsive gene , and azPC enhanced expression of CD36 in primary human monocytes .", "sentence_char_start_global": 389234, "sentence_char_end_global": 389368, "entities": [{"text": "scavenger receptor CD36", "type": "ENTITY", "char_start": 4, "char_end": 27, "token_start": 1, "token_end": 3}, {"text": "PPRE - responsive gene", "type": "ENTITY", "char_start": 44, "char_end": 66, "token_start": 8, "token_end": 11}, {"text": "CD36", "type": "ENTITY", "char_start": 101, "char_end": 105, "token_start": 18, "token_end": 18}], "entities_global": [{"text": "scavenger receptor CD36", "type": "ENTITY", "char_start": 389238, "char_end": 389261, "token_start": 1, "token_end": 3, "note": null}, {"text": "PPRE - responsive gene", "type": "ENTITY", "char_start": 389278, "char_end": 389300, "token_start": 8, "token_end": 11, "note": null}, {"text": "CD36", "type": "ENTITY", "char_start": 389335, "char_end": 389339, "token_start": 18, "token_end": 18, "note": null}]}
+{"sentence_id": 2351, "sentence_text": "We found that anti - CD36 inhibited azPC uptake , and it inhibited PPRE reporter induction .", "sentence_char_start_global": 389369, "sentence_char_end_global": 389461, "entities": [{"text": "anti - CD36", "type": "ENTITY", "char_start": 14, "char_end": 25, "token_start": 3, "token_end": 5}], "entities_global": [{"text": "anti - CD36", "type": "ENTITY", "char_start": 389383, "char_end": 389394, "token_start": 3, "token_end": 5, "note": null}]}
+{"sentence_id": 2352, "sentence_text": "Results with a small molecule phospholipid flippase mimetic suggest azPC acts intracellularly and that cellular azPC accumulation was efficient .", "sentence_char_start_global": 389462, "sentence_char_end_global": 389607, "entities": [{"text": "phospholipid flippase mimetic", "type": "ENTITY", "char_start": 30, "char_end": 59, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "phospholipid flippase mimetic", "type": "ENTITY", "char_start": 389492, "char_end": 389521, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 2353, "sentence_text": "Thus , certain alkyl phospholipid oxidation products in oxLDL are specific , high affinity extracellular ligands and agonists for PPARgamma that induce PPAR - responsive genes", "sentence_char_start_global": 389608, "sentence_char_end_global": 389783, "entities": [{"text": "oxLDL", "type": "ENTITY", "char_start": 56, "char_end": 61, "token_start": 8, "token_end": 8}, {"text": "PPARgamma", "type": "ENTITY", "char_start": 130, "char_end": 139, "token_start": 19, "token_end": 19}, {"text": "PPAR - responsive genes", "type": "ENTITY", "char_start": 152, "char_end": 175, "token_start": 22, "token_end": 25}], "entities_global": [{"text": "oxLDL", "type": "ENTITY", "char_start": 389664, "char_end": 389669, "token_start": 8, "token_end": 8, "note": null}, {"text": "PPARgamma", "type": "ENTITY", "char_start": 389738, "char_end": 389747, "token_start": 19, "token_end": 19, "note": null}, {"text": "PPAR - responsive genes", "type": "ENTITY", "char_start": 389760, "char_end": 389783, "token_start": 22, "token_end": 25, "note": null}]}
+{"sentence_id": 2354, "sentence_text": "Regulation of the human MAT2B gene encoding the regulatory beta subunit of methionine adenosyltransferase , MAT II .", "sentence_char_start_global": 389784, "sentence_char_end_global": 389900, "entities": [{"text": "human MAT2B gene", "type": "ENTITY", "char_start": 18, "char_end": 34, "token_start": 3, "token_end": 5}, {"text": "regulatory beta subunit", "type": "ENTITY", "char_start": 48, "char_end": 71, "token_start": 8, "token_end": 10}, {"text": "methionine adenosyltransferase", "type": "ENTITY", "char_start": 75, "char_end": 105, "token_start": 12, "token_end": 13}, {"text": "MAT II", "type": "ENTITY", "char_start": 108, "char_end": 114, "token_start": 15, "token_end": 16}], "entities_global": [{"text": "human MAT2B gene", "type": "ENTITY", "char_start": 389802, "char_end": 389818, "token_start": 3, "token_end": 5, "note": null}, {"text": "regulatory beta subunit", "type": "ENTITY", "char_start": 389832, "char_end": 389855, "token_start": 8, "token_end": 10, "note": null}, {"text": "methionine adenosyltransferase", "type": "ENTITY", "char_start": 389859, "char_end": 389889, "token_start": 12, "token_end": 13, "note": null}, {"text": "MAT II", "type": "ENTITY", "char_start": 389892, "char_end": 389898, "token_start": 15, "token_end": 16, "note": null}]}
+{"sentence_id": 2355, "sentence_text": "Methionine adenosyltransferase ( MAT ) catalyzes the biosynthesis of S - adenosylmethionine ( AdoMet ) , a key molecule in transmethylation reactions and polyamine biosynthesis .", "sentence_char_start_global": 389901, "sentence_char_end_global": 390079, "entities": [{"text": "Methionine adenosyltransferase", "type": "ENTITY", "char_start": 0, "char_end": 30, "token_start": 0, "token_end": 1}, {"text": "MAT", "type": "ENTITY", "char_start": 33, "char_end": 36, "token_start": 3, "token_end": 3}, {"text": "S - adenosylmethionine", "type": "ENTITY", "char_start": 69, "char_end": 91, "token_start": 9, "token_end": 11}, {"text": "AdoMet", "type": "ENTITY", "char_start": 94, "char_end": 100, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "Methionine adenosyltransferase", "type": "ENTITY", "char_start": 389901, "char_end": 389931, "token_start": 0, "token_end": 1, "note": null}, {"text": "MAT", "type": "ENTITY", "char_start": 389934, "char_end": 389937, "token_start": 3, "token_end": 3, "note": null}, {"text": "S - adenosylmethionine", "type": "ENTITY", "char_start": 389970, "char_end": 389992, "token_start": 9, "token_end": 11, "note": null}, {"text": "AdoMet", "type": "ENTITY", "char_start": 389995, "char_end": 390001, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 2356, "sentence_text": "The MAT II isozyme consists of a catalytic alpha2 and a regulatory beta subunit .", "sentence_char_start_global": 390080, "sentence_char_end_global": 390161, "entities": [{"text": "MAT II isozyme", "type": "ENTITY", "char_start": 4, "char_end": 18, "token_start": 1, "token_end": 3}, {"text": "catalytic alpha2 and a regulatory beta subunit", "type": "ENTITY", "char_start": 33, "char_end": 79, "token_start": 7, "token_end": 13}], "entities_global": [{"text": "MAT II isozyme", "type": "ENTITY", "char_start": 390084, "char_end": 390098, "token_start": 1, "token_end": 3, "note": null}, {"text": "catalytic alpha2 and a regulatory beta subunit", "type": "ENTITY", "char_start": 390113, "char_end": 390159, "token_start": 7, "token_end": 13, "note": null}]}
+{"sentence_id": 2357, "sentence_text": "Down - regulation of the MAT II beta subunit expression causes a 6 - 10 - fold increase in intracellular AdoMet levels .", "sentence_char_start_global": 390162, "sentence_char_end_global": 390282, "entities": [{"text": "MAT II beta subunit", "type": "ENTITY", "char_start": 25, "char_end": 44, "token_start": 5, "token_end": 8}, {"text": "AdoMet", "type": "ENTITY", "char_start": 105, "char_end": 111, "token_start": 20, "token_end": 20}], "entities_global": [{"text": "MAT II beta subunit", "type": "ENTITY", "char_start": 390187, "char_end": 390206, "token_start": 5, "token_end": 8, "note": null}, {"text": "AdoMet", "type": "ENTITY", "char_start": 390267, "char_end": 390273, "token_start": 20, "token_end": 20, "note": null}]}
+{"sentence_id": 2358, "sentence_text": "To understand the mechanism by which the beta subunit expression is regulated , we cloned the MAT2B gene , determined its organization , characterized its 5 ' - flanking sequences , and elucidated the in vitro and in vivo regulation of its promoter .", "sentence_char_start_global": 390283, "sentence_char_end_global": 390533, "entities": [{"text": "beta subunit", "type": "ENTITY", "char_start": 41, "char_end": 53, "token_start": 7, "token_end": 8}, {"text": "MAT2B gene", "type": "ENTITY", "char_start": 94, "char_end": 104, "token_start": 16, "token_end": 17}, {"text": "5 ' - flanking sequences", "type": "ENTITY", "char_start": 155, "char_end": 179, "token_start": 25, "token_end": 29}, {"text": "promoter", "type": "ENTITY", "char_start": 240, "char_end": 248, "token_start": 42, "token_end": 42}], "entities_global": [{"text": "beta subunit", "type": "ENTITY", "char_start": 390324, "char_end": 390336, "token_start": 7, "token_end": 8, "note": null}, {"text": "MAT2B gene", "type": "ENTITY", "char_start": 390377, "char_end": 390387, "token_start": 16, "token_end": 17, "note": null}, {"text": "5 ' - flanking sequences", "type": "ENTITY", "char_start": 390438, "char_end": 390462, "token_start": 25, "token_end": 29, "note": null}, {"text": "promoter", "type": "ENTITY", "char_start": 390523, "char_end": 390531, "token_start": 42, "token_end": 42, "note": null}]}
+{"sentence_id": 2359, "sentence_text": "Transcription of the MAT2B gene initiates at position - 203 relative to the translation start site .", "sentence_char_start_global": 390534, "sentence_char_end_global": 390634, "entities": [{"text": "MAT2B gene", "type": "ENTITY", "char_start": 21, "char_end": 31, "token_start": 3, "token_end": 4}, {"text": "translation start site", "type": "ENTITY", "char_start": 76, "char_end": 98, "token_start": 13, "token_end": 15}], "entities_global": [{"text": "MAT2B gene", "type": "ENTITY", "char_start": 390555, "char_end": 390565, "token_start": 3, "token_end": 4, "note": null}, {"text": "translation start site", "type": "ENTITY", "char_start": 390610, "char_end": 390632, "token_start": 13, "token_end": 15, "note": null}]}
+{"sentence_id": 2360, "sentence_text": "Promoter deletion analysis defined a minimal promoter between positions + 52 and + 93 base pairs , a GC - rich region .", "sentence_char_start_global": 390635, "sentence_char_end_global": 390754, "entities": [{"text": "Promoter deletion analysis", "type": "ENTITY", "char_start": 0, "char_end": 26, "token_start": 0, "token_end": 2}, {"text": "minimal promoter", "type": "ENTITY", "char_start": 37, "char_end": 53, "token_start": 5, "token_end": 6}, {"text": "positions + 52 and + 93", "type": "ENTITY", "char_start": 62, "char_end": 85, "token_start": 8, "token_end": 13}, {"text": "GC - rich region", "type": "ENTITY", "char_start": 101, "char_end": 117, "token_start": 18, "token_end": 21}], "entities_global": [{"text": "Promoter deletion analysis", "type": "ENTITY", "char_start": 390635, "char_end": 390661, "token_start": 0, "token_end": 2, "note": null}, {"text": "minimal promoter", "type": "ENTITY", "char_start": 390672, "char_end": 390688, "token_start": 5, "token_end": 6, "note": null}, {"text": "positions + 52 and + 93", "type": "ENTITY", "char_start": 390697, "char_end": 390720, "token_start": 8, "token_end": 13, "note": null}, {"text": "GC - rich region", "type": "ENTITY", "char_start": 390736, "char_end": 390752, "token_start": 18, "token_end": 21, "note": null}]}
+{"sentence_id": 2361, "sentence_text": "Inclusion of the sequences between - 4 and + 52 enhanced promoter activity ; this was primarily because of an Sp1 recognition site at + 9 / + 15 .", "sentence_char_start_global": 390755, "sentence_char_end_global": 390901, "entities": [{"text": "Sp1 recognition site", "type": "ENTITY", "char_start": 110, "char_end": 130, "token_start": 20, "token_end": 22}], "entities_global": [{"text": "Sp1 recognition site", "type": "ENTITY", "char_start": 390865, "char_end": 390885, "token_start": 20, "token_end": 22, "note": null}]}
+{"sentence_id": 2362, "sentence_text": "The inclusion of sequences up to position - 115 provided full activity ; this was attributed to a TATA at - 32 .", "sentence_char_start_global": 390902, "sentence_char_end_global": 391014, "entities": [{"text": "TATA", "type": "ENTITY", "char_start": 98, "char_end": 102, "token_start": 18, "token_end": 18}], "entities_global": [{"text": "TATA", "type": "ENTITY", "char_start": 391000, "char_end": 391004, "token_start": 18, "token_end": 18, "note": null}]}
+{"sentence_id": 2363, "sentence_text": "The Sp1 site at position + 9 was key for the formation of protein . DNA complexes .", "sentence_char_start_global": 391015, "sentence_char_end_global": 391098, "entities": [{"text": "Sp1 site", "type": "ENTITY", "char_start": 4, "char_end": 12, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "Sp1 site", "type": "ENTITY", "char_start": 391019, "char_end": 391027, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 2364, "sentence_text": "Mutation of both the Sp1 site at + 9 and the TATA at - 32 reduced promoter activity to its minimal level .", "sentence_char_start_global": 391099, "sentence_char_end_global": 391205, "entities": [{"text": "Sp1 site", "type": "ENTITY", "char_start": 21, "char_end": 29, "token_start": 4, "token_end": 5}, {"text": "TATA", "type": "ENTITY", "char_start": 45, "char_end": 49, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "Sp1 site", "type": "ENTITY", "char_start": 391120, "char_end": 391128, "token_start": 4, "token_end": 5, "note": null}, {"text": "TATA", "type": "ENTITY", "char_start": 391144, "char_end": 391148, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 2365, "sentence_text": "Supershift assays showed no effect of the anti - Sp1 antibody on complex formation , whereas the anti - Sp3 antibody had a strong effect on protein . DNA complex formation , suggesting that Sp3 is one of the main factors binding to this Sp1 site .", "sentence_char_start_global": 391206, "sentence_char_end_global": 391453, "entities": [{"text": "anti - Sp1 antibody", "type": "ENTITY", "char_start": 42, "char_end": 61, "token_start": 7, "token_end": 10}, {"text": "anti - Sp3 antibody", "type": "ENTITY", "char_start": 97, "char_end": 116, "token_start": 17, "token_end": 20}, {"text": "Sp3", "type": "ENTITY", "char_start": 190, "char_end": 193, "token_start": 34, "token_end": 34}, {"text": "Sp1 site", "type": "ENTITY", "char_start": 237, "char_end": 245, "token_start": 44, "token_end": 45}], "entities_global": [{"text": "anti - Sp1 antibody", "type": "ENTITY", "char_start": 391248, "char_end": 391267, "token_start": 7, "token_end": 10, "note": null}, {"text": "anti - Sp3 antibody", "type": "ENTITY", "char_start": 391303, "char_end": 391322, "token_start": 17, "token_end": 20, "note": null}, {"text": "Sp3", "type": "ENTITY", "char_start": 391396, "char_end": 391399, "token_start": 34, "token_end": 34, "note": null}, {"text": "Sp1 site", "type": "ENTITY", "char_start": 391443, "char_end": 391451, "token_start": 44, "token_end": 45, "note": null}]}
+{"sentence_id": 2366, "sentence_text": "Chromatin immunoprecipitation assays supported the involvement of both Sp1 and Sp3 in complexes formed on the MAT2B promoter .", "sentence_char_start_global": 391454, "sentence_char_end_global": 391580, "entities": [{"text": "Sp1", "type": "ENTITY", "char_start": 71, "char_end": 74, "token_start": 8, "token_end": 8}, {"text": "Sp3", "type": "ENTITY", "char_start": 79, "char_end": 82, "token_start": 10, "token_end": 10}, {"text": "MAT2B promoter", "type": "ENTITY", "char_start": 110, "char_end": 124, "token_start": 16, "token_end": 17}], "entities_global": [{"text": "Sp1", "type": "ENTITY", "char_start": 391525, "char_end": 391528, "token_start": 8, "token_end": 8, "note": null}, {"text": "Sp3", "type": "ENTITY", "char_start": 391533, "char_end": 391536, "token_start": 10, "token_end": 10, "note": null}, {"text": "MAT2B promoter", "type": "ENTITY", "char_start": 391564, "char_end": 391578, "token_start": 16, "token_end": 17, "note": null}]}
+{"sentence_id": 2367, "sentence_text": "The data show that the 5 ' - untranslated sequences play an important role in regulating the MAT2B gene and identifies the Sp1 site at + 9 as a potential target for modulating MAT2B expression , a process that can have a major effect on intracellular AdoMet levels .", "sentence_char_start_global": 391581, "sentence_char_end_global": 391847, "entities": [{"text": "5 ' - untranslated sequences", "type": "ENTITY", "char_start": 23, "char_end": 51, "token_start": 5, "token_end": 9}, {"text": "MAT2B gene", "type": "ENTITY", "char_start": 93, "char_end": 103, "token_start": 17, "token_end": 18}, {"text": "Sp1 site", "type": "ENTITY", "char_start": 123, "char_end": 131, "token_start": 22, "token_end": 23}, {"text": "AdoMet", "type": "ENTITY", "char_start": 251, "char_end": 257, "token_start": 46, "token_end": 46}], "entities_global": [{"text": "5 ' - untranslated sequences", "type": "ENTITY", "char_start": 391604, "char_end": 391632, "token_start": 5, "token_end": 9, "note": null}, {"text": "MAT2B gene", "type": "ENTITY", "char_start": 391674, "char_end": 391684, "token_start": 17, "token_end": 18, "note": null}, {"text": "Sp1 site", "type": "ENTITY", "char_start": 391704, "char_end": 391712, "token_start": 22, "token_end": 23, "note": null}, {"text": "AdoMet", "type": "ENTITY", "char_start": 391832, "char_end": 391838, "token_start": 46, "token_end": 46, "note": null}]}
+{"sentence_id": 2368, "sentence_text": "Molecular pathogenesis of influenza A virus infection and virus - induced regulation of cytokine gene expression .", "sentence_char_start_global": 391848, "sentence_char_end_global": 391962, "entities": [{"text": "cytokine gene", "type": "ENTITY", "char_start": 88, "char_end": 101, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "cytokine gene", "type": "ENTITY", "char_start": 391936, "char_end": 391949, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 2369, "sentence_text": "Despite vaccines and antiviral substances influenza still causes significant morbidity and mortality world wide .", "sentence_char_start_global": 391963, "sentence_char_end_global": 392076, "entities": [], "entities_global": []}
+{"sentence_id": 2370, "sentence_text": "Better understanding of the molecular mechanisms of influenza virus replication , pathogenesis and host immune responses is required for the development of more efficient means of prevention and treatment of influenza .", "sentence_char_start_global": 392077, "sentence_char_end_global": 392296, "entities": [], "entities_global": []}
+{"sentence_id": 2371, "sentence_text": "Influenza A virus , which replicates in epithelial cells and leukocytes , regulates host cell transcriptional and translational systems and activates , as well as downregulates apoptotic pathways .", "sentence_char_start_global": 392297, "sentence_char_end_global": 392494, "entities": [], "entities_global": []}
+{"sentence_id": 2372, "sentence_text": "Influenza A virus infection results in the production of chemotactic ( RANTES , MIP - 1 alpha , MCP - 1 , MCP - 3 , and IP - 10 ) , pro - inflammatory ( IL - 1 beta , IL - 6 , IL - 18 , and TNF - alpha ) , and antiviral ( IFN - alpha / beta ) cytokines .", "sentence_char_start_global": 392495, "sentence_char_end_global": 392749, "entities": [{"text": "RANTES", "type": "ENTITY", "char_start": 71, "char_end": 77, "token_start": 11, "token_end": 11}, {"text": "MIP - 1 alpha", "type": "ENTITY", "char_start": 80, "char_end": 93, "token_start": 13, "token_end": 16}, {"text": "MCP - 1", "type": "ENTITY", "char_start": 96, "char_end": 103, "token_start": 18, "token_end": 20}, {"text": "MCP - 3", "type": "ENTITY", "char_start": 106, "char_end": 113, "token_start": 22, "token_end": 24}, {"text": "IP - 10", "type": "ENTITY", "char_start": 120, "char_end": 127, "token_start": 27, "token_end": 29}, {"text": "IL - 1 beta", "type": "ENTITY", "char_start": 153, "char_end": 164, "token_start": 36, "token_end": 39}, {"text": "IL - 6", "type": "ENTITY", "char_start": 167, "char_end": 173, "token_start": 41, "token_end": 43}, {"text": "IL - 18", "type": "ENTITY", "char_start": 176, "char_end": 183, "token_start": 45, "token_end": 47}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 190, "char_end": 201, "token_start": 50, "token_end": 52}, {"text": "antiviral ( IFN - alpha / beta ) cytokines", "type": "ENTITY", "char_start": 210, "char_end": 252, "token_start": 56, "token_end": 64}], "entities_global": [{"text": "RANTES", "type": "ENTITY", "char_start": 392566, "char_end": 392572, "token_start": 11, "token_end": 11, "note": null}, {"text": "MIP - 1 alpha", "type": "ENTITY", "char_start": 392575, "char_end": 392588, "token_start": 13, "token_end": 16, "note": null}, {"text": "MCP - 1", "type": "ENTITY", "char_start": 392591, "char_end": 392598, "token_start": 18, "token_end": 20, "note": null}, {"text": "MCP - 3", "type": "ENTITY", "char_start": 392601, "char_end": 392608, "token_start": 22, "token_end": 24, "note": null}, {"text": "IP - 10", "type": "ENTITY", "char_start": 392615, "char_end": 392622, "token_start": 27, "token_end": 29, "note": null}, {"text": "IL - 1 beta", "type": "ENTITY", "char_start": 392648, "char_end": 392659, "token_start": 36, "token_end": 39, "note": null}, {"text": "IL - 6", "type": "ENTITY", "char_start": 392662, "char_end": 392668, "token_start": 41, "token_end": 43, "note": null}, {"text": "IL - 18", "type": "ENTITY", "char_start": 392671, "char_end": 392678, "token_start": 45, "token_end": 47, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 392685, "char_end": 392696, "token_start": 50, "token_end": 52, "note": null}, {"text": "antiviral ( IFN - alpha / beta ) cytokines", "type": "ENTITY", "char_start": 392705, "char_end": 392747, "token_start": 56, "token_end": 64, "note": null}]}
+{"sentence_id": 2373, "sentence_text": "Cytokine gene expression is associated with the activation of NF - kappa B , AP - 1 , STAT and IRF signal transducing molecules in influenza A virus - infected cells .", "sentence_char_start_global": 392750, "sentence_char_end_global": 392917, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 62, "char_end": 74, "token_start": 9, "token_end": 12}, {"text": "AP - 1", "type": "ENTITY", "char_start": 77, "char_end": 83, "token_start": 14, "token_end": 16}, {"text": "STAT", "type": "ENTITY", "char_start": 86, "char_end": 90, "token_start": 18, "token_end": 18}, {"text": "IRF signal transducing molecules", "type": "ENTITY", "char_start": 95, "char_end": 127, "token_start": 20, "token_end": 23}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 392812, "char_end": 392824, "token_start": 9, "token_end": 12, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 392827, "char_end": 392833, "token_start": 14, "token_end": 16, "note": null}, {"text": "STAT", "type": "ENTITY", "char_start": 392836, "char_end": 392840, "token_start": 18, "token_end": 18, "note": null}, {"text": "IRF signal transducing molecules", "type": "ENTITY", "char_start": 392845, "char_end": 392877, "token_start": 20, "token_end": 23, "note": null}]}
+{"sentence_id": 2374, "sentence_text": "In addition of upregulating cytokine gene expression , influenza A virus infection activates caspase - 1 enzyme , which is involved in the proteolytic processing of proIL - 1 beta and proIL - 18 into their biologically active forms .", "sentence_char_start_global": 392918, "sentence_char_end_global": 393151, "entities": [{"text": "cytokine gene", "type": "ENTITY", "char_start": 28, "char_end": 41, "token_start": 4, "token_end": 5}, {"text": "caspase - 1 enzyme", "type": "ENTITY", "char_start": 93, "char_end": 111, "token_start": 13, "token_end": 16}, {"text": "proIL - 1 beta", "type": "ENTITY", "char_start": 165, "char_end": 179, "token_start": 26, "token_end": 29}, {"text": "proIL - 18", "type": "ENTITY", "char_start": 184, "char_end": 194, "token_start": 31, "token_end": 33}], "entities_global": [{"text": "cytokine gene", "type": "ENTITY", "char_start": 392946, "char_end": 392959, "token_start": 4, "token_end": 5, "note": null}, {"text": "caspase - 1 enzyme", "type": "ENTITY", "char_start": 393011, "char_end": 393029, "token_start": 13, "token_end": 16, "note": null}, {"text": "proIL - 1 beta", "type": "ENTITY", "char_start": 393083, "char_end": 393097, "token_start": 26, "token_end": 29, "note": null}, {"text": "proIL - 18", "type": "ENTITY", "char_start": 393102, "char_end": 393112, "token_start": 31, "token_end": 33, "note": null}]}
+{"sentence_id": 2375, "sentence_text": "Influenza A virus - induced IFN - alpha / beta is essential in host ' s antiviral defence by activating the expression of antiviral Mx , PKR and oligoadenylate synthetase genes .", "sentence_char_start_global": 393152, "sentence_char_end_global": 393330, "entities": [{"text": "IFN - alpha / beta", "type": "ENTITY", "char_start": 28, "char_end": 46, "token_start": 5, "token_end": 9}, {"text": "antiviral Mx", "type": "ENTITY", "char_start": 122, "char_end": 134, "token_start": 23, "token_end": 24}, {"text": "PKR and oligoadenylate synthetase genes", "type": "ENTITY", "char_start": 137, "char_end": 176, "token_start": 26, "token_end": 30}], "entities_global": [{"text": "IFN - alpha / beta", "type": "ENTITY", "char_start": 393180, "char_end": 393198, "token_start": 5, "token_end": 9, "note": null}, {"text": "antiviral Mx", "type": "ENTITY", "char_start": 393274, "char_end": 393286, "token_start": 23, "token_end": 24, "note": null}, {"text": "PKR and oligoadenylate synthetase genes", "type": "ENTITY", "char_start": 393289, "char_end": 393328, "token_start": 26, "token_end": 30, "note": null}]}
+{"sentence_id": 2376, "sentence_text": "IFN - alpha / beta also prolongs T cell survival , upregulates IL - 12 and IL - 18 receptor gene expression and together with IL - 18 stimulates NK and T cell IFN - gamma production and the development of Th1 - type immune response .", "sentence_char_start_global": 393331, "sentence_char_end_global": 393564, "entities": [{"text": "IFN - alpha / beta", "type": "ENTITY", "char_start": 0, "char_end": 18, "token_start": 0, "token_end": 4}, {"text": "IL - 18", "type": "ENTITY", "char_start": 126, "char_end": 133, "token_start": 25, "token_end": 27}], "entities_global": [{"text": "IFN - alpha / beta", "type": "ENTITY", "char_start": 393331, "char_end": 393349, "token_start": 0, "token_end": 4, "note": null}, {"text": "IL - 18", "type": "ENTITY", "char_start": 393457, "char_end": 393464, "token_start": 25, "token_end": 27, "note": null}]}
+{"sentence_id": 2377, "sentence_text": "Comparison of hprt and lacI mutant frequency with DNA adduct formation in N - hydroxy - 2 - acetylaminofluorene - treated Big Blue rats .", "sentence_char_start_global": 393565, "sentence_char_end_global": 393702, "entities": [], "entities_global": []}
+{"sentence_id": 2378, "sentence_text": "N - Hydroxy - 2 - acetylaminofluorene ( N - OH - AAF ) is the proximate carcinogenic metabolite of the powerful rat liver carcinogen 2 - acetylaminofluorene .", "sentence_char_start_global": 393703, "sentence_char_end_global": 393861, "entities": [], "entities_global": []}
+{"sentence_id": 2379, "sentence_text": "In this study , transgenic Big Blue ( R ) rats were used to examine the relationship between in vivo mutagenicity and DNA adduct formation by N - OH - AAF in the target liver compared with that in nontarget tissues .", "sentence_char_start_global": 393862, "sentence_char_end_global": 394078, "entities": [], "entities_global": []}
+{"sentence_id": 2380, "sentence_text": "Male rats were given one , two , or four doses of 25 mg N - OH - AAF / kg body weight by i . p . injection at 4 - day intervals , and groups of treated and control rats were euthanized up to 10 weeks after beginning the dosing .", "sentence_char_start_global": 394079, "sentence_char_end_global": 394307, "entities": [], "entities_global": []}
+{"sentence_id": 2381, "sentence_text": "Mutant frequencies were measured in the spleen lymphocyte hprt gene , and lacI mutant frequencies were determined in the liver and spleen lymphocytes .", "sentence_char_start_global": 394308, "sentence_char_end_global": 394459, "entities": [{"text": "spleen lymphocyte hprt gene", "type": "ENTITY", "char_start": 40, "char_end": 67, "token_start": 6, "token_end": 9}], "entities_global": [{"text": "spleen lymphocyte hprt gene", "type": "ENTITY", "char_start": 394348, "char_end": 394375, "token_start": 6, "token_end": 9, "note": null}]}
+{"sentence_id": 2382, "sentence_text": "At 6 weeks after beginning the dosing , the hprt mutant frequency in spleen lymphocytes from the four - dose group was 16 . 5 x 10 ( - 6 ) compared with 3 . 2 x 10 ( - 6 ) in control animals .", "sentence_char_start_global": 394460, "sentence_char_end_global": 394652, "entities": [], "entities_global": []}
+{"sentence_id": 2383, "sentence_text": "Also at 6 weeks , rats given one , two , or four doses of N - OH - AAF had lacI mutant frequencies in the liver of 97 . 6 , 155 . 6 , and 406 . 8 x 10 ( - 6 ) , respectively , compared with a control frequency of 25 . 7 x 10 ( - 6 ) ; rats given four doses had lacI mutant frequencies in spleen lymphocytes of 55 . 8 x 10 ( - 6 ) compared with a control frequency of 20 . 4 x 10 ( - 6 ) .", "sentence_char_start_global": 394653, "sentence_char_end_global": 395041, "entities": [], "entities_global": []}
+{"sentence_id": 2384, "sentence_text": "Additional rats were evaluated for DNA adduct formation in the liver , spleen lymphocytes , and bone marrow by ( 32 ) P - postlabeling .", "sentence_char_start_global": 395042, "sentence_char_end_global": 395178, "entities": [], "entities_global": []}
+{"sentence_id": 2385, "sentence_text": "Adduct analysis was conducted 1 day after one , two , and four treatments with N - OH - AAF , 5 days after one treatment , and 9 days after two treatments .", "sentence_char_start_global": 395179, "sentence_char_end_global": 395335, "entities": [], "entities_global": []}
+{"sentence_id": 2386, "sentence_text": "N - ( Deoxyguanosin - 8 - yl ) - 2 - aminofluorene was the major DNA adduct identified in all the tissues examined .", "sentence_char_start_global": 395336, "sentence_char_end_global": 395452, "entities": [], "entities_global": []}
+{"sentence_id": 2387, "sentence_text": "Adduct concentrations increased with total dose to maximum values in samples taken 1 day after two doses , and remained essentially the same after four doses .", "sentence_char_start_global": 395453, "sentence_char_end_global": 395612, "entities": [], "entities_global": []}
+{"sentence_id": 2388, "sentence_text": "In samples taken after four doses , adduct levels were 103 , 28 , and 7 fmol / microg of DNA in liver , spleen lymphocytes , and bone marrow , respectively .", "sentence_char_start_global": 395613, "sentence_char_end_global": 395770, "entities": [], "entities_global": []}
+{"sentence_id": 2389, "sentence_text": "The results indicate that the extent of both DNA adduct formation and mutant induction correlates with the organ specificity for N - OH - AAF carcinogenesis in the rat .", "sentence_char_start_global": 395771, "sentence_char_end_global": 395940, "entities": [], "entities_global": []}
+{"sentence_id": 2390, "sentence_text": "Environ . Mol . Mutagen . 37 : 195 - 202 , 2001 .", "sentence_char_start_global": 395941, "sentence_char_end_global": 395990, "entities": [], "entities_global": []}
+{"sentence_id": 2391, "sentence_text": "Published 2001 Wiley - Liss , Inc .", "sentence_char_start_global": 395991, "sentence_char_end_global": 396026, "entities": [], "entities_global": []}
+{"sentence_id": 2392, "sentence_text": "Expression of Mad1 in T cells leads to reduced thymic cellularity and impaired mitogen - induced proliferation .", "sentence_char_start_global": 396027, "sentence_char_end_global": 396139, "entities": [{"text": "Mad1", "type": "ENTITY", "char_start": 14, "char_end": 18, "token_start": 2, "token_end": 2}], "entities_global": [{"text": "Mad1", "type": "ENTITY", "char_start": 396041, "char_end": 396045, "token_start": 2, "token_end": 2, "note": null}]}
+{"sentence_id": 2393, "sentence_text": "To investigate Mad1 function in vivo , transgenic mice were generated that express a Mad1 transgene in T lineage cells under the control of the proximal lck promoter .", "sentence_char_start_global": 396140, "sentence_char_end_global": 396307, "entities": [{"text": "Mad1", "type": "ENTITY", "char_start": 15, "char_end": 19, "token_start": 2, "token_end": 2}, {"text": "Mad1 transgene", "type": "ENTITY", "char_start": 85, "char_end": 99, "token_start": 14, "token_end": 15}, {"text": "proximal lck promoter", "type": "ENTITY", "char_start": 144, "char_end": 165, "token_start": 25, "token_end": 27}], "entities_global": [{"text": "Mad1", "type": "ENTITY", "char_start": 396155, "char_end": 396159, "token_start": 2, "token_end": 2, "note": null}, {"text": "Mad1 transgene", "type": "ENTITY", "char_start": 396225, "char_end": 396239, "token_start": 14, "token_end": 15, "note": null}, {"text": "proximal lck promoter", "type": "ENTITY", "char_start": 396284, "char_end": 396305, "token_start": 25, "token_end": 27, "note": null}]}
+{"sentence_id": 2394, "sentence_text": "Thymus size in lck - Mad1 transgenic mice is drastically reduced although representation of the various thymocyte sub populations appears normal .", "sentence_char_start_global": 396308, "sentence_char_end_global": 396454, "entities": [], "entities_global": []}
+{"sentence_id": 2395, "sentence_text": "To investigate more closely any effects of Mad1 expression on thymocytes , we examined thymic selection using MHC class I - restricted H - Y - TCR transgenic mice .", "sentence_char_start_global": 396455, "sentence_char_end_global": 396619, "entities": [], "entities_global": []}
+{"sentence_id": 2396, "sentence_text": "Mad1 expression in vivo reduces the efficiency of positive selection .", "sentence_char_start_global": 396620, "sentence_char_end_global": 396690, "entities": [], "entities_global": []}
+{"sentence_id": 2397, "sentence_text": "Furthermore , thymocytes and splenic T cells from lck - Mad1 transgenic mice display a profound proliferative defect in response to activation with either PMA / Ionomycin or immobilized anti - CD3 / CD28 antibody .", "sentence_char_start_global": 396691, "sentence_char_end_global": 396905, "entities": [{"text": "immobilized anti - CD3 / CD28 antibody", "type": "ENTITY", "char_start": 174, "char_end": 212, "token_start": 28, "token_end": 34}], "entities_global": [{"text": "immobilized anti - CD3 / CD28 antibody", "type": "ENTITY", "char_start": 396865, "char_end": 396903, "token_start": 28, "token_end": 34, "note": null}]}
+{"sentence_id": 2398, "sentence_text": "This proliferative defect is not reversed by addition of exogenous IL - 2 and is p53 - independent .", "sentence_char_start_global": 396906, "sentence_char_end_global": 397006, "entities": [{"text": "exogenous IL - 2", "type": "ENTITY", "char_start": 57, "char_end": 73, "token_start": 9, "token_end": 12}], "entities_global": [{"text": "exogenous IL - 2", "type": "ENTITY", "char_start": 396963, "char_end": 396979, "token_start": 9, "token_end": 12, "note": null}]}
+{"sentence_id": 2399, "sentence_text": "The growth inhibition caused by Mad1 is overcome by expression of active c - Myc .", "sentence_char_start_global": 397007, "sentence_char_end_global": 397089, "entities": [{"text": "Mad1", "type": "ENTITY", "char_start": 32, "char_end": 36, "token_start": 5, "token_end": 5}, {"text": "active c - Myc", "type": "ENTITY", "char_start": 66, "char_end": 80, "token_start": 11, "token_end": 14}], "entities_global": [{"text": "Mad1", "type": "ENTITY", "char_start": 397039, "char_end": 397043, "token_start": 5, "token_end": 5, "note": null}, {"text": "active c - Myc", "type": "ENTITY", "char_start": 397073, "char_end": 397087, "token_start": 11, "token_end": 14, "note": null}]}
+{"sentence_id": 2400, "sentence_text": "Differential requirement for the transcription factor PU . 1 in the generation of natural killer cells versus B and T cells .", "sentence_char_start_global": 397090, "sentence_char_end_global": 397215, "entities": [{"text": "transcription factor PU . 1", "type": "ENTITY", "char_start": 33, "char_end": 60, "token_start": 4, "token_end": 8}], "entities_global": [{"text": "transcription factor PU . 1", "type": "ENTITY", "char_start": 397123, "char_end": 397150, "token_start": 4, "token_end": 8, "note": null}]}
+{"sentence_id": 2401, "sentence_text": "PU . 1 is a member of the Ets family of transcription factors required for the development of various lymphoid and myeloid cell lineages , but its role in natural killer ( NK ) cell development is not known .", "sentence_char_start_global": 397216, "sentence_char_end_global": 397424, "entities": [{"text": "PU . 1", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 2}, {"text": "Ets family of transcription factors", "type": "ENTITY", "char_start": 26, "char_end": 61, "token_start": 8, "token_end": 12}], "entities_global": [{"text": "PU . 1", "type": "ENTITY", "char_start": 397216, "char_end": 397222, "token_start": 0, "token_end": 2, "note": null}, {"text": "Ets family of transcription factors", "type": "ENTITY", "char_start": 397242, "char_end": 397277, "token_start": 8, "token_end": 12, "note": null}]}
+{"sentence_id": 2402, "sentence_text": "The study shows that PU . 1 is expressed in NK cells and that , on cell transfer into alymphoid Rag2 / gammac ( - / - ) mice , hematopoietic progenitors of PU . 1 ( - / - ) fetal liver cells could generate functional NK cells but not B or T cells .", "sentence_char_start_global": 397425, "sentence_char_end_global": 397673, "entities": [{"text": "PU . 1", "type": "ENTITY", "char_start": 21, "char_end": 27, "token_start": 4, "token_end": 6}], "entities_global": [{"text": "PU . 1", "type": "ENTITY", "char_start": 397446, "char_end": 397452, "token_start": 4, "token_end": 6, "note": null}]}
+{"sentence_id": 2403, "sentence_text": "Nevertheless , the numbers of bone marrow NK cell precursors and splenic mature NK cells were reduced compared to controls .", "sentence_char_start_global": 397674, "sentence_char_end_global": 397798, "entities": [], "entities_global": []}
+{"sentence_id": 2404, "sentence_text": "Moreover , PU . 1 ( - / - ) NK cells displayed reduced expression of the receptors for stem cell factor and interleukin ( IL ) - 7 , suggesting a nonredundant role for PU . 1 in regulating the expression of these cytokine receptor genes during NK cell development .", "sentence_char_start_global": 397799, "sentence_char_end_global": 398064, "entities": [{"text": "stem cell factor", "type": "ENTITY", "char_start": 87, "char_end": 103, "token_start": 19, "token_end": 21}, {"text": "interleukin ( IL ) - 7", "type": "ENTITY", "char_start": 108, "char_end": 130, "token_start": 23, "token_end": 28}, {"text": "PU . 1", "type": "ENTITY", "char_start": 168, "char_end": 174, "token_start": 35, "token_end": 37}, {"text": "cytokine receptor genes", "type": "ENTITY", "char_start": 213, "char_end": 236, "token_start": 44, "token_end": 46}], "entities_global": [{"text": "stem cell factor", "type": "ENTITY", "char_start": 397886, "char_end": 397902, "token_start": 19, "token_end": 21, "note": null}, {"text": "interleukin ( IL ) - 7", "type": "ENTITY", "char_start": 397907, "char_end": 397929, "token_start": 23, "token_end": 28, "note": null}, {"text": "PU . 1", "type": "ENTITY", "char_start": 397967, "char_end": 397973, "token_start": 35, "token_end": 37, "note": null}, {"text": "cytokine receptor genes", "type": "ENTITY", "char_start": 398012, "char_end": 398035, "token_start": 44, "token_end": 46, "note": null}]}
+{"sentence_id": 2405, "sentence_text": "PU . 1 ( - / - ) NK cells also showed defective expression of inhibitory and activating members of the Ly49 family and failed to proliferate in response to IL - 2 and IL - 12 .", "sentence_char_start_global": 398065, "sentence_char_end_global": 398241, "entities": [{"text": "Ly49 family", "type": "ENTITY", "char_start": 103, "char_end": 114, "token_start": 21, "token_end": 22}, {"text": "IL - 2", "type": "ENTITY", "char_start": 156, "char_end": 162, "token_start": 30, "token_end": 32}, {"text": "IL - 12", "type": "ENTITY", "char_start": 167, "char_end": 174, "token_start": 34, "token_end": 36}], "entities_global": [{"text": "Ly49 family", "type": "ENTITY", "char_start": 398168, "char_end": 398179, "token_start": 21, "token_end": 22, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 398221, "char_end": 398227, "token_start": 30, "token_end": 32, "note": null}, {"text": "IL - 12", "type": "ENTITY", "char_start": 398232, "char_end": 398239, "token_start": 34, "token_end": 36, "note": null}]}
+{"sentence_id": 2406, "sentence_text": "Thus , despite the less stringent requirement for PU . 1 in NK cell development compared to B and T cells , PU . 1 regulates NK cell differentiation and homeostasis .", "sentence_char_start_global": 398242, "sentence_char_end_global": 398408, "entities": [{"text": "PU . 1", "type": "ENTITY", "char_start": 50, "char_end": 56, "token_start": 8, "token_end": 10}, {"text": "PU . 1", "type": "ENTITY", "char_start": 108, "char_end": 114, "token_start": 22, "token_end": 24}], "entities_global": [{"text": "PU . 1", "type": "ENTITY", "char_start": 398292, "char_end": 398298, "token_start": 8, "token_end": 10, "note": null}, {"text": "PU . 1", "type": "ENTITY", "char_start": 398350, "char_end": 398356, "token_start": 22, "token_end": 24, "note": null}]}
+{"sentence_id": 2407, "sentence_text": "Benzene - extracted components are important for the major activity of diesel exhaust particles : effect on interleukin - 8 gene expression in human bronchial epithelial cells .", "sentence_char_start_global": 398409, "sentence_char_end_global": 398586, "entities": [{"text": "interleukin - 8 gene", "type": "ENTITY", "char_start": 108, "char_end": 128, "token_start": 17, "token_end": 20}], "entities_global": [{"text": "interleukin - 8 gene", "type": "ENTITY", "char_start": 398517, "char_end": 398537, "token_start": 17, "token_end": 20, "note": null}]}
+{"sentence_id": 2408, "sentence_text": "Epidemiologic and experimental studies suggest that diesel exhaust particles ( DEPs ) may be related to increasing respiratory mortality and morbidity .", "sentence_char_start_global": 398587, "sentence_char_end_global": 398739, "entities": [], "entities_global": []}
+{"sentence_id": 2409, "sentence_text": "We have shown that DEPs augmented the production of inflammatory cytokines by human airway epithelial cells in vitro .", "sentence_char_start_global": 398740, "sentence_char_end_global": 398858, "entities": [{"text": "inflammatory cytokines", "type": "ENTITY", "char_start": 52, "char_end": 74, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "inflammatory cytokines", "type": "ENTITY", "char_start": 398792, "char_end": 398814, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 2410, "sentence_text": "To better understand the mechanisms of their proinflammatory activities , we studied the effects of several components extracted from DEPs on interleukin ( IL ) - 8 expression in human bronchial epithelial cell line BEAS - 2B and normal human airway epithelial cells obtained from very peripheral airways by an ultrathin bronchoscope .", "sentence_char_start_global": 398859, "sentence_char_end_global": 399194, "entities": [], "entities_global": []}
+{"sentence_id": 2411, "sentence_text": "We used several agents active on signal transduction pathways in cytokine expression , such as the protein kinase C inhibitor staurosporin , antioxidant agents including N - acetyl cysteine ( NAC ) and pyrrolidine dithiocarbamate ( PDTC ) , and p38 mitogen - activated protein kinase ( MAPK ) inhibitor SB203580 .", "sentence_char_start_global": 399195, "sentence_char_end_global": 399508, "entities": [{"text": "p38 mitogen - activated protein kinase", "type": "ENTITY", "char_start": 245, "char_end": 283, "token_start": 40, "token_end": 45}, {"text": "MAPK", "type": "ENTITY", "char_start": 286, "char_end": 290, "token_start": 47, "token_end": 47}], "entities_global": [{"text": "p38 mitogen - activated protein kinase", "type": "ENTITY", "char_start": 399440, "char_end": 399478, "token_start": 40, "token_end": 45, "note": null}, {"text": "MAPK", "type": "ENTITY", "char_start": 399481, "char_end": 399485, "token_start": 47, "token_end": 47, "note": null}]}
+{"sentence_id": 2412, "sentence_text": "Benzene - extracted components showed effects mimicking DEPs on IL - 8 gene expression , release of several cytokines ( IL - 8 ; granulocyte macrophage colony - stimulating factor ; and regulated on activation , normal T cells expressed and secreted ) and nuclear factor ( NF ) - kappa B activation .", "sentence_char_start_global": 399509, "sentence_char_end_global": 399809, "entities": [{"text": "cytokines", "type": "ENTITY", "char_start": 108, "char_end": 117, "token_start": 18, "token_end": 18}, {"text": "IL - 8", "type": "ENTITY", "char_start": 120, "char_end": 126, "token_start": 20, "token_end": 22}, {"text": "granulocyte macrophage colony - stimulating factor", "type": "ENTITY", "char_start": 129, "char_end": 179, "token_start": 24, "token_end": 29}], "entities_global": [{"text": "cytokines", "type": "ENTITY", "char_start": 399617, "char_end": 399626, "token_start": 18, "token_end": 18, "note": null}, {"text": "IL - 8", "type": "ENTITY", "char_start": 399629, "char_end": 399635, "token_start": 20, "token_end": 22, "note": null}, {"text": "granulocyte macrophage colony - stimulating factor", "type": "ENTITY", "char_start": 399638, "char_end": 399688, "token_start": 24, "token_end": 29, "note": null}]}
+{"sentence_id": 2413, "sentence_text": "We also found that NAC , PDTC , and SB203580 suppressed the activities of DEPs and their benzene extracts , suggesting the roles of oxidants - mediated NF - kappa B activation and p38MAPK pathways .", "sentence_char_start_global": 399810, "sentence_char_end_global": 400008, "entities": [{"text": "p38MAPK", "type": "ENTITY", "char_start": 180, "char_end": 187, "token_start": 33, "token_end": 33}], "entities_global": [{"text": "p38MAPK", "type": "ENTITY", "char_start": 399990, "char_end": 399997, "token_start": 33, "token_end": 33, "note": null}]}
+{"sentence_id": 2414, "sentence_text": "Finally , benzo [ a ] pyrene , one of the important compounds included in the benzene component , replicated the activities shown by DEPs .", "sentence_char_start_global": 400009, "sentence_char_end_global": 400148, "entities": [], "entities_global": []}
+{"sentence_id": 2415, "sentence_text": "The nuclear receptor PPAR gamma is expressed by mouse T lymphocytes and PPAR gamma agonists induce apoptosis .", "sentence_char_start_global": 400149, "sentence_char_end_global": 400259, "entities": [{"text": "nuclear receptor PPAR gamma", "type": "ENTITY", "char_start": 4, "char_end": 31, "token_start": 1, "token_end": 4}], "entities_global": [{"text": "nuclear receptor PPAR gamma", "type": "ENTITY", "char_start": 400153, "char_end": 400180, "token_start": 1, "token_end": 4, "note": null}]}
+{"sentence_id": 2416, "sentence_text": "Peroxisome proliferator - activated receptor ( PPAR ) - gamma is a nuclear hormone receptor that serves as a trans factor to regulate lipid metabolism .", "sentence_char_start_global": 400260, "sentence_char_end_global": 400412, "entities": [{"text": "Peroxisome proliferator - activated receptor ( PPAR ) - gamma", "type": "ENTITY", "char_start": 0, "char_end": 61, "token_start": 0, "token_end": 9}, {"text": "nuclear hormone receptor", "type": "ENTITY", "char_start": 67, "char_end": 91, "token_start": 12, "token_end": 14}], "entities_global": [{"text": "Peroxisome proliferator - activated receptor ( PPAR ) - gamma", "type": "ENTITY", "char_start": 400260, "char_end": 400321, "token_start": 0, "token_end": 9, "note": null}, {"text": "nuclear hormone receptor", "type": "ENTITY", "char_start": 400327, "char_end": 400351, "token_start": 12, "token_end": 14, "note": null}]}
+{"sentence_id": 2417, "sentence_text": "Intense interest is focused on PPAR - gamma and its ligands owing to its putative role in adipocyte differentiation .", "sentence_char_start_global": 400413, "sentence_char_end_global": 400530, "entities": [{"text": "PPAR - gamma", "type": "ENTITY", "char_start": 31, "char_end": 43, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "PPAR - gamma", "type": "ENTITY", "char_start": 400444, "char_end": 400456, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 2418, "sentence_text": "Little is known , however , about the functions of PPAR - gamma in the immune system , especially in T lymphocytes .", "sentence_char_start_global": 400531, "sentence_char_end_global": 400647, "entities": [{"text": "PPAR - gamma", "type": "ENTITY", "char_start": 51, "char_end": 63, "token_start": 10, "token_end": 12}], "entities_global": [{"text": "PPAR - gamma", "type": "ENTITY", "char_start": 400582, "char_end": 400594, "token_start": 10, "token_end": 12, "note": null}]}
+{"sentence_id": 2419, "sentence_text": "We demonstrate that both naive and activated ovalbumin - specific T cells from DO11 . 10 - transgenic mice express PPAR - gamma mRNA and protein .", "sentence_char_start_global": 400648, "sentence_char_end_global": 400794, "entities": [{"text": "PPAR - gamma", "type": "ENTITY", "char_start": 115, "char_end": 127, "token_start": 20, "token_end": 22}], "entities_global": [{"text": "PPAR - gamma", "type": "ENTITY", "char_start": 400763, "char_end": 400775, "token_start": 20, "token_end": 22, "note": null}]}
+{"sentence_id": 2420, "sentence_text": "In order to determine the function of PPAR - gamma , T cells were stimulated with phorbol 12 - myristate 13 - acetate and ionomycin or antigen and antigen - presenting cells .", "sentence_char_start_global": 400795, "sentence_char_end_global": 400970, "entities": [{"text": "PPAR - gamma", "type": "ENTITY", "char_start": 38, "char_end": 50, "token_start": 7, "token_end": 9}], "entities_global": [{"text": "PPAR - gamma", "type": "ENTITY", "char_start": 400833, "char_end": 400845, "token_start": 7, "token_end": 9, "note": null}]}
+{"sentence_id": 2421, "sentence_text": "Simultaneous exposure to PPAR - gamma ligands ( e . g . 15 - deoxy - Delta ( 12 , 14 ) - prostaglandin J ( 2 ) , troglitazone ) showed drastic inhibition of proliferation and significant decreases in cell viability .", "sentence_char_start_global": 400971, "sentence_char_end_global": 401187, "entities": [], "entities_global": []}
+{"sentence_id": 2422, "sentence_text": "The decrease in cell viability was due to apoptosis of the T lymphocytes , and occurred only when cells were treated with PPAR - gamma , and not PPAR - alpha agonists , revealing specificity of this response for PPAR - gamma .", "sentence_char_start_global": 401188, "sentence_char_end_global": 401414, "entities": [{"text": "PPAR - gamma", "type": "ENTITY", "char_start": 122, "char_end": 134, "token_start": 22, "token_end": 24}, {"text": "PPAR - gamma", "type": "ENTITY", "char_start": 212, "char_end": 224, "token_start": 39, "token_end": 41}], "entities_global": [{"text": "PPAR - gamma", "type": "ENTITY", "char_start": 401310, "char_end": 401322, "token_start": 22, "token_end": 24, "note": null}, {"text": "PPAR - gamma", "type": "ENTITY", "char_start": 401400, "char_end": 401412, "token_start": 39, "token_end": 41, "note": null}]}
+{"sentence_id": 2423, "sentence_text": "These observations suggest that PPAR - gamma agonists play an important role in regulating T cell - mediated immune responses by inducing apoptosis .", "sentence_char_start_global": 401415, "sentence_char_end_global": 401564, "entities": [], "entities_global": []}
+{"sentence_id": 2424, "sentence_text": "T cell death via PPAR - gamma ligation may act as a potent anti - inflammatory signal in the immune system , and ligands could possibly be used to control disorders in which excessive inflammation occurs .", "sentence_char_start_global": 401565, "sentence_char_end_global": 401770, "entities": [], "entities_global": []}
+{"sentence_id": 2425, "sentence_text": "Suppression of lung inflammation in rats by prevention of NF - kappaB activation in the liver .", "sentence_char_start_global": 401771, "sentence_char_end_global": 401866, "entities": [], "entities_global": []}
+{"sentence_id": 2426, "sentence_text": "Activation of NF - kappaB and production of NF - kappaB - dependent chemokines are thought to be involved in the pathogenesis of neutrophilic lung inflammation .", "sentence_char_start_global": 401867, "sentence_char_end_global": 402028, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 14, "char_end": 25, "token_start": 2, "token_end": 4}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 44, "char_end": 55, "token_start": 8, "token_end": 10}, {"text": "chemokines", "type": "ENTITY", "char_start": 68, "char_end": 78, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 401881, "char_end": 401892, "token_start": 2, "token_end": 4, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 401911, "char_end": 401922, "token_start": 8, "token_end": 10, "note": null}, {"text": "chemokines", "type": "ENTITY", "char_start": 401935, "char_end": 401945, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 2427, "sentence_text": "Calpain - 1 inhibitor ( CI - 1 ) blocks activation of NF - kappaB by preventing proteolysis of the inhibitory protein IkappaB - alpha by the ubiquitin / proteasome pathway .", "sentence_char_start_global": 402029, "sentence_char_end_global": 402202, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 54, "char_end": 65, "token_start": 12, "token_end": 14}, {"text": "IkappaB - alpha", "type": "ENTITY", "char_start": 118, "char_end": 133, "token_start": 22, "token_end": 24}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 402083, "char_end": 402094, "token_start": 12, "token_end": 14, "note": null}, {"text": "IkappaB - alpha", "type": "ENTITY", "char_start": 402147, "char_end": 402162, "token_start": 22, "token_end": 24, "note": null}]}
+{"sentence_id": 2428, "sentence_text": "We hypothesized that inhibition of proteasome function with CI - 1 would block NF - kappaB activation in vivo after intraperitoneal ( i . p . ) treatment with bacterial lipopolysaccharide ( LPS ) , and that NF - kappaB inhibition would be associated with suppression of chemokine gene expression and attenuation of neutrophilic alveolitis .", "sentence_char_start_global": 402203, "sentence_char_end_global": 402543, "entities": [], "entities_global": []}
+{"sentence_id": 2429, "sentence_text": "We treated rats with a single i . p . injection of CI - 1 ( 10 mg / kg ) two hours prior to i . p . LPS ( 7 mg / kg ) .", "sentence_char_start_global": 402544, "sentence_char_end_global": 402663, "entities": [], "entities_global": []}
+{"sentence_id": 2430, "sentence_text": "Treatment with Cl - 1 prevented degradation of IkappaB - alpha and activation of NF - kappaB in the liver in response to LPS ; however , Cl - 1 treatment had no detected effect on NF - kappaB activation in lung tissue .", "sentence_char_start_global": 402664, "sentence_char_end_global": 402883, "entities": [{"text": "IkappaB - alpha", "type": "ENTITY", "char_start": 47, "char_end": 62, "token_start": 8, "token_end": 10}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 81, "char_end": 92, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "IkappaB - alpha", "type": "ENTITY", "char_start": 402711, "char_end": 402726, "token_start": 8, "token_end": 10, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 402745, "char_end": 402756, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 2431, "sentence_text": "CI - 1 treatment prior to LPS resulted in 40 % lower MIP - 2 concentration in lung lavage fluid compared to rats treated with vehicle prior to LPS ( 502 + / - 112 pg / ml vs . 859 + / - 144 pg / ml , P < 0 . 05 ) .", "sentence_char_start_global": 402884, "sentence_char_end_global": 403098, "entities": [], "entities_global": []}
+{"sentence_id": 2432, "sentence_text": "In addition , CI - 1 treatment substantially inhibited LPS - induced neutrophilic alveolitis ( 2 . 7 + / - 1 . 2 x 10 ( 5 ) vs . 43 . 7 + / - 12 . 2 x 10 ( 5 ) lung lavage neutrophils , P < 0 . 01 ) .", "sentence_char_start_global": 403099, "sentence_char_end_global": 403299, "entities": [], "entities_global": []}
+{"sentence_id": 2433, "sentence_text": "These data indicate that NF - kappaB inhibition in the liver can alter lung inflammation induced by systemic LPS treatment and suggest that a liver - lung interaction contributes to the inflammatory response of the lung .", "sentence_char_start_global": 403300, "sentence_char_end_global": 403521, "entities": [], "entities_global": []}
+{"sentence_id": 2434, "sentence_text": "Notch1 regulates maturation of CD4 + and CD8 + thymocytes by modulating TCR signal strength .", "sentence_char_start_global": 403522, "sentence_char_end_global": 403615, "entities": [{"text": "Notch1", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "Notch1", "type": "ENTITY", "char_start": 403522, "char_end": 403528, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 2435, "sentence_text": "Notch signaling regulates cell fate decisions in multiple lineages .", "sentence_char_start_global": 403616, "sentence_char_end_global": 403684, "entities": [], "entities_global": []}
+{"sentence_id": 2436, "sentence_text": "We demonstrate in this report that retroviral expression of activated Notch1 in mouse thymocytes abrogates differentiation of immature CD4 + CD8 + thymocytes into both CD4 and CD8 mature single - positive T cells .", "sentence_char_start_global": 403685, "sentence_char_end_global": 403899, "entities": [{"text": "Notch1", "type": "ENTITY", "char_start": 70, "char_end": 76, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "Notch1", "type": "ENTITY", "char_start": 403755, "char_end": 403761, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 2437, "sentence_text": "The ability of Notch1 to inhibit T cell development was observed in vitro and in vivo with both normal and TCR transgenic thymocytes .", "sentence_char_start_global": 403900, "sentence_char_end_global": 404034, "entities": [{"text": "Notch1", "type": "ENTITY", "char_start": 15, "char_end": 21, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "Notch1", "type": "ENTITY", "char_start": 403915, "char_end": 403921, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 2438, "sentence_text": "Notch1 - mediated developmental arrest was dose dependent and was associated with impaired thymocyte responses to TCR stimulation .", "sentence_char_start_global": 404035, "sentence_char_end_global": 404166, "entities": [{"text": "Notch1", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "Notch1", "type": "ENTITY", "char_start": 404035, "char_end": 404041, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 2439, "sentence_text": "Notch1 also inhibited TCR - mediated signaling in Jurkat T cells .", "sentence_char_start_global": 404167, "sentence_char_end_global": 404233, "entities": [{"text": "Notch1", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "Notch1", "type": "ENTITY", "char_start": 404167, "char_end": 404173, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 2440, "sentence_text": "These data indicate that constitutively active Notch1 abrogates CD4 + and CD8 + maturation by interfering with TCR signal strength and provide an explanation for the physiological regulation of Notch expression during thymocyte development .", "sentence_char_start_global": 404234, "sentence_char_end_global": 404475, "entities": [{"text": "Notch1", "type": "ENTITY", "char_start": 47, "char_end": 53, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "Notch1", "type": "ENTITY", "char_start": 404281, "char_end": 404287, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 2441, "sentence_text": "Expression of SART3 antigen and induction of CTLs by SART3 - derived peptides in breast cancer patients .", "sentence_char_start_global": 404476, "sentence_char_end_global": 404581, "entities": [{"text": "SART3 antigen", "type": "ENTITY", "char_start": 14, "char_end": 27, "token_start": 2, "token_end": 3}], "entities_global": [{"text": "SART3 antigen", "type": "ENTITY", "char_start": 404490, "char_end": 404503, "token_start": 2, "token_end": 3, "note": null}]}
+{"sentence_id": 2442, "sentence_text": "We recently reported the SART3 tumour - rejection antigen as possessing tumour epitopes capable of inducing HLA - class I - restricted cytotoxic T lymphocytes ( CTLs ) .", "sentence_char_start_global": 404582, "sentence_char_end_global": 404751, "entities": [{"text": "SART3 tumour - rejection antigen", "type": "ENTITY", "char_start": 25, "char_end": 57, "token_start": 4, "token_end": 8}], "entities_global": [{"text": "SART3 tumour - rejection antigen", "type": "ENTITY", "char_start": 404607, "char_end": 404639, "token_start": 4, "token_end": 8, "note": null}]}
+{"sentence_id": 2443, "sentence_text": "This study investigated expression of the SART3 antigen in breast cancer to explore an appropriate molecule for use in specific immunotherapy of breast cancer patients .", "sentence_char_start_global": 404752, "sentence_char_end_global": 404921, "entities": [{"text": "SART3 antigen", "type": "ENTITY", "char_start": 42, "char_end": 55, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "SART3 antigen", "type": "ENTITY", "char_start": 404794, "char_end": 404807, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 2444, "sentence_text": "The SART3 antigen was detected in all of the breast cancer cell lines tested , 30 of 40 ( 75 % ) breast cancer tissue samples , and 0 of 3 non - tumourous breast tissue samples .", "sentence_char_start_global": 404922, "sentence_char_end_global": 405100, "entities": [{"text": "SART3 antigen", "type": "ENTITY", "char_start": 4, "char_end": 17, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "SART3 antigen", "type": "ENTITY", "char_start": 404926, "char_end": 404939, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 2445, "sentence_text": "SART3 derived peptides at positions 109 - 118 and 315 - 323 induced HLA - A24 restricted CTLs that reacted to breast cancer cells from the peripheral blood mononuclear cells ( PBMCs ) of breast cancer patients .", "sentence_char_start_global": 405101, "sentence_char_end_global": 405312, "entities": [{"text": "positions 109 - 118 and 315 - 323", "type": "ENTITY", "char_start": 26, "char_end": 59, "token_start": 4, "token_end": 11}], "entities_global": [{"text": "positions 109 - 118 and 315 - 323", "type": "ENTITY", "char_start": 405127, "char_end": 405160, "token_start": 4, "token_end": 11, "note": null}]}
+{"sentence_id": 2446, "sentence_text": "Therefore , the SART3 antigen and its peptides could be an appropriate molecule for use in specific immunotherapy of the majority of HLA - A24 - positive breast cancer patients", "sentence_char_start_global": 405313, "sentence_char_end_global": 405489, "entities": [{"text": "SART3 antigen", "type": "ENTITY", "char_start": 16, "char_end": 29, "token_start": 3, "token_end": 4}], "entities_global": [{"text": "SART3 antigen", "type": "ENTITY", "char_start": 405329, "char_end": 405342, "token_start": 3, "token_end": 4, "note": null}]}
+{"sentence_id": 2447, "sentence_text": "Autostimulation of the Epstein - Barr virus BRLF1 promoter is mediated through consensus Sp1 and Sp3 binding sites .", "sentence_char_start_global": 405490, "sentence_char_end_global": 405606, "entities": [{"text": "BRLF1 promoter", "type": "ENTITY", "char_start": 44, "char_end": 58, "token_start": 7, "token_end": 8}, {"text": "Sp1 and Sp3 binding sites", "type": "ENTITY", "char_start": 89, "char_end": 114, "token_start": 13, "token_end": 17}], "entities_global": [{"text": "BRLF1 promoter", "type": "ENTITY", "char_start": 405534, "char_end": 405548, "token_start": 7, "token_end": 8, "note": null}, {"text": "Sp1 and Sp3 binding sites", "type": "ENTITY", "char_start": 405579, "char_end": 405604, "token_start": 13, "token_end": 17, "note": null}]}
+{"sentence_id": 2448, "sentence_text": "As an essential step in the lytic cascade , the Rta homologues of gammaherpesviruses all activate their own expression .", "sentence_char_start_global": 405607, "sentence_char_end_global": 405727, "entities": [], "entities_global": []}
+{"sentence_id": 2449, "sentence_text": "Consistent with this biologic function , the Epstein - Barr virus ( EBV ) Rta protein powerfully stimulates the promoter of its own gene , Rp , in EBV - positive B cells in transient - transfection reporter - based assays .", "sentence_char_start_global": 405728, "sentence_char_end_global": 405951, "entities": [{"text": "Rta protein", "type": "ENTITY", "char_start": 74, "char_end": 85, "token_start": 14, "token_end": 15}, {"text": "promoter", "type": "ENTITY", "char_start": 112, "char_end": 120, "token_start": 19, "token_end": 19}, {"text": "Rp", "type": "ENTITY", "char_start": 139, "char_end": 141, "token_start": 25, "token_end": 25}], "entities_global": [{"text": "Rta protein", "type": "ENTITY", "char_start": 405802, "char_end": 405813, "token_start": 14, "token_end": 15, "note": null}, {"text": "promoter", "type": "ENTITY", "char_start": 405840, "char_end": 405848, "token_start": 19, "token_end": 19, "note": null}, {"text": "Rp", "type": "ENTITY", "char_start": 405867, "char_end": 405869, "token_start": 25, "token_end": 25, "note": null}]}
+{"sentence_id": 2450, "sentence_text": "We analyzed the activity of RpCAT in response to Rta by deletional and site - directed mutagenesis .", "sentence_char_start_global": 405952, "sentence_char_end_global": 406052, "entities": [{"text": "RpCAT", "type": "ENTITY", "char_start": 28, "char_end": 33, "token_start": 5, "token_end": 5}, {"text": "Rta", "type": "ENTITY", "char_start": 49, "char_end": 52, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "RpCAT", "type": "ENTITY", "char_start": 405980, "char_end": 405985, "token_start": 5, "token_end": 5, "note": null}, {"text": "Rta", "type": "ENTITY", "char_start": 406001, "char_end": 406004, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 2451, "sentence_text": "Two cognate Sp1 binding sites located at - 279 and - 45 relative to the transcriptional start site proved crucial for Rta - mediated activation .", "sentence_char_start_global": 406053, "sentence_char_end_global": 406198, "entities": [{"text": "cognate Sp1 binding sites", "type": "ENTITY", "char_start": 4, "char_end": 29, "token_start": 1, "token_end": 4}, {"text": "transcriptional start site", "type": "ENTITY", "char_start": 72, "char_end": 98, "token_start": 15, "token_end": 17}], "entities_global": [{"text": "cognate Sp1 binding sites", "type": "ENTITY", "char_start": 406057, "char_end": 406082, "token_start": 1, "token_end": 4, "note": null}, {"text": "transcriptional start site", "type": "ENTITY", "char_start": 406125, "char_end": 406151, "token_start": 15, "token_end": 17, "note": null}]}
+{"sentence_id": 2452, "sentence_text": "Previously described binding sites for the cellular transcription factor Zif268 and the viral transactivator ZEBRA were found to be dispensable for activation of RpCAT by Rta .", "sentence_char_start_global": 406199, "sentence_char_end_global": 406375, "entities": [{"text": "transcription factor Zif268", "type": "ENTITY", "char_start": 52, "char_end": 79, "token_start": 7, "token_end": 9}, {"text": "viral transactivator ZEBRA", "type": "ENTITY", "char_start": 88, "char_end": 114, "token_start": 12, "token_end": 14}, {"text": "RpCAT", "type": "ENTITY", "char_start": 162, "char_end": 167, "token_start": 23, "token_end": 23}, {"text": "Rta", "type": "ENTITY", "char_start": 171, "char_end": 174, "token_start": 25, "token_end": 25}], "entities_global": [{"text": "transcription factor Zif268", "type": "ENTITY", "char_start": 406251, "char_end": 406278, "token_start": 7, "token_end": 9, "note": null}, {"text": "viral transactivator ZEBRA", "type": "ENTITY", "char_start": 406287, "char_end": 406313, "token_start": 12, "token_end": 14, "note": null}, {"text": "RpCAT", "type": "ENTITY", "char_start": 406361, "char_end": 406366, "token_start": 23, "token_end": 23, "note": null}, {"text": "Rta", "type": "ENTITY", "char_start": 406370, "char_end": 406373, "token_start": 25, "token_end": 25, "note": null}]}
+{"sentence_id": 2453, "sentence_text": "Gel shift analysis , using extracts of B cells in latency or induced into the lytic cycle , identified Sp1 and Sp3 as the predominant cellular proteins bound to Rp near - 45 .", "sentence_char_start_global": 406376, "sentence_char_end_global": 406551, "entities": [{"text": "Sp1", "type": "ENTITY", "char_start": 103, "char_end": 106, "token_start": 19, "token_end": 19}, {"text": "Sp3", "type": "ENTITY", "char_start": 111, "char_end": 114, "token_start": 21, "token_end": 21}, {"text": "cellular proteins", "type": "ENTITY", "char_start": 134, "char_end": 151, "token_start": 25, "token_end": 26}, {"text": "Rp", "type": "ENTITY", "char_start": 161, "char_end": 163, "token_start": 29, "token_end": 29}], "entities_global": [{"text": "Sp1", "type": "ENTITY", "char_start": 406479, "char_end": 406482, "token_start": 19, "token_end": 19, "note": null}, {"text": "Sp3", "type": "ENTITY", "char_start": 406487, "char_end": 406490, "token_start": 21, "token_end": 21, "note": null}, {"text": "cellular proteins", "type": "ENTITY", "char_start": 406510, "char_end": 406527, "token_start": 25, "token_end": 26, "note": null}, {"text": "Rp", "type": "ENTITY", "char_start": 406537, "char_end": 406539, "token_start": 29, "token_end": 29, "note": null}]}
+{"sentence_id": 2454, "sentence_text": "During the lytic cycle , ZEBRA bound Rp near the Sp1 / Sp3 site .", "sentence_char_start_global": 406552, "sentence_char_end_global": 406617, "entities": [{"text": "ZEBRA", "type": "ENTITY", "char_start": 25, "char_end": 30, "token_start": 5, "token_end": 5}, {"text": "Rp", "type": "ENTITY", "char_start": 37, "char_end": 39, "token_start": 7, "token_end": 7}, {"text": "Sp1 / Sp3 site", "type": "ENTITY", "char_start": 49, "char_end": 63, "token_start": 10, "token_end": 13}], "entities_global": [{"text": "ZEBRA", "type": "ENTITY", "char_start": 406577, "char_end": 406582, "token_start": 5, "token_end": 5, "note": null}, {"text": "Rp", "type": "ENTITY", "char_start": 406589, "char_end": 406591, "token_start": 7, "token_end": 7, "note": null}, {"text": "Sp1 / Sp3 site", "type": "ENTITY", "char_start": 406601, "char_end": 406615, "token_start": 10, "token_end": 13, "note": null}]}
+{"sentence_id": 2455, "sentence_text": "The binding of Sp1 and Sp3 to Rp correlated with the reporter activities in the mutagenesis study , establishing a direct link between transcriptional activation of Rp by Rta and DNA binding by Sp1 and / or Sp3 .", "sentence_char_start_global": 406618, "sentence_char_end_global": 406830, "entities": [{"text": "Sp1", "type": "ENTITY", "char_start": 15, "char_end": 18, "token_start": 3, "token_end": 3}, {"text": "Sp3", "type": "ENTITY", "char_start": 23, "char_end": 26, "token_start": 5, "token_end": 5}, {"text": "Rp", "type": "ENTITY", "char_start": 30, "char_end": 32, "token_start": 7, "token_end": 7}, {"text": "Rp", "type": "ENTITY", "char_start": 165, "char_end": 167, "token_start": 26, "token_end": 26}, {"text": "Rta", "type": "ENTITY", "char_start": 171, "char_end": 174, "token_start": 28, "token_end": 28}, {"text": "Sp1", "type": "ENTITY", "char_start": 194, "char_end": 197, "token_start": 33, "token_end": 33}, {"text": "Sp3", "type": "ENTITY", "char_start": 207, "char_end": 210, "token_start": 37, "token_end": 37}], "entities_global": [{"text": "Sp1", "type": "ENTITY", "char_start": 406633, "char_end": 406636, "token_start": 3, "token_end": 3, "note": null}, {"text": "Sp3", "type": "ENTITY", "char_start": 406641, "char_end": 406644, "token_start": 5, "token_end": 5, "note": null}, {"text": "Rp", "type": "ENTITY", "char_start": 406648, "char_end": 406650, "token_start": 7, "token_end": 7, "note": null}, {"text": "Rp", "type": "ENTITY", "char_start": 406783, "char_end": 406785, "token_start": 26, "token_end": 26, "note": null}, {"text": "Rta", "type": "ENTITY", "char_start": 406789, "char_end": 406792, "token_start": 28, "token_end": 28, "note": null}, {"text": "Sp1", "type": "ENTITY", "char_start": 406812, "char_end": 406815, "token_start": 33, "token_end": 33, "note": null}, {"text": "Sp3", "type": "ENTITY", "char_start": 406825, "char_end": 406828, "token_start": 37, "token_end": 37, "note": null}]}
+{"sentence_id": 2456, "sentence_text": "The relative abundance or functional state of the cellular Sp1 and Sp3 transcription factors may be altered in response to stimuli that induce the BRLF1 promoter and thereby contribute to the activation of the viral lytic cycle .", "sentence_char_start_global": 406831, "sentence_char_end_global": 407060, "entities": [{"text": "Sp1", "type": "ENTITY", "char_start": 59, "char_end": 62, "token_start": 9, "token_end": 9}, {"text": "Sp3", "type": "ENTITY", "char_start": 67, "char_end": 70, "token_start": 11, "token_end": 11}, {"text": "transcription factors", "type": "ENTITY", "char_start": 71, "char_end": 92, "token_start": 12, "token_end": 13}, {"text": "BRLF1 promoter", "type": "ENTITY", "char_start": 147, "char_end": 161, "token_start": 24, "token_end": 25}], "entities_global": [{"text": "Sp1", "type": "ENTITY", "char_start": 406890, "char_end": 406893, "token_start": 9, "token_end": 9, "note": null}, {"text": "Sp3", "type": "ENTITY", "char_start": 406898, "char_end": 406901, "token_start": 11, "token_end": 11, "note": null}, {"text": "transcription factors", "type": "ENTITY", "char_start": 406902, "char_end": 406923, "token_start": 12, "token_end": 13, "note": null}, {"text": "BRLF1 promoter", "type": "ENTITY", "char_start": 406978, "char_end": 406992, "token_start": 24, "token_end": 25, "note": null}]}
+{"sentence_id": 2457, "sentence_text": "Gene transfer of antisense hypoxia inducible factor - 1 alpha enhances the therapeutic efficacy of cancer immunotherapy .", "sentence_char_start_global": 407061, "sentence_char_end_global": 407182, "entities": [{"text": "hypoxia inducible factor - 1 alpha", "type": "ENTITY", "char_start": 27, "char_end": 61, "token_start": 4, "token_end": 9}], "entities_global": [{"text": "hypoxia inducible factor - 1 alpha", "type": "ENTITY", "char_start": 407088, "char_end": 407122, "token_start": 4, "token_end": 9, "note": null}]}
+{"sentence_id": 2458, "sentence_text": "Solid tumors meet their demands for nascent blood vessels and increased glycolysis , to combat hypoxia , by activating multiple genes involved in angiogenesis and glucose metabolism .", "sentence_char_start_global": 407183, "sentence_char_end_global": 407366, "entities": [], "entities_global": []}
+{"sentence_id": 2459, "sentence_text": "Hypoxia inducible factor - 1 ( HIF - 1 ) is a constitutively expressed basic helix - loop - helix transcription factor , formed by the assembly of HIF - 1alpha and HIF - 1beta ( Arnt ) , that is stablized in response to hypoxia , and rapidly degraded under normoxic conditions .", "sentence_char_start_global": 407367, "sentence_char_end_global": 407645, "entities": [{"text": "Hypoxia inducible factor - 1", "type": "ENTITY", "char_start": 0, "char_end": 28, "token_start": 0, "token_end": 4}, {"text": "HIF - 1", "type": "ENTITY", "char_start": 31, "char_end": 38, "token_start": 6, "token_end": 8}, {"text": "helix - loop - helix transcription factor", "type": "ENTITY", "char_start": 77, "char_end": 118, "token_start": 15, "token_end": 21}, {"text": "HIF - 1alpha", "type": "ENTITY", "char_start": 147, "char_end": 159, "token_start": 28, "token_end": 30}, {"text": "HIF - 1beta", "type": "ENTITY", "char_start": 164, "char_end": 175, "token_start": 32, "token_end": 34}, {"text": "Arnt", "type": "ENTITY", "char_start": 178, "char_end": 182, "token_start": 36, "token_end": 36}], "entities_global": [{"text": "Hypoxia inducible factor - 1", "type": "ENTITY", "char_start": 407367, "char_end": 407395, "token_start": 0, "token_end": 4, "note": null}, {"text": "HIF - 1", "type": "ENTITY", "char_start": 407398, "char_end": 407405, "token_start": 6, "token_end": 8, "note": null}, {"text": "helix - loop - helix transcription factor", "type": "ENTITY", "char_start": 407444, "char_end": 407485, "token_start": 15, "token_end": 21, "note": null}, {"text": "HIF - 1alpha", "type": "ENTITY", "char_start": 407514, "char_end": 407526, "token_start": 28, "token_end": 30, "note": null}, {"text": "HIF - 1beta", "type": "ENTITY", "char_start": 407531, "char_end": 407542, "token_start": 32, "token_end": 34, "note": null}, {"text": "Arnt", "type": "ENTITY", "char_start": 407545, "char_end": 407549, "token_start": 36, "token_end": 36, "note": null}]}
+{"sentence_id": 2460, "sentence_text": "It activates the transcription of genes important for maintaining oxygen homeostasis .", "sentence_char_start_global": 407646, "sentence_char_end_global": 407732, "entities": [], "entities_global": []}
+{"sentence_id": 2461, "sentence_text": "Here , we demonstrate that engineered down - regulation of HIF - 1alpha by intratumoral gene transfer of an antisense HIF - 1alpha plasmid leads to the down - regulation of VEGF , and decreased tumor microvessel density .", "sentence_char_start_global": 407733, "sentence_char_end_global": 407954, "entities": [{"text": "HIF - 1alpha", "type": "ENTITY", "char_start": 59, "char_end": 71, "token_start": 10, "token_end": 12}, {"text": "antisense HIF - 1alpha plasmid", "type": "ENTITY", "char_start": 108, "char_end": 138, "token_start": 19, "token_end": 23}, {"text": "VEGF", "type": "ENTITY", "char_start": 173, "char_end": 177, "token_start": 31, "token_end": 31}], "entities_global": [{"text": "HIF - 1alpha", "type": "ENTITY", "char_start": 407792, "char_end": 407804, "token_start": 10, "token_end": 12, "note": null}, {"text": "antisense HIF - 1alpha plasmid", "type": "ENTITY", "char_start": 407841, "char_end": 407871, "token_start": 19, "token_end": 23, "note": null}, {"text": "VEGF", "type": "ENTITY", "char_start": 407906, "char_end": 407910, "token_start": 31, "token_end": 31, "note": null}]}
+{"sentence_id": 2462, "sentence_text": "Antisense HIF - 1alpha monotherapy resulted in the complete and permanent rejection of small ( 0 . 1 cm in diameter ) EL - 4 tumors , which is unusual for an anti - angiogenic agent where transient suppression of tumor growth is the norm .", "sentence_char_start_global": 407955, "sentence_char_end_global": 408194, "entities": [], "entities_global": []}
+{"sentence_id": 2463, "sentence_text": "It induced NK cell - dependent rejection of tumors , but failed to stimulate systemic T cell - mediated anti - tumor immunity , and synergized with B7 - 1 - mediated immunotherapy to cause the NK cell and CD8 T cell - dependent rejection of larger EL - 4 tumors ( 0 . 4 cm in diameter ) that were refractory to monotherapies .", "sentence_char_start_global": 408195, "sentence_char_end_global": 408521, "entities": [], "entities_global": []}
+{"sentence_id": 2464, "sentence_text": "Mice cured of their tumors by combination therapy resisted a rechallenge with parental tumor cells , indicating systemic antitumor immunity had been achieved .", "sentence_char_start_global": 408522, "sentence_char_end_global": 408681, "entities": [], "entities_global": []}
+{"sentence_id": 2465, "sentence_text": "In summary , whilst intensive investigations are in progress to target the many HIF - 1 effectors , the results herein indicate that blocking hypoxia - inducible pathways and enhancing NK - mediated antitumor immunity by targeting HIF - 1 itself may be advantageous , especially when combined with cancer immunotherapy .", "sentence_char_start_global": 408682, "sentence_char_end_global": 409002, "entities": [{"text": "HIF - 1", "type": "ENTITY", "char_start": 80, "char_end": 87, "token_start": 13, "token_end": 15}, {"text": "HIF - 1", "type": "ENTITY", "char_start": 231, "char_end": 238, "token_start": 37, "token_end": 39}], "entities_global": [{"text": "HIF - 1", "type": "ENTITY", "char_start": 408762, "char_end": 408769, "token_start": 13, "token_end": 15, "note": null}, {"text": "HIF - 1", "type": "ENTITY", "char_start": 408913, "char_end": 408920, "token_start": 37, "token_end": 39, "note": null}]}
+{"sentence_id": 2466, "sentence_text": "Runx2 : a novel oncogenic effector revealed by in vivo complementation and retroviral tagging .", "sentence_char_start_global": 409003, "sentence_char_end_global": 409098, "entities": [{"text": "Runx2", "type": "ENTITY", "char_start": 0, "char_end": 5, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "Runx2", "type": "ENTITY", "char_start": 409003, "char_end": 409008, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 2467, "sentence_text": "The Runx2 ( Cbfa1 , Pebp2alphaA , Aml3 ) gene was previously identified as a frequent target for transcriptional activation by proviral insertion in T - cell lymphomas of CD2 - MYC transgenic mice .", "sentence_char_start_global": 409099, "sentence_char_end_global": 409297, "entities": [{"text": "Runx2", "type": "ENTITY", "char_start": 4, "char_end": 9, "token_start": 1, "token_end": 1}, {"text": "Cbfa1", "type": "ENTITY", "char_start": 12, "char_end": 17, "token_start": 3, "token_end": 3}, {"text": "Pebp2alphaA", "type": "ENTITY", "char_start": 20, "char_end": 31, "token_start": 5, "token_end": 5}, {"text": "Aml3", "type": "ENTITY", "char_start": 34, "char_end": 38, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "Runx2", "type": "ENTITY", "char_start": 409103, "char_end": 409108, "token_start": 1, "token_end": 1, "note": null}, {"text": "Cbfa1", "type": "ENTITY", "char_start": 409111, "char_end": 409116, "token_start": 3, "token_end": 3, "note": null}, {"text": "Pebp2alphaA", "type": "ENTITY", "char_start": 409119, "char_end": 409130, "token_start": 5, "token_end": 5, "note": null}, {"text": "Aml3", "type": "ENTITY", "char_start": 409133, "char_end": 409137, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 2468, "sentence_text": "We have recently shown that over - expression of the full - length , most highly expressed Runx2 isoform in the thymus perturbs T - cell development , leads to development of spontaneous lymphomas at low frequency and is strongly synergistic with Myc .", "sentence_char_start_global": 409298, "sentence_char_end_global": 409550, "entities": [{"text": "Runx2", "type": "ENTITY", "char_start": 91, "char_end": 96, "token_start": 17, "token_end": 17}, {"text": "Myc", "type": "ENTITY", "char_start": 247, "char_end": 250, "token_start": 42, "token_end": 42}], "entities_global": [{"text": "Runx2", "type": "ENTITY", "char_start": 409389, "char_end": 409394, "token_start": 17, "token_end": 17, "note": null}, {"text": "Myc", "type": "ENTITY", "char_start": 409545, "char_end": 409548, "token_start": 42, "token_end": 42, "note": null}]}
+{"sentence_id": 2469, "sentence_text": "To gain further insight into the relationship of Runx2 to other lymphomagenic pathways , we tested the effect of combining the CD2 - Runx2 transgene either with a Pim1 transgene ( E ( mu ) - Pim1 ) or with the p53 null genotype , as each of these displays independent synergy with Myc .", "sentence_char_start_global": 409551, "sentence_char_end_global": 409837, "entities": [{"text": "Runx2", "type": "ENTITY", "char_start": 49, "char_end": 54, "token_start": 8, "token_end": 8}, {"text": "CD2 - Runx2 transgene", "type": "ENTITY", "char_start": 127, "char_end": 148, "token_start": 21, "token_end": 24}, {"text": "Pim1 transgene", "type": "ENTITY", "char_start": 163, "char_end": 177, "token_start": 28, "token_end": 29}, {"text": "E ( mu ) - Pim1", "type": "ENTITY", "char_start": 180, "char_end": 195, "token_start": 31, "token_end": 36}, {"text": "p53", "type": "ENTITY", "char_start": 210, "char_end": 213, "token_start": 41, "token_end": 41}, {"text": "Myc", "type": "ENTITY", "char_start": 281, "char_end": 284, "token_start": 53, "token_end": 53}], "entities_global": [{"text": "Runx2", "type": "ENTITY", "char_start": 409600, "char_end": 409605, "token_start": 8, "token_end": 8, "note": null}, {"text": "CD2 - Runx2 transgene", "type": "ENTITY", "char_start": 409678, "char_end": 409699, "token_start": 21, "token_end": 24, "note": null}, {"text": "Pim1 transgene", "type": "ENTITY", "char_start": 409714, "char_end": 409728, "token_start": 28, "token_end": 29, "note": null}, {"text": "E ( mu ) - Pim1", "type": "ENTITY", "char_start": 409731, "char_end": 409746, "token_start": 31, "token_end": 36, "note": null}, {"text": "p53", "type": "ENTITY", "char_start": 409761, "char_end": 409764, "token_start": 41, "token_end": 41, "note": null}, {"text": "Myc", "type": "ENTITY", "char_start": 409832, "char_end": 409835, "token_start": 53, "token_end": 53, "note": null}]}
+{"sentence_id": 2470, "sentence_text": "In both cases we observed synergistic tumour development .", "sentence_char_start_global": 409838, "sentence_char_end_global": 409896, "entities": [], "entities_global": []}
+{"sentence_id": 2471, "sentence_text": "However , Runx2 appeared to have a dominant effect on the tumour phenotype in each case , with most tumours conforming to the CD3 ( + ) , CD8 ( + ) , CD4 ( + / - ) phenotype seen in CD2 - Runx2 mice .", "sentence_char_start_global": 409897, "sentence_char_end_global": 410097, "entities": [{"text": "Runx2", "type": "ENTITY", "char_start": 10, "char_end": 15, "token_start": 2, "token_end": 2}], "entities_global": [{"text": "Runx2", "type": "ENTITY", "char_start": 409907, "char_end": 409912, "token_start": 2, "token_end": 2, "note": null}]}
+{"sentence_id": 2472, "sentence_text": "Neonatal infection of CD2 - Runx2 mice with Moloney murine leukaemia virus ( Moloney MLV ) also led to a dramatic acceleration of tumour onset .", "sentence_char_start_global": 410098, "sentence_char_end_global": 410242, "entities": [], "entities_global": []}
+{"sentence_id": 2473, "sentence_text": "Analysis of known Moloney MLV target genes in these lymphomas showed a high frequency of rearrangement at c - Myc or N - Myc ( 82 % ) , and a significant number at Pim1 or Pim2 ( 23 % ) , and at Pal1 / Gfi1 ( 18 % ) .", "sentence_char_start_global": 410243, "sentence_char_end_global": 410460, "entities": [{"text": "Moloney MLV target genes", "type": "ENTITY", "char_start": 18, "char_end": 42, "token_start": 3, "token_end": 6}, {"text": "c - Myc", "type": "ENTITY", "char_start": 106, "char_end": 113, "token_start": 17, "token_end": 19}, {"text": "N - Myc", "type": "ENTITY", "char_start": 117, "char_end": 124, "token_start": 21, "token_end": 23}, {"text": "Pim1", "type": "ENTITY", "char_start": 164, "char_end": 168, "token_start": 34, "token_end": 34}, {"text": "Pim2", "type": "ENTITY", "char_start": 172, "char_end": 176, "token_start": 36, "token_end": 36}, {"text": "Pal1 / Gfi1", "type": "ENTITY", "char_start": 195, "char_end": 206, "token_start": 44, "token_end": 46}], "entities_global": [{"text": "Moloney MLV target genes", "type": "ENTITY", "char_start": 410261, "char_end": 410285, "token_start": 3, "token_end": 6, "note": null}, {"text": "c - Myc", "type": "ENTITY", "char_start": 410349, "char_end": 410356, "token_start": 17, "token_end": 19, "note": null}, {"text": "N - Myc", "type": "ENTITY", "char_start": 410360, "char_end": 410367, "token_start": 21, "token_end": 23, "note": null}, {"text": "Pim1", "type": "ENTITY", "char_start": 410407, "char_end": 410411, "token_start": 34, "token_end": 34, "note": null}, {"text": "Pim2", "type": "ENTITY", "char_start": 410415, "char_end": 410419, "token_start": 36, "token_end": 36, "note": null}, {"text": "Pal1 / Gfi1", "type": "ENTITY", "char_start": 410438, "char_end": 410449, "token_start": 44, "token_end": 46, "note": null}]}
+{"sentence_id": 2474, "sentence_text": "These results indicate that Runx2 makes a distinct contribution to T - cell lymphoma development which does not coincide with any of the oncogene complementation groups previously identified by retroviral tagging .", "sentence_char_start_global": 410461, "sentence_char_end_global": 410675, "entities": [{"text": "Runx2", "type": "ENTITY", "char_start": 28, "char_end": 33, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "Runx2", "type": "ENTITY", "char_start": 410489, "char_end": 410494, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 2475, "sentence_text": "The involvement of TNF - alpha - related apoptosis - inducing ligand in the enhanced cytotoxicity of IFN - beta - stimulated human dendritic cells to tumor cells .", "sentence_char_start_global": 410676, "sentence_char_end_global": 410839, "entities": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 19, "char_end": 30, "token_start": 3, "token_end": 5}, {"text": "IFN - beta", "type": "ENTITY", "char_start": 101, "char_end": 111, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 410695, "char_end": 410706, "token_start": 3, "token_end": 5, "note": null}, {"text": "IFN - beta", "type": "ENTITY", "char_start": 410777, "char_end": 410787, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 2476, "sentence_text": "TNF - alpha - related apoptosis - inducing ligand ( TRAIL ) is characterized by its preferential induction of apoptosis of tumor cells but not normal cells .", "sentence_char_start_global": 410840, "sentence_char_end_global": 410997, "entities": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 0, "char_end": 11, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 410840, "char_end": 410851, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 2477, "sentence_text": "Dendritic cells ( DCs ) , besides their role as APCs , now have been demonstrated to exert cytotoxicity or cytostasis on some tumor cells .", "sentence_char_start_global": 410998, "sentence_char_end_global": 411137, "entities": [], "entities_global": []}
+{"sentence_id": 2478, "sentence_text": "Here , we report that both human CD34 ( + ) stem cell - derived DCs ( CD34DCs ) and human CD14 ( + ) monocyte - derived DCs ( MoDCs ) express TRAIL and exhibit cytotoxicity to some types of tumor cells partially through TRAIL .", "sentence_char_start_global": 411138, "sentence_char_end_global": 411365, "entities": [], "entities_global": []}
+{"sentence_id": 2479, "sentence_text": "Moderate expression of TRAIL appeared on CD34DCs from the 8th day of culture and was also seen on freshly isolated monocytes .", "sentence_char_start_global": 411366, "sentence_char_end_global": 411492, "entities": [], "entities_global": []}
+{"sentence_id": 2480, "sentence_text": "The level of TRAIL expression remained constant until DC maturation .", "sentence_char_start_global": 411493, "sentence_char_end_global": 411562, "entities": [], "entities_global": []}
+{"sentence_id": 2481, "sentence_text": "TRAIL expression on immature CD34DCs or MoDCs was greatly up - regulated after IFN - beta stimulation .", "sentence_char_start_global": 411563, "sentence_char_end_global": 411666, "entities": [{"text": "IFN - beta", "type": "ENTITY", "char_start": 79, "char_end": 89, "token_start": 13, "token_end": 15}], "entities_global": [{"text": "IFN - beta", "type": "ENTITY", "char_start": 411642, "char_end": 411652, "token_start": 13, "token_end": 15, "note": null}]}
+{"sentence_id": 2482, "sentence_text": "Moreover , IFN - beta could strikingly enhance the ability of CD34DCs or MoDCs to kill TRAIL - sensitive tumor cells , but LPS did not have such an effect .", "sentence_char_start_global": 411667, "sentence_char_end_global": 411823, "entities": [{"text": "IFN - beta", "type": "ENTITY", "char_start": 11, "char_end": 21, "token_start": 2, "token_end": 4}], "entities_global": [{"text": "IFN - beta", "type": "ENTITY", "char_start": 411678, "char_end": 411688, "token_start": 2, "token_end": 4, "note": null}]}
+{"sentence_id": 2483, "sentence_text": "The up - regulation of TRAIL on IFN - beta - stimulated DCs partially contributed to the increased cytotoxicity of DCS : Pretreatment of TRAIL - sensitive tumor cells with caspase - 3 inhibitor could significantly increase their resistance to the cytotoxicity of IFN - beta - stimulated DCS : In contrast , NF - kappaB inhibitor could significantly increase the sensitivity of tumor cells to the killing by nonstimulated or LPS - stimulated DCS : Our studies demonstrate that IFN - beta - stimulated DCs are functionally cytotoxic .", "sentence_char_start_global": 411824, "sentence_char_end_global": 412356, "entities": [{"text": "IFN - beta", "type": "ENTITY", "char_start": 32, "char_end": 42, "token_start": 7, "token_end": 9}, {"text": "IFN - beta", "type": "ENTITY", "char_start": 263, "char_end": 273, "token_start": 43, "token_end": 45}, {"text": "IFN - beta", "type": "ENTITY", "char_start": 476, "char_end": 486, "token_start": 80, "token_end": 82}], "entities_global": [{"text": "IFN - beta", "type": "ENTITY", "char_start": 411856, "char_end": 411866, "token_start": 7, "token_end": 9, "note": null}, {"text": "IFN - beta", "type": "ENTITY", "char_start": 412087, "char_end": 412097, "token_start": 43, "token_end": 45, "note": null}, {"text": "IFN - beta", "type": "ENTITY", "char_start": 412300, "char_end": 412310, "token_start": 80, "token_end": 82, "note": null}]}
+{"sentence_id": 2484, "sentence_text": "Thus , an innate mechanism of DC - mediated antitumor immunity might exist in vivo in which DCs act as effectors to directly kill tumor cells partially via TRAIL .", "sentence_char_start_global": 412357, "sentence_char_end_global": 412520, "entities": [], "entities_global": []}
+{"sentence_id": 2485, "sentence_text": "Subsequently , DCs act as APCs involved in the uptake , processing , and presentation of apoptotic tumor Ags to cross - prime CD8 ( + ) CTL cells .", "sentence_char_start_global": 412521, "sentence_char_end_global": 412668, "entities": [{"text": "apoptotic tumor Ags", "type": "ENTITY", "char_start": 89, "char_end": 108, "token_start": 16, "token_end": 18}], "entities_global": [{"text": "apoptotic tumor Ags", "type": "ENTITY", "char_start": 412610, "char_end": 412629, "token_start": 16, "token_end": 18, "note": null}]}
+{"sentence_id": 2486, "sentence_text": "Tumor cells regulate the lytic activity of tumor - specific cytotoxic t lymphocytes by modulating the inhibitory natural killer receptor function .", "sentence_char_start_global": 412669, "sentence_char_end_global": 412816, "entities": [], "entities_global": []}
+{"sentence_id": 2487, "sentence_text": "Tumor - infiltrating p58 + T cells from a renal tumor were specifically expanded in response to tumor cell stimulation and cloned .", "sentence_char_start_global": 412817, "sentence_char_end_global": 412948, "entities": [], "entities_global": []}
+{"sentence_id": 2488, "sentence_text": "These p58 + T cells were found to express a memory phenotype and corresponded to clonal TCRBV3 T - cell expansion .", "sentence_char_start_global": 412949, "sentence_char_end_global": 413064, "entities": [], "entities_global": []}
+{"sentence_id": 2489, "sentence_text": "Functionally , p58 ( + ) CTLs displayed a low lytic activity for HLA - A2 tumor and normal cells .", "sentence_char_start_global": 413065, "sentence_char_end_global": 413163, "entities": [], "entities_global": []}
+{"sentence_id": 2490, "sentence_text": "However , this lytic activity was significantly increased after blockade of p58 with specific monoclonal antibodies .", "sentence_char_start_global": 413164, "sentence_char_end_global": 413281, "entities": [{"text": "p58", "type": "ENTITY", "char_start": 76, "char_end": 79, "token_start": 11, "token_end": 11}, {"text": "monoclonal antibodies", "type": "ENTITY", "char_start": 94, "char_end": 115, "token_start": 14, "token_end": 15}], "entities_global": [{"text": "p58", "type": "ENTITY", "char_start": 413240, "char_end": 413243, "token_start": 11, "token_end": 11, "note": null}, {"text": "monoclonal antibodies", "type": "ENTITY", "char_start": 413258, "char_end": 413279, "token_start": 14, "token_end": 15, "note": null}]}
+{"sentence_id": 2491, "sentence_text": "Interestingly , we demonstrated that stimulation by tumor cells was required to trigger the inhibitory effect of p58 on the lytic activity of antigen - specific CTLs and that stimulation of the inhibitory function of p58 by tumor cells correlated with an inhibition of nuclear factor - kappaB activation in p58 + tumor - specific CTLS .", "sentence_char_start_global": 413282, "sentence_char_end_global": 413618, "entities": [{"text": "p58", "type": "ENTITY", "char_start": 113, "char_end": 116, "token_start": 17, "token_end": 17}, {"text": "p58", "type": "ENTITY", "char_start": 217, "char_end": 220, "token_start": 35, "token_end": 35}], "entities_global": [{"text": "p58", "type": "ENTITY", "char_start": 413395, "char_end": 413398, "token_start": 17, "token_end": 17, "note": null}, {"text": "p58", "type": "ENTITY", "char_start": 413499, "char_end": 413502, "token_start": 35, "token_end": 35, "note": null}]}
+{"sentence_id": 2492, "sentence_text": "T - cell factor - 1 expression during human natural killer cell development and in circulating CD56 ( + ) bright natural killer cells .", "sentence_char_start_global": 413619, "sentence_char_end_global": 413754, "entities": [{"text": "T - cell factor - 1", "type": "ENTITY", "char_start": 0, "char_end": 19, "token_start": 0, "token_end": 5}, {"text": "CD56 ( + )", "type": "ENTITY", "char_start": 95, "char_end": 105, "token_start": 16, "token_end": 19}], "entities_global": [{"text": "T - cell factor - 1", "type": "ENTITY", "char_start": 413619, "char_end": 413638, "token_start": 0, "token_end": 5, "note": null}, {"text": "CD56 ( + )", "type": "ENTITY", "char_start": 413714, "char_end": 413724, "token_start": 16, "token_end": 19, "note": null}]}
+{"sentence_id": 2493, "sentence_text": "Transcription factors are essential to govern differentiation along the lymphoid lineage from uncommitted hematopoietic stem cells .", "sentence_char_start_global": 413755, "sentence_char_end_global": 413887, "entities": [{"text": "Transcription factors", "type": "ENTITY", "char_start": 0, "char_end": 21, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "Transcription factors", "type": "ENTITY", "char_start": 413755, "char_end": 413776, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 2494, "sentence_text": "Although many of these transcription factors have putative roles based on murine knockout experiments , their function in human lymphoid development is less known and was studied further .", "sentence_char_start_global": 413888, "sentence_char_end_global": 414076, "entities": [{"text": "transcription factors", "type": "ENTITY", "char_start": 23, "char_end": 44, "token_start": 4, "token_end": 5}], "entities_global": [{"text": "transcription factors", "type": "ENTITY", "char_start": 413911, "char_end": 413932, "token_start": 4, "token_end": 5, "note": null}]}
+{"sentence_id": 2495, "sentence_text": "Transcription factor expression in fresh and cultured adult human bone marrow and umbilical cord blood progenitors was evaluated .", "sentence_char_start_global": 414077, "sentence_char_end_global": 414207, "entities": [], "entities_global": []}
+{"sentence_id": 2496, "sentence_text": "We found that fresh CD34 ( + ) Lin ( - ) cells that are human leukocyte antigen ( HLA ) - DR ( - ) or CD38 ( - ) constitutively express GATA - 3 but not T - cell factor - 1 ( TCF - 1 ) or Id - 3 .", "sentence_char_start_global": 414208, "sentence_char_end_global": 414404, "entities": [{"text": "GATA - 3", "type": "ENTITY", "char_start": 136, "char_end": 144, "token_start": 33, "token_end": 35}, {"text": "T - cell factor - 1", "type": "ENTITY", "char_start": 153, "char_end": 172, "token_start": 38, "token_end": 43}, {"text": "TCF - 1", "type": "ENTITY", "char_start": 175, "char_end": 182, "token_start": 45, "token_end": 47}, {"text": "Id - 3", "type": "ENTITY", "char_start": 188, "char_end": 194, "token_start": 50, "token_end": 52}], "entities_global": [{"text": "GATA - 3", "type": "ENTITY", "char_start": 414344, "char_end": 414352, "token_start": 33, "token_end": 35, "note": null}, {"text": "T - cell factor - 1", "type": "ENTITY", "char_start": 414361, "char_end": 414380, "token_start": 38, "token_end": 43, "note": null}, {"text": "TCF - 1", "type": "ENTITY", "char_start": 414383, "char_end": 414390, "token_start": 45, "token_end": 47, "note": null}, {"text": "Id - 3", "type": "ENTITY", "char_start": 414396, "char_end": 414402, "token_start": 50, "token_end": 52, "note": null}]}
+{"sentence_id": 2497, "sentence_text": "Culture with the murine fetal liver cell line AFT024 and defined cytokines was capable of inducing TCF - 1 mRNA .", "sentence_char_start_global": 414405, "sentence_char_end_global": 414518, "entities": [{"text": "cytokines", "type": "ENTITY", "char_start": 65, "char_end": 74, "token_start": 11, "token_end": 11}, {"text": "TCF - 1 mRNA", "type": "ENTITY", "char_start": 99, "char_end": 111, "token_start": 16, "token_end": 19}], "entities_global": [{"text": "cytokines", "type": "ENTITY", "char_start": 414470, "char_end": 414479, "token_start": 11, "token_end": 11, "note": null}, {"text": "TCF - 1 mRNA", "type": "ENTITY", "char_start": 414504, "char_end": 414516, "token_start": 16, "token_end": 19, "note": null}]}
+{"sentence_id": 2498, "sentence_text": "However , no T - cell receptor gene rearrangement was identified in cultured progeny .", "sentence_char_start_global": 414519, "sentence_char_end_global": 414605, "entities": [{"text": "T - cell receptor gene", "type": "ENTITY", "char_start": 13, "char_end": 35, "token_start": 3, "token_end": 7}], "entities_global": [{"text": "T - cell receptor gene", "type": "ENTITY", "char_start": 414532, "char_end": 414554, "token_start": 3, "token_end": 7, "note": null}]}
+{"sentence_id": 2499, "sentence_text": "Id - 3 , a basic helix loop helix factor with dominant negative function for T - cell differentiation transcription factors , also was upregulated and may explain unsuccessful T - cell maturation .", "sentence_char_start_global": 414606, "sentence_char_end_global": 414803, "entities": [{"text": "Id - 3", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 2}, {"text": "basic helix loop helix factor", "type": "ENTITY", "char_start": 11, "char_end": 40, "token_start": 5, "token_end": 9}, {"text": "transcription factors", "type": "ENTITY", "char_start": 102, "char_end": 123, "token_start": 19, "token_end": 20}], "entities_global": [{"text": "Id - 3", "type": "ENTITY", "char_start": 414606, "char_end": 414612, "token_start": 0, "token_end": 2, "note": null}, {"text": "basic helix loop helix factor", "type": "ENTITY", "char_start": 414617, "char_end": 414646, "token_start": 5, "token_end": 9, "note": null}, {"text": "transcription factors", "type": "ENTITY", "char_start": 414708, "char_end": 414729, "token_start": 19, "token_end": 20, "note": null}]}
+{"sentence_id": 2500, "sentence_text": "To better understand the developmental link between natural killer ( NK ) cells derived from progenitors , we studied NK cell subsets circulating in blood .", "sentence_char_start_global": 414804, "sentence_char_end_global": 414960, "entities": [], "entities_global": []}
+{"sentence_id": 2501, "sentence_text": "CD56 ( + bright ) , but not CD56 ( + dim ) , NK cells constitutively express TCF - 1 by reverse transcriptase polymerase chain reaction and Western blot analysis .", "sentence_char_start_global": 414961, "sentence_char_end_global": 415124, "entities": [{"text": "TCF - 1", "type": "ENTITY", "char_start": 77, "char_end": 84, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "TCF - 1", "type": "ENTITY", "char_start": 415038, "char_end": 415045, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 2502, "sentence_text": "The TCF - 1 isoform found in CD56 ( + bright ) cells , which express lectin but not immunoglobulin class I recognizing inhibitory receptors , was identical to that induced in NK cell differentiation culture and was distinctly different from isoforms in T cells .", "sentence_char_start_global": 415125, "sentence_char_end_global": 415387, "entities": [{"text": "TCF - 1 isoform", "type": "ENTITY", "char_start": 4, "char_end": 19, "token_start": 1, "token_end": 4}, {"text": "lectin", "type": "ENTITY", "char_start": 69, "char_end": 75, "token_start": 16, "token_end": 16}, {"text": "immunoglobulin class I", "type": "ENTITY", "char_start": 84, "char_end": 106, "token_start": 19, "token_end": 21}, {"text": "inhibitory receptors", "type": "ENTITY", "char_start": 119, "char_end": 139, "token_start": 23, "token_end": 24}], "entities_global": [{"text": "TCF - 1 isoform", "type": "ENTITY", "char_start": 415129, "char_end": 415144, "token_start": 1, "token_end": 4, "note": null}, {"text": "lectin", "type": "ENTITY", "char_start": 415194, "char_end": 415200, "token_start": 16, "token_end": 16, "note": null}, {"text": "immunoglobulin class I", "type": "ENTITY", "char_start": 415209, "char_end": 415231, "token_start": 19, "token_end": 21, "note": null}, {"text": "inhibitory receptors", "type": "ENTITY", "char_start": 415244, "char_end": 415264, "token_start": 23, "token_end": 24, "note": null}]}
+{"sentence_id": 2503, "sentence_text": "These results suggest that TCF - 1 does not target human killer immunoglobulin receptor genes , TCF - 1 is uniquely expressed in circulating CD56 ( + bright ) NK cells , and specific TCF - 1 isoforms may play an important role in regulating NK differentiation from a common NK / T - cell progenitor .", "sentence_char_start_global": 415388, "sentence_char_end_global": 415688, "entities": [{"text": "TCF - 1", "type": "ENTITY", "char_start": 27, "char_end": 34, "token_start": 4, "token_end": 6}, {"text": "human killer immunoglobulin receptor genes", "type": "ENTITY", "char_start": 51, "char_end": 93, "token_start": 10, "token_end": 14}, {"text": "TCF - 1", "type": "ENTITY", "char_start": 96, "char_end": 103, "token_start": 16, "token_end": 18}, {"text": "TCF - 1 isoforms", "type": "ENTITY", "char_start": 183, "char_end": 199, "token_start": 34, "token_end": 37}], "entities_global": [{"text": "TCF - 1", "type": "ENTITY", "char_start": 415415, "char_end": 415422, "token_start": 4, "token_end": 6, "note": null}, {"text": "human killer immunoglobulin receptor genes", "type": "ENTITY", "char_start": 415439, "char_end": 415481, "token_start": 10, "token_end": 14, "note": null}, {"text": "TCF - 1", "type": "ENTITY", "char_start": 415484, "char_end": 415491, "token_start": 16, "token_end": 18, "note": null}, {"text": "TCF - 1 isoforms", "type": "ENTITY", "char_start": 415571, "char_end": 415587, "token_start": 34, "token_end": 37, "note": null}]}
+{"sentence_id": 2504, "sentence_text": "Transcriptional activation by a matrix associating region - binding protein .", "sentence_char_start_global": 415689, "sentence_char_end_global": 415766, "entities": [{"text": "matrix associating region - binding protein", "type": "ENTITY", "char_start": 32, "char_end": 75, "token_start": 4, "token_end": 9}], "entities_global": [{"text": "matrix associating region - binding protein", "type": "ENTITY", "char_start": 415721, "char_end": 415764, "token_start": 4, "token_end": 9, "note": null}]}
+{"sentence_id": 2505, "sentence_text": "contextual requirements for the function of bright .", "sentence_char_start_global": 415767, "sentence_char_end_global": 415819, "entities": [{"text": "bright", "type": "ENTITY", "char_start": 44, "char_end": 50, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "bright", "type": "ENTITY", "char_start": 415811, "char_end": 415817, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 2506, "sentence_text": "Bright ( B cell regulator of IgH transcription ) is a B cell - specific , matrix associating region - binding protein that transactivates gene expression from the IgH intronic enhancer ( E mu ) .", "sentence_char_start_global": 415820, "sentence_char_end_global": 416015, "entities": [{"text": "Bright", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 0}, {"text": "B cell regulator of IgH transcription", "type": "ENTITY", "char_start": 9, "char_end": 46, "token_start": 2, "token_end": 7}, {"text": "matrix associating region - binding protein", "type": "ENTITY", "char_start": 74, "char_end": 117, "token_start": 16, "token_end": 21}, {"text": "IgH intronic enhancer", "type": "ENTITY", "char_start": 163, "char_end": 184, "token_start": 28, "token_end": 30}, {"text": "E mu", "type": "ENTITY", "char_start": 187, "char_end": 191, "token_start": 32, "token_end": 33}], "entities_global": [{"text": "Bright", "type": "ENTITY", "char_start": 415820, "char_end": 415826, "token_start": 0, "token_end": 0, "note": null}, {"text": "B cell regulator of IgH transcription", "type": "ENTITY", "char_start": 415829, "char_end": 415866, "token_start": 2, "token_end": 7, "note": null}, {"text": "matrix associating region - binding protein", "type": "ENTITY", "char_start": 415894, "char_end": 415937, "token_start": 16, "token_end": 21, "note": null}, {"text": "IgH intronic enhancer", "type": "ENTITY", "char_start": 415983, "char_end": 416004, "token_start": 28, "token_end": 30, "note": null}, {"text": "E mu", "type": "ENTITY", "char_start": 416007, "char_end": 416011, "token_start": 32, "token_end": 33, "note": null}]}
+{"sentence_id": 2507, "sentence_text": "We show here that Bright has multiple contextual requirements to function as a transcriptional activator .", "sentence_char_start_global": 416016, "sentence_char_end_global": 416122, "entities": [{"text": "Bright", "type": "ENTITY", "char_start": 18, "char_end": 24, "token_start": 4, "token_end": 4}, {"text": "transcriptional activator", "type": "ENTITY", "char_start": 79, "char_end": 104, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "Bright", "type": "ENTITY", "char_start": 416034, "char_end": 416040, "token_start": 4, "token_end": 4, "note": null}, {"text": "transcriptional activator", "type": "ENTITY", "char_start": 416095, "char_end": 416120, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 2508, "sentence_text": "Bright can not transactivate via out of context , concatenated binding sites .", "sentence_char_start_global": 416123, "sentence_char_end_global": 416201, "entities": [{"text": "Bright", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 0}, {"text": "concatenated binding sites", "type": "ENTITY", "char_start": 50, "char_end": 76, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "Bright", "type": "ENTITY", "char_start": 416123, "char_end": 416129, "token_start": 0, "token_end": 0, "note": null}, {"text": "concatenated binding sites", "type": "ENTITY", "char_start": 416173, "char_end": 416199, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 2509, "sentence_text": "Transactivation is maximal on integrated substrates .", "sentence_char_start_global": 416202, "sentence_char_end_global": 416255, "entities": [], "entities_global": []}
+{"sentence_id": 2510, "sentence_text": "Two of the three previously identified binding sites in E mu are required for full Bright transactivation .", "sentence_char_start_global": 416256, "sentence_char_end_global": 416363, "entities": [{"text": "binding sites", "type": "ENTITY", "char_start": 39, "char_end": 52, "token_start": 6, "token_end": 7}, {"text": "E mu", "type": "ENTITY", "char_start": 56, "char_end": 60, "token_start": 9, "token_end": 10}, {"text": "Bright", "type": "ENTITY", "char_start": 83, "char_end": 89, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "binding sites", "type": "ENTITY", "char_start": 416295, "char_end": 416308, "token_start": 6, "token_end": 7, "note": null}, {"text": "E mu", "type": "ENTITY", "char_start": 416312, "char_end": 416316, "token_start": 9, "token_end": 10, "note": null}, {"text": "Bright", "type": "ENTITY", "char_start": 416339, "char_end": 416345, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 2511, "sentence_text": "The Bright DNA binding domain defined a new family , which includes SWI1 , a component of the SWI . SNF complex shown to have high mobility group - like DNA binding characteristics .", "sentence_char_start_global": 416364, "sentence_char_end_global": 416546, "entities": [{"text": "Bright DNA binding domain", "type": "ENTITY", "char_start": 4, "char_end": 29, "token_start": 1, "token_end": 4}, {"text": "SWI1", "type": "ENTITY", "char_start": 68, "char_end": 72, "token_start": 12, "token_end": 12}, {"text": "SWI . SNF complex", "type": "ENTITY", "char_start": 94, "char_end": 111, "token_start": 18, "token_end": 21}], "entities_global": [{"text": "Bright DNA binding domain", "type": "ENTITY", "char_start": 416368, "char_end": 416393, "token_start": 1, "token_end": 4, "note": null}, {"text": "SWI1", "type": "ENTITY", "char_start": 416432, "char_end": 416436, "token_start": 12, "token_end": 12, "note": null}, {"text": "SWI . SNF complex", "type": "ENTITY", "char_start": 416458, "char_end": 416475, "token_start": 18, "token_end": 21, "note": null}]}
+{"sentence_id": 2512, "sentence_text": "Similar to one group of high mobility group box proteins , Bright distorts E mu binding site - containing DNA on binding , supporting the concept that it mediates E mu remodeling .", "sentence_char_start_global": 416547, "sentence_char_end_global": 416727, "entities": [{"text": "high mobility group box proteins", "type": "ENTITY", "char_start": 24, "char_end": 56, "token_start": 5, "token_end": 9}, {"text": "Bright", "type": "ENTITY", "char_start": 59, "char_end": 65, "token_start": 11, "token_end": 11}, {"text": "E mu binding site", "type": "ENTITY", "char_start": 75, "char_end": 92, "token_start": 13, "token_end": 16}, {"text": "E mu", "type": "ENTITY", "char_start": 163, "char_end": 167, "token_start": 29, "token_end": 30}], "entities_global": [{"text": "high mobility group box proteins", "type": "ENTITY", "char_start": 416571, "char_end": 416603, "token_start": 5, "token_end": 9, "note": null}, {"text": "Bright", "type": "ENTITY", "char_start": 416606, "char_end": 416612, "token_start": 11, "token_end": 11, "note": null}, {"text": "E mu binding site", "type": "ENTITY", "char_start": 416622, "char_end": 416639, "token_start": 13, "token_end": 16, "note": null}, {"text": "E mu", "type": "ENTITY", "char_start": 416710, "char_end": 416714, "token_start": 29, "token_end": 30, "note": null}]}
+{"sentence_id": 2513, "sentence_text": "Transfection studies further implicate Bright in facilitating spatially separated promoter - enhancer interactions in both transient and stable assays .", "sentence_char_start_global": 416728, "sentence_char_end_global": 416880, "entities": [{"text": "Bright", "type": "ENTITY", "char_start": 39, "char_end": 45, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "Bright", "type": "ENTITY", "char_start": 416767, "char_end": 416773, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 2514, "sentence_text": "Finally , we show that overexpression of Bright leads to enhanced DNase I sensitivity of the endogenous E mu matrix associating regions .", "sentence_char_start_global": 416881, "sentence_char_end_global": 417018, "entities": [{"text": "Bright", "type": "ENTITY", "char_start": 41, "char_end": 47, "token_start": 7, "token_end": 7}, {"text": "E mu", "type": "ENTITY", "char_start": 104, "char_end": 108, "token_start": 17, "token_end": 18}], "entities_global": [{"text": "Bright", "type": "ENTITY", "char_start": 416922, "char_end": 416928, "token_start": 7, "token_end": 7, "note": null}, {"text": "E mu", "type": "ENTITY", "char_start": 416985, "char_end": 416989, "token_start": 17, "token_end": 18, "note": null}]}
+{"sentence_id": 2515, "sentence_text": "These data further suggest that Bright may contribute to increased gene expression by remodeling the immunoglobulin locus during B cell development .", "sentence_char_start_global": 417019, "sentence_char_end_global": 417168, "entities": [{"text": "Bright", "type": "ENTITY", "char_start": 32, "char_end": 38, "token_start": 5, "token_end": 5}, {"text": "immunoglobulin locus", "type": "ENTITY", "char_start": 101, "char_end": 121, "token_start": 15, "token_end": 16}], "entities_global": [{"text": "Bright", "type": "ENTITY", "char_start": 417051, "char_end": 417057, "token_start": 5, "token_end": 5, "note": null}, {"text": "immunoglobulin locus", "type": "ENTITY", "char_start": 417120, "char_end": 417140, "token_start": 15, "token_end": 16, "note": null}]}
+{"sentence_id": 2516, "sentence_text": "Analysis of BCL - 6 mutations in classic Hodgkin disease of the B - and T - cell type .", "sentence_char_start_global": 417169, "sentence_char_end_global": 417256, "entities": [], "entities_global": []}
+{"sentence_id": 2517, "sentence_text": "BCL - 6 is essential for germinal center formation and thus for affinity maturation of immunoglobulin ( Ig ) genes by somatic mutations .", "sentence_char_start_global": 417257, "sentence_char_end_global": 417394, "entities": [{"text": "BCL - 6", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 2}, {"text": "immunoglobulin ( Ig ) genes", "type": "ENTITY", "char_start": 87, "char_end": 114, "token_start": 15, "token_end": 19}], "entities_global": [{"text": "BCL - 6", "type": "ENTITY", "char_start": 417257, "char_end": 417264, "token_start": 0, "token_end": 2, "note": null}, {"text": "immunoglobulin ( Ig ) genes", "type": "ENTITY", "char_start": 417344, "char_end": 417371, "token_start": 15, "token_end": 19, "note": null}]}
+{"sentence_id": 2518, "sentence_text": "The 5 ' - noncoding region of the BCL - 6 gene is even a target for the mutation machinery .", "sentence_char_start_global": 417395, "sentence_char_end_global": 417487, "entities": [{"text": "5 ' - noncoding region", "type": "ENTITY", "char_start": 4, "char_end": 26, "token_start": 1, "token_end": 5}, {"text": "BCL - 6 gene", "type": "ENTITY", "char_start": 34, "char_end": 46, "token_start": 8, "token_end": 11}], "entities_global": [{"text": "5 ' - noncoding region", "type": "ENTITY", "char_start": 417399, "char_end": 417421, "token_start": 1, "token_end": 5, "note": null}, {"text": "BCL - 6 gene", "type": "ENTITY", "char_start": 417429, "char_end": 417441, "token_start": 8, "token_end": 11, "note": null}]}
+{"sentence_id": 2519, "sentence_text": "Translocations of the BCL - 6 gene to heterologous promoters and mutations of its 5 ' - noncoding regulatory region were reported to be potential mechanisms for deregulating BCL - 6 expression and for playing a role in the genesis of non - Hodgkin lymphoma .", "sentence_char_start_global": 417488, "sentence_char_end_global": 417746, "entities": [{"text": "BCL - 6 gene", "type": "ENTITY", "char_start": 22, "char_end": 34, "token_start": 3, "token_end": 6}, {"text": "heterologous promoters", "type": "ENTITY", "char_start": 38, "char_end": 60, "token_start": 8, "token_end": 9}, {"text": "5 ' - noncoding regulatory region", "type": "ENTITY", "char_start": 82, "char_end": 115, "token_start": 14, "token_end": 19}, {"text": "BCL - 6", "type": "ENTITY", "char_start": 174, "char_end": 181, "token_start": 28, "token_end": 30}], "entities_global": [{"text": "BCL - 6 gene", "type": "ENTITY", "char_start": 417510, "char_end": 417522, "token_start": 3, "token_end": 6, "note": null}, {"text": "heterologous promoters", "type": "ENTITY", "char_start": 417526, "char_end": 417548, "token_start": 8, "token_end": 9, "note": null}, {"text": "5 ' - noncoding regulatory region", "type": "ENTITY", "char_start": 417570, "char_end": 417603, "token_start": 14, "token_end": 19, "note": null}, {"text": "BCL - 6", "type": "ENTITY", "char_start": 417662, "char_end": 417669, "token_start": 28, "token_end": 30, "note": null}]}
+{"sentence_id": 2520, "sentence_text": "In line with this hypothesis is the observation that B - cell lymphoma with somatic mutations , such as diffuse large B - cell lymphoma and follicular lymphoma , also carry BCL - 6 mutations , some of which are recurrently detectable .", "sentence_char_start_global": 417747, "sentence_char_end_global": 417982, "entities": [], "entities_global": []}
+{"sentence_id": 2521, "sentence_text": "Classic Hodgkin disease ( cHD ) is also derived from B cells with high loads of somatic mutations and thus a further candidate for BCL - 6 mutations .", "sentence_char_start_global": 417983, "sentence_char_end_global": 418133, "entities": [], "entities_global": []}
+{"sentence_id": 2522, "sentence_text": "To determine the presence and potential role of BCL - 6 mutations in cHD , the 5 ' - noncoding BCL - 6 proportion of single Hodgkin and Reed - Sternberg ( HRS ) cells from 6 cases of cHD and 6 cases of HD - derived cell lines was analyzed .", "sentence_char_start_global": 418134, "sentence_char_end_global": 418374, "entities": [{"text": "5 ' - noncoding BCL - 6", "type": "ENTITY", "char_start": 79, "char_end": 102, "token_start": 16, "token_end": 22}], "entities_global": [{"text": "5 ' - noncoding BCL - 6", "type": "ENTITY", "char_start": 418213, "char_end": 418236, "token_start": 16, "token_end": 22, "note": null}]}
+{"sentence_id": 2523, "sentence_text": "All B - cell - derived HD cases and cell lines harbored BCL - 6 mutations .", "sentence_char_start_global": 418375, "sentence_char_end_global": 418450, "entities": [], "entities_global": []}
+{"sentence_id": 2524, "sentence_text": "In contrast , both T - cell - derived HD cases and cell lines were devoid of BCL - 6 mutations .", "sentence_char_start_global": 418451, "sentence_char_end_global": 418547, "entities": [], "entities_global": []}
+{"sentence_id": 2525, "sentence_text": "With only one exception , there were no lymphoma - specific recurrent BCL - 6 mutations detected , and BCL - 6 protein was absent from the HRS cells of most cases .", "sentence_char_start_global": 418548, "sentence_char_end_global": 418712, "entities": [{"text": "BCL - 6 protein", "type": "ENTITY", "char_start": 103, "char_end": 118, "token_start": 19, "token_end": 22}], "entities_global": [{"text": "BCL - 6 protein", "type": "ENTITY", "char_start": 418651, "char_end": 418666, "token_start": 19, "token_end": 22, "note": null}]}
+{"sentence_id": 2526, "sentence_text": "In conclusion , ( 1 ) somatic BCL - 6 mutations are restricted to cHD cases of B - cell origin , and ( 2 ) the BCL - 6 mutations represent mostly irrelevant somatic base substitutions without consequences for BCL - 6 protein expression and the pathogenesis of cHD .", "sentence_char_start_global": 418713, "sentence_char_end_global": 418978, "entities": [{"text": "BCL - 6 protein", "type": "ENTITY", "char_start": 209, "char_end": 224, "token_start": 40, "token_end": 43}], "entities_global": [{"text": "BCL - 6 protein", "type": "ENTITY", "char_start": 418922, "char_end": 418937, "token_start": 40, "token_end": 43, "note": null}]}
+{"sentence_id": 2527, "sentence_text": "Gadd45gamma is dispensable for normal mouse development and T - cell proliferation .", "sentence_char_start_global": 418979, "sentence_char_end_global": 419063, "entities": [{"text": "Gadd45gamma", "type": "ENTITY", "char_start": 0, "char_end": 11, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "Gadd45gamma", "type": "ENTITY", "char_start": 418979, "char_end": 418990, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 2528, "sentence_text": "Gadd45gamma , a family member of the growth arrest and DNA damage - inducible gene family 45 ( Gadd45 ) , is strongly induced by interleukin - 2 ( IL - 2 ) in peripheral T cells .", "sentence_char_start_global": 419064, "sentence_char_end_global": 419243, "entities": [{"text": "Gadd45gamma", "type": "ENTITY", "char_start": 0, "char_end": 11, "token_start": 0, "token_end": 0}, {"text": "growth arrest and DNA damage - inducible gene family 45", "type": "ENTITY", "char_start": 37, "char_end": 92, "token_start": 7, "token_end": 16}, {"text": "Gadd45", "type": "ENTITY", "char_start": 95, "char_end": 101, "token_start": 18, "token_end": 18}, {"text": "interleukin - 2", "type": "ENTITY", "char_start": 129, "char_end": 144, "token_start": 25, "token_end": 27}, {"text": "IL - 2", "type": "ENTITY", "char_start": 147, "char_end": 153, "token_start": 29, "token_end": 31}], "entities_global": [{"text": "Gadd45gamma", "type": "ENTITY", "char_start": 419064, "char_end": 419075, "token_start": 0, "token_end": 0, "note": null}, {"text": "growth arrest and DNA damage - inducible gene family 45", "type": "ENTITY", "char_start": 419101, "char_end": 419156, "token_start": 7, "token_end": 16, "note": null}, {"text": "Gadd45", "type": "ENTITY", "char_start": 419159, "char_end": 419165, "token_start": 18, "token_end": 18, "note": null}, {"text": "interleukin - 2", "type": "ENTITY", "char_start": 419193, "char_end": 419208, "token_start": 25, "token_end": 27, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 419211, "char_end": 419217, "token_start": 29, "token_end": 31, "note": null}]}
+{"sentence_id": 2529, "sentence_text": "While in most tissues all Gadd45 family members are expressed , Gadd45gamma is the only member that is induced by IL - 2 .", "sentence_char_start_global": 419244, "sentence_char_end_global": 419366, "entities": [{"text": "Gadd45 family members", "type": "ENTITY", "char_start": 26, "char_end": 47, "token_start": 5, "token_end": 7}, {"text": "Gadd45gamma", "type": "ENTITY", "char_start": 64, "char_end": 75, "token_start": 11, "token_end": 11}, {"text": "IL - 2", "type": "ENTITY", "char_start": 114, "char_end": 120, "token_start": 20, "token_end": 22}], "entities_global": [{"text": "Gadd45 family members", "type": "ENTITY", "char_start": 419270, "char_end": 419291, "token_start": 5, "token_end": 7, "note": null}, {"text": "Gadd45gamma", "type": "ENTITY", "char_start": 419308, "char_end": 419319, "token_start": 11, "token_end": 11, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 419358, "char_end": 419364, "token_start": 20, "token_end": 22, "note": null}]}
+{"sentence_id": 2530, "sentence_text": "Here we show that the IL - 2 - induced expression of Gadd45gamma is dependent on a signaling pathway mediated by the tyrosine kinase Jak3 and the transcription factors Stat5a and Stat5b ( signal transducer and activator of transcription ) .", "sentence_char_start_global": 419367, "sentence_char_end_global": 419607, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 22, "char_end": 28, "token_start": 5, "token_end": 7}, {"text": "Gadd45gamma", "type": "ENTITY", "char_start": 53, "char_end": 64, "token_start": 12, "token_end": 12}, {"text": "tyrosine kinase Jak3", "type": "ENTITY", "char_start": 117, "char_end": 137, "token_start": 22, "token_end": 24}, {"text": "transcription factors", "type": "ENTITY", "char_start": 146, "char_end": 167, "token_start": 27, "token_end": 28}, {"text": "Stat5a", "type": "ENTITY", "char_start": 168, "char_end": 174, "token_start": 29, "token_end": 29}, {"text": "Stat5b", "type": "ENTITY", "char_start": 179, "char_end": 185, "token_start": 31, "token_end": 31}, {"text": "signal transducer and activator of transcription", "type": "ENTITY", "char_start": 188, "char_end": 236, "token_start": 33, "token_end": 38}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 419389, "char_end": 419395, "token_start": 5, "token_end": 7, "note": null}, {"text": "Gadd45gamma", "type": "ENTITY", "char_start": 419420, "char_end": 419431, "token_start": 12, "token_end": 12, "note": null}, {"text": "tyrosine kinase Jak3", "type": "ENTITY", "char_start": 419484, "char_end": 419504, "token_start": 22, "token_end": 24, "note": null}, {"text": "transcription factors", "type": "ENTITY", "char_start": 419513, "char_end": 419534, "token_start": 27, "token_end": 28, "note": null}, {"text": "Stat5a", "type": "ENTITY", "char_start": 419535, "char_end": 419541, "token_start": 29, "token_end": 29, "note": null}, {"text": "Stat5b", "type": "ENTITY", "char_start": 419546, "char_end": 419552, "token_start": 31, "token_end": 31, "note": null}, {"text": "signal transducer and activator of transcription", "type": "ENTITY", "char_start": 419555, "char_end": 419603, "token_start": 33, "token_end": 38, "note": null}]}
+{"sentence_id": 2531, "sentence_text": "Previous studies with ectopically overexpressed Gadd45gamma in various cell lines implicated its function in negative growth control .", "sentence_char_start_global": 419608, "sentence_char_end_global": 419742, "entities": [{"text": "Gadd45gamma", "type": "ENTITY", "char_start": 48, "char_end": 59, "token_start": 5, "token_end": 5}], "entities_global": [{"text": "Gadd45gamma", "type": "ENTITY", "char_start": 419656, "char_end": 419667, "token_start": 5, "token_end": 5, "note": null}]}
+{"sentence_id": 2532, "sentence_text": "To analyze the physiological role of Gadd45gamma we used homologous recombination to generate mice lacking Gadd45gamma .", "sentence_char_start_global": 419743, "sentence_char_end_global": 419863, "entities": [{"text": "Gadd45gamma", "type": "ENTITY", "char_start": 37, "char_end": 48, "token_start": 6, "token_end": 6}, {"text": "Gadd45gamma", "type": "ENTITY", "char_start": 107, "char_end": 118, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "Gadd45gamma", "type": "ENTITY", "char_start": 419780, "char_end": 419791, "token_start": 6, "token_end": 6, "note": null}, {"text": "Gadd45gamma", "type": "ENTITY", "char_start": 419850, "char_end": 419861, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 2533, "sentence_text": "Gadd45gamma - deficient mice develop normally , are indistinguishable from their littermates , and are fertile .", "sentence_char_start_global": 419864, "sentence_char_end_global": 419976, "entities": [{"text": "Gadd45gamma", "type": "ENTITY", "char_start": 0, "char_end": 11, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "Gadd45gamma", "type": "ENTITY", "char_start": 419864, "char_end": 419875, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 2534, "sentence_text": "Furthermore , hematopoiesis in mice lacking Gadd45gamma is not impaired and Gadd45gamma - deficient T lymphocytes show normal responses to IL - 2 .", "sentence_char_start_global": 419977, "sentence_char_end_global": 420124, "entities": [{"text": "Gadd45gamma", "type": "ENTITY", "char_start": 44, "char_end": 55, "token_start": 6, "token_end": 6}, {"text": "Gadd45gamma", "type": "ENTITY", "char_start": 76, "char_end": 87, "token_start": 11, "token_end": 11}, {"text": "IL - 2", "type": "ENTITY", "char_start": 139, "char_end": 145, "token_start": 20, "token_end": 22}], "entities_global": [{"text": "Gadd45gamma", "type": "ENTITY", "char_start": 420021, "char_end": 420032, "token_start": 6, "token_end": 6, "note": null}, {"text": "Gadd45gamma", "type": "ENTITY", "char_start": 420053, "char_end": 420064, "token_start": 11, "token_end": 11, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 420116, "char_end": 420122, "token_start": 20, "token_end": 22, "note": null}]}
+{"sentence_id": 2535, "sentence_text": "These data demonstrate that Gadd45gamma is not essential for normal mouse development and hematopoiesis , possibly due to functional redundancy among the Gadd45 family members .", "sentence_char_start_global": 420125, "sentence_char_end_global": 420302, "entities": [{"text": "Gadd45gamma", "type": "ENTITY", "char_start": 28, "char_end": 39, "token_start": 4, "token_end": 4}, {"text": "Gadd45 family members", "type": "ENTITY", "char_start": 154, "char_end": 175, "token_start": 22, "token_end": 24}], "entities_global": [{"text": "Gadd45gamma", "type": "ENTITY", "char_start": 420153, "char_end": 420164, "token_start": 4, "token_end": 4, "note": null}, {"text": "Gadd45 family members", "type": "ENTITY", "char_start": 420279, "char_end": 420300, "token_start": 22, "token_end": 24, "note": null}]}
+{"sentence_id": 2536, "sentence_text": "Gadd45gamma is also dispensable for IL - 2 - induced T - cell proliferation .", "sentence_char_start_global": 420303, "sentence_char_end_global": 420380, "entities": [{"text": "Gadd45gamma", "type": "ENTITY", "char_start": 0, "char_end": 11, "token_start": 0, "token_end": 0}, {"text": "IL - 2", "type": "ENTITY", "char_start": 36, "char_end": 42, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "Gadd45gamma", "type": "ENTITY", "char_start": 420303, "char_end": 420314, "token_start": 0, "token_end": 0, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 420339, "char_end": 420345, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 2537, "sentence_text": "Decreased expression of c - myc family genes in thymuses from myasthenia gravis patients .", "sentence_char_start_global": 420381, "sentence_char_end_global": 420471, "entities": [{"text": "c - myc family genes", "type": "ENTITY", "char_start": 24, "char_end": 44, "token_start": 3, "token_end": 7}], "entities_global": [{"text": "c - myc family genes", "type": "ENTITY", "char_start": 420405, "char_end": 420425, "token_start": 3, "token_end": 7, "note": null}]}
+{"sentence_id": 2538, "sentence_text": "The thymus is a critical organ for the elimination of autoreactive T cells by apoptosis .", "sentence_char_start_global": 420472, "sentence_char_end_global": 420561, "entities": [], "entities_global": []}
+{"sentence_id": 2539, "sentence_text": "We studied the expression of apoptosis - associated genes , bcl - xL , bad , caspase - 3 , and c - myc family genes in myasthenia gravis ( MG ) thymuses .", "sentence_char_start_global": 420562, "sentence_char_end_global": 420716, "entities": [{"text": "bcl - xL", "type": "ENTITY", "char_start": 60, "char_end": 68, "token_start": 10, "token_end": 12}, {"text": "bad", "type": "ENTITY", "char_start": 71, "char_end": 74, "token_start": 14, "token_end": 14}, {"text": "caspase - 3", "type": "ENTITY", "char_start": 77, "char_end": 88, "token_start": 16, "token_end": 18}, {"text": "c - myc family genes", "type": "ENTITY", "char_start": 95, "char_end": 115, "token_start": 21, "token_end": 25}], "entities_global": [{"text": "bcl - xL", "type": "ENTITY", "char_start": 420622, "char_end": 420630, "token_start": 10, "token_end": 12, "note": null}, {"text": "bad", "type": "ENTITY", "char_start": 420633, "char_end": 420636, "token_start": 14, "token_end": 14, "note": null}, {"text": "caspase - 3", "type": "ENTITY", "char_start": 420639, "char_end": 420650, "token_start": 16, "token_end": 18, "note": null}, {"text": "c - myc family genes", "type": "ENTITY", "char_start": 420657, "char_end": 420677, "token_start": 21, "token_end": 25, "note": null}]}
+{"sentence_id": 2540, "sentence_text": "We observed that the mRNA levels of myc family genes , c - myc and max , were markedly reduced in MG thymuses .", "sentence_char_start_global": 420717, "sentence_char_end_global": 420828, "entities": [{"text": "myc family genes", "type": "ENTITY", "char_start": 36, "char_end": 52, "token_start": 7, "token_end": 9}, {"text": "c - myc", "type": "ENTITY", "char_start": 55, "char_end": 62, "token_start": 11, "token_end": 13}, {"text": "max", "type": "ENTITY", "char_start": 67, "char_end": 70, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "myc family genes", "type": "ENTITY", "char_start": 420753, "char_end": 420769, "token_start": 7, "token_end": 9, "note": null}, {"text": "c - myc", "type": "ENTITY", "char_start": 420772, "char_end": 420779, "token_start": 11, "token_end": 13, "note": null}, {"text": "max", "type": "ENTITY", "char_start": 420784, "char_end": 420787, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 2541, "sentence_text": "These results indicate that c - myc - mediated signaling is abnormal in MG thymuses .", "sentence_char_start_global": 420829, "sentence_char_end_global": 420914, "entities": [{"text": "c - myc", "type": "ENTITY", "char_start": 28, "char_end": 35, "token_start": 4, "token_end": 6}], "entities_global": [{"text": "c - myc", "type": "ENTITY", "char_start": 420857, "char_end": 420864, "token_start": 4, "token_end": 6, "note": null}]}
+{"sentence_id": 2542, "sentence_text": "The levels of molecules whose expressions are associated with myc , such as STAM , prothymosin - alpha , and NFkappaB", "sentence_char_start_global": 420915, "sentence_char_end_global": 421032, "entities": [{"text": "myc", "type": "ENTITY", "char_start": 62, "char_end": 65, "token_start": 9, "token_end": 9}, {"text": "STAM", "type": "ENTITY", "char_start": 76, "char_end": 80, "token_start": 13, "token_end": 13}, {"text": "prothymosin - alpha", "type": "ENTITY", "char_start": 83, "char_end": 102, "token_start": 15, "token_end": 17}, {"text": "NFkappaB", "type": "ENTITY", "char_start": 109, "char_end": 117, "token_start": 20, "token_end": 20}], "entities_global": [{"text": "myc", "type": "ENTITY", "char_start": 420977, "char_end": 420980, "token_start": 9, "token_end": 9, "note": null}, {"text": "STAM", "type": "ENTITY", "char_start": 420991, "char_end": 420995, "token_start": 13, "token_end": 13, "note": null}, {"text": "prothymosin - alpha", "type": "ENTITY", "char_start": 420998, "char_end": 421017, "token_start": 15, "token_end": 17, "note": null}, {"text": "NFkappaB", "type": "ENTITY", "char_start": 421024, "char_end": 421032, "token_start": 20, "token_end": 20, "note": null}]}
+{"sentence_id": 2543, "sentence_text": "Immunohistochemical detection of interferon - gamma - producing cells in dermatophytosis .", "sentence_char_start_global": 421033, "sentence_char_end_global": 421123, "entities": [], "entities_global": []}
+{"sentence_id": 2544, "sentence_text": "Skin lesions of dermatophytosis are thought to be a result of a T cell - dependent inflammatory response that is mediated by various cytokines .", "sentence_char_start_global": 421124, "sentence_char_end_global": 421268, "entities": [{"text": "cytokines", "type": "ENTITY", "char_start": 133, "char_end": 142, "token_start": 23, "token_end": 23}], "entities_global": [{"text": "cytokines", "type": "ENTITY", "char_start": 421257, "char_end": 421266, "token_start": 23, "token_end": 23, "note": null}]}
+{"sentence_id": 2545, "sentence_text": "We examined whether IFN - gamma - positive cells ( as expression of Th1 response ) were present in the skin lesions of dermatophytosis in situ by immunohistochemical techniques .", "sentence_char_start_global": 421269, "sentence_char_end_global": 421447, "entities": [], "entities_global": []}
+{"sentence_id": 2546, "sentence_text": "Mixtures of CD4 - positive T cells and CD8 - positive T cells were found to be present in the dermal infiltrates of the lesions .", "sentence_char_start_global": 421448, "sentence_char_end_global": 421577, "entities": [], "entities_global": []}
+{"sentence_id": 2547, "sentence_text": "Considerable numbers of CD1a - positive cells were detected in the upper dermis and epidermis .", "sentence_char_start_global": 421578, "sentence_char_end_global": 421673, "entities": [], "entities_global": []}
+{"sentence_id": 2548, "sentence_text": "A marked accumulation of CD68 - positive cells was found in the upper dermis .", "sentence_char_start_global": 421674, "sentence_char_end_global": 421752, "entities": [], "entities_global": []}
+{"sentence_id": 2549, "sentence_text": "IFN - gamma - positive cells were present in the upper dermis of the lesions .", "sentence_char_start_global": 421753, "sentence_char_end_global": 421831, "entities": [], "entities_global": []}
+{"sentence_id": 2550, "sentence_text": "The pattern of IFN - gamma staining appeared to be intracellular in mononuclear lymphoid cells .", "sentence_char_start_global": 421832, "sentence_char_end_global": 421928, "entities": [{"text": "IFN - gamma", "type": "ENTITY", "char_start": 15, "char_end": 26, "token_start": 3, "token_end": 5}], "entities_global": [{"text": "IFN - gamma", "type": "ENTITY", "char_start": 421847, "char_end": 421858, "token_start": 3, "token_end": 5, "note": null}]}
+{"sentence_id": 2551, "sentence_text": "The staining was considered to be highly specific because it could be completely blocked by preabsorption with recombinant IFN - gamma .", "sentence_char_start_global": 421929, "sentence_char_end_global": 422065, "entities": [{"text": "recombinant IFN - gamma", "type": "ENTITY", "char_start": 111, "char_end": 134, "token_start": 17, "token_end": 20}], "entities_global": [{"text": "recombinant IFN - gamma", "type": "ENTITY", "char_start": 422040, "char_end": 422063, "token_start": 17, "token_end": 20, "note": null}]}
+{"sentence_id": 2552, "sentence_text": "Our data support the hypothesis that the skin lesions of dermatophytosis may be associated with a Th1 response .", "sentence_char_start_global": 422066, "sentence_char_end_global": 422178, "entities": [], "entities_global": []}
+{"sentence_id": 2553, "sentence_text": "Th1 response , which is characterized by IFN - gamma release , is thought to be involved in the host defense against dermatophytes and to reflect cutaneous reaction in dermatophytosis .", "sentence_char_start_global": 422179, "sentence_char_end_global": 422364, "entities": [{"text": "IFN - gamma", "type": "ENTITY", "char_start": 41, "char_end": 52, "token_start": 7, "token_end": 9}], "entities_global": [{"text": "IFN - gamma", "type": "ENTITY", "char_start": 422220, "char_end": 422231, "token_start": 7, "token_end": 9, "note": null}]}
+{"sentence_id": 2554, "sentence_text": "Regulation of the helix - loop - helix proteins , E2A and Id3 , by the Ras - ERK MAPK cascade .", "sentence_char_start_global": 422365, "sentence_char_end_global": 422460, "entities": [{"text": "helix - loop - helix proteins", "type": "ENTITY", "char_start": 18, "char_end": 47, "token_start": 3, "token_end": 8}, {"text": "E2A", "type": "ENTITY", "char_start": 50, "char_end": 53, "token_start": 10, "token_end": 10}, {"text": "Id3", "type": "ENTITY", "char_start": 58, "char_end": 61, "token_start": 12, "token_end": 12}, {"text": "Ras", "type": "ENTITY", "char_start": 71, "char_end": 74, "token_start": 16, "token_end": 16}, {"text": "ERK", "type": "ENTITY", "char_start": 77, "char_end": 80, "token_start": 18, "token_end": 18}, {"text": "MAPK", "type": "ENTITY", "char_start": 81, "char_end": 85, "token_start": 19, "token_end": 19}], "entities_global": [{"text": "helix - loop - helix proteins", "type": "ENTITY", "char_start": 422383, "char_end": 422412, "token_start": 3, "token_end": 8, "note": null}, {"text": "E2A", "type": "ENTITY", "char_start": 422415, "char_end": 422418, "token_start": 10, "token_end": 10, "note": null}, {"text": "Id3", "type": "ENTITY", "char_start": 422423, "char_end": 422426, "token_start": 12, "token_end": 12, "note": null}, {"text": "Ras", "type": "ENTITY", "char_start": 422436, "char_end": 422439, "token_start": 16, "token_end": 16, "note": null}, {"text": "ERK", "type": "ENTITY", "char_start": 422442, "char_end": 422445, "token_start": 18, "token_end": 18, "note": null}, {"text": "MAPK", "type": "ENTITY", "char_start": 422446, "char_end": 422450, "token_start": 19, "token_end": 19, "note": null}]}
+{"sentence_id": 2555, "sentence_text": "Activation of mitogen - activated protein kinase ( MAPK ) pathways leads to cellular differentiation and / or proliferation in a wide variety of cell types , including developing thymocytes .", "sentence_char_start_global": 422461, "sentence_char_end_global": 422652, "entities": [{"text": "mitogen - activated protein kinase", "type": "ENTITY", "char_start": 14, "char_end": 48, "token_start": 2, "token_end": 6}, {"text": "MAPK", "type": "ENTITY", "char_start": 51, "char_end": 55, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "mitogen - activated protein kinase", "type": "ENTITY", "char_start": 422475, "char_end": 422509, "token_start": 2, "token_end": 6, "note": null}, {"text": "MAPK", "type": "ENTITY", "char_start": 422512, "char_end": 422516, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 2556, "sentence_text": "The basic helix - loop - helix ( bHLH ) proteins E12 and E47 and an inhibitor HLH protein , Id3 , play key roles in thymocyte differentiation .", "sentence_char_start_global": 422653, "sentence_char_end_global": 422796, "entities": [{"text": "basic helix - loop - helix ( bHLH ) proteins", "type": "ENTITY", "char_start": 4, "char_end": 48, "token_start": 1, "token_end": 10}, {"text": "E12", "type": "ENTITY", "char_start": 49, "char_end": 52, "token_start": 11, "token_end": 11}, {"text": "E47", "type": "ENTITY", "char_start": 57, "char_end": 60, "token_start": 13, "token_end": 13}, {"text": "inhibitor HLH protein", "type": "ENTITY", "char_start": 68, "char_end": 89, "token_start": 16, "token_end": 18}, {"text": "Id3", "type": "ENTITY", "char_start": 92, "char_end": 95, "token_start": 20, "token_end": 20}], "entities_global": [{"text": "basic helix - loop - helix ( bHLH ) proteins", "type": "ENTITY", "char_start": 422657, "char_end": 422701, "token_start": 1, "token_end": 10, "note": null}, {"text": "E12", "type": "ENTITY", "char_start": 422702, "char_end": 422705, "token_start": 11, "token_end": 11, "note": null}, {"text": "E47", "type": "ENTITY", "char_start": 422710, "char_end": 422713, "token_start": 13, "token_end": 13, "note": null}, {"text": "inhibitor HLH protein", "type": "ENTITY", "char_start": 422721, "char_end": 422742, "token_start": 16, "token_end": 18, "note": null}, {"text": "Id3", "type": "ENTITY", "char_start": 422745, "char_end": 422748, "token_start": 20, "token_end": 20, "note": null}]}
+{"sentence_id": 2557, "sentence_text": "We show here that E2A DNA binding is lowered in primary immature thymocytes consequent to T cell receptor ( TCR ) - mediated ligation .", "sentence_char_start_global": 422797, "sentence_char_end_global": 422932, "entities": [{"text": "E2A", "type": "ENTITY", "char_start": 18, "char_end": 21, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "E2A", "type": "ENTITY", "char_start": 422815, "char_end": 422818, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 2558, "sentence_text": "Whereas expression of E2A mRNA and protein are unaltered , Id3 transcripts are rapidly induced upon signaling from the TCR .", "sentence_char_start_global": 422933, "sentence_char_end_global": 423057, "entities": [{"text": "Id3 transcripts", "type": "ENTITY", "char_start": 59, "char_end": 74, "token_start": 10, "token_end": 11}, {"text": "TCR", "type": "ENTITY", "char_start": 119, "char_end": 122, "token_start": 19, "token_end": 19}], "entities_global": [{"text": "Id3 transcripts", "type": "ENTITY", "char_start": 422992, "char_end": 423007, "token_start": 10, "token_end": 11, "note": null}, {"text": "TCR", "type": "ENTITY", "char_start": 423052, "char_end": 423055, "token_start": 19, "token_end": 19, "note": null}]}
+{"sentence_id": 2559, "sentence_text": "Activation of Id3 transcription is regulated in a dose - dependent manner by the extracellular signal - regulated kinase ( ERK ) MAPK module .", "sentence_char_start_global": 423058, "sentence_char_end_global": 423200, "entities": [{"text": "ERK", "type": "ENTITY", "char_start": 123, "char_end": 126, "token_start": 20, "token_end": 20}, {"text": "MAPK", "type": "ENTITY", "char_start": 129, "char_end": 133, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "ERK", "type": "ENTITY", "char_start": 423181, "char_end": 423184, "token_start": 20, "token_end": 20, "note": null}, {"text": "MAPK", "type": "ENTITY", "char_start": 423187, "char_end": 423191, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 2560, "sentence_text": "These observations directly connect the ERK MAPK cascade and HLH proteins in a linear pathway .", "sentence_char_start_global": 423201, "sentence_char_end_global": 423296, "entities": [{"text": "ERK", "type": "ENTITY", "char_start": 40, "char_end": 43, "token_start": 5, "token_end": 5}, {"text": "MAPK", "type": "ENTITY", "char_start": 44, "char_end": 48, "token_start": 6, "token_end": 6}, {"text": "HLH proteins", "type": "ENTITY", "char_start": 61, "char_end": 73, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "ERK", "type": "ENTITY", "char_start": 423241, "char_end": 423244, "token_start": 5, "token_end": 5, "note": null}, {"text": "MAPK", "type": "ENTITY", "char_start": 423245, "char_end": 423249, "token_start": 6, "token_end": 6, "note": null}, {"text": "HLH proteins", "type": "ENTITY", "char_start": 423262, "char_end": 423274, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 2561, "sentence_text": "Retinoic acid up - regulates myeloid ICAM - 3 expression and function in a cell - specific fashion - - evidence for retinoid signaling pathways in the mast cell lineage .", "sentence_char_start_global": 423297, "sentence_char_end_global": 423467, "entities": [], "entities_global": []}
+{"sentence_id": 2562, "sentence_text": "Investigation of mast cell responsiveness toward retinoic acid ( RA ) revealed selective promotion of ICAM - 3 expression in the human mast cell line HMC - 1 .", "sentence_char_start_global": 423468, "sentence_char_end_global": 423627, "entities": [{"text": "ICAM - 3", "type": "ENTITY", "char_start": 102, "char_end": 110, "token_start": 15, "token_end": 17}], "entities_global": [{"text": "ICAM - 3", "type": "ENTITY", "char_start": 423570, "char_end": 423578, "token_start": 15, "token_end": 17, "note": null}]}
+{"sentence_id": 2563, "sentence_text": "This process was dose - and time - dependent and detectable by flow cytometry , Western blot analysis , ELISA , and Northern blot analysis .", "sentence_char_start_global": 423628, "sentence_char_end_global": 423768, "entities": [], "entities_global": []}
+{"sentence_id": 2564, "sentence_text": "ICAM - 3 modulation was found to be cell - type dependent , detectable also for HL - 60 cells and monocytes but not U - 937 and only weakly for KU812 cells .", "sentence_char_start_global": 423769, "sentence_char_end_global": 423926, "entities": [{"text": "ICAM - 3", "type": "ENTITY", "char_start": 0, "char_end": 8, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "ICAM - 3", "type": "ENTITY", "char_start": 423769, "char_end": 423777, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 2565, "sentence_text": "Terminally differentiated skin mast cells also failed to up - modulate their ICAM - 3 , suggesting the requirement for some degree of immaturity for the process .", "sentence_char_start_global": 423927, "sentence_char_end_global": 424089, "entities": [{"text": "ICAM - 3", "type": "ENTITY", "char_start": 77, "char_end": 85, "token_start": 12, "token_end": 14}], "entities_global": [{"text": "ICAM - 3", "type": "ENTITY", "char_start": 424004, "char_end": 424012, "token_start": 12, "token_end": 14, "note": null}]}
+{"sentence_id": 2566, "sentence_text": "RA - mediated effects on ICAM - 1 expression , studied in parallel , were clearly distinct from those on ICAM - 3 .", "sentence_char_start_global": 424090, "sentence_char_end_global": 424205, "entities": [{"text": "ICAM - 1", "type": "ENTITY", "char_start": 25, "char_end": 33, "token_start": 5, "token_end": 7}, {"text": "ICAM - 3", "type": "ENTITY", "char_start": 105, "char_end": 113, "token_start": 20, "token_end": 22}], "entities_global": [{"text": "ICAM - 1", "type": "ENTITY", "char_start": 424115, "char_end": 424123, "token_start": 5, "token_end": 7, "note": null}, {"text": "ICAM - 3", "type": "ENTITY", "char_start": 424195, "char_end": 424203, "token_start": 20, "token_end": 22, "note": null}]}
+{"sentence_id": 2567, "sentence_text": "Investigation of retinoid receptor expression , known to mediate intracellular RA signaling , revealed presence of RAR alpha , RAR gamma , RXR beta , and RXR gamma transcripts in all cell lines studied , and HMC - 1 cells were the only line lacking RXR alpha .", "sentence_char_start_global": 424206, "sentence_char_end_global": 424466, "entities": [{"text": "retinoid receptor", "type": "ENTITY", "char_start": 17, "char_end": 34, "token_start": 2, "token_end": 3}, {"text": "RAR alpha , RAR gamma , RXR beta , and RXR gamma transcripts", "type": "ENTITY", "char_start": 115, "char_end": 175, "token_start": 16, "token_end": 28}, {"text": "RXR alpha", "type": "ENTITY", "char_start": 249, "char_end": 258, "token_start": 45, "token_end": 46}], "entities_global": [{"text": "retinoid receptor", "type": "ENTITY", "char_start": 424223, "char_end": 424240, "token_start": 2, "token_end": 3, "note": null}, {"text": "RAR alpha , RAR gamma , RXR beta , and RXR gamma transcripts", "type": "ENTITY", "char_start": 424321, "char_end": 424381, "token_start": 16, "token_end": 28, "note": null}, {"text": "RXR alpha", "type": "ENTITY", "char_start": 424455, "char_end": 424464, "token_start": 45, "token_end": 46, "note": null}]}
+{"sentence_id": 2568, "sentence_text": "RAR beta , not expressed at baseline , was induced by RA in a fashion obviously correlating with ICAM - 3 up - regulation .", "sentence_char_start_global": 424467, "sentence_char_end_global": 424590, "entities": [{"text": "RAR beta", "type": "ENTITY", "char_start": 0, "char_end": 8, "token_start": 0, "token_end": 1}, {"text": "ICAM - 3", "type": "ENTITY", "char_start": 97, "char_end": 105, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "RAR beta", "type": "ENTITY", "char_start": 424467, "char_end": 424475, "token_start": 0, "token_end": 1, "note": null}, {"text": "ICAM - 3", "type": "ENTITY", "char_start": 424564, "char_end": 424572, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 2569, "sentence_text": "Increased ICAM - 3 expression was of functional significance , such that processes stimulated or co - stimulated via ICAM - 3 ( homotypic aggregation , IL - 8 secretion ) were clearly enhanced upon RA pretreatment , suggesting that RA may contribute via hitherto unrecognized pathways to immune function and host defense .", "sentence_char_start_global": 424591, "sentence_char_end_global": 424913, "entities": [{"text": "ICAM - 3", "type": "ENTITY", "char_start": 10, "char_end": 18, "token_start": 1, "token_end": 3}, {"text": "ICAM - 3", "type": "ENTITY", "char_start": 117, "char_end": 125, "token_start": 19, "token_end": 21}], "entities_global": [{"text": "ICAM - 3", "type": "ENTITY", "char_start": 424601, "char_end": 424609, "token_start": 1, "token_end": 3, "note": null}, {"text": "ICAM - 3", "type": "ENTITY", "char_start": 424708, "char_end": 424716, "token_start": 19, "token_end": 21, "note": null}]}
+{"sentence_id": 2570, "sentence_text": "CD28 and T cell co - stimulation .", "sentence_char_start_global": 424914, "sentence_char_end_global": 424948, "entities": [{"text": "CD28", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "CD28", "type": "ENTITY", "char_start": 424914, "char_end": 424918, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 2571, "sentence_text": "Over the last decade the concept of T cell co - stimulation has emerged to take a central role in the process of T cell activation .", "sentence_char_start_global": 424949, "sentence_char_end_global": 425081, "entities": [], "entities_global": []}
+{"sentence_id": 2572, "sentence_text": "However , the exact definition of co - stimulation is still unclear .", "sentence_char_start_global": 425082, "sentence_char_end_global": 425151, "entities": [], "entities_global": []}
+{"sentence_id": 2573, "sentence_text": "In this review , we re - examine the concept of co - stimulation .", "sentence_char_start_global": 425152, "sentence_char_end_global": 425218, "entities": [], "entities_global": []}
+{"sentence_id": 2574, "sentence_text": "We suggest that while co - stimulation is important , there is little evidence to link co - stimulation with T cell anergy .", "sentence_char_start_global": 425219, "sentence_char_end_global": 425343, "entities": [], "entities_global": []}
+{"sentence_id": 2575, "sentence_text": "We then suggest a framework for studying co - stimulation .", "sentence_char_start_global": 425344, "sentence_char_end_global": 425403, "entities": [], "entities_global": []}
+{"sentence_id": 2576, "sentence_text": "Focusing on recent advances in our understanding of CD28 , we discuss four areas of T cell activation where co - stimulation may play a role .", "sentence_char_start_global": 425404, "sentence_char_end_global": 425546, "entities": [{"text": "CD28", "type": "ENTITY", "char_start": 52, "char_end": 56, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "CD28", "type": "ENTITY", "char_start": 425456, "char_end": 425460, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 2577, "sentence_text": "Regulation of activator protein - 1 and NF - kappa B in CD8 + T cells exposed to peripheral self - antigens .", "sentence_char_start_global": 425547, "sentence_char_end_global": 425656, "entities": [{"text": "activator protein - 1", "type": "ENTITY", "char_start": 14, "char_end": 35, "token_start": 2, "token_end": 5}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 40, "char_end": 52, "token_start": 7, "token_end": 10}, {"text": "peripheral self - antigens", "type": "ENTITY", "char_start": 81, "char_end": 107, "token_start": 18, "token_end": 21}], "entities_global": [{"text": "activator protein - 1", "type": "ENTITY", "char_start": 425561, "char_end": 425582, "token_start": 2, "token_end": 5, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 425587, "char_end": 425599, "token_start": 7, "token_end": 10, "note": null}, {"text": "peripheral self - antigens", "type": "ENTITY", "char_start": 425628, "char_end": 425654, "token_start": 18, "token_end": 21, "note": null}]}
+{"sentence_id": 2578, "sentence_text": "The transcriptional events that control T cell tolerance to peripheral self Ags are still unknown .", "sentence_char_start_global": 425657, "sentence_char_end_global": 425756, "entities": [{"text": "peripheral self Ags", "type": "ENTITY", "char_start": 60, "char_end": 79, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "peripheral self Ags", "type": "ENTITY", "char_start": 425717, "char_end": 425736, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 2579, "sentence_text": "In this study , we analyzed the regulation of AP - 1 - and NF - kappa B - mediated transcription during in vivo induction of tolerance to a self Ag expressed exclusively on hepatocytes .", "sentence_char_start_global": 425757, "sentence_char_end_global": 425943, "entities": [{"text": "AP - 1", "type": "ENTITY", "char_start": 46, "char_end": 52, "token_start": 9, "token_end": 11}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 59, "char_end": 71, "token_start": 14, "token_end": 17}, {"text": "self Ag", "type": "ENTITY", "char_start": 140, "char_end": 147, "token_start": 29, "token_end": 30}], "entities_global": [{"text": "AP - 1", "type": "ENTITY", "char_start": 425803, "char_end": 425809, "token_start": 9, "token_end": 11, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 425816, "char_end": 425828, "token_start": 14, "token_end": 17, "note": null}, {"text": "self Ag", "type": "ENTITY", "char_start": 425897, "char_end": 425904, "token_start": 29, "token_end": 30, "note": null}]}
+{"sentence_id": 2580, "sentence_text": "Naive CD8 ( + ) Desire ( Des ) ( + ) T cells isolated from the Des TCR - transgenic mice that are specific for the H - 2K ( b ) class I Ag were transferred into Alb - K ( b ) - transgenic mice that express the H - 2K ( b ) Ag on hepatocytes only .", "sentence_char_start_global": 425944, "sentence_char_end_global": 426191, "entities": [{"text": "H - 2K ( b ) class I Ag", "type": "ENTITY", "char_start": 115, "char_end": 138, "token_start": 27, "token_end": 35}, {"text": "H - 2K ( b ) Ag", "type": "ENTITY", "char_start": 210, "char_end": 225, "token_start": 51, "token_end": 57}], "entities_global": [{"text": "H - 2K ( b ) class I Ag", "type": "ENTITY", "char_start": 426059, "char_end": 426082, "token_start": 27, "token_end": 35, "note": null}, {"text": "H - 2K ( b ) Ag", "type": "ENTITY", "char_start": 426154, "char_end": 426169, "token_start": 51, "token_end": 57, "note": null}]}
+{"sentence_id": 2581, "sentence_text": "Tolerance develops in these mice .", "sentence_char_start_global": 426192, "sentence_char_end_global": 426226, "entities": [], "entities_global": []}
+{"sentence_id": 2582, "sentence_text": "We found that the self - reactive CD8 ( + ) Des ( + ) T cells were transiently activated , then became unresponsive and were further deleted .", "sentence_char_start_global": 426227, "sentence_char_end_global": 426369, "entities": [], "entities_global": []}
+{"sentence_id": 2583, "sentence_text": "In contrast to CD8 ( + ) Des ( + ) T cells activated in vivo with APCs , which express high AP - 1 and high NF - kappa B transcriptional activity , the unresponsive CD8 ( + ) Des ( + ) T cells expressed no AP - 1 and only weak NF - kappa B transcriptional activity .", "sentence_char_start_global": 426370, "sentence_char_end_global": 426636, "entities": [{"text": "AP - 1", "type": "ENTITY", "char_start": 92, "char_end": 98, "token_start": 22, "token_end": 24}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 108, "char_end": 120, "token_start": 27, "token_end": 30}, {"text": "AP - 1", "type": "ENTITY", "char_start": 206, "char_end": 212, "token_start": 48, "token_end": 50}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 227, "char_end": 239, "token_start": 54, "token_end": 57}], "entities_global": [{"text": "AP - 1", "type": "ENTITY", "char_start": 426462, "char_end": 426468, "token_start": 22, "token_end": 24, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 426478, "char_end": 426490, "token_start": 27, "token_end": 30, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 426576, "char_end": 426582, "token_start": 48, "token_end": 50, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 426597, "char_end": 426609, "token_start": 54, "token_end": 57, "note": null}]}
+{"sentence_id": 2584, "sentence_text": "The differences in NF - kappa B transcriptional activity correlated with the generation of distinct NF - kappa B complexes .", "sentence_char_start_global": 426637, "sentence_char_end_global": 426761, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 19, "char_end": 31, "token_start": 3, "token_end": 6}, {"text": "NF - kappa B complexes", "type": "ENTITY", "char_start": 100, "char_end": 122, "token_start": 15, "token_end": 19}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 426656, "char_end": 426668, "token_start": 3, "token_end": 6, "note": null}, {"text": "NF - kappa B complexes", "type": "ENTITY", "char_start": 426737, "char_end": 426759, "token_start": 15, "token_end": 19, "note": null}]}
+{"sentence_id": 2585, "sentence_text": "Indeed , in vivo primed T cells predominantly express p50 / p50 and p65 / p50 dimers , whereas these p50 - containing complexes are barely detectable in tolerant T cells that express p65 - and c - Rel - containing complexes .", "sentence_char_start_global": 426762, "sentence_char_end_global": 426987, "entities": [{"text": "p50 / p50 and p65 / p50 dimers", "type": "ENTITY", "char_start": 54, "char_end": 84, "token_start": 9, "token_end": 16}, {"text": "p50 - containing complexes", "type": "ENTITY", "char_start": 101, "char_end": 127, "token_start": 20, "token_end": 23}, {"text": "p65 - and c - Rel - containing complexes", "type": "ENTITY", "char_start": 183, "char_end": 223, "token_start": 33, "token_end": 41}], "entities_global": [{"text": "p50 / p50 and p65 / p50 dimers", "type": "ENTITY", "char_start": 426816, "char_end": 426846, "token_start": 9, "token_end": 16, "note": null}, {"text": "p50 - containing complexes", "type": "ENTITY", "char_start": 426863, "char_end": 426889, "token_start": 20, "token_end": 23, "note": null}, {"text": "p65 - and c - Rel - containing complexes", "type": "ENTITY", "char_start": 426945, "char_end": 426985, "token_start": 33, "token_end": 41, "note": null}]}
+{"sentence_id": 2586, "sentence_text": "These observations suggest that fine regulation of NF - kappa B complex formation may determine T cell fate .", "sentence_char_start_global": 426988, "sentence_char_end_global": 427097, "entities": [{"text": "NF - kappa B complex", "type": "ENTITY", "char_start": 51, "char_end": 71, "token_start": 7, "token_end": 11}], "entities_global": [{"text": "NF - kappa B complex", "type": "ENTITY", "char_start": 427039, "char_end": 427059, "token_start": 7, "token_end": 11, "note": null}]}
+{"sentence_id": 2587, "sentence_text": "Transcriptional regulation in lymphocytes .", "sentence_char_start_global": 427098, "sentence_char_end_global": 427141, "entities": [], "entities_global": []}
+{"sentence_id": 2588, "sentence_text": "Lymphocytes have been used to investigate many cellular processes , including lineage commitment , differentiation , proliferation and apoptosis .", "sentence_char_start_global": 427142, "sentence_char_end_global": 427288, "entities": [], "entities_global": []}
+{"sentence_id": 2589, "sentence_text": "The transcription factors that mediate these processes are often expressed broadly in many cell types .", "sentence_char_start_global": 427289, "sentence_char_end_global": 427392, "entities": [{"text": "transcription factors", "type": "ENTITY", "char_start": 4, "char_end": 25, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "transcription factors", "type": "ENTITY", "char_start": 427293, "char_end": 427314, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 2590, "sentence_text": "The emerging theme is one of cell - type - specific regulation , affecting not only the functional activation of transcription factors but also their access to appropriate regions of DNA .", "sentence_char_start_global": 427393, "sentence_char_end_global": 427581, "entities": [{"text": "transcription factors", "type": "ENTITY", "char_start": 113, "char_end": 134, "token_start": 20, "token_end": 21}], "entities_global": [{"text": "transcription factors", "type": "ENTITY", "char_start": 427506, "char_end": 427527, "token_start": 20, "token_end": 21, "note": null}]}
+{"sentence_id": 2591, "sentence_text": "Existence of retinoic acid - receptor - independent retinoid X - receptor - dependent pathway in myeloid cell function .", "sentence_char_start_global": 427582, "sentence_char_end_global": 427702, "entities": [{"text": "retinoic acid - receptor", "type": "ENTITY", "char_start": 13, "char_end": 37, "token_start": 2, "token_end": 5}, {"text": "retinoid X - receptor", "type": "ENTITY", "char_start": 52, "char_end": 73, "token_start": 8, "token_end": 11}], "entities_global": [{"text": "retinoic acid - receptor", "type": "ENTITY", "char_start": 427595, "char_end": 427619, "token_start": 2, "token_end": 5, "note": null}, {"text": "retinoid X - receptor", "type": "ENTITY", "char_start": 427634, "char_end": 427655, "token_start": 8, "token_end": 11, "note": null}]}
+{"sentence_id": 2592, "sentence_text": "We previously reported that ER - 27191 ( 4 - [ 4 , 5 , 7 , 8 , 9 , 10 - hexahydro - 7 , 7 , 10 , 10 - tetramethyl - 1 - ( 3 - pyridylmethyl ) anthra [ 1 , 2 - b ] pyrrol - 3 - yl ] benzoic acid ) is a potent antagonist of retinoic acid receptor ( RAR ) , and ER - 35795 ( ( 2E , 4E , 6E ) - 7 - [ 1 - ( 1 - methylethyl ) - 8 - chloro - 1 , 2 , 3 , 4 - tetrahydroquinolin - 6 - yl ] - 6 - fluoro - 3 - methyl - 2 , 4 , 6 - nonatrienoic acid ) is a novel retinoid X receptor ( RXR ) - specific agonist .", "sentence_char_start_global": 427703, "sentence_char_end_global": 428204, "entities": [{"text": "retinoic acid receptor", "type": "ENTITY", "char_start": 222, "char_end": 244, "token_start": 64, "token_end": 66}, {"text": "RAR", "type": "ENTITY", "char_start": 247, "char_end": 250, "token_start": 68, "token_end": 68}, {"text": "retinoid X receptor", "type": "ENTITY", "char_start": 453, "char_end": 472, "token_start": 134, "token_end": 136}, {"text": "RXR", "type": "ENTITY", "char_start": 475, "char_end": 478, "token_start": 138, "token_end": 138}], "entities_global": [{"text": "retinoic acid receptor", "type": "ENTITY", "char_start": 427925, "char_end": 427947, "token_start": 64, "token_end": 66, "note": null}, {"text": "RAR", "type": "ENTITY", "char_start": 427950, "char_end": 427953, "token_start": 68, "token_end": 68, "note": null}, {"text": "retinoid X receptor", "type": "ENTITY", "char_start": 428156, "char_end": 428175, "token_start": 134, "token_end": 136, "note": null}, {"text": "RXR", "type": "ENTITY", "char_start": 428178, "char_end": 428181, "token_start": 138, "token_end": 138, "note": null}]}
+{"sentence_id": 2593, "sentence_text": "By using these compounds , we investigated whether distinct RAR - dependent and RXR - dependent pathways operate to mediate the diverse activities of retinoids , particularly , the effects of the RXR pathway on cellular function .", "sentence_char_start_global": 428205, "sentence_char_end_global": 428435, "entities": [{"text": "RAR", "type": "ENTITY", "char_start": 60, "char_end": 63, "token_start": 9, "token_end": 9}, {"text": "RXR", "type": "ENTITY", "char_start": 80, "char_end": 83, "token_start": 13, "token_end": 13}, {"text": "RXR", "type": "ENTITY", "char_start": 196, "char_end": 199, "token_start": 32, "token_end": 32}], "entities_global": [{"text": "RAR", "type": "ENTITY", "char_start": 428265, "char_end": 428268, "token_start": 9, "token_end": 9, "note": null}, {"text": "RXR", "type": "ENTITY", "char_start": 428285, "char_end": 428288, "token_start": 13, "token_end": 13, "note": null}, {"text": "RXR", "type": "ENTITY", "char_start": 428401, "char_end": 428404, "token_start": 32, "token_end": 32, "note": null}]}
+{"sentence_id": 2594, "sentence_text": "ER - 27191 completely antagonized HL60 cell differentiation induced by all - trans - retinoic acid ( atRA ) .", "sentence_char_start_global": 428436, "sentence_char_end_global": 428545, "entities": [], "entities_global": []}
+{"sentence_id": 2595, "sentence_text": "However , the differentiation induced by the ER - 35795 was not antagonized at all by the RAR antagonist , but was inhibited by an RXR homodimer antagonist ( LGD100754 , ( 2E , 4E , 6Z ) - 7 - ( 3 - n - propoxy - 5 , 6 , 7 , 8 - tetrahydro - 5 , 5 , 8 , 8 - tetramethylnaphthale - 2 - yl ) - 3 - methylocta - 2 , 4 , 6 - trienoic acid ) .", "sentence_char_start_global": 428546, "sentence_char_end_global": 428884, "entities": [{"text": "RAR", "type": "ENTITY", "char_start": 90, "char_end": 93, "token_start": 17, "token_end": 17}, {"text": "RXR homodimer", "type": "ENTITY", "char_start": 131, "char_end": 144, "token_start": 25, "token_end": 26}], "entities_global": [{"text": "RAR", "type": "ENTITY", "char_start": 428636, "char_end": 428639, "token_start": 17, "token_end": 17, "note": null}, {"text": "RXR homodimer", "type": "ENTITY", "char_start": 428677, "char_end": 428690, "token_start": 25, "token_end": 26, "note": null}]}
+{"sentence_id": 2596, "sentence_text": "Its agonistic action on RXR / RAR heterodimer , on the other hand , was neutralized by the RAR antagonist .", "sentence_char_start_global": 428885, "sentence_char_end_global": 428992, "entities": [{"text": "RXR / RAR heterodimer", "type": "ENTITY", "char_start": 24, "char_end": 45, "token_start": 4, "token_end": 7}, {"text": "RAR", "type": "ENTITY", "char_start": 91, "char_end": 94, "token_start": 18, "token_end": 18}], "entities_global": [{"text": "RXR / RAR heterodimer", "type": "ENTITY", "char_start": 428909, "char_end": 428930, "token_start": 4, "token_end": 7, "note": null}, {"text": "RAR", "type": "ENTITY", "char_start": 428976, "char_end": 428979, "token_start": 18, "token_end": 18, "note": null}]}
+{"sentence_id": 2597, "sentence_text": "During HL60 cell differentiation , atRA induced RARbeta mRNA , while the RXR had no effect .", "sentence_char_start_global": 428993, "sentence_char_end_global": 429085, "entities": [{"text": "RARbeta mRNA", "type": "ENTITY", "char_start": 48, "char_end": 60, "token_start": 7, "token_end": 8}, {"text": "RXR", "type": "ENTITY", "char_start": 73, "char_end": 76, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "RARbeta mRNA", "type": "ENTITY", "char_start": 429041, "char_end": 429053, "token_start": 7, "token_end": 8, "note": null}, {"text": "RXR", "type": "ENTITY", "char_start": 429066, "char_end": 429069, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 2598, "sentence_text": "Interestingly , a functional RXR - pathway was also seen in lipopolysaccharide - induced inhibition of mouse splenocyte proliferation .", "sentence_char_start_global": 429086, "sentence_char_end_global": 429221, "entities": [{"text": "RXR", "type": "ENTITY", "char_start": 29, "char_end": 32, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "RXR", "type": "ENTITY", "char_start": 429115, "char_end": 429118, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 2599, "sentence_text": "These results strongly suggest the existence of a pharmacological RXR - dependent pathway that is activated by a ligand that can bind to RXR .", "sentence_char_start_global": 429222, "sentence_char_end_global": 429364, "entities": [{"text": "RXR", "type": "ENTITY", "char_start": 66, "char_end": 69, "token_start": 9, "token_end": 9}, {"text": "RXR", "type": "ENTITY", "char_start": 137, "char_end": 140, "token_start": 23, "token_end": 23}], "entities_global": [{"text": "RXR", "type": "ENTITY", "char_start": 429288, "char_end": 429291, "token_start": 9, "token_end": 9, "note": null}, {"text": "RXR", "type": "ENTITY", "char_start": 429359, "char_end": 429362, "token_start": 23, "token_end": 23, "note": null}]}
+{"sentence_id": 2600, "sentence_text": "Targeting Src homology 2 domain - containing tyrosine phosphatase ( SHP - 1 ) into lipid rafts inhibits CD3 - induced T cell activation .", "sentence_char_start_global": 429365, "sentence_char_end_global": 429502, "entities": [{"text": "Src homology 2 domain - containing tyrosine phosphatase", "type": "ENTITY", "char_start": 10, "char_end": 65, "token_start": 1, "token_end": 8}, {"text": "SHP - 1", "type": "ENTITY", "char_start": 68, "char_end": 75, "token_start": 10, "token_end": 12}, {"text": "CD3", "type": "ENTITY", "char_start": 104, "char_end": 107, "token_start": 18, "token_end": 18}], "entities_global": [{"text": "Src homology 2 domain - containing tyrosine phosphatase", "type": "ENTITY", "char_start": 429375, "char_end": 429430, "token_start": 1, "token_end": 8, "note": null}, {"text": "SHP - 1", "type": "ENTITY", "char_start": 429433, "char_end": 429440, "token_start": 10, "token_end": 12, "note": null}, {"text": "CD3", "type": "ENTITY", "char_start": 429469, "char_end": 429472, "token_start": 18, "token_end": 18, "note": null}]}
+{"sentence_id": 2601, "sentence_text": "To study the mechanism by which protein tyrosine phosphatases ( PTPs ) regulate CD3 - induced tyrosine phosphorylation , we investigated the distribution of PTPs in subdomains of plasma membrane .", "sentence_char_start_global": 429503, "sentence_char_end_global": 429699, "entities": [{"text": "protein tyrosine phosphatases", "type": "ENTITY", "char_start": 32, "char_end": 61, "token_start": 6, "token_end": 8}, {"text": "PTPs", "type": "ENTITY", "char_start": 64, "char_end": 68, "token_start": 10, "token_end": 10}, {"text": "CD3", "type": "ENTITY", "char_start": 80, "char_end": 83, "token_start": 13, "token_end": 13}, {"text": "PTPs", "type": "ENTITY", "char_start": 157, "char_end": 161, "token_start": 24, "token_end": 24}], "entities_global": [{"text": "protein tyrosine phosphatases", "type": "ENTITY", "char_start": 429535, "char_end": 429564, "token_start": 6, "token_end": 8, "note": null}, {"text": "PTPs", "type": "ENTITY", "char_start": 429567, "char_end": 429571, "token_start": 10, "token_end": 10, "note": null}, {"text": "CD3", "type": "ENTITY", "char_start": 429583, "char_end": 429586, "token_start": 13, "token_end": 13, "note": null}, {"text": "PTPs", "type": "ENTITY", "char_start": 429660, "char_end": 429664, "token_start": 24, "token_end": 24, "note": null}]}
+{"sentence_id": 2602, "sentence_text": "We report here that the bulk PTP activity associated with T cell membrane is present outside the lipid rafts , as determined by sucrose density gradient sedimentation .", "sentence_char_start_global": 429700, "sentence_char_end_global": 429868, "entities": [{"text": "PTP", "type": "ENTITY", "char_start": 29, "char_end": 32, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "PTP", "type": "ENTITY", "char_start": 429729, "char_end": 429732, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 2603, "sentence_text": "In Jurkat T cells , approximately 5 - - 10 % of Src homology 2 domain - containing tyrosine phosphatase ( SHP - 1 ) is constitutively associated with plasma membrane , and nearly 50 % of SHP - 2 is translocated to plasma membrane after vanadate treatment .", "sentence_char_start_global": 429869, "sentence_char_end_global": 430125, "entities": [{"text": "Src homology 2 domain - containing tyrosine phosphatase", "type": "ENTITY", "char_start": 48, "char_end": 103, "token_start": 12, "token_end": 19}, {"text": "SHP - 1", "type": "ENTITY", "char_start": 106, "char_end": 113, "token_start": 21, "token_end": 23}, {"text": "SHP - 2", "type": "ENTITY", "char_start": 187, "char_end": 194, "token_start": 37, "token_end": 39}], "entities_global": [{"text": "Src homology 2 domain - containing tyrosine phosphatase", "type": "ENTITY", "char_start": 429917, "char_end": 429972, "token_start": 12, "token_end": 19, "note": null}, {"text": "SHP - 1", "type": "ENTITY", "char_start": 429975, "char_end": 429982, "token_start": 21, "token_end": 23, "note": null}, {"text": "SHP - 2", "type": "ENTITY", "char_start": 430056, "char_end": 430063, "token_start": 37, "token_end": 39, "note": null}]}
+{"sentence_id": 2604, "sentence_text": "Similar to transmembrane PTP , CD45 , the membrane - associated populations of SHP - 1 and SHP - 2 are essentially excluded from lipid rafts , where other signaling molecules such as Lck , linker for activation of T cells , and CD3 zeta are enriched .", "sentence_char_start_global": 430126, "sentence_char_end_global": 430377, "entities": [{"text": "transmembrane PTP", "type": "ENTITY", "char_start": 11, "char_end": 28, "token_start": 2, "token_end": 3}, {"text": "CD45", "type": "ENTITY", "char_start": 31, "char_end": 35, "token_start": 5, "token_end": 5}, {"text": "SHP - 1", "type": "ENTITY", "char_start": 79, "char_end": 86, "token_start": 13, "token_end": 15}, {"text": "SHP - 2", "type": "ENTITY", "char_start": 91, "char_end": 98, "token_start": 17, "token_end": 19}, {"text": "signaling molecules", "type": "ENTITY", "char_start": 155, "char_end": 174, "token_start": 29, "token_end": 30}, {"text": "Lck , linker for activation of T cells", "type": "ENTITY", "char_start": 183, "char_end": 221, "token_start": 33, "token_end": 40}, {"text": "CD3 zeta", "type": "ENTITY", "char_start": 228, "char_end": 236, "token_start": 43, "token_end": 44}], "entities_global": [{"text": "transmembrane PTP", "type": "ENTITY", "char_start": 430137, "char_end": 430154, "token_start": 2, "token_end": 3, "note": null}, {"text": "CD45", "type": "ENTITY", "char_start": 430157, "char_end": 430161, "token_start": 5, "token_end": 5, "note": null}, {"text": "SHP - 1", "type": "ENTITY", "char_start": 430205, "char_end": 430212, "token_start": 13, "token_end": 15, "note": null}, {"text": "SHP - 2", "type": "ENTITY", "char_start": 430217, "char_end": 430224, "token_start": 17, "token_end": 19, "note": null}, {"text": "signaling molecules", "type": "ENTITY", "char_start": 430281, "char_end": 430300, "token_start": 29, "token_end": 30, "note": null}, {"text": "Lck , linker for activation of T cells", "type": "ENTITY", "char_start": 430309, "char_end": 430347, "token_start": 33, "token_end": 40, "note": null}, {"text": "CD3 zeta", "type": "ENTITY", "char_start": 430354, "char_end": 430362, "token_start": 43, "token_end": 44, "note": null}]}
+{"sentence_id": 2605, "sentence_text": "We further demonstrated that CD3 - induced tyrosine phosphorylation of these substrates is largely restricted to lipid rafts , unless PTPs are inhibited .", "sentence_char_start_global": 430378, "sentence_char_end_global": 430532, "entities": [{"text": "CD3", "type": "ENTITY", "char_start": 29, "char_end": 32, "token_start": 4, "token_end": 4}, {"text": "PTPs", "type": "ENTITY", "char_start": 134, "char_end": 138, "token_start": 20, "token_end": 20}], "entities_global": [{"text": "CD3", "type": "ENTITY", "char_start": 430407, "char_end": 430410, "token_start": 4, "token_end": 4, "note": null}, {"text": "PTPs", "type": "ENTITY", "char_start": 430512, "char_end": 430516, "token_start": 20, "token_end": 20, "note": null}]}
+{"sentence_id": 2606, "sentence_text": "It suggests that a restricted partition of PTPs among membrane subdomains may regulate protein tyrosine phosphorylation in T cell membrane .", "sentence_char_start_global": 430533, "sentence_char_end_global": 430673, "entities": [{"text": "PTPs", "type": "ENTITY", "char_start": 43, "char_end": 47, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "PTPs", "type": "ENTITY", "char_start": 430576, "char_end": 430580, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 2607, "sentence_text": "To test this hypothesis , we targeted SHP - 1 into lipid rafts by using the N - terminal region of Lck ( residues 1 - - 14 ) .", "sentence_char_start_global": 430674, "sentence_char_end_global": 430800, "entities": [{"text": "SHP - 1", "type": "ENTITY", "char_start": 38, "char_end": 45, "token_start": 7, "token_end": 9}, {"text": "N - terminal region of Lck", "type": "ENTITY", "char_start": 76, "char_end": 102, "token_start": 16, "token_end": 21}, {"text": "residues 1 - - 14", "type": "ENTITY", "char_start": 105, "char_end": 122, "token_start": 23, "token_end": 27}], "entities_global": [{"text": "SHP - 1", "type": "ENTITY", "char_start": 430712, "char_end": 430719, "token_start": 7, "token_end": 9, "note": null}, {"text": "N - terminal region of Lck", "type": "ENTITY", "char_start": 430750, "char_end": 430776, "token_start": 16, "token_end": 21, "note": null}, {"text": "residues 1 - - 14", "type": "ENTITY", "char_start": 430779, "char_end": 430796, "token_start": 23, "token_end": 27, "note": null}]}
+{"sentence_id": 2608, "sentence_text": "The results indicate that the expression of Lck / SHP - 1 chimera inside lipid rafts profoundly inhibits CD3 - induced tyrosine phosphorylation of CD3 zeta / epsilon , IL - 2 generation , and nuclear mobilization of NF - AT .", "sentence_char_start_global": 430801, "sentence_char_end_global": 431026, "entities": [{"text": "Lck / SHP - 1 chimera", "type": "ENTITY", "char_start": 44, "char_end": 65, "token_start": 7, "token_end": 12}, {"text": "CD3", "type": "ENTITY", "char_start": 105, "char_end": 108, "token_start": 18, "token_end": 18}, {"text": "CD3 zeta / epsilon", "type": "ENTITY", "char_start": 147, "char_end": 165, "token_start": 24, "token_end": 27}, {"text": "NF - AT", "type": "ENTITY", "char_start": 216, "char_end": 223, "token_start": 38, "token_end": 40}], "entities_global": [{"text": "Lck / SHP - 1 chimera", "type": "ENTITY", "char_start": 430845, "char_end": 430866, "token_start": 7, "token_end": 12, "note": null}, {"text": "CD3", "type": "ENTITY", "char_start": 430906, "char_end": 430909, "token_start": 18, "token_end": 18, "note": null}, {"text": "CD3 zeta / epsilon", "type": "ENTITY", "char_start": 430948, "char_end": 430966, "token_start": 24, "token_end": 27, "note": null}, {"text": "NF - AT", "type": "ENTITY", "char_start": 431017, "char_end": 431024, "token_start": 38, "token_end": 40, "note": null}]}
+{"sentence_id": 2609, "sentence_text": "Collectively , these results suggest that the exclusion of PTPs from lipid rafts may be a mechanism that potentiates TCR / CD3 activation", "sentence_char_start_global": 431027, "sentence_char_end_global": 431164, "entities": [{"text": "PTPs", "type": "ENTITY", "char_start": 59, "char_end": 63, "token_start": 9, "token_end": 9}, {"text": "TCR", "type": "ENTITY", "char_start": 117, "char_end": 120, "token_start": 19, "token_end": 19}, {"text": "CD3", "type": "ENTITY", "char_start": 123, "char_end": 126, "token_start": 21, "token_end": 21}], "entities_global": [{"text": "PTPs", "type": "ENTITY", "char_start": 431086, "char_end": 431090, "token_start": 9, "token_end": 9, "note": null}, {"text": "TCR", "type": "ENTITY", "char_start": 431144, "char_end": 431147, "token_start": 19, "token_end": 19, "note": null}, {"text": "CD3", "type": "ENTITY", "char_start": 431150, "char_end": 431153, "token_start": 21, "token_end": 21, "note": null}]}
+{"sentence_id": 2610, "sentence_text": "An instructive component in T helper cell type 2 ( Th2 ) development mediated by GATA - 3 .", "sentence_char_start_global": 431165, "sentence_char_end_global": 431256, "entities": [{"text": "GATA - 3", "type": "ENTITY", "char_start": 81, "char_end": 89, "token_start": 15, "token_end": 17}], "entities_global": [{"text": "GATA - 3", "type": "ENTITY", "char_start": 431246, "char_end": 431254, "token_start": 15, "token_end": 17, "note": null}]}
+{"sentence_id": 2611, "sentence_text": "Although interleukin ( IL ) - 12 and IL - 4 polarize naive CD4 ( + ) T cells toward T helper cell type 1 ( Th1 ) or Th2 phenotypes , it is not known whether cytokines instruct the developmental fate in uncommitted progenitors or select for outgrowth of cells that have stochastically committed to a particular fate .", "sentence_char_start_global": 431257, "sentence_char_end_global": 431573, "entities": [{"text": "interleukin ( IL ) - 12", "type": "ENTITY", "char_start": 9, "char_end": 32, "token_start": 1, "token_end": 6}, {"text": "IL - 4", "type": "ENTITY", "char_start": 37, "char_end": 43, "token_start": 8, "token_end": 10}, {"text": "cytokines", "type": "ENTITY", "char_start": 157, "char_end": 166, "token_start": 37, "token_end": 37}], "entities_global": [{"text": "interleukin ( IL ) - 12", "type": "ENTITY", "char_start": 431266, "char_end": 431289, "token_start": 1, "token_end": 6, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 431294, "char_end": 431300, "token_start": 8, "token_end": 10, "note": null}, {"text": "cytokines", "type": "ENTITY", "char_start": 431414, "char_end": 431423, "token_start": 37, "token_end": 37, "note": null}]}
+{"sentence_id": 2612, "sentence_text": "To distinguish these instructive and selective models , we used surface affinity matrix technology to isolate committed progenitors based on cytokine secretion phenotype and developed retroviral - based tagging approaches to directly monitor individual progenitor fate decisions at the clonal and population levels .", "sentence_char_start_global": 431574, "sentence_char_end_global": 431890, "entities": [], "entities_global": []}
+{"sentence_id": 2613, "sentence_text": "We observe IL - 4 - dependent redirection of phenotype in cells that have already committed to a non - IL - 4 - producing fate , inconsistent with predictions of the selective model .", "sentence_char_start_global": 431891, "sentence_char_end_global": 432074, "entities": [{"text": "IL - 4", "type": "ENTITY", "char_start": 11, "char_end": 17, "token_start": 2, "token_end": 4}], "entities_global": [{"text": "IL - 4", "type": "ENTITY", "char_start": 431902, "char_end": 431908, "token_start": 2, "token_end": 4, "note": null}]}
+{"sentence_id": 2614, "sentence_text": "Further , retroviral tagging of naive progenitors with the Th2 - specific transcription factor GATA - 3 provided direct evidence for instructive differentiation , and no evidence for the selective outgrowth of cells committed to either the Th1 or Th2 fate .", "sentence_char_start_global": 432075, "sentence_char_end_global": 432332, "entities": [{"text": "Th2 - specific transcription factor GATA - 3", "type": "ENTITY", "char_start": 59, "char_end": 103, "token_start": 9, "token_end": 16}], "entities_global": [{"text": "Th2 - specific transcription factor GATA - 3", "type": "ENTITY", "char_start": 432134, "char_end": 432178, "token_start": 9, "token_end": 16, "note": null}]}
+{"sentence_id": 2615, "sentence_text": "These data would seem to exclude selection as an exclusive mechanism in Th1 / Th2 differentiation , and support an instructive model of cytokine - driven transcriptional programming of cell fate decisions .", "sentence_char_start_global": 432333, "sentence_char_end_global": 432539, "entities": [], "entities_global": []}
+{"sentence_id": 2616, "sentence_text": "In vitro - activated human lupus T cells express normal estrogen receptor proteins which bind to the estrogen response element .", "sentence_char_start_global": 432540, "sentence_char_end_global": 432668, "entities": [{"text": "estrogen receptor proteins", "type": "ENTITY", "char_start": 56, "char_end": 82, "token_start": 10, "token_end": 12}, {"text": "estrogen response element", "type": "ENTITY", "char_start": 101, "char_end": 126, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "estrogen receptor proteins", "type": "ENTITY", "char_start": 432596, "char_end": 432622, "token_start": 10, "token_end": 12, "note": null}, {"text": "estrogen response element", "type": "ENTITY", "char_start": 432641, "char_end": 432666, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 2617, "sentence_text": "We have shown that estrogen receptor ( ERalpha , ERbeta ) transcripts are expressed in SLE and normal T cells .", "sentence_char_start_global": 432669, "sentence_char_end_global": 432780, "entities": [{"text": "estrogen receptor", "type": "ENTITY", "char_start": 19, "char_end": 36, "token_start": 4, "token_end": 5}, {"text": "ERalpha", "type": "ENTITY", "char_start": 39, "char_end": 46, "token_start": 7, "token_end": 7}, {"text": "ERbeta", "type": "ENTITY", "char_start": 49, "char_end": 55, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "estrogen receptor", "type": "ENTITY", "char_start": 432688, "char_end": 432705, "token_start": 4, "token_end": 5, "note": null}, {"text": "ERalpha", "type": "ENTITY", "char_start": 432708, "char_end": 432715, "token_start": 7, "token_end": 7, "note": null}, {"text": "ERbeta", "type": "ENTITY", "char_start": 432718, "char_end": 432724, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 2618, "sentence_text": "In this study , T cell nuclear extracts from female lupus patients and normal donors were tested for biologically active ER proteins capable of binding to the human estrogen response element ( hERE ) by electrophoretic mobility shift assays .", "sentence_char_start_global": 432781, "sentence_char_end_global": 433023, "entities": [{"text": "ER proteins", "type": "ENTITY", "char_start": 121, "char_end": 132, "token_start": 20, "token_end": 21}, {"text": "human estrogen response element", "type": "ENTITY", "char_start": 159, "char_end": 190, "token_start": 27, "token_end": 30}, {"text": "hERE", "type": "ENTITY", "char_start": 193, "char_end": 197, "token_start": 32, "token_end": 32}], "entities_global": [{"text": "ER proteins", "type": "ENTITY", "char_start": 432902, "char_end": 432913, "token_start": 20, "token_end": 21, "note": null}, {"text": "human estrogen response element", "type": "ENTITY", "char_start": 432940, "char_end": 432971, "token_start": 27, "token_end": 30, "note": null}, {"text": "hERE", "type": "ENTITY", "char_start": 432974, "char_end": 432978, "token_start": 32, "token_end": 32, "note": null}]}
+{"sentence_id": 2619, "sentence_text": "When peripheral blood T cells were stimulated with 17beta - estradiol ( E2 ) , PMA and ionomycin , two major retarded bands in T cell nuclear extracts exhibited a migration pattern similar to slow migrating protein - ERE complexes in human breast cancer cell extracts .", "sentence_char_start_global": 433024, "sentence_char_end_global": 433293, "entities": [{"text": "protein - ERE complexes", "type": "ENTITY", "char_start": 207, "char_end": 230, "token_start": 36, "token_end": 39}], "entities_global": [{"text": "protein - ERE complexes", "type": "ENTITY", "char_start": 433231, "char_end": 433254, "token_start": 36, "token_end": 39, "note": null}]}
+{"sentence_id": 2620, "sentence_text": "T cells cultured only with E2 did not have these complexes .", "sentence_char_start_global": 433294, "sentence_char_end_global": 433354, "entities": [], "entities_global": []}
+{"sentence_id": 2621, "sentence_text": "The formation of the complexes was inhibited by competition with the hERE cold oligonucleotide and partially with anti - ERalpha antibodies .", "sentence_char_start_global": 433355, "sentence_char_end_global": 433496, "entities": [{"text": "anti - ERalpha antibodies", "type": "ENTITY", "char_start": 114, "char_end": 139, "token_start": 17, "token_end": 20}], "entities_global": [{"text": "anti - ERalpha antibodies", "type": "ENTITY", "char_start": 433469, "char_end": 433494, "token_start": 17, "token_end": 20, "note": null}]}
+{"sentence_id": 2622, "sentence_text": "There was no notable difference in the migration pattern of ERE - binding proteins between the SLE and normal T cell extracts .", "sentence_char_start_global": 433497, "sentence_char_end_global": 433624, "entities": [{"text": "ERE - binding proteins", "type": "ENTITY", "char_start": 60, "char_end": 82, "token_start": 10, "token_end": 13}], "entities_global": [{"text": "ERE - binding proteins", "type": "ENTITY", "char_start": 433557, "char_end": 433579, "token_start": 10, "token_end": 13, "note": null}]}
+{"sentence_id": 2623, "sentence_text": "Together , these results suggest that activated human T cells , whether lupus - derived or normal - derived , contain biologically active ERalpha proteins .", "sentence_char_start_global": 433625, "sentence_char_end_global": 433781, "entities": [{"text": "ERalpha proteins", "type": "ENTITY", "char_start": 138, "char_end": 154, "token_start": 23, "token_end": 24}], "entities_global": [{"text": "ERalpha proteins", "type": "ENTITY", "char_start": 433763, "char_end": 433779, "token_start": 23, "token_end": 24, "note": null}]}
+{"sentence_id": 2624, "sentence_text": "Other factors may be responsible for differential sensitivity of lupus T cells to estrogen .", "sentence_char_start_global": 433782, "sentence_char_end_global": 433874, "entities": [], "entities_global": []}
+{"sentence_id": 2625, "sentence_text": "Mechanism of the inhibitory effect of protease inhibitor on tumor necrosis factor alpha production of monocytes .", "sentence_char_start_global": 433875, "sentence_char_end_global": 433988, "entities": [{"text": "tumor necrosis factor alpha", "type": "ENTITY", "char_start": 60, "char_end": 87, "token_start": 9, "token_end": 12}], "entities_global": [{"text": "tumor necrosis factor alpha", "type": "ENTITY", "char_start": 433935, "char_end": 433962, "token_start": 9, "token_end": 12, "note": null}]}
+{"sentence_id": 2626, "sentence_text": "If the inflammatory response becomes excessive or uncontrolled by some stimuli , inappropriate inflammatory responses occur .", "sentence_char_start_global": 433989, "sentence_char_end_global": 434114, "entities": [], "entities_global": []}
+{"sentence_id": 2627, "sentence_text": "Monocytes are extremely important cells for regulating the cytokine network and tumor necrosis factor alpha ( TNFalpha ) and interleukin - ( IL ) 10 , which are mainly synthesized by monocytes , are representative cytokines that play a central role in the cytokine network .", "sentence_char_start_global": 434115, "sentence_char_end_global": 434389, "entities": [{"text": "tumor necrosis factor alpha", "type": "ENTITY", "char_start": 80, "char_end": 107, "token_start": 11, "token_end": 14}, {"text": "TNFalpha", "type": "ENTITY", "char_start": 110, "char_end": 118, "token_start": 16, "token_end": 16}, {"text": "interleukin - ( IL ) 10", "type": "ENTITY", "char_start": 125, "char_end": 148, "token_start": 19, "token_end": 24}, {"text": "cytokines", "type": "ENTITY", "char_start": 214, "char_end": 223, "token_start": 35, "token_end": 35}], "entities_global": [{"text": "tumor necrosis factor alpha", "type": "ENTITY", "char_start": 434195, "char_end": 434222, "token_start": 11, "token_end": 14, "note": null}, {"text": "TNFalpha", "type": "ENTITY", "char_start": 434225, "char_end": 434233, "token_start": 16, "token_end": 16, "note": null}, {"text": "interleukin - ( IL ) 10", "type": "ENTITY", "char_start": 434240, "char_end": 434263, "token_start": 19, "token_end": 24, "note": null}, {"text": "cytokines", "type": "ENTITY", "char_start": 434329, "char_end": 434338, "token_start": 35, "token_end": 35, "note": null}]}
+{"sentence_id": 2628, "sentence_text": "Protease inhibitors such as gabexate mesilate ( GM ) and ulinastatin ( UTI ) have been shown to have various beneficial effects by inhibiting the activation of leukocytes , but the mechanism for this has yet to be fully elucidated .", "sentence_char_start_global": 434390, "sentence_char_end_global": 434622, "entities": [], "entities_global": []}
+{"sentence_id": 2629, "sentence_text": "In this study we investigated the mechanism of the inhibitory effect of protease inhibitors on the proinflammatory cytokine production of lipopolysaccharide - ( LPS ) stimulated monocytes .", "sentence_char_start_global": 434623, "sentence_char_end_global": 434812, "entities": [], "entities_global": []}
+{"sentence_id": 2630, "sentence_text": "LPS - stimulated monocytes were treated with GM or UTI .", "sentence_char_start_global": 434813, "sentence_char_end_global": 434869, "entities": [], "entities_global": []}
+{"sentence_id": 2631, "sentence_text": "The value of TNFalpha and IL - 10 in the culture medium of monocytes was measured and each mRNA expression was assayed .", "sentence_char_start_global": 434870, "sentence_char_end_global": 434990, "entities": [{"text": "TNFalpha", "type": "ENTITY", "char_start": 13, "char_end": 21, "token_start": 3, "token_end": 3}, {"text": "IL - 10", "type": "ENTITY", "char_start": 26, "char_end": 33, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "TNFalpha", "type": "ENTITY", "char_start": 434883, "char_end": 434891, "token_start": 3, "token_end": 3, "note": null}, {"text": "IL - 10", "type": "ENTITY", "char_start": 434896, "char_end": 434903, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 2632, "sentence_text": "The inhibitory effect of protease inhibitors on the activity of intracellular signal transduction pathways such as protein kinase C ( PKC ) and nuclear factor kappa B ( NFkappaB ) were also evaluated .", "sentence_char_start_global": 434991, "sentence_char_end_global": 435192, "entities": [{"text": "protein kinase C", "type": "ENTITY", "char_start": 115, "char_end": 131, "token_start": 16, "token_end": 18}, {"text": "PKC", "type": "ENTITY", "char_start": 134, "char_end": 137, "token_start": 20, "token_end": 20}, {"text": "nuclear factor kappa B", "type": "ENTITY", "char_start": 144, "char_end": 166, "token_start": 23, "token_end": 26}, {"text": "NFkappaB", "type": "ENTITY", "char_start": 169, "char_end": 177, "token_start": 28, "token_end": 28}], "entities_global": [{"text": "protein kinase C", "type": "ENTITY", "char_start": 435106, "char_end": 435122, "token_start": 16, "token_end": 18, "note": null}, {"text": "PKC", "type": "ENTITY", "char_start": 435125, "char_end": 435128, "token_start": 20, "token_end": 20, "note": null}, {"text": "nuclear factor kappa B", "type": "ENTITY", "char_start": 435135, "char_end": 435157, "token_start": 23, "token_end": 26, "note": null}, {"text": "NFkappaB", "type": "ENTITY", "char_start": 435160, "char_end": 435168, "token_start": 28, "token_end": 28, "note": null}]}
+{"sentence_id": 2633, "sentence_text": "GM decreased the TNFalpha production of LPS - stimulated monocytes as shown by the inhibition of mRNA expression and increased the IL - 10 production of LPS - stimulated monocytes .", "sentence_char_start_global": 435193, "sentence_char_end_global": 435374, "entities": [{"text": "TNFalpha", "type": "ENTITY", "char_start": 17, "char_end": 25, "token_start": 3, "token_end": 3}, {"text": "IL - 10", "type": "ENTITY", "char_start": 131, "char_end": 138, "token_start": 21, "token_end": 23}], "entities_global": [{"text": "TNFalpha", "type": "ENTITY", "char_start": 435210, "char_end": 435218, "token_start": 3, "token_end": 3, "note": null}, {"text": "IL - 10", "type": "ENTITY", "char_start": 435324, "char_end": 435331, "token_start": 21, "token_end": 23, "note": null}]}
+{"sentence_id": 2634, "sentence_text": "GM also suppressed the NFkappaB activity of LPS - stimulated monocytes .", "sentence_char_start_global": 435375, "sentence_char_end_global": 435447, "entities": [{"text": "NFkappaB", "type": "ENTITY", "char_start": 23, "char_end": 31, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "NFkappaB", "type": "ENTITY", "char_start": 435398, "char_end": 435406, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 2635, "sentence_text": "UTI decreased the TNFalpha production of LPS - stimulated monocytes , but did not inhibit the TNFalpha mRNA expression .", "sentence_char_start_global": 435448, "sentence_char_end_global": 435568, "entities": [{"text": "TNFalpha", "type": "ENTITY", "char_start": 18, "char_end": 26, "token_start": 3, "token_end": 3}, {"text": "TNFalpha mRNA", "type": "ENTITY", "char_start": 94, "char_end": 107, "token_start": 16, "token_end": 17}], "entities_global": [{"text": "TNFalpha", "type": "ENTITY", "char_start": 435466, "char_end": 435474, "token_start": 3, "token_end": 3, "note": null}, {"text": "TNFalpha mRNA", "type": "ENTITY", "char_start": 435542, "char_end": 435555, "token_start": 16, "token_end": 17, "note": null}]}
+{"sentence_id": 2636, "sentence_text": "The present study shows that the inhibitory effect of GM on the TNFalpha production of activated human monocytes is mediated by the suppression of NFkappaB activation , while the mechanism of UTI inhibiting TNFalpha production of human monocytes may be due to the inhibition of either the translation or secretion of TNFalpha .", "sentence_char_start_global": 435569, "sentence_char_end_global": 435896, "entities": [{"text": "TNFalpha", "type": "ENTITY", "char_start": 64, "char_end": 72, "token_start": 12, "token_end": 12}, {"text": "NFkappaB", "type": "ENTITY", "char_start": 147, "char_end": 155, "token_start": 24, "token_end": 24}, {"text": "TNFalpha", "type": "ENTITY", "char_start": 207, "char_end": 215, "token_start": 33, "token_end": 33}, {"text": "TNFalpha", "type": "ENTITY", "char_start": 317, "char_end": 325, "token_start": 51, "token_end": 51}], "entities_global": [{"text": "TNFalpha", "type": "ENTITY", "char_start": 435633, "char_end": 435641, "token_start": 12, "token_end": 12, "note": null}, {"text": "NFkappaB", "type": "ENTITY", "char_start": 435716, "char_end": 435724, "token_start": 24, "token_end": 24, "note": null}, {"text": "TNFalpha", "type": "ENTITY", "char_start": 435776, "char_end": 435784, "token_start": 33, "token_end": 33, "note": null}, {"text": "TNFalpha", "type": "ENTITY", "char_start": 435886, "char_end": 435894, "token_start": 51, "token_end": 51, "note": null}]}
+{"sentence_id": 2637, "sentence_text": "Homocysteine stimulates the expression of monocyte chemoattractant protein - 1 in endothelial cells leading to enhanced monocyte chemotaxis .", "sentence_char_start_global": 435897, "sentence_char_end_global": 436038, "entities": [{"text": "monocyte chemoattractant protein - 1", "type": "ENTITY", "char_start": 42, "char_end": 78, "token_start": 5, "token_end": 9}], "entities_global": [{"text": "monocyte chemoattractant protein - 1", "type": "ENTITY", "char_start": 435939, "char_end": 435975, "token_start": 5, "token_end": 9, "note": null}]}
+{"sentence_id": 2638, "sentence_text": "Hyperhomocysteinemia has been identified as an independent risk factor for atherosclerosis .", "sentence_char_start_global": 436039, "sentence_char_end_global": 436131, "entities": [], "entities_global": []}
+{"sentence_id": 2639, "sentence_text": "The infiltration of monocytes into the arterial wall is one of the key events during atherogenesis .", "sentence_char_start_global": 436132, "sentence_char_end_global": 436232, "entities": [], "entities_global": []}
+{"sentence_id": 2640, "sentence_text": "Monocyte chemoattractant protein - 1 ( MCP - 1 ) is a potent chemokine that stimulates the migration of monocytes into the intima of the arterial wall .", "sentence_char_start_global": 436233, "sentence_char_end_global": 436385, "entities": [{"text": "Monocyte chemoattractant protein - 1", "type": "ENTITY", "char_start": 0, "char_end": 36, "token_start": 0, "token_end": 4}, {"text": "MCP - 1", "type": "ENTITY", "char_start": 39, "char_end": 46, "token_start": 6, "token_end": 8}, {"text": "chemokine", "type": "ENTITY", "char_start": 61, "char_end": 70, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "Monocyte chemoattractant protein - 1", "type": "ENTITY", "char_start": 436233, "char_end": 436269, "token_start": 0, "token_end": 4, "note": null}, {"text": "MCP - 1", "type": "ENTITY", "char_start": 436272, "char_end": 436279, "token_start": 6, "token_end": 8, "note": null}, {"text": "chemokine", "type": "ENTITY", "char_start": 436294, "char_end": 436303, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 2641, "sentence_text": "The mechanism by which increased monocyte infiltration occurs in atherosclerotic lesions in patients with hyperhomocysteinemia has not been delineated .", "sentence_char_start_global": 436386, "sentence_char_end_global": 436538, "entities": [], "entities_global": []}
+{"sentence_id": 2642, "sentence_text": "The objective of the present study was to investigate the effect of homocysteine on MCP - 1 production in endothelial cells .", "sentence_char_start_global": 436539, "sentence_char_end_global": 436664, "entities": [{"text": "MCP - 1", "type": "ENTITY", "char_start": 84, "char_end": 91, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "MCP - 1", "type": "ENTITY", "char_start": 436623, "char_end": 436630, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 2643, "sentence_text": "Cells were incubated with homocysteine .", "sentence_char_start_global": 436665, "sentence_char_end_global": 436705, "entities": [], "entities_global": []}
+{"sentence_id": 2644, "sentence_text": "The secretion of MCP - 1 protein was significantly increased ( 195 % as compared to the control ) in cells treated with pathological concentrations of homocysteine .", "sentence_char_start_global": 436706, "sentence_char_end_global": 436871, "entities": [{"text": "MCP - 1 protein", "type": "ENTITY", "char_start": 17, "char_end": 32, "token_start": 3, "token_end": 6}], "entities_global": [{"text": "MCP - 1 protein", "type": "ENTITY", "char_start": 436723, "char_end": 436738, "token_start": 3, "token_end": 6, "note": null}]}
+{"sentence_id": 2645, "sentence_text": "Such effect was accompanied by an increased expression of MCP - 1 mRNA ( 176 % as compared to the control ) in endothelial cells which resulted in enhanced monocyte chemotaxis .", "sentence_char_start_global": 436872, "sentence_char_end_global": 437049, "entities": [{"text": "MCP - 1 mRNA", "type": "ENTITY", "char_start": 58, "char_end": 70, "token_start": 9, "token_end": 12}], "entities_global": [{"text": "MCP - 1 mRNA", "type": "ENTITY", "char_start": 436930, "char_end": 436942, "token_start": 9, "token_end": 12, "note": null}]}
+{"sentence_id": 2646, "sentence_text": "The p38 MAP kinase as well as other members of the p38 MAP kinase pathway , including MKK3 , MKK6 , ATF - 2 and Elk - 1 , were activated in homocysteine - treated cells .", "sentence_char_start_global": 437050, "sentence_char_end_global": 437220, "entities": [{"text": "p38 MAP kinase", "type": "ENTITY", "char_start": 4, "char_end": 18, "token_start": 1, "token_end": 3}, {"text": "MKK3", "type": "ENTITY", "char_start": 86, "char_end": 90, "token_start": 17, "token_end": 17}, {"text": "MKK6", "type": "ENTITY", "char_start": 93, "char_end": 97, "token_start": 19, "token_end": 19}, {"text": "ATF - 2", "type": "ENTITY", "char_start": 100, "char_end": 107, "token_start": 21, "token_end": 23}, {"text": "Elk - 1", "type": "ENTITY", "char_start": 112, "char_end": 119, "token_start": 25, "token_end": 27}], "entities_global": [{"text": "p38 MAP kinase", "type": "ENTITY", "char_start": 437054, "char_end": 437068, "token_start": 1, "token_end": 3, "note": null}, {"text": "MKK3", "type": "ENTITY", "char_start": 437136, "char_end": 437140, "token_start": 17, "token_end": 17, "note": null}, {"text": "MKK6", "type": "ENTITY", "char_start": 437143, "char_end": 437147, "token_start": 19, "token_end": 19, "note": null}, {"text": "ATF - 2", "type": "ENTITY", "char_start": 437150, "char_end": 437157, "token_start": 21, "token_end": 23, "note": null}, {"text": "Elk - 1", "type": "ENTITY", "char_start": 437162, "char_end": 437169, "token_start": 25, "token_end": 27, "note": null}]}
+{"sentence_id": 2647, "sentence_text": "Homocysteine - induced MCP - 1 expression and subsequent monocyte chemotaxis were blocked by a p38 MAP kinase inhibitor ( SB203580 ) suggesting that the p38 MAP kinase pathway might be involved in homocysteine - induced MCP - 1 expression in endothelial cells .", "sentence_char_start_global": 437221, "sentence_char_end_global": 437482, "entities": [{"text": "MCP - 1", "type": "ENTITY", "char_start": 23, "char_end": 30, "token_start": 3, "token_end": 5}, {"text": "p38 MAP kinase", "type": "ENTITY", "char_start": 95, "char_end": 109, "token_start": 15, "token_end": 17}, {"text": "p38 MAP kinase", "type": "ENTITY", "char_start": 153, "char_end": 167, "token_start": 25, "token_end": 27}, {"text": "MCP - 1", "type": "ENTITY", "char_start": 220, "char_end": 227, "token_start": 36, "token_end": 38}], "entities_global": [{"text": "MCP - 1", "type": "ENTITY", "char_start": 437244, "char_end": 437251, "token_start": 3, "token_end": 5, "note": null}, {"text": "p38 MAP kinase", "type": "ENTITY", "char_start": 437316, "char_end": 437330, "token_start": 15, "token_end": 17, "note": null}, {"text": "p38 MAP kinase", "type": "ENTITY", "char_start": 437374, "char_end": 437388, "token_start": 25, "token_end": 27, "note": null}, {"text": "MCP - 1", "type": "ENTITY", "char_start": 437441, "char_end": 437448, "token_start": 36, "token_end": 38, "note": null}]}
+{"sentence_id": 2648, "sentence_text": "In contrast , staurosporine , a protein kinase C inhibitor , had no effect on homocysteine - induced MCP - 1 expression .", "sentence_char_start_global": 437483, "sentence_char_end_global": 437604, "entities": [{"text": "protein kinase C", "type": "ENTITY", "char_start": 32, "char_end": 48, "token_start": 6, "token_end": 8}, {"text": "MCP - 1", "type": "ENTITY", "char_start": 101, "char_end": 108, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "protein kinase C", "type": "ENTITY", "char_start": 437515, "char_end": 437531, "token_start": 6, "token_end": 8, "note": null}, {"text": "MCP - 1", "type": "ENTITY", "char_start": 437584, "char_end": 437591, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 2649, "sentence_text": "In conclusion , our results indicate that homocysteine stimulates MCP - 1 expression in endothelial cells leading to enhanced monocyte chemotaxis .", "sentence_char_start_global": 437605, "sentence_char_end_global": 437752, "entities": [{"text": "MCP - 1", "type": "ENTITY", "char_start": 66, "char_end": 73, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "MCP - 1", "type": "ENTITY", "char_start": 437671, "char_end": 437678, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 2650, "sentence_text": "Inducible resistance to Fas - mediated apoptosis in B cells .", "sentence_char_start_global": 437753, "sentence_char_end_global": 437814, "entities": [], "entities_global": []}
+{"sentence_id": 2651, "sentence_text": "Apoptosis produced in B cells through Fas ( APO - 1 , CD95 ) triggering is regulated by signals derived from other surface receptors : CD40 engagement produces upregulation of Fas expression and marked susceptibility to Fas - induced cell death , whereas antigen receptor engagement , or IL - 4R engagement , inhibits Fas killing and in so doing induces a state of Fas - resistance , even in otherwise sensitive , CD40 - stimulated targets .", "sentence_char_start_global": 437815, "sentence_char_end_global": 438256, "entities": [{"text": "Fas", "type": "ENTITY", "char_start": 38, "char_end": 41, "token_start": 6, "token_end": 6}, {"text": "APO - 1", "type": "ENTITY", "char_start": 44, "char_end": 51, "token_start": 8, "token_end": 10}, {"text": "CD95", "type": "ENTITY", "char_start": 54, "char_end": 58, "token_start": 12, "token_end": 12}, {"text": "Fas", "type": "ENTITY", "char_start": 176, "char_end": 179, "token_start": 30, "token_end": 30}, {"text": "Fas", "type": "ENTITY", "char_start": 220, "char_end": 223, "token_start": 36, "token_end": 36}, {"text": "Fas", "type": "ENTITY", "char_start": 318, "char_end": 321, "token_start": 54, "token_end": 54}, {"text": "Fas", "type": "ENTITY", "char_start": 365, "char_end": 368, "token_start": 64, "token_end": 64}, {"text": "CD40", "type": "ENTITY", "char_start": 414, "char_end": 418, "token_start": 73, "token_end": 73}], "entities_global": [{"text": "Fas", "type": "ENTITY", "char_start": 437853, "char_end": 437856, "token_start": 6, "token_end": 6, "note": null}, {"text": "APO - 1", "type": "ENTITY", "char_start": 437859, "char_end": 437866, "token_start": 8, "token_end": 10, "note": null}, {"text": "CD95", "type": "ENTITY", "char_start": 437869, "char_end": 437873, "token_start": 12, "token_end": 12, "note": null}, {"text": "Fas", "type": "ENTITY", "char_start": 437991, "char_end": 437994, "token_start": 30, "token_end": 30, "note": null}, {"text": "Fas", "type": "ENTITY", "char_start": 438035, "char_end": 438038, "token_start": 36, "token_end": 36, "note": null}, {"text": "Fas", "type": "ENTITY", "char_start": 438133, "char_end": 438136, "token_start": 54, "token_end": 54, "note": null}, {"text": "Fas", "type": "ENTITY", "char_start": 438180, "char_end": 438183, "token_start": 64, "token_end": 64, "note": null}, {"text": "CD40", "type": "ENTITY", "char_start": 438229, "char_end": 438233, "token_start": 73, "token_end": 73, "note": null}]}
+{"sentence_id": 2652, "sentence_text": "Surface immunoglobulin and IL - 4R utilize at least partially distinct pathways to produce Fas - resistance that differentially depend on PKC and STAT6 , respectively .", "sentence_char_start_global": 438257, "sentence_char_end_global": 438425, "entities": [{"text": "Surface immunoglobulin", "type": "ENTITY", "char_start": 0, "char_end": 22, "token_start": 0, "token_end": 1}, {"text": "IL - 4R", "type": "ENTITY", "char_start": 27, "char_end": 34, "token_start": 3, "token_end": 5}, {"text": "Fas", "type": "ENTITY", "char_start": 91, "char_end": 94, "token_start": 14, "token_end": 14}, {"text": "PKC", "type": "ENTITY", "char_start": 138, "char_end": 141, "token_start": 21, "token_end": 21}, {"text": "STAT6", "type": "ENTITY", "char_start": 146, "char_end": 151, "token_start": 23, "token_end": 23}], "entities_global": [{"text": "Surface immunoglobulin", "type": "ENTITY", "char_start": 438257, "char_end": 438279, "token_start": 0, "token_end": 1, "note": null}, {"text": "IL - 4R", "type": "ENTITY", "char_start": 438284, "char_end": 438291, "token_start": 3, "token_end": 5, "note": null}, {"text": "Fas", "type": "ENTITY", "char_start": 438348, "char_end": 438351, "token_start": 14, "token_end": 14, "note": null}, {"text": "PKC", "type": "ENTITY", "char_start": 438395, "char_end": 438398, "token_start": 21, "token_end": 21, "note": null}, {"text": "STAT6", "type": "ENTITY", "char_start": 438403, "char_end": 438408, "token_start": 23, "token_end": 23, "note": null}]}
+{"sentence_id": 2653, "sentence_text": "Further , surface immunoglobulin signaling for inducible Fas - resistance bypasses Btk , requires NF - kappaB , and entails new macromolecular synthesis .", "sentence_char_start_global": 438426, "sentence_char_end_global": 438580, "entities": [{"text": "Fas", "type": "ENTITY", "char_start": 57, "char_end": 60, "token_start": 7, "token_end": 7}, {"text": "Btk", "type": "ENTITY", "char_start": 83, "char_end": 86, "token_start": 11, "token_end": 11}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 98, "char_end": 109, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "Fas", "type": "ENTITY", "char_start": 438483, "char_end": 438486, "token_start": 7, "token_end": 7, "note": null}, {"text": "Btk", "type": "ENTITY", "char_start": 438509, "char_end": 438512, "token_start": 11, "token_end": 11, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 438524, "char_end": 438535, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 2654, "sentence_text": "Terminal effectors of B cell Fas - resistance include the known anti - apoptotic gene products , Bcl - xL and FLIP , and a novel anti - apoptotic gene that encodes FAIM ( Fas Apoptosis Inhibitory Molecule ) .", "sentence_char_start_global": 438581, "sentence_char_end_global": 438789, "entities": [{"text": "Fas", "type": "ENTITY", "char_start": 29, "char_end": 32, "token_start": 5, "token_end": 5}, {"text": "anti - apoptotic gene products", "type": "ENTITY", "char_start": 64, "char_end": 94, "token_start": 11, "token_end": 15}, {"text": "Bcl - xL", "type": "ENTITY", "char_start": 97, "char_end": 105, "token_start": 17, "token_end": 19}, {"text": "FLIP", "type": "ENTITY", "char_start": 110, "char_end": 114, "token_start": 21, "token_end": 21}, {"text": "anti - apoptotic gene", "type": "ENTITY", "char_start": 129, "char_end": 150, "token_start": 26, "token_end": 29}, {"text": "FAIM", "type": "ENTITY", "char_start": 164, "char_end": 168, "token_start": 32, "token_end": 32}, {"text": "Fas Apoptosis Inhibitory Molecule", "type": "ENTITY", "char_start": 171, "char_end": 204, "token_start": 34, "token_end": 37}], "entities_global": [{"text": "Fas", "type": "ENTITY", "char_start": 438610, "char_end": 438613, "token_start": 5, "token_end": 5, "note": null}, {"text": "anti - apoptotic gene products", "type": "ENTITY", "char_start": 438645, "char_end": 438675, "token_start": 11, "token_end": 15, "note": null}, {"text": "Bcl - xL", "type": "ENTITY", "char_start": 438678, "char_end": 438686, "token_start": 17, "token_end": 19, "note": null}, {"text": "FLIP", "type": "ENTITY", "char_start": 438691, "char_end": 438695, "token_start": 21, "token_end": 21, "note": null}, {"text": "anti - apoptotic gene", "type": "ENTITY", "char_start": 438710, "char_end": 438731, "token_start": 26, "token_end": 29, "note": null}, {"text": "FAIM", "type": "ENTITY", "char_start": 438745, "char_end": 438749, "token_start": 32, "token_end": 32, "note": null}, {"text": "Fas Apoptosis Inhibitory Molecule", "type": "ENTITY", "char_start": 438752, "char_end": 438785, "token_start": 34, "token_end": 37, "note": null}]}
+{"sentence_id": 2655, "sentence_text": "faim was identified by differential display and exists in two alternatively spliced forms ; faim - S is broadly expressed , but faim - L expression is tissue - specific .", "sentence_char_start_global": 438790, "sentence_char_end_global": 438960, "entities": [{"text": "faim", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}, {"text": "faim - S", "type": "ENTITY", "char_start": 92, "char_end": 100, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "faim", "type": "ENTITY", "char_start": 438790, "char_end": 438794, "token_start": 0, "token_end": 0, "note": null}, {"text": "faim - S", "type": "ENTITY", "char_start": 438882, "char_end": 438890, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 2656, "sentence_text": "The FAIM sequence is highly evolu - tionarily conserved , suggesting an important role for this molecule throughout phylogeny .", "sentence_char_start_global": 438961, "sentence_char_end_global": 439088, "entities": [{"text": "FAIM sequence", "type": "ENTITY", "char_start": 4, "char_end": 17, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "FAIM sequence", "type": "ENTITY", "char_start": 438965, "char_end": 438978, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 2657, "sentence_text": "Inducible resistance to Fas killing is hypothesized to protect foreign antigen - specific B cells during potentially hazardous interactions with FasL - bearing T cells , whereas autoreactive B cells fail to become Fas - resistant and are deleted via Fas - dependent cytotoxicity .", "sentence_char_start_global": 439089, "sentence_char_end_global": 439369, "entities": [{"text": "Fas", "type": "ENTITY", "char_start": 24, "char_end": 27, "token_start": 3, "token_end": 3}, {"text": "Fas", "type": "ENTITY", "char_start": 214, "char_end": 217, "token_start": 33, "token_end": 33}, {"text": "Fas", "type": "ENTITY", "char_start": 250, "char_end": 253, "token_start": 40, "token_end": 40}], "entities_global": [{"text": "Fas", "type": "ENTITY", "char_start": 439113, "char_end": 439116, "token_start": 3, "token_end": 3, "note": null}, {"text": "Fas", "type": "ENTITY", "char_start": 439303, "char_end": 439306, "token_start": 33, "token_end": 33, "note": null}, {"text": "Fas", "type": "ENTITY", "char_start": 439339, "char_end": 439342, "token_start": 40, "token_end": 40, "note": null}]}
+{"sentence_id": 2658, "sentence_text": "Inadvertent or aberrant acquisition of Fas - resistance may permit autoreactive B cells to escape Fas deletion , and malignant lymphocytes to impede anti - tumor immunity .", "sentence_char_start_global": 439370, "sentence_char_end_global": 439542, "entities": [{"text": "Fas", "type": "ENTITY", "char_start": 39, "char_end": 42, "token_start": 5, "token_end": 5}, {"text": "Fas", "type": "ENTITY", "char_start": 98, "char_end": 101, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "Fas", "type": "ENTITY", "char_start": 439409, "char_end": 439412, "token_start": 5, "token_end": 5, "note": null}, {"text": "Fas", "type": "ENTITY", "char_start": 439468, "char_end": 439471, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 2659, "sentence_text": "Stromal cell - derived factor 1 alpha - induced chemotaxis in T cells is mediated by nitric oxide signaling pathways .", "sentence_char_start_global": 439543, "sentence_char_end_global": 439661, "entities": [{"text": "Stromal cell - derived factor 1 alpha", "type": "ENTITY", "char_start": 0, "char_end": 37, "token_start": 0, "token_end": 6}], "entities_global": [{"text": "Stromal cell - derived factor 1 alpha", "type": "ENTITY", "char_start": 439543, "char_end": 439580, "token_start": 0, "token_end": 6, "note": null}]}
+{"sentence_id": 2660, "sentence_text": "Stromal cell - derived factor 1 alpha ( SDF1 alpha ) and its cognate chemokine receptor CXCR4 act as potent chemoattractants and regulate trafficking and homing of hematopoietic progenitor cells and lymphocytes .", "sentence_char_start_global": 439662, "sentence_char_end_global": 439874, "entities": [{"text": "Stromal cell - derived factor 1 alpha", "type": "ENTITY", "char_start": 0, "char_end": 37, "token_start": 0, "token_end": 6}, {"text": "SDF1 alpha", "type": "ENTITY", "char_start": 40, "char_end": 50, "token_start": 8, "token_end": 9}, {"text": "chemokine receptor CXCR4", "type": "ENTITY", "char_start": 69, "char_end": 93, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "Stromal cell - derived factor 1 alpha", "type": "ENTITY", "char_start": 439662, "char_end": 439699, "token_start": 0, "token_end": 6, "note": null}, {"text": "SDF1 alpha", "type": "ENTITY", "char_start": 439702, "char_end": 439712, "token_start": 8, "token_end": 9, "note": null}, {"text": "chemokine receptor CXCR4", "type": "ENTITY", "char_start": 439731, "char_end": 439755, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 2661, "sentence_text": "However , the molecular mechanisms regulating SDF1 alpha - driven cell migration are not well defined .", "sentence_char_start_global": 439875, "sentence_char_end_global": 439978, "entities": [{"text": "SDF1 alpha", "type": "ENTITY", "char_start": 46, "char_end": 56, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "SDF1 alpha", "type": "ENTITY", "char_start": 439921, "char_end": 439931, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 2662, "sentence_text": "In this study , we have explored the roles of the second messenger NO and the transcription factor NF - kappa B in SDF1 alpha - induced T cell migration .", "sentence_char_start_global": 439979, "sentence_char_end_global": 440133, "entities": [{"text": "transcription factor NF - kappa B", "type": "ENTITY", "char_start": 78, "char_end": 111, "token_start": 16, "token_end": 21}, {"text": "SDF1 alpha", "type": "ENTITY", "char_start": 115, "char_end": 125, "token_start": 23, "token_end": 24}], "entities_global": [{"text": "transcription factor NF - kappa B", "type": "ENTITY", "char_start": 440057, "char_end": 440090, "token_start": 16, "token_end": 21, "note": null}, {"text": "SDF1 alpha", "type": "ENTITY", "char_start": 440094, "char_end": 440104, "token_start": 23, "token_end": 24, "note": null}]}
+{"sentence_id": 2663, "sentence_text": "SDF1 alpha treatment of Jurkat T cells increased the activity of NO synthase , which catalyzes the generation of NO .", "sentence_char_start_global": 440134, "sentence_char_end_global": 440251, "entities": [{"text": "SDF1 alpha", "type": "ENTITY", "char_start": 0, "char_end": 10, "token_start": 0, "token_end": 1}, {"text": "NO synthase", "type": "ENTITY", "char_start": 65, "char_end": 76, "token_start": 11, "token_end": 12}], "entities_global": [{"text": "SDF1 alpha", "type": "ENTITY", "char_start": 440134, "char_end": 440144, "token_start": 0, "token_end": 1, "note": null}, {"text": "NO synthase", "type": "ENTITY", "char_start": 440199, "char_end": 440210, "token_start": 11, "token_end": 12, "note": null}]}
+{"sentence_id": 2664, "sentence_text": "We observed that pretreatment of Jurkat cells or activated PBLs with several NO donors significantly enhanced the SDF1 alpha - induced migration , whereas various inhibitors of NO synthase markedly abrogated the chemotactic response in a concentration - dependent manner .", "sentence_char_start_global": 440252, "sentence_char_end_global": 440524, "entities": [{"text": "SDF1 alpha", "type": "ENTITY", "char_start": 114, "char_end": 124, "token_start": 17, "token_end": 18}, {"text": "NO synthase", "type": "ENTITY", "char_start": 177, "char_end": 188, "token_start": 27, "token_end": 28}], "entities_global": [{"text": "SDF1 alpha", "type": "ENTITY", "char_start": 440366, "char_end": 440376, "token_start": 17, "token_end": 18, "note": null}, {"text": "NO synthase", "type": "ENTITY", "char_start": 440429, "char_end": 440440, "token_start": 27, "token_end": 28, "note": null}]}
+{"sentence_id": 2665, "sentence_text": "Furthermore , we observed that inhibitors of the transcription factor NF - kappa B , which is linked to NO signaling pathways , also significantly blocked the SDF1 alpha - induced chemotactic response .", "sentence_char_start_global": 440525, "sentence_char_end_global": 440727, "entities": [{"text": "transcription factor NF - kappa B", "type": "ENTITY", "char_start": 49, "char_end": 82, "token_start": 8, "token_end": 13}, {"text": "SDF1 alpha", "type": "ENTITY", "char_start": 159, "char_end": 169, "token_start": 27, "token_end": 28}], "entities_global": [{"text": "transcription factor NF - kappa B", "type": "ENTITY", "char_start": 440574, "char_end": 440607, "token_start": 8, "token_end": 13, "note": null}, {"text": "SDF1 alpha", "type": "ENTITY", "char_start": 440684, "char_end": 440694, "token_start": 27, "token_end": 28, "note": null}]}
+{"sentence_id": 2666, "sentence_text": "However , these compounds did not have a significant effect on SDF1 alpha - induced mitogen - activated protein kinase activity .", "sentence_char_start_global": 440728, "sentence_char_end_global": 440857, "entities": [{"text": "SDF1 alpha", "type": "ENTITY", "char_start": 63, "char_end": 73, "token_start": 11, "token_end": 12}], "entities_global": [{"text": "SDF1 alpha", "type": "ENTITY", "char_start": 440791, "char_end": 440801, "token_start": 11, "token_end": 12, "note": null}]}
+{"sentence_id": 2667, "sentence_text": "In addition , the MAP / Erk kinase kinase inhibitor PD98059 did not abrogate SDF1 alpha - induced chemotaxis .", "sentence_char_start_global": 440858, "sentence_char_end_global": 440968, "entities": [{"text": "SDF1 alpha", "type": "ENTITY", "char_start": 77, "char_end": 87, "token_start": 14, "token_end": 15}], "entities_global": [{"text": "SDF1 alpha", "type": "ENTITY", "char_start": 440935, "char_end": 440945, "token_start": 14, "token_end": 15, "note": null}]}
+{"sentence_id": 2668, "sentence_text": "AKT , which has been shown to mediate NO production , was also phosphorylated upon SDF1 alpha stimulation .", "sentence_char_start_global": 440969, "sentence_char_end_global": 441076, "entities": [{"text": "AKT", "type": "ENTITY", "char_start": 0, "char_end": 3, "token_start": 0, "token_end": 0}, {"text": "SDF1 alpha", "type": "ENTITY", "char_start": 83, "char_end": 93, "token_start": 15, "token_end": 16}], "entities_global": [{"text": "AKT", "type": "ENTITY", "char_start": 440969, "char_end": 440972, "token_start": 0, "token_end": 0, "note": null}, {"text": "SDF1 alpha", "type": "ENTITY", "char_start": 441052, "char_end": 441062, "token_start": 15, "token_end": 16, "note": null}]}
+{"sentence_id": 2669, "sentence_text": "These studies suggest that NO - related signaling pathways may mediate SDF1 alpha - induced chemotaxis , but not mitogen - activated protein kinase activation .", "sentence_char_start_global": 441077, "sentence_char_end_global": 441237, "entities": [{"text": "SDF1 alpha", "type": "ENTITY", "char_start": 71, "char_end": 81, "token_start": 11, "token_end": 12}, {"text": "mitogen - activated protein kinase", "type": "ENTITY", "char_start": 113, "char_end": 147, "token_start": 19, "token_end": 23}], "entities_global": [{"text": "SDF1 alpha", "type": "ENTITY", "char_start": 441148, "char_end": 441158, "token_start": 11, "token_end": 12, "note": null}, {"text": "mitogen - activated protein kinase", "type": "ENTITY", "char_start": 441190, "char_end": 441224, "token_start": 19, "token_end": 23, "note": null}]}
+{"sentence_id": 2670, "sentence_text": "The lack of NF - kappa B transactivation and PKC epsilon expression in CD4 ( + ) CD8 ( + ) thymocytes correlates with negative selection .", "sentence_char_start_global": 441238, "sentence_char_end_global": 441376, "entities": [], "entities_global": []}
+{"sentence_id": 2671, "sentence_text": "Deletion of autoreactive thymocytes at the DP stage is the basis for tolerance to thymus - expressed self antigens .", "sentence_char_start_global": 441377, "sentence_char_end_global": 441493, "entities": [{"text": "thymus - expressed self antigens", "type": "ENTITY", "char_start": 82, "char_end": 114, "token_start": 14, "token_end": 18}], "entities_global": [{"text": "thymus - expressed self antigens", "type": "ENTITY", "char_start": 441459, "char_end": 441491, "token_start": 14, "token_end": 18, "note": null}]}
+{"sentence_id": 2672, "sentence_text": "In this study we investigated whether distinct signalling pathways are induced in DP thymocytes as compared to mature T cells upon stimulation with antigen .", "sentence_char_start_global": 441494, "sentence_char_end_global": 441651, "entities": [], "entities_global": []}
+{"sentence_id": 2673, "sentence_text": "Using triple transgenic mice expressing a TCR transgene , dominant negative ras / Mek proteins and a reporter gene construct with AP - 1 or NF - kappa B binding sites , we showed a complete lack of transcriptional activity of NF - kappa B but not AP - 1 in DP thymocytes , whereas both were transcriptionally active in mature T cells after antigenic stimulation .", "sentence_char_start_global": 441652, "sentence_char_end_global": 442015, "entities": [{"text": "TCR transgene", "type": "ENTITY", "char_start": 42, "char_end": 55, "token_start": 6, "token_end": 7}, {"text": "dominant negative ras / Mek proteins", "type": "ENTITY", "char_start": 58, "char_end": 94, "token_start": 9, "token_end": 14}, {"text": "reporter gene construct", "type": "ENTITY", "char_start": 101, "char_end": 124, "token_start": 17, "token_end": 19}, {"text": "AP - 1 or NF - kappa B binding sites", "type": "ENTITY", "char_start": 130, "char_end": 166, "token_start": 21, "token_end": 30}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 226, "char_end": 238, "token_start": 41, "token_end": 44}, {"text": "AP - 1", "type": "ENTITY", "char_start": 247, "char_end": 253, "token_start": 47, "token_end": 49}], "entities_global": [{"text": "TCR transgene", "type": "ENTITY", "char_start": 441694, "char_end": 441707, "token_start": 6, "token_end": 7, "note": null}, {"text": "dominant negative ras / Mek proteins", "type": "ENTITY", "char_start": 441710, "char_end": 441746, "token_start": 9, "token_end": 14, "note": null}, {"text": "reporter gene construct", "type": "ENTITY", "char_start": 441753, "char_end": 441776, "token_start": 17, "token_end": 19, "note": null}, {"text": "AP - 1 or NF - kappa B binding sites", "type": "ENTITY", "char_start": 441782, "char_end": 441818, "token_start": 21, "token_end": 30, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 441878, "char_end": 441890, "token_start": 41, "token_end": 44, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 441899, "char_end": 441905, "token_start": 47, "token_end": 49, "note": null}]}
+{"sentence_id": 2674, "sentence_text": "Lack of NF - kappa B induction correlated with increased death in response to antigen .", "sentence_char_start_global": 442016, "sentence_char_end_global": 442103, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 8, "char_end": 20, "token_start": 2, "token_end": 5}, {"text": "antigen", "type": "ENTITY", "char_start": 78, "char_end": 85, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 442024, "char_end": 442036, "token_start": 2, "token_end": 5, "note": null}, {"text": "antigen", "type": "ENTITY", "char_start": 442094, "char_end": 442101, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 2675, "sentence_text": "AP - 1 induction was dependent on the integrity of the ras / Mek pathway indicating that this pathway was activated in the DP thymocytes .", "sentence_char_start_global": 442104, "sentence_char_end_global": 442242, "entities": [{"text": "AP - 1", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "AP - 1", "type": "ENTITY", "char_start": 442104, "char_end": 442110, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 2676, "sentence_text": "In contrast , we found a complete lack of constitutive expression of the epsilon isoform of Protein Kinase C ( PKC ) in DP thymocytes , although it was present in mature thymocytes and peripheral T cells .", "sentence_char_start_global": 442243, "sentence_char_end_global": 442448, "entities": [{"text": "epsilon isoform of Protein Kinase C", "type": "ENTITY", "char_start": 73, "char_end": 108, "token_start": 13, "token_end": 18}, {"text": "PKC", "type": "ENTITY", "char_start": 111, "char_end": 114, "token_start": 20, "token_end": 20}], "entities_global": [{"text": "epsilon isoform of Protein Kinase C", "type": "ENTITY", "char_start": 442316, "char_end": 442351, "token_start": 13, "token_end": 18, "note": null}, {"text": "PKC", "type": "ENTITY", "char_start": 442354, "char_end": 442357, "token_start": 20, "token_end": 20, "note": null}]}
+{"sentence_id": 2677, "sentence_text": "Taken together the results suggest that the lack of PKC epsilon in DP thymocytes could lead to the absence of NF - kappa B activity after antigenic stimulation contributing to negative selection .", "sentence_char_start_global": 442449, "sentence_char_end_global": 442645, "entities": [{"text": "PKC epsilon", "type": "ENTITY", "char_start": 52, "char_end": 63, "token_start": 9, "token_end": 10}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 110, "char_end": 122, "token_start": 20, "token_end": 23}], "entities_global": [{"text": "PKC epsilon", "type": "ENTITY", "char_start": 442501, "char_end": 442512, "token_start": 9, "token_end": 10, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 442559, "char_end": 442571, "token_start": 20, "token_end": 23, "note": null}]}
+{"sentence_id": 2678, "sentence_text": "Cell Death and Differentiation ( 2000 ) 7 , 1253 - 1262 .", "sentence_char_start_global": 442646, "sentence_char_end_global": 442703, "entities": [], "entities_global": []}
+{"sentence_id": 2679, "sentence_text": "CD2 stimulation leads to the delayed and prolonged activation of STAT1 in T cells but not NK cells .", "sentence_char_start_global": 442704, "sentence_char_end_global": 442804, "entities": [{"text": "STAT1", "type": "ENTITY", "char_start": 65, "char_end": 70, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "STAT1", "type": "ENTITY", "char_start": 442769, "char_end": 442774, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 2680, "sentence_text": "OBJECTIVE : T lymphocytes can be activated by soluble factors such as cytokines or through direct cell - cell interactions .", "sentence_char_start_global": 442805, "sentence_char_end_global": 442929, "entities": [{"text": "cytokines", "type": "ENTITY", "char_start": 70, "char_end": 79, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "cytokines", "type": "ENTITY", "char_start": 442875, "char_end": 442884, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 2681, "sentence_text": "Although cytokine receptors are known to signal through STAT family transcription factors , the mechanisms by which other cell - surface molecules , such as CD2 , transduce signals is unclear .", "sentence_char_start_global": 442930, "sentence_char_end_global": 443123, "entities": [{"text": "cytokine receptors", "type": "ENTITY", "char_start": 9, "char_end": 27, "token_start": 1, "token_end": 2}, {"text": "STAT family transcription factors", "type": "ENTITY", "char_start": 56, "char_end": 89, "token_start": 8, "token_end": 11}, {"text": "cell - surface molecules", "type": "ENTITY", "char_start": 122, "char_end": 146, "token_start": 18, "token_end": 21}, {"text": "CD2", "type": "ENTITY", "char_start": 157, "char_end": 160, "token_start": 25, "token_end": 25}], "entities_global": [{"text": "cytokine receptors", "type": "ENTITY", "char_start": 442939, "char_end": 442957, "token_start": 1, "token_end": 2, "note": null}, {"text": "STAT family transcription factors", "type": "ENTITY", "char_start": 442986, "char_end": 443019, "token_start": 8, "token_end": 11, "note": null}, {"text": "cell - surface molecules", "type": "ENTITY", "char_start": 443052, "char_end": 443076, "token_start": 18, "token_end": 21, "note": null}, {"text": "CD2", "type": "ENTITY", "char_start": 443087, "char_end": 443090, "token_start": 25, "token_end": 25, "note": null}]}
+{"sentence_id": 2682, "sentence_text": "The goal of this study was to determine whether stimulation of T cells through CD2 recapitulates aspects of cytokine - induced T - cell activation by use of STAT transcription factors .", "sentence_char_start_global": 443124, "sentence_char_end_global": 443309, "entities": [{"text": "CD2", "type": "ENTITY", "char_start": 79, "char_end": 82, "token_start": 14, "token_end": 14}, {"text": "cytokine", "type": "ENTITY", "char_start": 108, "char_end": 116, "token_start": 18, "token_end": 18}, {"text": "STAT transcription factors", "type": "ENTITY", "char_start": 157, "char_end": 183, "token_start": 28, "token_end": 30}], "entities_global": [{"text": "CD2", "type": "ENTITY", "char_start": 443203, "char_end": 443206, "token_start": 14, "token_end": 14, "note": null}, {"text": "cytokine", "type": "ENTITY", "char_start": 443232, "char_end": 443240, "token_start": 18, "token_end": 18, "note": null}, {"text": "STAT transcription factors", "type": "ENTITY", "char_start": 443281, "char_end": 443307, "token_start": 28, "token_end": 30, "note": null}]}
+{"sentence_id": 2683, "sentence_text": "MATERIALS AND METHODS : T cells were treated with anti - CD2 antibodies or cells bearing the natural CD2 ligand CD58 , after which signaling through STAT transcription factors was assessed .", "sentence_char_start_global": 443310, "sentence_char_end_global": 443500, "entities": [{"text": "anti - CD2 antibodies", "type": "ENTITY", "char_start": 50, "char_end": 71, "token_start": 9, "token_end": 12}, {"text": "CD2 ligand CD58", "type": "ENTITY", "char_start": 101, "char_end": 116, "token_start": 18, "token_end": 20}, {"text": "STAT transcription factors", "type": "ENTITY", "char_start": 149, "char_end": 175, "token_start": 26, "token_end": 28}], "entities_global": [{"text": "anti - CD2 antibodies", "type": "ENTITY", "char_start": 443360, "char_end": 443381, "token_start": 9, "token_end": 12, "note": null}, {"text": "CD2 ligand CD58", "type": "ENTITY", "char_start": 443411, "char_end": 443426, "token_start": 18, "token_end": 20, "note": null}, {"text": "STAT transcription factors", "type": "ENTITY", "char_start": 443459, "char_end": 443485, "token_start": 26, "token_end": 28, "note": null}]}
+{"sentence_id": 2684, "sentence_text": "RESULTS : Stimulation of CD2 on primary T lymphocytes leads to the tyrosine phosphorylation , nuclear translocation , and DNA binding of STAT1 .", "sentence_char_start_global": 443501, "sentence_char_end_global": 443645, "entities": [{"text": "CD2", "type": "ENTITY", "char_start": 25, "char_end": 28, "token_start": 4, "token_end": 4}, {"text": "STAT1", "type": "ENTITY", "char_start": 137, "char_end": 142, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "CD2", "type": "ENTITY", "char_start": 443526, "char_end": 443529, "token_start": 4, "token_end": 4, "note": null}, {"text": "STAT1", "type": "ENTITY", "char_start": 443638, "char_end": 443643, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 2685, "sentence_text": "In contrast to stimulation by cytokines , the activation of STAT1 in response to CD2 ligation is delayed and does not involve Jak kinases .", "sentence_char_start_global": 443646, "sentence_char_end_global": 443785, "entities": [{"text": "cytokines", "type": "ENTITY", "char_start": 30, "char_end": 39, "token_start": 5, "token_end": 5}, {"text": "STAT1", "type": "ENTITY", "char_start": 60, "char_end": 65, "token_start": 10, "token_end": 10}, {"text": "Jak kinases", "type": "ENTITY", "char_start": 126, "char_end": 137, "token_start": 22, "token_end": 23}], "entities_global": [{"text": "cytokines", "type": "ENTITY", "char_start": 443676, "char_end": 443685, "token_start": 5, "token_end": 5, "note": null}, {"text": "STAT1", "type": "ENTITY", "char_start": 443706, "char_end": 443711, "token_start": 10, "token_end": 10, "note": null}, {"text": "Jak kinases", "type": "ENTITY", "char_start": 443772, "char_end": 443783, "token_start": 22, "token_end": 23, "note": null}]}
+{"sentence_id": 2686, "sentence_text": "Furthermore , while STAT phosphorylation induced by cytokines is generally transient , STAT1 phosphorylation following CD2 stimulation persists for a period of days .", "sentence_char_start_global": 443786, "sentence_char_end_global": 443952, "entities": [{"text": "cytokines", "type": "ENTITY", "char_start": 52, "char_end": 61, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "cytokines", "type": "ENTITY", "char_start": 443838, "char_end": 443847, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 2687, "sentence_text": "Transcription of key target genes such as IRF1 and c - fos proceeds with delayed kinetics following CD2 stimulation , suggesting that this unique pattern of STAT activation may lead to a distinct cellular response following CD2 ligation .", "sentence_char_start_global": 443953, "sentence_char_end_global": 444191, "entities": [{"text": "IRF1", "type": "ENTITY", "char_start": 42, "char_end": 46, "token_start": 7, "token_end": 7}, {"text": "c - fos", "type": "ENTITY", "char_start": 51, "char_end": 58, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "IRF1", "type": "ENTITY", "char_start": 443995, "char_end": 443999, "token_start": 7, "token_end": 7, "note": null}, {"text": "c - fos", "type": "ENTITY", "char_start": 444004, "char_end": 444011, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 2688, "sentence_text": "This pathway appears to be restricted to T cells , as stimulation of CD2 on NK cells does not lead to STAT1 activation .", "sentence_char_start_global": 444192, "sentence_char_end_global": 444312, "entities": [{"text": "CD2", "type": "ENTITY", "char_start": 69, "char_end": 72, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "CD2", "type": "ENTITY", "char_start": 444261, "char_end": 444264, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 2689, "sentence_text": "CONCLUSION : Stimulation of T cells through cell - surface molecules such as CD2 involves activation of STAT transcription factors , thus recapitulating elements of cytokine signaling .", "sentence_char_start_global": 444313, "sentence_char_end_global": 444498, "entities": [{"text": "cell - surface molecules", "type": "ENTITY", "char_start": 44, "char_end": 68, "token_start": 7, "token_end": 10}, {"text": "CD2", "type": "ENTITY", "char_start": 77, "char_end": 80, "token_start": 13, "token_end": 13}, {"text": "STAT transcription factors", "type": "ENTITY", "char_start": 104, "char_end": 130, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "cell - surface molecules", "type": "ENTITY", "char_start": 444357, "char_end": 444381, "token_start": 7, "token_end": 10, "note": null}, {"text": "CD2", "type": "ENTITY", "char_start": 444390, "char_end": 444393, "token_start": 13, "token_end": 13, "note": null}, {"text": "STAT transcription factors", "type": "ENTITY", "char_start": 444417, "char_end": 444443, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 2690, "sentence_text": "NFATc1 and NFATc2 together control both T and B cell activation and differentiation .", "sentence_char_start_global": 444499, "sentence_char_end_global": 444584, "entities": [{"text": "NFATc1", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 0}, {"text": "NFATc2", "type": "ENTITY", "char_start": 11, "char_end": 17, "token_start": 2, "token_end": 2}], "entities_global": [{"text": "NFATc1", "type": "ENTITY", "char_start": 444499, "char_end": 444505, "token_start": 0, "token_end": 0, "note": null}, {"text": "NFATc2", "type": "ENTITY", "char_start": 444510, "char_end": 444516, "token_start": 2, "token_end": 2, "note": null}]}
+{"sentence_id": 2691, "sentence_text": "NFAT transcription factors play critical roles in gene transcription during immune responses .", "sentence_char_start_global": 444585, "sentence_char_end_global": 444679, "entities": [{"text": "NFAT transcription factors", "type": "ENTITY", "char_start": 0, "char_end": 26, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "NFAT transcription factors", "type": "ENTITY", "char_start": 444585, "char_end": 444611, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 2692, "sentence_text": "To investigate further the two most prominent NFAT family members , NFATc1 and NFATc2 , we generated mice bearing lymphoid systems devoid of both .", "sentence_char_start_global": 444680, "sentence_char_end_global": 444827, "entities": [{"text": "NFAT family members", "type": "ENTITY", "char_start": 46, "char_end": 65, "token_start": 7, "token_end": 9}, {"text": "NFATc1", "type": "ENTITY", "char_start": 68, "char_end": 74, "token_start": 11, "token_end": 11}, {"text": "NFATc2", "type": "ENTITY", "char_start": 79, "char_end": 85, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "NFAT family members", "type": "ENTITY", "char_start": 444726, "char_end": 444745, "token_start": 7, "token_end": 9, "note": null}, {"text": "NFATc1", "type": "ENTITY", "char_start": 444748, "char_end": 444754, "token_start": 11, "token_end": 11, "note": null}, {"text": "NFATc2", "type": "ENTITY", "char_start": 444759, "char_end": 444765, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 2693, "sentence_text": "Doubly deficient T cells displayed cell surface markers of activation yet were significantly deficient in the development of multiple effector functions , including Th cytokine production , surface effector molecule expression , and cytolytic activity .", "sentence_char_start_global": 444828, "sentence_char_end_global": 445081, "entities": [{"text": "Th cytokine", "type": "ENTITY", "char_start": 165, "char_end": 176, "token_start": 23, "token_end": 24}, {"text": "surface effector molecule", "type": "ENTITY", "char_start": 190, "char_end": 215, "token_start": 27, "token_end": 29}], "entities_global": [{"text": "Th cytokine", "type": "ENTITY", "char_start": 444993, "char_end": 445004, "token_start": 23, "token_end": 24, "note": null}, {"text": "surface effector molecule", "type": "ENTITY", "char_start": 445018, "char_end": 445043, "token_start": 27, "token_end": 29, "note": null}]}
+{"sentence_id": 2694, "sentence_text": "Nevertheless , doubly deficient B cells were hyperactivated , as evidenced by extremely elevated serum IgG1 and IgE , as well as plasma cell expansion and infiltration of end organs .", "sentence_char_start_global": 445082, "sentence_char_end_global": 445265, "entities": [{"text": "IgG1", "type": "ENTITY", "char_start": 103, "char_end": 107, "token_start": 15, "token_end": 15}, {"text": "IgE", "type": "ENTITY", "char_start": 112, "char_end": 115, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "IgG1", "type": "ENTITY", "char_start": 445185, "char_end": 445189, "token_start": 15, "token_end": 15, "note": null}, {"text": "IgE", "type": "ENTITY", "char_start": 445194, "char_end": 445197, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 2695, "sentence_text": "Thus , in T cells , NFATc1 and NFATc2 are dispensable for inflammatory reactivity but are required for effector differentiation , while in B cells , NFATs regulate both normal homeostasis and differentiation .", "sentence_char_start_global": 445266, "sentence_char_end_global": 445475, "entities": [{"text": "NFATc1", "type": "ENTITY", "char_start": 20, "char_end": 26, "token_start": 6, "token_end": 6}, {"text": "NFATc2", "type": "ENTITY", "char_start": 31, "char_end": 37, "token_start": 8, "token_end": 8}, {"text": "NFATs", "type": "ENTITY", "char_start": 149, "char_end": 154, "token_start": 26, "token_end": 26}], "entities_global": [{"text": "NFATc1", "type": "ENTITY", "char_start": 445286, "char_end": 445292, "token_start": 6, "token_end": 6, "note": null}, {"text": "NFATc2", "type": "ENTITY", "char_start": 445297, "char_end": 445303, "token_start": 8, "token_end": 8, "note": null}, {"text": "NFATs", "type": "ENTITY", "char_start": 445415, "char_end": 445420, "token_start": 26, "token_end": 26, "note": null}]}
+{"sentence_id": 2696, "sentence_text": "Epstein - barr virus immediate - early protein BZLF1 is SUMO - 1 modified and disrupts promyelocytic leukemia bodies .", "sentence_char_start_global": 445476, "sentence_char_end_global": 445594, "entities": [{"text": "immediate - early protein BZLF1", "type": "ENTITY", "char_start": 21, "char_end": 52, "token_start": 4, "token_end": 8}], "entities_global": [{"text": "immediate - early protein BZLF1", "type": "ENTITY", "char_start": 445497, "char_end": 445528, "token_start": 4, "token_end": 8, "note": null}]}
+{"sentence_id": 2697, "sentence_text": "Although the immediate - early proteins of both herpes simplex virus ( HSV ) and cytomegalovirus ( CMV ) are known to modify promyelocytic leukemia ( PML ) ( ND10 ) bodies in the nucleus of the host cell , it has been unclear whether lytic infection with gamma herpesviruses induces a similar effect .", "sentence_char_start_global": 445595, "sentence_char_end_global": 445896, "entities": [{"text": "immediate - early proteins", "type": "ENTITY", "char_start": 13, "char_end": 39, "token_start": 2, "token_end": 5}], "entities_global": [{"text": "immediate - early proteins", "type": "ENTITY", "char_start": 445608, "char_end": 445634, "token_start": 2, "token_end": 5, "note": null}]}
+{"sentence_id": 2698, "sentence_text": "The PML protein is induced by interferon , involved in major histocompatibility complex class I presentation , and necessary for certain types of apoptosis .", "sentence_char_start_global": 445897, "sentence_char_end_global": 446054, "entities": [{"text": "PML protein", "type": "ENTITY", "char_start": 4, "char_end": 15, "token_start": 1, "token_end": 2}, {"text": "interferon", "type": "ENTITY", "char_start": 30, "char_end": 40, "token_start": 6, "token_end": 6}, {"text": "major histocompatibility complex class I", "type": "ENTITY", "char_start": 55, "char_end": 95, "token_start": 10, "token_end": 14}], "entities_global": [{"text": "PML protein", "type": "ENTITY", "char_start": 445901, "char_end": 445912, "token_start": 1, "token_end": 2, "note": null}, {"text": "interferon", "type": "ENTITY", "char_start": 445927, "char_end": 445937, "token_start": 6, "token_end": 6, "note": null}, {"text": "major histocompatibility complex class I", "type": "ENTITY", "char_start": 445952, "char_end": 445992, "token_start": 10, "token_end": 14, "note": null}]}
+{"sentence_id": 2699, "sentence_text": "Therefore , it is likely that PML bodies function in an antiviral capacity .", "sentence_char_start_global": 446055, "sentence_char_end_global": 446131, "entities": [], "entities_global": []}
+{"sentence_id": 2700, "sentence_text": "SUMO - 1 modification of PML is known to be required for the formation of PML bodies .", "sentence_char_start_global": 446132, "sentence_char_end_global": 446218, "entities": [{"text": "PML", "type": "ENTITY", "char_start": 25, "char_end": 28, "token_start": 5, "token_end": 5}], "entities_global": [{"text": "PML", "type": "ENTITY", "char_start": 446157, "char_end": 446160, "token_start": 5, "token_end": 5, "note": null}]}
+{"sentence_id": 2701, "sentence_text": "To examine whether Epstein - Barr virus ( EBV ) lytic replication interferes with PML bodies , we expressed the EBV immediate - early genes BZLF1 ( Z ) and BRLF1 ( R ) in EBV - positive cell lines and examined PML localization .", "sentence_char_start_global": 446219, "sentence_char_end_global": 446447, "entities": [{"text": "EBV immediate - early genes", "type": "ENTITY", "char_start": 112, "char_end": 139, "token_start": 20, "token_end": 24}, {"text": "BZLF1 ( Z )", "type": "ENTITY", "char_start": 140, "char_end": 151, "token_start": 25, "token_end": 28}, {"text": "BRLF1 ( R )", "type": "ENTITY", "char_start": 156, "char_end": 167, "token_start": 30, "token_end": 33}, {"text": "PML", "type": "ENTITY", "char_start": 210, "char_end": 213, "token_start": 42, "token_end": 42}], "entities_global": [{"text": "EBV immediate - early genes", "type": "ENTITY", "char_start": 446331, "char_end": 446358, "token_start": 20, "token_end": 24, "note": null}, {"text": "BZLF1 ( Z )", "type": "ENTITY", "char_start": 446359, "char_end": 446370, "token_start": 25, "token_end": 28, "note": null}, {"text": "BRLF1 ( R )", "type": "ENTITY", "char_start": 446375, "char_end": 446386, "token_start": 30, "token_end": 33, "note": null}, {"text": "PML", "type": "ENTITY", "char_start": 446429, "char_end": 446432, "token_start": 42, "token_end": 42, "note": null}]}
+{"sentence_id": 2702, "sentence_text": "Both Z and R expression resulted in PML dispersion in EBV - positive cells .", "sentence_char_start_global": 446448, "sentence_char_end_global": 446524, "entities": [{"text": "PML", "type": "ENTITY", "char_start": 36, "char_end": 39, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "PML", "type": "ENTITY", "char_start": 446484, "char_end": 446487, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 2703, "sentence_text": "Z but not R expression is sufficient to disrupt PML bodies in EBV - negative cell lines .", "sentence_char_start_global": 446525, "sentence_char_end_global": 446614, "entities": [], "entities_global": []}
+{"sentence_id": 2704, "sentence_text": "We show that dispersion of PML bodies by Z requires a portion of the transcriptional activation domain of Z but not the DNA - binding function .", "sentence_char_start_global": 446615, "sentence_char_end_global": 446759, "entities": [{"text": "Z", "type": "ENTITY", "char_start": 41, "char_end": 42, "token_start": 8, "token_end": 8}, {"text": "transcriptional activation domain", "type": "ENTITY", "char_start": 69, "char_end": 102, "token_start": 14, "token_end": 16}, {"text": "Z", "type": "ENTITY", "char_start": 106, "char_end": 107, "token_start": 18, "token_end": 18}], "entities_global": [{"text": "Z", "type": "ENTITY", "char_start": 446656, "char_end": 446657, "token_start": 8, "token_end": 8, "note": null}, {"text": "transcriptional activation domain", "type": "ENTITY", "char_start": 446684, "char_end": 446717, "token_start": 14, "token_end": 16, "note": null}, {"text": "Z", "type": "ENTITY", "char_start": 446721, "char_end": 446722, "token_start": 18, "token_end": 18, "note": null}]}
+{"sentence_id": 2705, "sentence_text": "As was previously reported for the HSV - 1 ICP0 and CMV IE1 proteins , Z reduces the amount of SUMO - 1 - modified PML .", "sentence_char_start_global": 446760, "sentence_char_end_global": 446880, "entities": [{"text": "HSV - 1 ICP0 and CMV IE1 proteins", "type": "ENTITY", "char_start": 35, "char_end": 68, "token_start": 6, "token_end": 13}, {"text": "Z", "type": "ENTITY", "char_start": 71, "char_end": 72, "token_start": 15, "token_end": 15}, {"text": "SUMO - 1 - modified PML", "type": "ENTITY", "char_start": 95, "char_end": 118, "token_start": 20, "token_end": 25}], "entities_global": [{"text": "HSV - 1 ICP0 and CMV IE1 proteins", "type": "ENTITY", "char_start": 446795, "char_end": 446828, "token_start": 6, "token_end": 13, "note": null}, {"text": "Z", "type": "ENTITY", "char_start": 446831, "char_end": 446832, "token_start": 15, "token_end": 15, "note": null}, {"text": "SUMO - 1 - modified PML", "type": "ENTITY", "char_start": 446855, "char_end": 446878, "token_start": 20, "token_end": 25, "note": null}]}
+{"sentence_id": 2706, "sentence_text": "We also found that Z itself is SUMO - 1 modified ( through amino acid 12 ) and that Z competes with PML for limiting amounts of SUMO - 1 .", "sentence_char_start_global": 446881, "sentence_char_end_global": 447019, "entities": [{"text": "Z", "type": "ENTITY", "char_start": 19, "char_end": 20, "token_start": 4, "token_end": 4}, {"text": "Z", "type": "ENTITY", "char_start": 84, "char_end": 85, "token_start": 19, "token_end": 19}, {"text": "PML", "type": "ENTITY", "char_start": 100, "char_end": 103, "token_start": 22, "token_end": 22}, {"text": "SUMO - 1", "type": "ENTITY", "char_start": 128, "char_end": 136, "token_start": 27, "token_end": 29}], "entities_global": [{"text": "Z", "type": "ENTITY", "char_start": 446900, "char_end": 446901, "token_start": 4, "token_end": 4, "note": null}, {"text": "Z", "type": "ENTITY", "char_start": 446965, "char_end": 446966, "token_start": 19, "token_end": 19, "note": null}, {"text": "PML", "type": "ENTITY", "char_start": 446981, "char_end": 446984, "token_start": 22, "token_end": 22, "note": null}, {"text": "SUMO - 1", "type": "ENTITY", "char_start": 447009, "char_end": 447017, "token_start": 27, "token_end": 29, "note": null}]}
+{"sentence_id": 2707, "sentence_text": "These results suggest that disruption of PML bodies is important for efficient lytic replication of EBV .", "sentence_char_start_global": 447020, "sentence_char_end_global": 447125, "entities": [], "entities_global": []}
+{"sentence_id": 2708, "sentence_text": "Furthermore , Z may potentially alter the function of a variety of cellular proteins by inhibiting SUMO - 1 modification", "sentence_char_start_global": 447126, "sentence_char_end_global": 447246, "entities": [{"text": "Z", "type": "ENTITY", "char_start": 14, "char_end": 15, "token_start": 2, "token_end": 2}], "entities_global": [{"text": "Z", "type": "ENTITY", "char_start": 447140, "char_end": 447141, "token_start": 2, "token_end": 2, "note": null}]}
+{"sentence_id": 2709, "sentence_text": "Suppression of nuclear factor - kappaB and stimulation of inhibitor kappaB by troglitazone : evidence for an anti - inflammatory effect and a potential antiatherosclerotic effect in the obese .", "sentence_char_start_global": 447247, "sentence_char_end_global": 447440, "entities": [{"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 15, "char_end": 38, "token_start": 2, "token_end": 5}, {"text": "inhibitor kappaB", "type": "ENTITY", "char_start": 58, "char_end": 74, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 447262, "char_end": 447285, "token_start": 2, "token_end": 5, "note": null}, {"text": "inhibitor kappaB", "type": "ENTITY", "char_start": 447305, "char_end": 447321, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 2710, "sentence_text": "To elucidate whether troglitazone exerts an antiinflammatory effect in humans , in vivo , we investigated the suppression of nuclear factor kappaB ( NFkappaB ) in mononuclear cells ( MNC ) by this drug .", "sentence_char_start_global": 447441, "sentence_char_end_global": 447644, "entities": [{"text": "nuclear factor kappaB", "type": "ENTITY", "char_start": 125, "char_end": 146, "token_start": 19, "token_end": 21}, {"text": "NFkappaB", "type": "ENTITY", "char_start": 149, "char_end": 157, "token_start": 23, "token_end": 23}], "entities_global": [{"text": "nuclear factor kappaB", "type": "ENTITY", "char_start": 447566, "char_end": 447587, "token_start": 19, "token_end": 21, "note": null}, {"text": "NFkappaB", "type": "ENTITY", "char_start": 447590, "char_end": 447598, "token_start": 23, "token_end": 23, "note": null}]}
+{"sentence_id": 2711, "sentence_text": "We measured intranuclear NFkappaB , total cellular NFkappaB , inhibitor kappaB ( IkappaB ) alpha , reactive oxygen species ( ROS ) generation , and p47 ( phox ) subunit ( a key component protein of nicotinamide adenine dinucleotide phosphate oxidase ) in MNC .", "sentence_char_start_global": 447645, "sentence_char_end_global": 447905, "entities": [{"text": "intranuclear NFkappaB", "type": "ENTITY", "char_start": 12, "char_end": 33, "token_start": 2, "token_end": 3}, {"text": "cellular NFkappaB", "type": "ENTITY", "char_start": 42, "char_end": 59, "token_start": 6, "token_end": 7}, {"text": "inhibitor kappaB ( IkappaB ) alpha", "type": "ENTITY", "char_start": 62, "char_end": 96, "token_start": 9, "token_end": 14}, {"text": "p47 ( phox ) subunit", "type": "ENTITY", "char_start": 148, "char_end": 168, "token_start": 25, "token_end": 29}, {"text": "nicotinamide adenine dinucleotide phosphate oxidase", "type": "ENTITY", "char_start": 198, "char_end": 249, "token_start": 36, "token_end": 40}], "entities_global": [{"text": "intranuclear NFkappaB", "type": "ENTITY", "char_start": 447657, "char_end": 447678, "token_start": 2, "token_end": 3, "note": null}, {"text": "cellular NFkappaB", "type": "ENTITY", "char_start": 447687, "char_end": 447704, "token_start": 6, "token_end": 7, "note": null}, {"text": "inhibitor kappaB ( IkappaB ) alpha", "type": "ENTITY", "char_start": 447707, "char_end": 447741, "token_start": 9, "token_end": 14, "note": null}, {"text": "p47 ( phox ) subunit", "type": "ENTITY", "char_start": 447793, "char_end": 447813, "token_start": 25, "token_end": 29, "note": null}, {"text": "nicotinamide adenine dinucleotide phosphate oxidase", "type": "ENTITY", "char_start": 447843, "char_end": 447894, "token_start": 36, "token_end": 40, "note": null}]}
+{"sentence_id": 2712, "sentence_text": "Plasma tumor necrosis factor ( TNF ) - alpha , soluble intercellular adhesion molecule - 1 ( sICAM - 1 ) , monocyte chemoattractant protein - 1 ( MCP - 1 ) , plasminogen activator inhibitor type 1 ( PAI - 1 ) , C - reactive protein ( CRP ) , and interleukin ( IL ) - 10 ( antiinflammatory cytokine ) concentrations were also measured as mediators of inflammatory activity that are regulated by the proinflammatory transcription factor NFkappaB .", "sentence_char_start_global": 447906, "sentence_char_end_global": 448351, "entities": [{"text": "Plasma tumor necrosis factor ( TNF ) - alpha", "type": "ENTITY", "char_start": 0, "char_end": 44, "token_start": 0, "token_end": 8}, {"text": "soluble intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 47, "char_end": 90, "token_start": 10, "token_end": 15}, {"text": "sICAM - 1", "type": "ENTITY", "char_start": 93, "char_end": 102, "token_start": 17, "token_end": 19}, {"text": "monocyte chemoattractant protein - 1 ( MCP - 1 )", "type": "ENTITY", "char_start": 107, "char_end": 155, "token_start": 22, "token_end": 31}, {"text": "plasminogen activator inhibitor type 1", "type": "ENTITY", "char_start": 158, "char_end": 196, "token_start": 33, "token_end": 37}, {"text": "PAI - 1", "type": "ENTITY", "char_start": 199, "char_end": 206, "token_start": 39, "token_end": 41}, {"text": "C - reactive protein ( CRP )", "type": "ENTITY", "char_start": 211, "char_end": 239, "token_start": 44, "token_end": 50}, {"text": "interleukin ( IL ) - 10", "type": "ENTITY", "char_start": 246, "char_end": 269, "token_start": 53, "token_end": 58}, {"text": "antiinflammatory cytokine", "type": "ENTITY", "char_start": 272, "char_end": 297, "token_start": 60, "token_end": 61}, {"text": "proinflammatory transcription factor NFkappaB", "type": "ENTITY", "char_start": 398, "char_end": 443, "token_start": 77, "token_end": 80}], "entities_global": [{"text": "Plasma tumor necrosis factor ( TNF ) - alpha", "type": "ENTITY", "char_start": 447906, "char_end": 447950, "token_start": 0, "token_end": 8, "note": null}, {"text": "soluble intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 447953, "char_end": 447996, "token_start": 10, "token_end": 15, "note": null}, {"text": "sICAM - 1", "type": "ENTITY", "char_start": 447999, "char_end": 448008, "token_start": 17, "token_end": 19, "note": null}, {"text": "monocyte chemoattractant protein - 1 ( MCP - 1 )", "type": "ENTITY", "char_start": 448013, "char_end": 448061, "token_start": 22, "token_end": 31, "note": null}, {"text": "plasminogen activator inhibitor type 1", "type": "ENTITY", "char_start": 448064, "char_end": 448102, "token_start": 33, "token_end": 37, "note": null}, {"text": "PAI - 1", "type": "ENTITY", "char_start": 448105, "char_end": 448112, "token_start": 39, "token_end": 41, "note": null}, {"text": "C - reactive protein ( CRP )", "type": "ENTITY", "char_start": 448117, "char_end": 448145, "token_start": 44, "token_end": 50, "note": null}, {"text": "interleukin ( IL ) - 10", "type": "ENTITY", "char_start": 448152, "char_end": 448175, "token_start": 53, "token_end": 58, "note": null}, {"text": "antiinflammatory cytokine", "type": "ENTITY", "char_start": 448178, "char_end": 448203, "token_start": 60, "token_end": 61, "note": null}, {"text": "proinflammatory transcription factor NFkappaB", "type": "ENTITY", "char_start": 448304, "char_end": 448349, "token_start": 77, "token_end": 80, "note": null}]}
+{"sentence_id": 2713, "sentence_text": "Seven nondiabetic obese patients were given 400 mg troglitazone daily for 4 weeks .", "sentence_char_start_global": 448352, "sentence_char_end_global": 448435, "entities": [], "entities_global": []}
+{"sentence_id": 2714, "sentence_text": "Blood samples were collected before and at weekly intervals thereafter .", "sentence_char_start_global": 448436, "sentence_char_end_global": 448508, "entities": [], "entities_global": []}
+{"sentence_id": 2715, "sentence_text": "MNC were separated ; and the levels of intranuclear NFkappaB , total cellular NFkappaB , IkappaBalpha , and p47 ( phox ) subunit and ROS generation were determined .", "sentence_char_start_global": 448509, "sentence_char_end_global": 448674, "entities": [{"text": "intranuclear NFkappaB", "type": "ENTITY", "char_start": 39, "char_end": 60, "token_start": 8, "token_end": 9}, {"text": "cellular NFkappaB", "type": "ENTITY", "char_start": 69, "char_end": 86, "token_start": 12, "token_end": 13}, {"text": "IkappaBalpha", "type": "ENTITY", "char_start": 89, "char_end": 101, "token_start": 15, "token_end": 15}, {"text": "p47 ( phox ) subunit", "type": "ENTITY", "char_start": 108, "char_end": 128, "token_start": 18, "token_end": 22}], "entities_global": [{"text": "intranuclear NFkappaB", "type": "ENTITY", "char_start": 448548, "char_end": 448569, "token_start": 8, "token_end": 9, "note": null}, {"text": "cellular NFkappaB", "type": "ENTITY", "char_start": 448578, "char_end": 448595, "token_start": 12, "token_end": 13, "note": null}, {"text": "IkappaBalpha", "type": "ENTITY", "char_start": 448598, "char_end": 448610, "token_start": 15, "token_end": 15, "note": null}, {"text": "p47 ( phox ) subunit", "type": "ENTITY", "char_start": 448617, "char_end": 448637, "token_start": 18, "token_end": 22, "note": null}]}
+{"sentence_id": 2716, "sentence_text": "Plasma was used to measure insulin glucose , TNFalpha , sICAM , MCP - 1 , PAI - 1 , CRP , and IL - 10 .", "sentence_char_start_global": 448675, "sentence_char_end_global": 448778, "entities": [{"text": "TNFalpha", "type": "ENTITY", "char_start": 45, "char_end": 53, "token_start": 8, "token_end": 8}, {"text": "sICAM", "type": "ENTITY", "char_start": 56, "char_end": 61, "token_start": 10, "token_end": 10}, {"text": "MCP - 1", "type": "ENTITY", "char_start": 64, "char_end": 71, "token_start": 12, "token_end": 14}, {"text": "PAI - 1", "type": "ENTITY", "char_start": 74, "char_end": 81, "token_start": 16, "token_end": 18}, {"text": "CRP", "type": "ENTITY", "char_start": 84, "char_end": 87, "token_start": 20, "token_end": 20}, {"text": "IL - 10", "type": "ENTITY", "char_start": 94, "char_end": 101, "token_start": 23, "token_end": 25}], "entities_global": [{"text": "TNFalpha", "type": "ENTITY", "char_start": 448720, "char_end": 448728, "token_start": 8, "token_end": 8, "note": null}, {"text": "sICAM", "type": "ENTITY", "char_start": 448731, "char_end": 448736, "token_start": 10, "token_end": 10, "note": null}, {"text": "MCP - 1", "type": "ENTITY", "char_start": 448739, "char_end": 448746, "token_start": 12, "token_end": 14, "note": null}, {"text": "PAI - 1", "type": "ENTITY", "char_start": 448749, "char_end": 448756, "token_start": 16, "token_end": 18, "note": null}, {"text": "CRP", "type": "ENTITY", "char_start": 448759, "char_end": 448762, "token_start": 20, "token_end": 20, "note": null}, {"text": "IL - 10", "type": "ENTITY", "char_start": 448769, "char_end": 448776, "token_start": 23, "token_end": 25, "note": null}]}
+{"sentence_id": 2717, "sentence_text": "Plasma insulin concentrations fell significantly at week 1 , from 31 . 2 + / - 29 . 1 to 14 . 2 + / - 11 . 4 mU / L ( P < 0 . 01 ) and remained low throughout 4 weeks .", "sentence_char_start_global": 448779, "sentence_char_end_global": 448947, "entities": [], "entities_global": []}
+{"sentence_id": 2718, "sentence_text": "Plasma glucose concentrations did not alter significantly .", "sentence_char_start_global": 448948, "sentence_char_end_global": 449007, "entities": [], "entities_global": []}
+{"sentence_id": 2719, "sentence_text": "There was a fall in intranuclear NFkappaB , total cellular NFkappaB , and p47 ( phox ) subunit , with an increase in cellular IkappaBalpha at week 2 , which persisted until week 4 .", "sentence_char_start_global": 449008, "sentence_char_end_global": 449189, "entities": [{"text": "intranuclear NFkappaB", "type": "ENTITY", "char_start": 20, "char_end": 41, "token_start": 5, "token_end": 6}, {"text": "cellular NFkappaB", "type": "ENTITY", "char_start": 50, "char_end": 67, "token_start": 9, "token_end": 10}, {"text": "p47 ( phox ) subunit", "type": "ENTITY", "char_start": 74, "char_end": 94, "token_start": 13, "token_end": 17}, {"text": "IkappaBalpha", "type": "ENTITY", "char_start": 126, "char_end": 138, "token_start": 24, "token_end": 24}], "entities_global": [{"text": "intranuclear NFkappaB", "type": "ENTITY", "char_start": 449028, "char_end": 449049, "token_start": 5, "token_end": 6, "note": null}, {"text": "cellular NFkappaB", "type": "ENTITY", "char_start": 449058, "char_end": 449075, "token_start": 9, "token_end": 10, "note": null}, {"text": "p47 ( phox ) subunit", "type": "ENTITY", "char_start": 449082, "char_end": 449102, "token_start": 13, "token_end": 17, "note": null}, {"text": "IkappaBalpha", "type": "ENTITY", "char_start": 449134, "char_end": 449146, "token_start": 24, "token_end": 24, "note": null}]}
+{"sentence_id": 2720, "sentence_text": "There was a parallel fall in ROS generation by MNC at week 1 ; this progressed and persisted until week 4 ( P < 0 . 001 ) .", "sentence_char_start_global": 449190, "sentence_char_end_global": 449313, "entities": [], "entities_global": []}
+{"sentence_id": 2721, "sentence_text": "Plasma TNF - alpha , sICAM - 1 , MCP - 1 , and PAI - 1 concentrations fell significantly at week 4 .", "sentence_char_start_global": 449314, "sentence_char_end_global": 449414, "entities": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 7, "char_end": 18, "token_start": 1, "token_end": 3}, {"text": "sICAM - 1", "type": "ENTITY", "char_start": 21, "char_end": 30, "token_start": 5, "token_end": 7}, {"text": "MCP - 1", "type": "ENTITY", "char_start": 33, "char_end": 40, "token_start": 9, "token_end": 11}, {"text": "PAI - 1", "type": "ENTITY", "char_start": 47, "char_end": 54, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 449321, "char_end": 449332, "token_start": 1, "token_end": 3, "note": null}, {"text": "sICAM - 1", "type": "ENTITY", "char_start": 449335, "char_end": 449344, "token_start": 5, "token_end": 7, "note": null}, {"text": "MCP - 1", "type": "ENTITY", "char_start": 449347, "char_end": 449354, "token_start": 9, "token_end": 11, "note": null}, {"text": "PAI - 1", "type": "ENTITY", "char_start": 449361, "char_end": 449368, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 2722, "sentence_text": "Plasma IL - 10 concentration increased significantly , whereas plasma CRP concentrations decreased .", "sentence_char_start_global": 449415, "sentence_char_end_global": 449515, "entities": [{"text": "IL - 10", "type": "ENTITY", "char_start": 7, "char_end": 14, "token_start": 1, "token_end": 3}, {"text": "plasma CRP", "type": "ENTITY", "char_start": 63, "char_end": 73, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "IL - 10", "type": "ENTITY", "char_start": 449422, "char_end": 449429, "token_start": 1, "token_end": 3, "note": null}, {"text": "plasma CRP", "type": "ENTITY", "char_start": 449478, "char_end": 449488, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 2723, "sentence_text": "We conclude that troglitazone has an antiinflammatory action that may contribute to its putative antiatherosclerotic effects .", "sentence_char_start_global": 449516, "sentence_char_end_global": 449642, "entities": [], "entities_global": []}
+{"sentence_id": 2724, "sentence_text": "Tyrosine phosphorylation - dependent activation of NF - kappa B .", "sentence_char_start_global": 449643, "sentence_char_end_global": 449708, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 51, "char_end": 63, "token_start": 6, "token_end": 9}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 449694, "char_end": 449706, "token_start": 6, "token_end": 9, "note": null}]}
+{"sentence_id": 2725, "sentence_text": "Requirement for p56 LCK and ZAP - 70 protein tyrosine kinases .", "sentence_char_start_global": 449709, "sentence_char_end_global": 449772, "entities": [{"text": "p56 LCK and ZAP - 70 protein tyrosine kinases", "type": "ENTITY", "char_start": 16, "char_end": 61, "token_start": 2, "token_end": 10}], "entities_global": [{"text": "p56 LCK and ZAP - 70 protein tyrosine kinases", "type": "ENTITY", "char_start": 449725, "char_end": 449770, "token_start": 2, "token_end": 10, "note": null}]}
+{"sentence_id": 2726, "sentence_text": "Phosphorylation of the N - terminal domain of I kappa B inhibitory subunits induces activation of the transcription factor NF - kappa B .", "sentence_char_start_global": 449773, "sentence_char_end_global": 449910, "entities": [{"text": "N - terminal domain", "type": "ENTITY", "char_start": 23, "char_end": 42, "token_start": 3, "token_end": 6}, {"text": "I kappa B inhibitory subunits", "type": "ENTITY", "char_start": 46, "char_end": 75, "token_start": 8, "token_end": 12}, {"text": "transcription factor NF - kappa B", "type": "ENTITY", "char_start": 102, "char_end": 135, "token_start": 17, "token_end": 22}], "entities_global": [{"text": "N - terminal domain", "type": "ENTITY", "char_start": 449796, "char_end": 449815, "token_start": 3, "token_end": 6, "note": null}, {"text": "I kappa B inhibitory subunits", "type": "ENTITY", "char_start": 449819, "char_end": 449848, "token_start": 8, "token_end": 12, "note": null}, {"text": "transcription factor NF - kappa B", "type": "ENTITY", "char_start": 449875, "char_end": 449908, "token_start": 17, "token_end": 22, "note": null}]}
+{"sentence_id": 2727, "sentence_text": "Although serine phosphorylation has been shown to induce ubiquitination and subsequent proteasome - mediated degradation of I kappa B - alpha , little is known about the mechanisms that lead to release of active NF - kappa B in T cells as a consequence of tyrosine phosphorylation of I kappa B - alpha [ Imbert , V . , Rupec , R . A . , Livolsi , A . , Pahl , H . L . , Traenckner , B . M . , Mueller - Dieckmann , C . , Farahifar , D . , Rossi , B . , Auberger , P . , Baeuerle , P . & Peyron , J . F . ( 1996 ) Cell 86 , 787 - - 798 ] .", "sentence_char_start_global": 449911, "sentence_char_end_global": 450449, "entities": [{"text": "I kappa B - alpha", "type": "ENTITY", "char_start": 124, "char_end": 141, "token_start": 16, "token_end": 20}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 212, "char_end": 224, "token_start": 34, "token_end": 37}, {"text": "I kappa B - alpha", "type": "ENTITY", "char_start": 284, "char_end": 301, "token_start": 48, "token_end": 52}], "entities_global": [{"text": "I kappa B - alpha", "type": "ENTITY", "char_start": 450035, "char_end": 450052, "token_start": 16, "token_end": 20, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 450123, "char_end": 450135, "token_start": 34, "token_end": 37, "note": null}, {"text": "I kappa B - alpha", "type": "ENTITY", "char_start": 450195, "char_end": 450212, "token_start": 48, "token_end": 52, "note": null}]}
+{"sentence_id": 2728, "sentence_text": "The involvement of the tyrosine kinases p56 ( lck ) and ZAP - 70 in this reaction is demonstrated here using specific pharmacological inhibitors and Jurkat mutants unable to express these kinases .", "sentence_char_start_global": 450450, "sentence_char_end_global": 450647, "entities": [{"text": "tyrosine kinases", "type": "ENTITY", "char_start": 23, "char_end": 39, "token_start": 4, "token_end": 5}, {"text": "p56 ( lck )", "type": "ENTITY", "char_start": 40, "char_end": 51, "token_start": 6, "token_end": 9}, {"text": "ZAP - 70", "type": "ENTITY", "char_start": 56, "char_end": 64, "token_start": 11, "token_end": 13}, {"text": "kinases", "type": "ENTITY", "char_start": 188, "char_end": 195, "token_start": 31, "token_end": 31}], "entities_global": [{"text": "tyrosine kinases", "type": "ENTITY", "char_start": 450473, "char_end": 450489, "token_start": 4, "token_end": 5, "note": null}, {"text": "p56 ( lck )", "type": "ENTITY", "char_start": 450490, "char_end": 450501, "token_start": 6, "token_end": 9, "note": null}, {"text": "ZAP - 70", "type": "ENTITY", "char_start": 450506, "char_end": 450514, "token_start": 11, "token_end": 13, "note": null}, {"text": "kinases", "type": "ENTITY", "char_start": 450638, "char_end": 450645, "token_start": 31, "token_end": 31, "note": null}]}
+{"sentence_id": 2729, "sentence_text": "Although the inhibitors prevented both pervanadate - induced phosphorylation of I kappa B - alpha on Tyr42 and NF - kappa B activation , we observed that , in p56 ( lck ) - deficient Jurkat mutants , NF - kappa B could still associate with I kappa B - alpha despite phosphorylation on Tyr42 .", "sentence_char_start_global": 450648, "sentence_char_end_global": 450940, "entities": [{"text": "I kappa B - alpha", "type": "ENTITY", "char_start": 80, "char_end": 97, "token_start": 10, "token_end": 14}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 111, "char_end": 123, "token_start": 18, "token_end": 21}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 200, "char_end": 212, "token_start": 38, "token_end": 41}, {"text": "I kappa B - alpha", "type": "ENTITY", "char_start": 240, "char_end": 257, "token_start": 46, "token_end": 50}], "entities_global": [{"text": "I kappa B - alpha", "type": "ENTITY", "char_start": 450728, "char_end": 450745, "token_start": 10, "token_end": 14, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 450759, "char_end": 450771, "token_start": 18, "token_end": 21, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 450848, "char_end": 450860, "token_start": 38, "token_end": 41, "note": null}, {"text": "I kappa B - alpha", "type": "ENTITY", "char_start": 450888, "char_end": 450905, "token_start": 46, "token_end": 50, "note": null}]}
+{"sentence_id": 2730, "sentence_text": "Furthermore , the SH2 domain of p56 ( lck ) appeared to be required for pervanadate - induced NF - kappa B activation but not for Tyr42 phosphorylation .", "sentence_char_start_global": 450941, "sentence_char_end_global": 451094, "entities": [{"text": "SH2 domain", "type": "ENTITY", "char_start": 18, "char_end": 28, "token_start": 3, "token_end": 4}, {"text": "p56 ( lck )", "type": "ENTITY", "char_start": 32, "char_end": 43, "token_start": 6, "token_end": 9}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 94, "char_end": 106, "token_start": 18, "token_end": 21}], "entities_global": [{"text": "SH2 domain", "type": "ENTITY", "char_start": 450959, "char_end": 450969, "token_start": 3, "token_end": 4, "note": null}, {"text": "p56 ( lck )", "type": "ENTITY", "char_start": 450973, "char_end": 450984, "token_start": 6, "token_end": 9, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 451035, "char_end": 451047, "token_start": 18, "token_end": 21, "note": null}]}
+{"sentence_id": 2731, "sentence_text": "These results show that p56 ( lck ) and ZAP - 70 are key components of the signaling pathway that leads to phosphotyrosine - dependent NF - kappa B activation in T cells and confirm that tyrosine kinases must control at least two different steps to induce activation of NF - kappa B .", "sentence_char_start_global": 451095, "sentence_char_end_global": 451379, "entities": [{"text": "p56 ( lck )", "type": "ENTITY", "char_start": 24, "char_end": 35, "token_start": 4, "token_end": 7}, {"text": "ZAP - 70", "type": "ENTITY", "char_start": 40, "char_end": 48, "token_start": 9, "token_end": 11}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 135, "char_end": 147, "token_start": 25, "token_end": 28}, {"text": "tyrosine kinases", "type": "ENTITY", "char_start": 187, "char_end": 203, "token_start": 36, "token_end": 37}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 270, "char_end": 282, "token_start": 49, "token_end": 52}], "entities_global": [{"text": "p56 ( lck )", "type": "ENTITY", "char_start": 451119, "char_end": 451130, "token_start": 4, "token_end": 7, "note": null}, {"text": "ZAP - 70", "type": "ENTITY", "char_start": 451135, "char_end": 451143, "token_start": 9, "token_end": 11, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 451230, "char_end": 451242, "token_start": 25, "token_end": 28, "note": null}, {"text": "tyrosine kinases", "type": "ENTITY", "char_start": 451282, "char_end": 451298, "token_start": 36, "token_end": 37, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 451365, "char_end": 451377, "token_start": 49, "token_end": 52, "note": null}]}
+{"sentence_id": 2732, "sentence_text": "Finally , we show that H ( 2 ) O ( 2 ) , which stimulates p56 ( lck ) and ZAP - 70 in T cells , is an activator of NF - kappa B through tyrosine phosphorylation of I kappa B - alpha .", "sentence_char_start_global": 451380, "sentence_char_end_global": 451563, "entities": [{"text": "p56 ( lck )", "type": "ENTITY", "char_start": 58, "char_end": 69, "token_start": 16, "token_end": 19}, {"text": "ZAP - 70", "type": "ENTITY", "char_start": 74, "char_end": 82, "token_start": 21, "token_end": 23}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 115, "char_end": 127, "token_start": 32, "token_end": 35}, {"text": "I kappa B - alpha", "type": "ENTITY", "char_start": 164, "char_end": 181, "token_start": 40, "token_end": 44}], "entities_global": [{"text": "p56 ( lck )", "type": "ENTITY", "char_start": 451438, "char_end": 451449, "token_start": 16, "token_end": 19, "note": null}, {"text": "ZAP - 70", "type": "ENTITY", "char_start": 451454, "char_end": 451462, "token_start": 21, "token_end": 23, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 451495, "char_end": 451507, "token_start": 32, "token_end": 35, "note": null}, {"text": "I kappa B - alpha", "type": "ENTITY", "char_start": 451544, "char_end": 451561, "token_start": 40, "token_end": 44, "note": null}]}
+{"sentence_id": 2733, "sentence_text": "Specific missense mutations in NEMO result in hyper - IgM syndrome with hypohydrotic ectodermal dysplasia .", "sentence_char_start_global": 451564, "sentence_char_end_global": 451671, "entities": [{"text": "NEMO", "type": "ENTITY", "char_start": 31, "char_end": 35, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "NEMO", "type": "ENTITY", "char_start": 451595, "char_end": 451599, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 2734, "sentence_text": "The gene that encodes nuclear factor kappaB ( NF - kappaB ) essential modulator ( or NEMO , also known as IKKgamma ) is required for activation of the transcription factor NF - kappaB .", "sentence_char_start_global": 451672, "sentence_char_end_global": 451857, "entities": [{"text": "nuclear factor kappaB ( NF - kappaB ) essential modulator", "type": "ENTITY", "char_start": 22, "char_end": 79, "token_start": 4, "token_end": 13}, {"text": "NEMO", "type": "ENTITY", "char_start": 85, "char_end": 89, "token_start": 16, "token_end": 16}, {"text": "IKKgamma", "type": "ENTITY", "char_start": 106, "char_end": 114, "token_start": 21, "token_end": 21}, {"text": "transcription factor NF - kappaB", "type": "ENTITY", "char_start": 151, "char_end": 183, "token_start": 29, "token_end": 33}], "entities_global": [{"text": "nuclear factor kappaB ( NF - kappaB ) essential modulator", "type": "ENTITY", "char_start": 451694, "char_end": 451751, "token_start": 4, "token_end": 13, "note": null}, {"text": "NEMO", "type": "ENTITY", "char_start": 451757, "char_end": 451761, "token_start": 16, "token_end": 16, "note": null}, {"text": "IKKgamma", "type": "ENTITY", "char_start": 451778, "char_end": 451786, "token_start": 21, "token_end": 21, "note": null}, {"text": "transcription factor NF - kappaB", "type": "ENTITY", "char_start": 451823, "char_end": 451855, "token_start": 29, "token_end": 33, "note": null}]}
+{"sentence_id": 2735, "sentence_text": "We describe mutations in the putative zinc - finger domain of NEMO that result in an X - linked primary immunodeficiency characterized by hyper - IgM syndrome and hypohydrotic ectodermal dysplasia ( XHM - ED ) .", "sentence_char_start_global": 451858, "sentence_char_end_global": 452069, "entities": [{"text": "putative zinc - finger domain", "type": "ENTITY", "char_start": 29, "char_end": 58, "token_start": 5, "token_end": 9}, {"text": "NEMO", "type": "ENTITY", "char_start": 62, "char_end": 66, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "putative zinc - finger domain", "type": "ENTITY", "char_start": 451887, "char_end": 451916, "token_start": 5, "token_end": 9, "note": null}, {"text": "NEMO", "type": "ENTITY", "char_start": 451920, "char_end": 451924, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 2736, "sentence_text": "These mutations prevent CD40 ligand ( CD40L ) - mediated degradation of inhibitor of NF - kappaB alpha ( IkappaB - alpha ) and account for the following observations : B cells from XHM - ED patients are unable to undergo immunoglobulin class - switch recombination and antigen - presenting cells ( APCs ) are unable to synthesize the NF - kappaB - regulated cytokines interleukin 12 ( IL - 12 ) or tumor necrosis factor alpha ( TNF - alpha ) when stimulated with CD40L .", "sentence_char_start_global": 452070, "sentence_char_end_global": 452540, "entities": [{"text": "CD40 ligand", "type": "ENTITY", "char_start": 24, "char_end": 35, "token_start": 3, "token_end": 4}, {"text": "CD40L", "type": "ENTITY", "char_start": 38, "char_end": 43, "token_start": 6, "token_end": 6}, {"text": "NF - kappaB alpha", "type": "ENTITY", "char_start": 85, "char_end": 102, "token_start": 14, "token_end": 17}, {"text": "IkappaB - alpha", "type": "ENTITY", "char_start": 105, "char_end": 120, "token_start": 19, "token_end": 21}, {"text": "NF - kappaB - regulated cytokines", "type": "ENTITY", "char_start": 334, "char_end": 367, "token_start": 59, "token_end": 64}, {"text": "interleukin 12", "type": "ENTITY", "char_start": 368, "char_end": 382, "token_start": 65, "token_end": 66}, {"text": "IL - 12", "type": "ENTITY", "char_start": 385, "char_end": 392, "token_start": 68, "token_end": 70}, {"text": "tumor necrosis factor alpha", "type": "ENTITY", "char_start": 398, "char_end": 425, "token_start": 73, "token_end": 76}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 428, "char_end": 439, "token_start": 78, "token_end": 80}, {"text": "CD40L", "type": "ENTITY", "char_start": 463, "char_end": 468, "token_start": 85, "token_end": 85}], "entities_global": [{"text": "CD40 ligand", "type": "ENTITY", "char_start": 452094, "char_end": 452105, "token_start": 3, "token_end": 4, "note": null}, {"text": "CD40L", "type": "ENTITY", "char_start": 452108, "char_end": 452113, "token_start": 6, "token_end": 6, "note": null}, {"text": "NF - kappaB alpha", "type": "ENTITY", "char_start": 452155, "char_end": 452172, "token_start": 14, "token_end": 17, "note": null}, {"text": "IkappaB - alpha", "type": "ENTITY", "char_start": 452175, "char_end": 452190, "token_start": 19, "token_end": 21, "note": null}, {"text": "NF - kappaB - regulated cytokines", "type": "ENTITY", "char_start": 452404, "char_end": 452437, "token_start": 59, "token_end": 64, "note": null}, {"text": "interleukin 12", "type": "ENTITY", "char_start": 452438, "char_end": 452452, "token_start": 65, "token_end": 66, "note": null}, {"text": "IL - 12", "type": "ENTITY", "char_start": 452455, "char_end": 452462, "token_start": 68, "token_end": 70, "note": null}, {"text": "tumor necrosis factor alpha", "type": "ENTITY", "char_start": 452468, "char_end": 452495, "token_start": 73, "token_end": 76, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 452498, "char_end": 452509, "token_start": 78, "token_end": 80, "note": null}, {"text": "CD40L", "type": "ENTITY", "char_start": 452533, "char_end": 452538, "token_start": 85, "token_end": 85, "note": null}]}
+{"sentence_id": 2737, "sentence_text": "Nevertheless , innate immunity is preserved in XHM - ED patients because APCs retain the capacity to respond to stimulation by lipopolysaccharide or Staphylococcus aureus Cowan ' s antigen ( SAC ) .", "sentence_char_start_global": 452541, "sentence_char_end_global": 452739, "entities": [{"text": "Staphylococcus aureus Cowan ' s antigen", "type": "ENTITY", "char_start": 149, "char_end": 188, "token_start": 23, "token_end": 28}, {"text": "SAC", "type": "ENTITY", "char_start": 191, "char_end": 194, "token_start": 30, "token_end": 30}], "entities_global": [{"text": "Staphylococcus aureus Cowan ' s antigen", "type": "ENTITY", "char_start": 452690, "char_end": 452729, "token_start": 23, "token_end": 28, "note": null}, {"text": "SAC", "type": "ENTITY", "char_start": 452732, "char_end": 452735, "token_start": 30, "token_end": 30, "note": null}]}
+{"sentence_id": 2738, "sentence_text": "Overall , the phenotype observed in XHM - ED patients shows that the putative zinc - finger domain of NEMO has a regulatory function and demonstrates the definite requirement of CD40 - mediated NF - kappaB activation for B cell immunoglobulin class - switching .", "sentence_char_start_global": 452740, "sentence_char_end_global": 453002, "entities": [{"text": "putative zinc - finger domain", "type": "ENTITY", "char_start": 69, "char_end": 98, "token_start": 13, "token_end": 17}, {"text": "NEMO", "type": "ENTITY", "char_start": 102, "char_end": 106, "token_start": 19, "token_end": 19}, {"text": "CD40", "type": "ENTITY", "char_start": 178, "char_end": 182, "token_start": 30, "token_end": 30}], "entities_global": [{"text": "putative zinc - finger domain", "type": "ENTITY", "char_start": 452809, "char_end": 452838, "token_start": 13, "token_end": 17, "note": null}, {"text": "NEMO", "type": "ENTITY", "char_start": 452842, "char_end": 452846, "token_start": 19, "token_end": 19, "note": null}, {"text": "CD40", "type": "ENTITY", "char_start": 452918, "char_end": 452922, "token_start": 30, "token_end": 30, "note": null}]}
+{"sentence_id": 2739, "sentence_text": "Granulocytic differentiation of human NB4 promyelocytic leukemia cells induced by all - trans retinoic acid metabolites .", "sentence_char_start_global": 453003, "sentence_char_end_global": 453124, "entities": [], "entities_global": []}
+{"sentence_id": 2740, "sentence_text": "The metabolism of all - trans retinoic acid ( ATRA ) has been reported to be partly responsible for the in vivo resistance to ATRA seen in the treatment of human acute promyelocytic leukemia ( APL ) .", "sentence_char_start_global": 453125, "sentence_char_end_global": 453325, "entities": [], "entities_global": []}
+{"sentence_id": 2741, "sentence_text": "However , ATRA metabolism appears to be involved in the growth inhibition of several cancer cell lines in vitro .", "sentence_char_start_global": 453326, "sentence_char_end_global": 453439, "entities": [], "entities_global": []}
+{"sentence_id": 2742, "sentence_text": "The purpose of this study was to evaluate the in vitro activity of the principal metabolites of ATRA [ 4 - hydroxy - retinoic acid ( 4 - OH - RA ) , 18 - hydroxy - retinoic acid ( 18 - OH - RA ) , 4 - oxo - retinoic acid ( 4 - oxo - RA ) , and 5 , 6 - epoxy - retinoic acid ( 5 , 6 - epoxy - RA ) ] in NB4 , a human promyelocytic leukemia cell line that exhibits the APL diagnostic t ( 15 ; 17 ) chromosomal translocation and expresses the PML - RAR alpha fusion protein .", "sentence_char_start_global": 453440, "sentence_char_end_global": 453912, "entities": [{"text": "PML - RAR alpha fusion protein", "type": "ENTITY", "char_start": 440, "char_end": 470, "token_start": 105, "token_end": 110}], "entities_global": [{"text": "PML - RAR alpha fusion protein", "type": "ENTITY", "char_start": 453880, "char_end": 453910, "token_start": 105, "token_end": 110, "note": null}]}
+{"sentence_id": 2743, "sentence_text": "We established that the four ATRA metabolites were indeed formed by the NB4 cells in vitro .", "sentence_char_start_global": 453913, "sentence_char_end_global": 454005, "entities": [], "entities_global": []}
+{"sentence_id": 2744, "sentence_text": "NB4 cell growth was inhibited ( 69 - 78 % at 120 h ) and cell cycle progression in the G1 phase ( 82 - 85 % at 120 h ) was blocked by ATRA and all of the metabolites at 1 microM concentration .", "sentence_char_start_global": 454006, "sentence_char_end_global": 454199, "entities": [], "entities_global": []}
+{"sentence_id": 2745, "sentence_text": "ATRA and its metabolites could induce NB4 cells differentiation with similar activity , as evaluated by cell morphology , by the nitroblue tetrazolium reduction test ( 82 - 88 % at 120 h ) or by the expression of the maturation specific cell surface marker CD11c .", "sentence_char_start_global": 454200, "sentence_char_end_global": 454464, "entities": [{"text": "maturation specific cell surface marker CD11c", "type": "ENTITY", "char_start": 217, "char_end": 262, "token_start": 40, "token_end": 45}], "entities_global": [{"text": "maturation specific cell surface marker CD11c", "type": "ENTITY", "char_start": 454417, "char_end": 454462, "token_start": 40, "token_end": 45, "note": null}]}
+{"sentence_id": 2746, "sentence_text": "In addition , nuclear body reorganization to macropunctated structures , as well as the degradation of PML - RAR alpha , was found to be similar for ATRA and all of its metabolites .", "sentence_char_start_global": 454465, "sentence_char_end_global": 454647, "entities": [{"text": "PML - RAR alpha", "type": "ENTITY", "char_start": 103, "char_end": 118, "token_start": 16, "token_end": 19}], "entities_global": [{"text": "PML - RAR alpha", "type": "ENTITY", "char_start": 454568, "char_end": 454583, "token_start": 16, "token_end": 19, "note": null}]}
+{"sentence_id": 2747, "sentence_text": "Comparison of the relative potency of the retinoids using the nitroblue tetrazolium reduction test showed effective concentrations required to differentiate 50 % of cells in 72 h as follows : ATRA , 15 . 8 + / - 1 . 7 nM ; 4 - oxo - RA , 38 . 3 + / - 1 . 3 nM ; 18 - OH - RA , 55 . 5 + / - 1 . 8 nM ; 4 - OH - RA , 79 . 8 + / - 1 . 8 nM ; and 5 , 6 - epoxy - RA , 99 . 5 + / - 1 . 5 nM .", "sentence_char_start_global": 454648, "sentence_char_end_global": 455035, "entities": [], "entities_global": []}
+{"sentence_id": 2748, "sentence_text": "The ATRA metabolites were found to exert their differentiation effects via the RAR alpha nuclear receptors , because the RAR alpha - specific antagonist BMS614 blocked metabolite - induced CD11c expression in NB4 cells .", "sentence_char_start_global": 455036, "sentence_char_end_global": 455256, "entities": [{"text": "RAR alpha nuclear receptors", "type": "ENTITY", "char_start": 79, "char_end": 106, "token_start": 12, "token_end": 15}], "entities_global": [{"text": "RAR alpha nuclear receptors", "type": "ENTITY", "char_start": 455115, "char_end": 455142, "token_start": 12, "token_end": 15, "note": null}]}
+{"sentence_id": 2749, "sentence_text": "These data demonstrate that the principal ATRA Phase 1 metabolites can elicit leukemia cell growth inhibition and differentiation in vitro through the RAR alpha signaling pathway , and they suggest that these metabolites may play a role in ATRA antileukemic activity in vivo .", "sentence_char_start_global": 455257, "sentence_char_end_global": 455533, "entities": [], "entities_global": []}
+{"sentence_id": 2750, "sentence_text": "Expression of oestrogen and progesterone receptors by mast cells alone , but not lymphocytes , macrophages or other immune cells in human upper airways .", "sentence_char_start_global": 455534, "sentence_char_end_global": 455687, "entities": [{"text": "oestrogen and progesterone receptors", "type": "ENTITY", "char_start": 14, "char_end": 50, "token_start": 2, "token_end": 5}], "entities_global": [{"text": "oestrogen and progesterone receptors", "type": "ENTITY", "char_start": 455548, "char_end": 455584, "token_start": 2, "token_end": 5, "note": null}]}
+{"sentence_id": 2751, "sentence_text": "BACKGROUND : Nasal polyposis often coexists with asthma in airway inflammatory conditions characterised by the infiltration of a range of immune cells .", "sentence_char_start_global": 455688, "sentence_char_end_global": 455840, "entities": [], "entities_global": []}
+{"sentence_id": 2752, "sentence_text": "A potentially important role for ovarian hormones has been implicated in airway inflammation but the cellular target for such action is not known .", "sentence_char_start_global": 455841, "sentence_char_end_global": 455988, "entities": [], "entities_global": []}
+{"sentence_id": 2753, "sentence_text": "METHODS : Expression of oestrogen receptors ( ER ) and progesterone receptors ( PR ) was examined using immunohistochemistry in formalin fixed nasal polyp tissues from 47 subjects .", "sentence_char_start_global": 455989, "sentence_char_end_global": 456170, "entities": [{"text": "oestrogen receptors", "type": "ENTITY", "char_start": 24, "char_end": 43, "token_start": 4, "token_end": 5}, {"text": "ER", "type": "ENTITY", "char_start": 46, "char_end": 48, "token_start": 7, "token_end": 7}, {"text": "progesterone receptors", "type": "ENTITY", "char_start": 55, "char_end": 77, "token_start": 10, "token_end": 11}, {"text": "PR", "type": "ENTITY", "char_start": 80, "char_end": 82, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "oestrogen receptors", "type": "ENTITY", "char_start": 456013, "char_end": 456032, "token_start": 4, "token_end": 5, "note": null}, {"text": "ER", "type": "ENTITY", "char_start": 456035, "char_end": 456037, "token_start": 7, "token_end": 7, "note": null}, {"text": "progesterone receptors", "type": "ENTITY", "char_start": 456044, "char_end": 456066, "token_start": 10, "token_end": 11, "note": null}, {"text": "PR", "type": "ENTITY", "char_start": 456069, "char_end": 456071, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 2754, "sentence_text": "The cells positive for ER or PR were confirmed by spatial location , dual immunolabelling , and histochemical staining .", "sentence_char_start_global": 456171, "sentence_char_end_global": 456291, "entities": [{"text": "ER", "type": "ENTITY", "char_start": 23, "char_end": 25, "token_start": 4, "token_end": 4}, {"text": "PR", "type": "ENTITY", "char_start": 29, "char_end": 31, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "ER", "type": "ENTITY", "char_start": 456194, "char_end": 456196, "token_start": 4, "token_end": 4, "note": null}, {"text": "PR", "type": "ENTITY", "char_start": 456200, "char_end": 456202, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 2755, "sentence_text": "RESULTS : Consistent with the known features of nasal polyps , CD4 + ( T helper / inducer ) , CD8 + ( cytotoxic / suppressor ) , CD68 + ( macrophages ) , mast cells , eosinophils and neutrophils were all clearly detected by their relevant monoclonal antibodies or appropriate histochemical staining , but only mast cells tested positive for ER / PR labelling with their polyclonal and monoclonal antibodies .", "sentence_char_start_global": 456292, "sentence_char_end_global": 456700, "entities": [{"text": "monoclonal antibodies", "type": "ENTITY", "char_start": 239, "char_end": 260, "token_start": 47, "token_end": 48}, {"text": "ER", "type": "ENTITY", "char_start": 341, "char_end": 343, "token_start": 61, "token_end": 61}, {"text": "polyclonal and monoclonal antibodies", "type": "ENTITY", "char_start": 370, "char_end": 406, "token_start": 67, "token_end": 70}], "entities_global": [{"text": "monoclonal antibodies", "type": "ENTITY", "char_start": 456531, "char_end": 456552, "token_start": 47, "token_end": 48, "note": null}, {"text": "ER", "type": "ENTITY", "char_start": 456633, "char_end": 456635, "token_start": 61, "token_end": 61, "note": null}, {"text": "polyclonal and monoclonal antibodies", "type": "ENTITY", "char_start": 456662, "char_end": 456698, "token_start": 67, "token_end": 70, "note": null}]}
+{"sentence_id": 2756, "sentence_text": "The frequencies for expression were 61 . 7 % for ER positive and 59 . 6 % for PR positive cells .", "sentence_char_start_global": 456701, "sentence_char_end_global": 456798, "entities": [], "entities_global": []}
+{"sentence_id": 2757, "sentence_text": "The expression of ER / PR was independent of patient sex and age but was highly correlated with the numbers of mast cells ( r = 0 . 973 , p < 0 . 001 for ER ; r = 0 . 955 , p < 0 . 001 for PR ) .", "sentence_char_start_global": 456799, "sentence_char_end_global": 456994, "entities": [{"text": "ER", "type": "ENTITY", "char_start": 18, "char_end": 20, "token_start": 3, "token_end": 3}, {"text": "PR", "type": "ENTITY", "char_start": 23, "char_end": 25, "token_start": 5, "token_end": 5}, {"text": "ER", "type": "ENTITY", "char_start": 154, "char_end": 156, "token_start": 36, "token_end": 36}, {"text": "PR", "type": "ENTITY", "char_start": 189, "char_end": 191, "token_start": 50, "token_end": 50}], "entities_global": [{"text": "ER", "type": "ENTITY", "char_start": 456817, "char_end": 456819, "token_start": 3, "token_end": 3, "note": null}, {"text": "PR", "type": "ENTITY", "char_start": 456822, "char_end": 456824, "token_start": 5, "token_end": 5, "note": null}, {"text": "ER", "type": "ENTITY", "char_start": 456953, "char_end": 456955, "token_start": 36, "token_end": 36, "note": null}, {"text": "PR", "type": "ENTITY", "char_start": 456988, "char_end": 456990, "token_start": 50, "token_end": 50, "note": null}]}
+{"sentence_id": 2758, "sentence_text": "Fewer than 5 % of mast cells were found to be negative for ER / PR expression .", "sentence_char_start_global": 456995, "sentence_char_end_global": 457074, "entities": [{"text": "ER", "type": "ENTITY", "char_start": 59, "char_end": 61, "token_start": 13, "token_end": 13}, {"text": "PR", "type": "ENTITY", "char_start": 64, "char_end": 66, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "ER", "type": "ENTITY", "char_start": 457054, "char_end": 457056, "token_start": 13, "token_end": 13, "note": null}, {"text": "PR", "type": "ENTITY", "char_start": 457059, "char_end": 457061, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 2759, "sentence_text": "CONCLUSIONS : Mast cells alone , but not lymphocytes , macrophages , or other immune cells , express ER / PR in human upper airways .", "sentence_char_start_global": 457075, "sentence_char_end_global": 457208, "entities": [{"text": "ER", "type": "ENTITY", "char_start": 101, "char_end": 103, "token_start": 18, "token_end": 18}, {"text": "PR", "type": "ENTITY", "char_start": 106, "char_end": 108, "token_start": 20, "token_end": 20}], "entities_global": [{"text": "ER", "type": "ENTITY", "char_start": 457176, "char_end": 457178, "token_start": 18, "token_end": 18, "note": null}, {"text": "PR", "type": "ENTITY", "char_start": 457181, "char_end": 457183, "token_start": 20, "token_end": 20, "note": null}]}
+{"sentence_id": 2760, "sentence_text": "Numerous ER / PR positive mast cells exist in nasal polyps , indicating that this may be a major route for the involvement of sex hormones in airway inflammation when exposed to the higher and varying concentration of oestrogen and progesterone characteristic of females .", "sentence_char_start_global": 457209, "sentence_char_end_global": 457481, "entities": [], "entities_global": []}
+{"sentence_id": 2761, "sentence_text": "NF kappa b signaling in posthypoxic endothelial cells : relevance to E - selectin expression and neutrophil adhesion .", "sentence_char_start_global": 457482, "sentence_char_end_global": 457600, "entities": [], "entities_global": []}
+{"sentence_id": 2762, "sentence_text": "Our previous studies have implicated the nuclear transcription factor kappa B ( NF kappa B ) in the regulation of adhesion molecule expression in endothelial cells exposed to anoxia - reoxygenation ( A / R ) or a redox imbalance .", "sentence_char_start_global": 457601, "sentence_char_end_global": 457831, "entities": [{"text": "NF kappa B", "type": "ENTITY", "char_start": 80, "char_end": 90, "token_start": 12, "token_end": 14}, {"text": "adhesion molecule", "type": "ENTITY", "char_start": 114, "char_end": 131, "token_start": 20, "token_end": 21}], "entities_global": [{"text": "NF kappa B", "type": "ENTITY", "char_start": 457681, "char_end": 457691, "token_start": 12, "token_end": 14, "note": null}, {"text": "adhesion molecule", "type": "ENTITY", "char_start": 457715, "char_end": 457732, "token_start": 20, "token_end": 21, "note": null}]}
+{"sentence_id": 2763, "sentence_text": "The objectives of this study were ( 1 ) to define the kinetics of NF kappa B activation by examining I kappa B alpha degradation and the nuclear translocation of p65 in response to A / R or redox imbalance ( induced by treatment of cells with diamide and buthionine sulfoximine ) and ( 2 ) to determine whether the signal for I kappa B alpha degradation , nuclear translocation of p65 , and E - selectin - mediated neutrophil adhesion is related to the activity of protein tyrosine kinase ( PTK ) , protein tyrosine phosphatase ( PTPase ) and / or protein kinase C ( PKC ) .", "sentence_char_start_global": 457832, "sentence_char_end_global": 458406, "entities": [{"text": "NF kappa B", "type": "ENTITY", "char_start": 66, "char_end": 76, "token_start": 14, "token_end": 16}, {"text": "p65", "type": "ENTITY", "char_start": 162, "char_end": 165, "token_start": 30, "token_end": 30}, {"text": "p65", "type": "ENTITY", "char_start": 381, "char_end": 384, "token_start": 71, "token_end": 71}, {"text": "E - selectin", "type": "ENTITY", "char_start": 391, "char_end": 403, "token_start": 74, "token_end": 76}, {"text": "protein tyrosine kinase", "type": "ENTITY", "char_start": 465, "char_end": 488, "token_start": 87, "token_end": 89}, {"text": "PTK", "type": "ENTITY", "char_start": 491, "char_end": 494, "token_start": 91, "token_end": 91}, {"text": "protein tyrosine phosphatase", "type": "ENTITY", "char_start": 499, "char_end": 527, "token_start": 94, "token_end": 96}, {"text": "PTPase", "type": "ENTITY", "char_start": 530, "char_end": 536, "token_start": 98, "token_end": 98}, {"text": "protein kinase C", "type": "ENTITY", "char_start": 548, "char_end": 564, "token_start": 103, "token_end": 105}, {"text": "PKC", "type": "ENTITY", "char_start": 567, "char_end": 570, "token_start": 107, "token_end": 107}], "entities_global": [{"text": "NF kappa B", "type": "ENTITY", "char_start": 457898, "char_end": 457908, "token_start": 14, "token_end": 16, "note": null}, {"text": "p65", "type": "ENTITY", "char_start": 457994, "char_end": 457997, "token_start": 30, "token_end": 30, "note": null}, {"text": "p65", "type": "ENTITY", "char_start": 458213, "char_end": 458216, "token_start": 71, "token_end": 71, "note": null}, {"text": "E - selectin", "type": "ENTITY", "char_start": 458223, "char_end": 458235, "token_start": 74, "token_end": 76, "note": null}, {"text": "protein tyrosine kinase", "type": "ENTITY", "char_start": 458297, "char_end": 458320, "token_start": 87, "token_end": 89, "note": null}, {"text": "PTK", "type": "ENTITY", "char_start": 458323, "char_end": 458326, "token_start": 91, "token_end": 91, "note": null}, {"text": "protein tyrosine phosphatase", "type": "ENTITY", "char_start": 458331, "char_end": 458359, "token_start": 94, "token_end": 96, "note": null}, {"text": "PTPase", "type": "ENTITY", "char_start": 458362, "char_end": 458368, "token_start": 98, "token_end": 98, "note": null}, {"text": "protein kinase C", "type": "ENTITY", "char_start": 458380, "char_end": 458396, "token_start": 103, "token_end": 105, "note": null}, {"text": "PKC", "type": "ENTITY", "char_start": 458399, "char_end": 458402, "token_start": 107, "token_end": 107, "note": null}]}
+{"sentence_id": 2764, "sentence_text": "The results demonstrate that both A / R and redox imbalance led to I kappa B alpha degradation within 30 min and the concomitant appearance of p65 in the nucleus , consistent with rapid cytosolic activation of NF kappa B and subsequent nuclear translocation of the activated p65 subunit .", "sentence_char_start_global": 458407, "sentence_char_end_global": 458695, "entities": [{"text": "p65", "type": "ENTITY", "char_start": 143, "char_end": 146, "token_start": 26, "token_end": 26}, {"text": "NF kappa B", "type": "ENTITY", "char_start": 210, "char_end": 220, "token_start": 37, "token_end": 39}, {"text": "activated p65 subunit", "type": "ENTITY", "char_start": 265, "char_end": 286, "token_start": 46, "token_end": 48}], "entities_global": [{"text": "p65", "type": "ENTITY", "char_start": 458550, "char_end": 458553, "token_start": 26, "token_end": 26, "note": null}, {"text": "NF kappa B", "type": "ENTITY", "char_start": 458617, "char_end": 458627, "token_start": 37, "token_end": 39, "note": null}, {"text": "activated p65 subunit", "type": "ENTITY", "char_start": 458672, "char_end": 458693, "token_start": 46, "token_end": 48, "note": null}]}
+{"sentence_id": 2765, "sentence_text": "Inhibition of PKC blocked I kappa B alpha degradation and p65 translocation in A / R - challenged , but not redox - altered , endothelial cells .", "sentence_char_start_global": 458696, "sentence_char_end_global": 458841, "entities": [{"text": "PKC", "type": "ENTITY", "char_start": 14, "char_end": 17, "token_start": 2, "token_end": 2}, {"text": "I kappa B alpha", "type": "ENTITY", "char_start": 26, "char_end": 41, "token_start": 4, "token_end": 7}, {"text": "p65", "type": "ENTITY", "char_start": 58, "char_end": 61, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "PKC", "type": "ENTITY", "char_start": 458710, "char_end": 458713, "token_start": 2, "token_end": 2, "note": null}, {"text": "I kappa B alpha", "type": "ENTITY", "char_start": 458722, "char_end": 458737, "token_start": 4, "token_end": 7, "note": null}, {"text": "p65", "type": "ENTITY", "char_start": 458754, "char_end": 458757, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 2766, "sentence_text": "However , both A / R - and redox - induced NF kappa B activation was blocked by inhibition of PTK .", "sentence_char_start_global": 458842, "sentence_char_end_global": 458941, "entities": [{"text": "PTK", "type": "ENTITY", "char_start": 94, "char_end": 97, "token_start": 20, "token_end": 20}], "entities_global": [{"text": "PTK", "type": "ENTITY", "char_start": 458936, "char_end": 458939, "token_start": 20, "token_end": 20, "note": null}]}
+{"sentence_id": 2767, "sentence_text": "Similarly , A / R - induced E - selectin expression and neutrophil - endothelial cell adhesion were blocked by inhibition of PKC or PTK , while only PTK inhibited the redox - induced adhesion response .", "sentence_char_start_global": 458942, "sentence_char_end_global": 459144, "entities": [{"text": "PKC", "type": "ENTITY", "char_start": 125, "char_end": 128, "token_start": 22, "token_end": 22}, {"text": "PTK", "type": "ENTITY", "char_start": 132, "char_end": 135, "token_start": 24, "token_end": 24}, {"text": "PTK", "type": "ENTITY", "char_start": 149, "char_end": 152, "token_start": 28, "token_end": 28}], "entities_global": [{"text": "PKC", "type": "ENTITY", "char_start": 459067, "char_end": 459070, "token_start": 22, "token_end": 22, "note": null}, {"text": "PTK", "type": "ENTITY", "char_start": 459074, "char_end": 459077, "token_start": 24, "token_end": 24, "note": null}, {"text": "PTK", "type": "ENTITY", "char_start": 459091, "char_end": 459094, "token_start": 28, "token_end": 28, "note": null}]}
+{"sentence_id": 2768, "sentence_text": "Pretreatment of cells with N - acetyl cysteine effectively blocked A / R - or redox - induced I kappa B degradation and significantly attenuated the respective neutrophil adhesion responses .", "sentence_char_start_global": 459145, "sentence_char_end_global": 459336, "entities": [], "entities_global": []}
+{"sentence_id": 2769, "sentence_text": "Collectively , these findings indicate that A / R - induced E - selectin expression and neutrophil - endothelial cell adhesion are mediated by both PKC and PTK , which signal rapid activation of NF kappa B .", "sentence_char_start_global": 459337, "sentence_char_end_global": 459544, "entities": [{"text": "PKC", "type": "ENTITY", "char_start": 148, "char_end": 151, "token_start": 25, "token_end": 25}, {"text": "PTK", "type": "ENTITY", "char_start": 156, "char_end": 159, "token_start": 27, "token_end": 27}, {"text": "NF kappa B", "type": "ENTITY", "char_start": 195, "char_end": 205, "token_start": 34, "token_end": 36}], "entities_global": [{"text": "PKC", "type": "ENTITY", "char_start": 459485, "char_end": 459488, "token_start": 25, "token_end": 25, "note": null}, {"text": "PTK", "type": "ENTITY", "char_start": 459493, "char_end": 459496, "token_start": 27, "token_end": 27, "note": null}, {"text": "NF kappa B", "type": "ENTITY", "char_start": 459532, "char_end": 459542, "token_start": 34, "token_end": 36, "note": null}]}
+{"sentence_id": 2770, "sentence_text": "This A / R - induced NF kappa B signaling response appears to be mediated , at least in part , by intracellular redox imbalance .", "sentence_char_start_global": 459545, "sentence_char_end_global": 459674, "entities": [{"text": "NF kappa B", "type": "ENTITY", "char_start": 21, "char_end": 31, "token_start": 6, "token_end": 8}], "entities_global": [{"text": "NF kappa B", "type": "ENTITY", "char_start": 459566, "char_end": 459576, "token_start": 6, "token_end": 8, "note": null}]}
+{"sentence_id": 2771, "sentence_text": "Copyright 2001 S . Karger AG , Basel", "sentence_char_start_global": 459675, "sentence_char_end_global": 459711, "entities": [], "entities_global": []}
+{"sentence_id": 2772, "sentence_text": "Induction of apoptosis in human lymphocytes by the herbicide 2 , 4 - dichlorophenoxyaceti acid .", "sentence_char_start_global": 459712, "sentence_char_end_global": 459808, "entities": [], "entities_global": []}
+{"sentence_id": 2773, "sentence_text": "Dimethylammonium salt of 2 , 4 - dichlorophenoxyaceti acid ( DMA - 2 , 4 - D ) is a widely used herbicide that is considered moderately toxic .", "sentence_char_start_global": 459809, "sentence_char_end_global": 459952, "entities": [], "entities_global": []}
+{"sentence_id": 2774, "sentence_text": "In the present study we found that DMA - 2 , 4 - D is able to cause apoptosis in peripheral blood lymphocytes of healthy individuals and Jurkat T cells .", "sentence_char_start_global": 459953, "sentence_char_end_global": 460106, "entities": [], "entities_global": []}
+{"sentence_id": 2775, "sentence_text": "Apoptosis induced by DMA - 2 , 4 - D was dose and time dependent , independent of Fas , TNF receptor 1 or the aromatic hydrocarbon receptor , and involved disruption of the mitochondrial transmembrane potential and activation of caspase - 9 .", "sentence_char_start_global": 460107, "sentence_char_end_global": 460349, "entities": [{"text": "Fas", "type": "ENTITY", "char_start": 82, "char_end": 85, "token_start": 18, "token_end": 18}, {"text": "TNF receptor 1", "type": "ENTITY", "char_start": 88, "char_end": 102, "token_start": 20, "token_end": 22}, {"text": "aromatic hydrocarbon receptor", "type": "ENTITY", "char_start": 110, "char_end": 139, "token_start": 25, "token_end": 27}, {"text": "caspase - 9", "type": "ENTITY", "char_start": 229, "char_end": 240, "token_start": 40, "token_end": 42}], "entities_global": [{"text": "Fas", "type": "ENTITY", "char_start": 460189, "char_end": 460192, "token_start": 18, "token_end": 18, "note": null}, {"text": "TNF receptor 1", "type": "ENTITY", "char_start": 460195, "char_end": 460209, "token_start": 20, "token_end": 22, "note": null}, {"text": "aromatic hydrocarbon receptor", "type": "ENTITY", "char_start": 460217, "char_end": 460246, "token_start": 25, "token_end": 27, "note": null}, {"text": "caspase - 9", "type": "ENTITY", "char_start": 460336, "char_end": 460347, "token_start": 40, "token_end": 42, "note": null}]}
+{"sentence_id": 2776, "sentence_text": "ZVAD - FMK , a broad - spectrum inhibitor of caspases , blocked DMA - 2 , 4 - D - induced apoptosis completely .", "sentence_char_start_global": 460350, "sentence_char_end_global": 460462, "entities": [{"text": "caspases", "type": "ENTITY", "char_start": 45, "char_end": 53, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "caspases", "type": "ENTITY", "char_start": 460395, "char_end": 460403, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 2777, "sentence_text": "While an inhibitor of caspase - 9 , as well as caspase - 9 and caspase - 3 inhibitors in combination , strongly blocked DMA - 2 , 4 - D - induced apoptosis , an inhibitor of caspase - 3 had a moderate inhibitory effect .", "sentence_char_start_global": 460463, "sentence_char_end_global": 460683, "entities": [{"text": "caspase - 9", "type": "ENTITY", "char_start": 22, "char_end": 33, "token_start": 4, "token_end": 6}, {"text": "caspase - 9", "type": "ENTITY", "char_start": 47, "char_end": 58, "token_start": 11, "token_end": 13}, {"text": "caspase - 3", "type": "ENTITY", "char_start": 174, "char_end": 185, "token_start": 38, "token_end": 40}], "entities_global": [{"text": "caspase - 9", "type": "ENTITY", "char_start": 460485, "char_end": 460496, "token_start": 4, "token_end": 6, "note": null}, {"text": "caspase - 9", "type": "ENTITY", "char_start": 460510, "char_end": 460521, "token_start": 11, "token_end": 13, "note": null}, {"text": "caspase - 3", "type": "ENTITY", "char_start": 460637, "char_end": 460648, "token_start": 38, "token_end": 40, "note": null}]}
+{"sentence_id": 2778, "sentence_text": "Unlike Fas - mediated apoptosis , the initiator caspase , caspase - 8 , was not involved in DMA - 2 , 4 - D - induced apoptosis .", "sentence_char_start_global": 460684, "sentence_char_end_global": 460813, "entities": [{"text": "Fas", "type": "ENTITY", "char_start": 7, "char_end": 10, "token_start": 1, "token_end": 1}, {"text": "initiator caspase", "type": "ENTITY", "char_start": 38, "char_end": 55, "token_start": 7, "token_end": 8}, {"text": "caspase - 8", "type": "ENTITY", "char_start": 58, "char_end": 69, "token_start": 10, "token_end": 12}], "entities_global": [{"text": "Fas", "type": "ENTITY", "char_start": 460691, "char_end": 460694, "token_start": 1, "token_end": 1, "note": null}, {"text": "initiator caspase", "type": "ENTITY", "char_start": 460722, "char_end": 460739, "token_start": 7, "token_end": 8, "note": null}, {"text": "caspase - 8", "type": "ENTITY", "char_start": 460742, "char_end": 460753, "token_start": 10, "token_end": 12, "note": null}]}
+{"sentence_id": 2779, "sentence_text": "Transfection of Jurkat cells with Bcl - 2 prevented DMA - 2 , 4 - D - induced disruption of the mitochondrial transmembrane potential and led to a complete blockage of apoptosis .", "sentence_char_start_global": 460814, "sentence_char_end_global": 460993, "entities": [{"text": "Bcl - 2", "type": "ENTITY", "char_start": 34, "char_end": 41, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "Bcl - 2", "type": "ENTITY", "char_start": 460848, "char_end": 460855, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 2780, "sentence_text": "Our data indicate that DMA - 2 , 4 - D kills human lymphocytes by initiating apoptosis via a direct effect on mitochondria .", "sentence_char_start_global": 460994, "sentence_char_end_global": 461118, "entities": [], "entities_global": []}
+{"sentence_id": 2781, "sentence_text": "The activation of caspases occurs downstream of mitochondrial damage , and the dysfunction of mitochondria appears to be sufficient for triggering all downstream events leading to apoptosis .", "sentence_char_start_global": 461119, "sentence_char_end_global": 461310, "entities": [{"text": "caspases", "type": "ENTITY", "char_start": 18, "char_end": 26, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "caspases", "type": "ENTITY", "char_start": 461137, "char_end": 461145, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 2782, "sentence_text": "Inhibition of Th1 differentiation by IL - 6 is mediated by SOCS1 .", "sentence_char_start_global": 461311, "sentence_char_end_global": 461377, "entities": [{"text": "IL - 6", "type": "ENTITY", "char_start": 37, "char_end": 43, "token_start": 5, "token_end": 7}, {"text": "SOCS1", "type": "ENTITY", "char_start": 59, "char_end": 64, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "IL - 6", "type": "ENTITY", "char_start": 461348, "char_end": 461354, "token_start": 5, "token_end": 7, "note": null}, {"text": "SOCS1", "type": "ENTITY", "char_start": 461370, "char_end": 461375, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 2783, "sentence_text": "Interleukin 6 ( IL - 6 ) is a cytokine produced by immune and nonimmune cells and exhibits functional pleiotropy and redundancy .", "sentence_char_start_global": 461378, "sentence_char_end_global": 461507, "entities": [{"text": "Interleukin 6", "type": "ENTITY", "char_start": 0, "char_end": 13, "token_start": 0, "token_end": 1}, {"text": "IL - 6", "type": "ENTITY", "char_start": 16, "char_end": 22, "token_start": 3, "token_end": 5}, {"text": "cytokine", "type": "ENTITY", "char_start": 30, "char_end": 38, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "Interleukin 6", "type": "ENTITY", "char_start": 461378, "char_end": 461391, "token_start": 0, "token_end": 1, "note": null}, {"text": "IL - 6", "type": "ENTITY", "char_start": 461394, "char_end": 461400, "token_start": 3, "token_end": 5, "note": null}, {"text": "cytokine", "type": "ENTITY", "char_start": 461408, "char_end": 461416, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 2784, "sentence_text": "IL - 6 plays an important role in the differentiation of several cell types .", "sentence_char_start_global": 461508, "sentence_char_end_global": 461585, "entities": [{"text": "IL - 6", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "IL - 6", "type": "ENTITY", "char_start": 461508, "char_end": 461514, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 2785, "sentence_text": "Here , we describe a novel function of IL - 6 : the negative regulation of CD4 + Th1 cell differentiation .", "sentence_char_start_global": 461586, "sentence_char_end_global": 461693, "entities": [{"text": "IL - 6", "type": "ENTITY", "char_start": 39, "char_end": 45, "token_start": 8, "token_end": 10}, {"text": "CD4", "type": "ENTITY", "char_start": 75, "char_end": 78, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "IL - 6", "type": "ENTITY", "char_start": 461625, "char_end": 461631, "token_start": 8, "token_end": 10, "note": null}, {"text": "CD4", "type": "ENTITY", "char_start": 461661, "char_end": 461664, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 2786, "sentence_text": "While IL - 6 - directed CD4 + Th2 differentiation is mediated by IL - 4 , inhibition of Th1 differentiation by IL - 6 is independent of IL - 4 .", "sentence_char_start_global": 461694, "sentence_char_end_global": 461838, "entities": [{"text": "IL - 6", "type": "ENTITY", "char_start": 6, "char_end": 12, "token_start": 1, "token_end": 3}, {"text": "CD4", "type": "ENTITY", "char_start": 24, "char_end": 27, "token_start": 6, "token_end": 6}, {"text": "IL - 4", "type": "ENTITY", "char_start": 65, "char_end": 71, "token_start": 13, "token_end": 15}, {"text": "IL - 6", "type": "ENTITY", "char_start": 111, "char_end": 117, "token_start": 22, "token_end": 24}, {"text": "IL - 4", "type": "ENTITY", "char_start": 136, "char_end": 142, "token_start": 28, "token_end": 30}], "entities_global": [{"text": "IL - 6", "type": "ENTITY", "char_start": 461700, "char_end": 461706, "token_start": 1, "token_end": 3, "note": null}, {"text": "CD4", "type": "ENTITY", "char_start": 461718, "char_end": 461721, "token_start": 6, "token_end": 6, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 461759, "char_end": 461765, "token_start": 13, "token_end": 15, "note": null}, {"text": "IL - 6", "type": "ENTITY", "char_start": 461805, "char_end": 461811, "token_start": 22, "token_end": 24, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 461830, "char_end": 461836, "token_start": 28, "token_end": 30, "note": null}]}
+{"sentence_id": 2787, "sentence_text": "IL - 6 upregulates suppressor of cytokine signaling 1 ( SOCS1 ) expression in activated CD4 + T cells , thereby interfering with signal transducer and activator of transcription 1 ( STAT1 ) phosphorylation induced by interferon gamma ( IFNgamma ) .", "sentence_char_start_global": 461839, "sentence_char_end_global": 462087, "entities": [{"text": "IL - 6", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 2}, {"text": "suppressor of cytokine signaling 1", "type": "ENTITY", "char_start": 19, "char_end": 53, "token_start": 4, "token_end": 8}, {"text": "SOCS1", "type": "ENTITY", "char_start": 56, "char_end": 61, "token_start": 10, "token_end": 10}, {"text": "signal transducer and activator of transcription 1", "type": "ENTITY", "char_start": 129, "char_end": 179, "token_start": 23, "token_end": 29}, {"text": "STAT1", "type": "ENTITY", "char_start": 182, "char_end": 187, "token_start": 31, "token_end": 31}, {"text": "interferon gamma", "type": "ENTITY", "char_start": 217, "char_end": 233, "token_start": 36, "token_end": 37}, {"text": "IFNgamma", "type": "ENTITY", "char_start": 236, "char_end": 244, "token_start": 39, "token_end": 39}], "entities_global": [{"text": "IL - 6", "type": "ENTITY", "char_start": 461839, "char_end": 461845, "token_start": 0, "token_end": 2, "note": null}, {"text": "suppressor of cytokine signaling 1", "type": "ENTITY", "char_start": 461858, "char_end": 461892, "token_start": 4, "token_end": 8, "note": null}, {"text": "SOCS1", "type": "ENTITY", "char_start": 461895, "char_end": 461900, "token_start": 10, "token_end": 10, "note": null}, {"text": "signal transducer and activator of transcription 1", "type": "ENTITY", "char_start": 461968, "char_end": 462018, "token_start": 23, "token_end": 29, "note": null}, {"text": "STAT1", "type": "ENTITY", "char_start": 462021, "char_end": 462026, "token_start": 31, "token_end": 31, "note": null}, {"text": "interferon gamma", "type": "ENTITY", "char_start": 462056, "char_end": 462072, "token_start": 36, "token_end": 37, "note": null}, {"text": "IFNgamma", "type": "ENTITY", "char_start": 462075, "char_end": 462083, "token_start": 39, "token_end": 39, "note": null}]}
+{"sentence_id": 2788, "sentence_text": "Inhibition of IFNgamma receptor - mediated signals by IL - 6 prevents autoregulation of IFNgamma gene expression by IFNgamma during CD4 + T cell activation , thereby preventing Th1 differentiation .", "sentence_char_start_global": 462088, "sentence_char_end_global": 462286, "entities": [{"text": "IFNgamma", "type": "ENTITY", "char_start": 14, "char_end": 22, "token_start": 2, "token_end": 2}, {"text": "IL - 6", "type": "ENTITY", "char_start": 54, "char_end": 60, "token_start": 8, "token_end": 10}, {"text": "IFNgamma gene", "type": "ENTITY", "char_start": 88, "char_end": 101, "token_start": 14, "token_end": 15}, {"text": "IFNgamma", "type": "ENTITY", "char_start": 116, "char_end": 124, "token_start": 18, "token_end": 18}], "entities_global": [{"text": "IFNgamma", "type": "ENTITY", "char_start": 462102, "char_end": 462110, "token_start": 2, "token_end": 2, "note": null}, {"text": "IL - 6", "type": "ENTITY", "char_start": 462142, "char_end": 462148, "token_start": 8, "token_end": 10, "note": null}, {"text": "IFNgamma gene", "type": "ENTITY", "char_start": 462176, "char_end": 462189, "token_start": 14, "token_end": 15, "note": null}, {"text": "IFNgamma", "type": "ENTITY", "char_start": 462204, "char_end": 462212, "token_start": 18, "token_end": 18, "note": null}]}
+{"sentence_id": 2789, "sentence_text": "Thus , IL - 6 promotes CD4 + Th2 differentiation and inhibits Th1 differentiation by two independent molecular mechanisms .", "sentence_char_start_global": 462287, "sentence_char_end_global": 462410, "entities": [{"text": "IL - 6", "type": "ENTITY", "char_start": 7, "char_end": 13, "token_start": 2, "token_end": 4}, {"text": "CD4", "type": "ENTITY", "char_start": 23, "char_end": 26, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "IL - 6", "type": "ENTITY", "char_start": 462294, "char_end": 462300, "token_start": 2, "token_end": 4, "note": null}, {"text": "CD4", "type": "ENTITY", "char_start": 462310, "char_end": 462313, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 2790, "sentence_text": "Interaction between CCAAT / enhancer binding protein and cyclic AMP response element binding protein 1 regulates human immunodeficiency virus type 1 transcription in cells of the monocyte / macrophage lineage .", "sentence_char_start_global": 462411, "sentence_char_end_global": 462621, "entities": [{"text": "CCAAT / enhancer binding protein", "type": "ENTITY", "char_start": 20, "char_end": 52, "token_start": 2, "token_end": 6}, {"text": "cyclic AMP response element binding protein 1", "type": "ENTITY", "char_start": 57, "char_end": 102, "token_start": 8, "token_end": 14}], "entities_global": [{"text": "CCAAT / enhancer binding protein", "type": "ENTITY", "char_start": 462431, "char_end": 462463, "token_start": 2, "token_end": 6, "note": null}, {"text": "cyclic AMP response element binding protein 1", "type": "ENTITY", "char_start": 462468, "char_end": 462513, "token_start": 8, "token_end": 14, "note": null}]}
+{"sentence_id": 2791, "sentence_text": "Recent observations have shown two CCAAT / enhancer binding protein ( C / EBP ) binding sites to be critically important for efficient human immunodeficiency virus type 1 ( HIV - 1 ) replication within cells of the monocyte / macrophage lineage , a cell type likely involved in transport of the virus to the brain .", "sentence_char_start_global": 462622, "sentence_char_end_global": 462937, "entities": [{"text": "CCAAT / enhancer binding protein ( C / EBP ) binding sites", "type": "ENTITY", "char_start": 35, "char_end": 93, "token_start": 5, "token_end": 16}], "entities_global": [{"text": "CCAAT / enhancer binding protein ( C / EBP ) binding sites", "type": "ENTITY", "char_start": 462657, "char_end": 462715, "token_start": 5, "token_end": 16, "note": null}]}
+{"sentence_id": 2792, "sentence_text": "Additionally , sequence variation at C / EBP site I , which lies immediately upstream of the distal nuclear factor kappa B site and immediately downstream of a binding site for activating transcription factor ( ATF ) / cyclic AMP response element binding protein ( CREB ) , has been shown to affect HIV - 1 long terminal repeat ( LTR ) activity .", "sentence_char_start_global": 462938, "sentence_char_end_global": 463284, "entities": [{"text": "C / EBP site I", "type": "ENTITY", "char_start": 37, "char_end": 51, "token_start": 5, "token_end": 9}, {"text": "distal nuclear factor kappa B site", "type": "ENTITY", "char_start": 93, "char_end": 127, "token_start": 17, "token_end": 22}, {"text": "activating transcription factor", "type": "ENTITY", "char_start": 177, "char_end": 208, "token_start": 31, "token_end": 33}, {"text": "ATF", "type": "ENTITY", "char_start": 211, "char_end": 214, "token_start": 35, "token_end": 35}, {"text": "cyclic AMP response element binding protein", "type": "ENTITY", "char_start": 219, "char_end": 262, "token_start": 38, "token_end": 43}, {"text": "CREB", "type": "ENTITY", "char_start": 265, "char_end": 269, "token_start": 45, "token_end": 45}, {"text": "HIV - 1 long terminal repeat", "type": "ENTITY", "char_start": 299, "char_end": 327, "token_start": 53, "token_end": 58}, {"text": "LTR", "type": "ENTITY", "char_start": 330, "char_end": 333, "token_start": 60, "token_end": 60}], "entities_global": [{"text": "C / EBP site I", "type": "ENTITY", "char_start": 462975, "char_end": 462989, "token_start": 5, "token_end": 9, "note": null}, {"text": "distal nuclear factor kappa B site", "type": "ENTITY", "char_start": 463031, "char_end": 463065, "token_start": 17, "token_end": 22, "note": null}, {"text": "activating transcription factor", "type": "ENTITY", "char_start": 463115, "char_end": 463146, "token_start": 31, "token_end": 33, "note": null}, {"text": "ATF", "type": "ENTITY", "char_start": 463149, "char_end": 463152, "token_start": 35, "token_end": 35, "note": null}, {"text": "cyclic AMP response element binding protein", "type": "ENTITY", "char_start": 463157, "char_end": 463200, "token_start": 38, "token_end": 43, "note": null}, {"text": "CREB", "type": "ENTITY", "char_start": 463203, "char_end": 463207, "token_start": 45, "token_end": 45, "note": null}, {"text": "HIV - 1 long terminal repeat", "type": "ENTITY", "char_start": 463237, "char_end": 463265, "token_start": 53, "token_end": 58, "note": null}, {"text": "LTR", "type": "ENTITY", "char_start": 463268, "char_end": 463271, "token_start": 60, "token_end": 60, "note": null}]}
+{"sentence_id": 2793, "sentence_text": "Given that C / EBP proteins have been shown to interact with many other transcription factors including members of the ATF / CREB family , we proceeded to determine whether an adjacent ATF / CREB binding site could affect C / EBP protein binding to C / EBP site I .", "sentence_char_start_global": 463285, "sentence_char_end_global": 463550, "entities": [{"text": "C / EBP proteins", "type": "ENTITY", "char_start": 11, "char_end": 27, "token_start": 2, "token_end": 5}, {"text": "transcription factors", "type": "ENTITY", "char_start": 72, "char_end": 93, "token_start": 14, "token_end": 15}, {"text": "ATF / CREB family", "type": "ENTITY", "char_start": 119, "char_end": 136, "token_start": 20, "token_end": 23}, {"text": "ATF / CREB binding site", "type": "ENTITY", "char_start": 185, "char_end": 208, "token_start": 32, "token_end": 36}, {"text": "C / EBP protein", "type": "ENTITY", "char_start": 222, "char_end": 237, "token_start": 39, "token_end": 42}, {"text": "C / EBP site I", "type": "ENTITY", "char_start": 249, "char_end": 263, "token_start": 45, "token_end": 49}], "entities_global": [{"text": "C / EBP proteins", "type": "ENTITY", "char_start": 463296, "char_end": 463312, "token_start": 2, "token_end": 5, "note": null}, {"text": "transcription factors", "type": "ENTITY", "char_start": 463357, "char_end": 463378, "token_start": 14, "token_end": 15, "note": null}, {"text": "ATF / CREB family", "type": "ENTITY", "char_start": 463404, "char_end": 463421, "token_start": 20, "token_end": 23, "note": null}, {"text": "ATF / CREB binding site", "type": "ENTITY", "char_start": 463470, "char_end": 463493, "token_start": 32, "token_end": 36, "note": null}, {"text": "C / EBP protein", "type": "ENTITY", "char_start": 463507, "char_end": 463522, "token_start": 39, "token_end": 42, "note": null}, {"text": "C / EBP site I", "type": "ENTITY", "char_start": 463534, "char_end": 463548, "token_start": 45, "token_end": 49, "note": null}]}
+{"sentence_id": 2794, "sentence_text": "Electrophoretic mobility shift analyses indicated that selected ATF / CREB site variants assisted in the recruitment of C / EBP proteins to an adjacent , naturally occurring , low - affinity C / EBP site .", "sentence_char_start_global": 463551, "sentence_char_end_global": 463756, "entities": [{"text": "ATF / CREB site variants", "type": "ENTITY", "char_start": 64, "char_end": 88, "token_start": 7, "token_end": 11}, {"text": "C / EBP proteins", "type": "ENTITY", "char_start": 120, "char_end": 136, "token_start": 17, "token_end": 20}, {"text": "C / EBP site", "type": "ENTITY", "char_start": 191, "char_end": 203, "token_start": 31, "token_end": 34}], "entities_global": [{"text": "ATF / CREB site variants", "type": "ENTITY", "char_start": 463615, "char_end": 463639, "token_start": 7, "token_end": 11, "note": null}, {"text": "C / EBP proteins", "type": "ENTITY", "char_start": 463671, "char_end": 463687, "token_start": 17, "token_end": 20, "note": null}, {"text": "C / EBP site", "type": "ENTITY", "char_start": 463742, "char_end": 463754, "token_start": 31, "token_end": 34, "note": null}]}
+{"sentence_id": 2795, "sentence_text": "This biophysical interaction appears to occur via at least two mechanisms .", "sentence_char_start_global": 463757, "sentence_char_end_global": 463832, "entities": [], "entities_global": []}
+{"sentence_id": 2796, "sentence_text": "First , low amounts of CREB - 1 and C / EBP appear to heterodimerize and bind to a site consisting of a half site from both the ATF / CREB and C / EBP binding sites .", "sentence_char_start_global": 463833, "sentence_char_end_global": 463999, "entities": [{"text": "CREB - 1", "type": "ENTITY", "char_start": 23, "char_end": 31, "token_start": 5, "token_end": 7}, {"text": "C / EBP", "type": "ENTITY", "char_start": 36, "char_end": 43, "token_start": 9, "token_end": 11}, {"text": "ATF / CREB and C / EBP binding sites", "type": "ENTITY", "char_start": 128, "char_end": 164, "token_start": 28, "token_end": 36}], "entities_global": [{"text": "CREB - 1", "type": "ENTITY", "char_start": 463856, "char_end": 463864, "token_start": 5, "token_end": 7, "note": null}, {"text": "C / EBP", "type": "ENTITY", "char_start": 463869, "char_end": 463876, "token_start": 9, "token_end": 11, "note": null}, {"text": "ATF / CREB and C / EBP binding sites", "type": "ENTITY", "char_start": 463961, "char_end": 463997, "token_start": 28, "token_end": 36, "note": null}]}
+{"sentence_id": 2797, "sentence_text": "In addition , CREB - 1 homodimers bind to the ATF / CREB site and recruit C / EBP dimers to their cognate weak binding sites .", "sentence_char_start_global": 464000, "sentence_char_end_global": 464126, "entities": [{"text": "CREB - 1 homodimers", "type": "ENTITY", "char_start": 14, "char_end": 33, "token_start": 3, "token_end": 6}, {"text": "ATF / CREB site", "type": "ENTITY", "char_start": 46, "char_end": 61, "token_start": 10, "token_end": 13}, {"text": "C / EBP dimers", "type": "ENTITY", "char_start": 74, "char_end": 88, "token_start": 16, "token_end": 19}, {"text": "weak binding sites", "type": "ENTITY", "char_start": 106, "char_end": 124, "token_start": 23, "token_end": 25}], "entities_global": [{"text": "CREB - 1 homodimers", "type": "ENTITY", "char_start": 464014, "char_end": 464033, "token_start": 3, "token_end": 6, "note": null}, {"text": "ATF / CREB site", "type": "ENTITY", "char_start": 464046, "char_end": 464061, "token_start": 10, "token_end": 13, "note": null}, {"text": "C / EBP dimers", "type": "ENTITY", "char_start": 464074, "char_end": 464088, "token_start": 16, "token_end": 19, "note": null}, {"text": "weak binding sites", "type": "ENTITY", "char_start": 464106, "char_end": 464124, "token_start": 23, "token_end": 25, "note": null}]}
+{"sentence_id": 2798, "sentence_text": "This interaction is reciprocal , since C / EBP dimer binding to a strong C / EBP site leads to enhanced CREB - 1 recruitment to ATF / CREB sites that are weakly bound by CREB .", "sentence_char_start_global": 464127, "sentence_char_end_global": 464303, "entities": [{"text": "C / EBP dimer", "type": "ENTITY", "char_start": 39, "char_end": 52, "token_start": 6, "token_end": 9}, {"text": "C / EBP site", "type": "ENTITY", "char_start": 73, "char_end": 85, "token_start": 14, "token_end": 17}, {"text": "CREB - 1", "type": "ENTITY", "char_start": 104, "char_end": 112, "token_start": 21, "token_end": 23}, {"text": "ATF / CREB sites", "type": "ENTITY", "char_start": 128, "char_end": 144, "token_start": 26, "token_end": 29}, {"text": "CREB", "type": "ENTITY", "char_start": 170, "char_end": 174, "token_start": 35, "token_end": 35}], "entities_global": [{"text": "C / EBP dimer", "type": "ENTITY", "char_start": 464166, "char_end": 464179, "token_start": 6, "token_end": 9, "note": null}, {"text": "C / EBP site", "type": "ENTITY", "char_start": 464200, "char_end": 464212, "token_start": 14, "token_end": 17, "note": null}, {"text": "CREB - 1", "type": "ENTITY", "char_start": 464231, "char_end": 464239, "token_start": 21, "token_end": 23, "note": null}, {"text": "ATF / CREB sites", "type": "ENTITY", "char_start": 464255, "char_end": 464271, "token_start": 26, "token_end": 29, "note": null}, {"text": "CREB", "type": "ENTITY", "char_start": 464297, "char_end": 464301, "token_start": 35, "token_end": 35, "note": null}]}
+{"sentence_id": 2799, "sentence_text": "Sequence variation at both C / EBP and ATF / CREB sites affects the molecular interactions involved in mediating both of these mechanisms .", "sentence_char_start_global": 464304, "sentence_char_end_global": 464443, "entities": [{"text": "C / EBP and ATF / CREB sites", "type": "ENTITY", "char_start": 27, "char_end": 55, "token_start": 4, "token_end": 11}], "entities_global": [{"text": "C / EBP and ATF / CREB sites", "type": "ENTITY", "char_start": 464331, "char_end": 464359, "token_start": 4, "token_end": 11, "note": null}]}
+{"sentence_id": 2800, "sentence_text": "Most importantly , sequence variation at the ATF / CREB binding site affected basal LTR activity as well as LTR function following interleukin - 6 stimulation , a treatment that leads to increases in C / EBP activation .", "sentence_char_start_global": 464444, "sentence_char_end_global": 464664, "entities": [{"text": "ATF / CREB binding site", "type": "ENTITY", "char_start": 45, "char_end": 68, "token_start": 7, "token_end": 11}, {"text": "LTR", "type": "ENTITY", "char_start": 84, "char_end": 87, "token_start": 14, "token_end": 14}, {"text": "LTR", "type": "ENTITY", "char_start": 108, "char_end": 111, "token_start": 19, "token_end": 19}, {"text": "interleukin - 6", "type": "ENTITY", "char_start": 131, "char_end": 146, "token_start": 22, "token_end": 24}], "entities_global": [{"text": "ATF / CREB binding site", "type": "ENTITY", "char_start": 464489, "char_end": 464512, "token_start": 7, "token_end": 11, "note": null}, {"text": "LTR", "type": "ENTITY", "char_start": 464528, "char_end": 464531, "token_start": 14, "token_end": 14, "note": null}, {"text": "LTR", "type": "ENTITY", "char_start": 464552, "char_end": 464555, "token_start": 19, "token_end": 19, "note": null}, {"text": "interleukin - 6", "type": "ENTITY", "char_start": 464575, "char_end": 464590, "token_start": 22, "token_end": 24, "note": null}]}
+{"sentence_id": 2801, "sentence_text": "Thus , HIV - 1 LTR ATF / CREB binding site sequence variation may modulate cellular signaling at the viral promoter through the C / EBP pathway", "sentence_char_start_global": 464665, "sentence_char_end_global": 464808, "entities": [{"text": "HIV - 1 LTR", "type": "ENTITY", "char_start": 7, "char_end": 18, "token_start": 2, "token_end": 5}, {"text": "ATF / CREB binding site", "type": "ENTITY", "char_start": 19, "char_end": 42, "token_start": 6, "token_end": 10}, {"text": "viral promoter", "type": "ENTITY", "char_start": 101, "char_end": 115, "token_start": 19, "token_end": 20}], "entities_global": [{"text": "HIV - 1 LTR", "type": "ENTITY", "char_start": 464672, "char_end": 464683, "token_start": 2, "token_end": 5, "note": null}, {"text": "ATF / CREB binding site", "type": "ENTITY", "char_start": 464684, "char_end": 464707, "token_start": 6, "token_end": 10, "note": null}, {"text": "viral promoter", "type": "ENTITY", "char_start": 464766, "char_end": 464780, "token_start": 19, "token_end": 20, "note": null}]}
+{"sentence_id": 2802, "sentence_text": "Selective inhibition of interleukin - 4 gene expression in human T cells by aspirin .", "sentence_char_start_global": 464809, "sentence_char_end_global": 464894, "entities": [], "entities_global": []}
+{"sentence_id": 2803, "sentence_text": "Previous studies indicated that aspirin ( acetylsalicylic acid [ ASA ] ) can have profound immunomodulatory effects by regulating cytokine gene expression in several types of cells .", "sentence_char_start_global": 464895, "sentence_char_end_global": 465077, "entities": [], "entities_global": []}
+{"sentence_id": 2804, "sentence_text": "This study is the first in which concentrations of ASA in the therapeutic range were found to significantly reduce interleukin ( IL ) - 4 secretion and RNA expression in freshly isolated and mitogen - primed human CD4 + T cells .", "sentence_char_start_global": 465078, "sentence_char_end_global": 465307, "entities": [{"text": "interleukin ( IL ) - 4", "type": "ENTITY", "char_start": 115, "char_end": 137, "token_start": 19, "token_end": 24}], "entities_global": [{"text": "interleukin ( IL ) - 4", "type": "ENTITY", "char_start": 465193, "char_end": 465215, "token_start": 19, "token_end": 24, "note": null}]}
+{"sentence_id": 2805, "sentence_text": "In contrast , ASA did not affect IL - 13 , interferon - gamma , and IL - 2 expression .", "sentence_char_start_global": 465308, "sentence_char_end_global": 465395, "entities": [{"text": "IL - 13", "type": "ENTITY", "char_start": 33, "char_end": 40, "token_start": 7, "token_end": 9}, {"text": "interferon - gamma", "type": "ENTITY", "char_start": 43, "char_end": 61, "token_start": 11, "token_end": 13}, {"text": "IL - 2", "type": "ENTITY", "char_start": 68, "char_end": 74, "token_start": 16, "token_end": 18}], "entities_global": [{"text": "IL - 13", "type": "ENTITY", "char_start": 465341, "char_end": 465348, "token_start": 7, "token_end": 9, "note": null}, {"text": "interferon - gamma", "type": "ENTITY", "char_start": 465351, "char_end": 465369, "token_start": 11, "token_end": 13, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 465376, "char_end": 465382, "token_start": 16, "token_end": 18, "note": null}]}
+{"sentence_id": 2806, "sentence_text": "ASA inhibited IL - 4 , but not IL - 2 , promoter - driven chloramphenicol acetyltransferase expression in transiently transfected Jurkat T cells .", "sentence_char_start_global": 465396, "sentence_char_end_global": 465542, "entities": [{"text": "IL - 4", "type": "ENTITY", "char_start": 14, "char_end": 20, "token_start": 2, "token_end": 4}, {"text": "IL - 2", "type": "ENTITY", "char_start": 31, "char_end": 37, "token_start": 8, "token_end": 10}], "entities_global": [{"text": "IL - 4", "type": "ENTITY", "char_start": 465410, "char_end": 465416, "token_start": 2, "token_end": 4, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 465427, "char_end": 465433, "token_start": 8, "token_end": 10, "note": null}]}
+{"sentence_id": 2807, "sentence_text": "The structurally unrelated nonsteroidal anti - inflammatory drugs indomethacin and flurbiprofen did not affect cytokine gene expression in T cells , whereas the weak cyclo - oxygenase inhibitor salicylic acid was at least as effective as ASA in inhibiting IL - 4 expression and promoter activity .", "sentence_char_start_global": 465543, "sentence_char_end_global": 465840, "entities": [{"text": "IL - 4", "type": "ENTITY", "char_start": 256, "char_end": 262, "token_start": 39, "token_end": 41}], "entities_global": [{"text": "IL - 4", "type": "ENTITY", "char_start": 465799, "char_end": 465805, "token_start": 39, "token_end": 41, "note": null}]}
+{"sentence_id": 2808, "sentence_text": "The inhibitory effect of ASA on IL - 4 transcription was not mediated by decreased nuclear expression of the known salicylate target nuclear factor ( NF ) - kappaB and was accompanied by reduced binding of an inducible factor to an IL - 4 promoter region upstream of , but not overlapping , the NF of activated T cells - and NF - kappaB - binding P1 element .", "sentence_char_start_global": 465841, "sentence_char_end_global": 466200, "entities": [{"text": "salicylate target nuclear factor ( NF ) - kappaB", "type": "ENTITY", "char_start": 115, "char_end": 163, "token_start": 20, "token_end": 28}, {"text": "IL - 4 promoter region", "type": "ENTITY", "char_start": 232, "char_end": 254, "token_start": 41, "token_end": 45}, {"text": "NF of activated T cells - and NF - kappaB - binding P1 element", "type": "ENTITY", "char_start": 295, "char_end": 357, "token_start": 54, "token_end": 67}], "entities_global": [{"text": "salicylate target nuclear factor ( NF ) - kappaB", "type": "ENTITY", "char_start": 465956, "char_end": 466004, "token_start": 20, "token_end": 28, "note": null}, {"text": "IL - 4 promoter region", "type": "ENTITY", "char_start": 466073, "char_end": 466095, "token_start": 41, "token_end": 45, "note": null}, {"text": "NF of activated T cells - and NF - kappaB - binding P1 element", "type": "ENTITY", "char_start": 466136, "char_end": 466198, "token_start": 54, "token_end": 67, "note": null}]}
+{"sentence_id": 2809, "sentence_text": "It is concluded that anti - inflammatory salicylates , by means of a previously unrecognized mechanism of action , can influence the nature of adaptive immune responses by selectively inhibiting the expression of IL - 4 , a critical effector of these responses , in CD4 + T cells .", "sentence_char_start_global": 466201, "sentence_char_end_global": 466482, "entities": [{"text": "IL - 4", "type": "ENTITY", "char_start": 213, "char_end": 219, "token_start": 33, "token_end": 35}], "entities_global": [{"text": "IL - 4", "type": "ENTITY", "char_start": 466414, "char_end": 466420, "token_start": 33, "token_end": 35, "note": null}]}
+{"sentence_id": 2810, "sentence_text": "Molecular and cellular mediators of interleukin - 1 - dependent acute inflammatory arthritis .", "sentence_char_start_global": 466483, "sentence_char_end_global": 466577, "entities": [{"text": "interleukin - 1", "type": "ENTITY", "char_start": 36, "char_end": 51, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "interleukin - 1", "type": "ENTITY", "char_start": 466519, "char_end": 466534, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 2811, "sentence_text": "OBJECTIVE : To examine the molecular and cellular mechanisms in a model of acute inflammatory monarticular arthritis induced by methylated bovine serum albumin ( mBSA ) and interleukin - 1 ( IL - 1 ) .", "sentence_char_start_global": 466578, "sentence_char_end_global": 466779, "entities": [{"text": "methylated bovine serum albumin", "type": "ENTITY", "char_start": 128, "char_end": 159, "token_start": 19, "token_end": 22}, {"text": "mBSA", "type": "ENTITY", "char_start": 162, "char_end": 166, "token_start": 24, "token_end": 24}, {"text": "interleukin - 1", "type": "ENTITY", "char_start": 173, "char_end": 188, "token_start": 27, "token_end": 29}, {"text": "IL - 1", "type": "ENTITY", "char_start": 191, "char_end": 197, "token_start": 31, "token_end": 33}], "entities_global": [{"text": "methylated bovine serum albumin", "type": "ENTITY", "char_start": 466706, "char_end": 466737, "token_start": 19, "token_end": 22, "note": null}, {"text": "mBSA", "type": "ENTITY", "char_start": 466740, "char_end": 466744, "token_start": 24, "token_end": 24, "note": null}, {"text": "interleukin - 1", "type": "ENTITY", "char_start": 466751, "char_end": 466766, "token_start": 27, "token_end": 29, "note": null}, {"text": "IL - 1", "type": "ENTITY", "char_start": 466769, "char_end": 466775, "token_start": 31, "token_end": 33, "note": null}]}
+{"sentence_id": 2812, "sentence_text": "METHODS : Mice were injected intraarticularly with mBSA on day 0 and subcutaneously with recombinant human IL - 1beta on days 0 - 2 .", "sentence_char_start_global": 466780, "sentence_char_end_global": 466913, "entities": [{"text": "mBSA", "type": "ENTITY", "char_start": 51, "char_end": 55, "token_start": 7, "token_end": 7}, {"text": "recombinant human IL - 1beta", "type": "ENTITY", "char_start": 89, "char_end": 117, "token_start": 14, "token_end": 18}], "entities_global": [{"text": "mBSA", "type": "ENTITY", "char_start": 466831, "char_end": 466835, "token_start": 7, "token_end": 7, "note": null}, {"text": "recombinant human IL - 1beta", "type": "ENTITY", "char_start": 466869, "char_end": 466897, "token_start": 14, "token_end": 18, "note": null}]}
+{"sentence_id": 2813, "sentence_text": "At day 7 , knee joints were removed and assessed histologically .", "sentence_char_start_global": 466914, "sentence_char_end_global": 466979, "entities": [], "entities_global": []}
+{"sentence_id": 2814, "sentence_text": "Flow cytometry and RNase protection were used to analyze IL - 1 - dependent events .", "sentence_char_start_global": 466980, "sentence_char_end_global": 467064, "entities": [{"text": "IL - 1", "type": "ENTITY", "char_start": 57, "char_end": 63, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "IL - 1", "type": "ENTITY", "char_start": 467037, "char_end": 467043, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 2815, "sentence_text": "RESULTS : C57BL / 6 ( B6 ) , 129 / Sv , and ( B6 x 129 / Sv ) F1 hybrid mice , all H - 2b strains , were susceptible to mBSA / IL - 1 - induced arthritis , whereas C3H / HeJ ( H - 2k ) mice were not .", "sentence_char_start_global": 467065, "sentence_char_end_global": 467265, "entities": [{"text": "mBSA", "type": "ENTITY", "char_start": 120, "char_end": 124, "token_start": 34, "token_end": 34}], "entities_global": [{"text": "mBSA", "type": "ENTITY", "char_start": 467185, "char_end": 467189, "token_start": 34, "token_end": 34, "note": null}]}
+{"sentence_id": 2816, "sentence_text": "B6 mice lacking T and B cells ( RAG1 - / - ) or major histocompatibility complex ( MHC ) class II antigens ( MHCII - / - ) , and B6 mice treated with a CD4 + T cell - depleting monoclonal antibody , were resistant to disease .", "sentence_char_start_global": 467266, "sentence_char_end_global": 467492, "entities": [{"text": "major histocompatibility complex ( MHC ) class II antigens", "type": "ENTITY", "char_start": 48, "char_end": 106, "token_start": 14, "token_end": 22}, {"text": "CD4 + T cell - depleting monoclonal antibody", "type": "ENTITY", "char_start": 152, "char_end": 196, "token_start": 36, "token_end": 43}], "entities_global": [{"text": "major histocompatibility complex ( MHC ) class II antigens", "type": "ENTITY", "char_start": 467314, "char_end": 467372, "token_start": 14, "token_end": 22, "note": null}, {"text": "CD4 + T cell - depleting monoclonal antibody", "type": "ENTITY", "char_start": 467418, "char_end": 467462, "token_start": 36, "token_end": 43, "note": null}]}
+{"sentence_id": 2817, "sentence_text": "In contrast , B cell - deficient ( muMT / muMT ) mice developed arthritis at an incidence and severity similar to that of controls .", "sentence_char_start_global": 467493, "sentence_char_end_global": 467625, "entities": [], "entities_global": []}
+{"sentence_id": 2818, "sentence_text": "RelB - deficient ( RelB - / - ) bone marrow chimeric mice had arthritis that was significantly reduced in incidence and severity .", "sentence_char_start_global": 467626, "sentence_char_end_global": 467756, "entities": [], "entities_global": []}
+{"sentence_id": 2819, "sentence_text": "In B6 mice , flow cytometry demonstrated an IL - 1 - dependent leukocyte infiltration into the synovial compartment and RNase protection assays revealed induction of messenger RNA ( mRNA ) for the chemokines monocyte chemoattractant protein 1 , macrophage inhibitory protein 2 ( MIP - 2 ) , RANTES , MIP - 1alpha , and MIP - 1beta , in vivo and in vitro .", "sentence_char_start_global": 467757, "sentence_char_end_global": 468112, "entities": [{"text": "messenger RNA", "type": "ENTITY", "char_start": 166, "char_end": 179, "token_start": 26, "token_end": 27}, {"text": "mRNA", "type": "ENTITY", "char_start": 182, "char_end": 186, "token_start": 29, "token_end": 29}, {"text": "chemokines", "type": "ENTITY", "char_start": 197, "char_end": 207, "token_start": 33, "token_end": 33}, {"text": "monocyte chemoattractant protein 1", "type": "ENTITY", "char_start": 208, "char_end": 242, "token_start": 34, "token_end": 37}, {"text": "macrophage inhibitory protein 2", "type": "ENTITY", "char_start": 245, "char_end": 276, "token_start": 39, "token_end": 42}, {"text": "MIP - 2", "type": "ENTITY", "char_start": 279, "char_end": 286, "token_start": 44, "token_end": 46}, {"text": "RANTES", "type": "ENTITY", "char_start": 291, "char_end": 297, "token_start": 49, "token_end": 49}, {"text": "MIP - 1alpha", "type": "ENTITY", "char_start": 300, "char_end": 312, "token_start": 51, "token_end": 53}, {"text": "MIP - 1beta", "type": "ENTITY", "char_start": 319, "char_end": 330, "token_start": 56, "token_end": 58}], "entities_global": [{"text": "messenger RNA", "type": "ENTITY", "char_start": 467923, "char_end": 467936, "token_start": 26, "token_end": 27, "note": null}, {"text": "mRNA", "type": "ENTITY", "char_start": 467939, "char_end": 467943, "token_start": 29, "token_end": 29, "note": null}, {"text": "chemokines", "type": "ENTITY", "char_start": 467954, "char_end": 467964, "token_start": 33, "token_end": 33, "note": null}, {"text": "monocyte chemoattractant protein 1", "type": "ENTITY", "char_start": 467965, "char_end": 467999, "token_start": 34, "token_end": 37, "note": null}, {"text": "macrophage inhibitory protein 2", "type": "ENTITY", "char_start": 468002, "char_end": 468033, "token_start": 39, "token_end": 42, "note": null}, {"text": "MIP - 2", "type": "ENTITY", "char_start": 468036, "char_end": 468043, "token_start": 44, "token_end": 46, "note": null}, {"text": "RANTES", "type": "ENTITY", "char_start": 468048, "char_end": 468054, "token_start": 49, "token_end": 49, "note": null}, {"text": "MIP - 1alpha", "type": "ENTITY", "char_start": 468057, "char_end": 468069, "token_start": 51, "token_end": 53, "note": null}, {"text": "MIP - 1beta", "type": "ENTITY", "char_start": 468076, "char_end": 468087, "token_start": 56, "token_end": 58, "note": null}]}
+{"sentence_id": 2820, "sentence_text": "CONCLUSION : Arthritis induced by mBSA / IL - 1 is strain specific and dependent on CD4 + T lymphocytes and at least partially on RelB , but not on B lymphocytes or antibody .", "sentence_char_start_global": 468113, "sentence_char_end_global": 468288, "entities": [{"text": "mBSA", "type": "ENTITY", "char_start": 34, "char_end": 38, "token_start": 5, "token_end": 5}, {"text": "IL - 1", "type": "ENTITY", "char_start": 41, "char_end": 47, "token_start": 7, "token_end": 9}, {"text": "RelB", "type": "ENTITY", "char_start": 130, "char_end": 134, "token_start": 25, "token_end": 25}, {"text": "antibody", "type": "ENTITY", "char_start": 165, "char_end": 173, "token_start": 33, "token_end": 33}], "entities_global": [{"text": "mBSA", "type": "ENTITY", "char_start": 468147, "char_end": 468151, "token_start": 5, "token_end": 5, "note": null}, {"text": "IL - 1", "type": "ENTITY", "char_start": 468154, "char_end": 468160, "token_start": 7, "token_end": 9, "note": null}, {"text": "RelB", "type": "ENTITY", "char_start": 468243, "char_end": 468247, "token_start": 25, "token_end": 25, "note": null}, {"text": "antibody", "type": "ENTITY", "char_start": 468278, "char_end": 468286, "token_start": 33, "token_end": 33, "note": null}]}
+{"sentence_id": 2821, "sentence_text": "IL - 1 contributes to leukocyte recruitment to the synovium and directly induces chemokine mRNA production by synovial cells .", "sentence_char_start_global": 468289, "sentence_char_end_global": 468415, "entities": [{"text": "IL - 1", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "IL - 1", "type": "ENTITY", "char_start": 468289, "char_end": 468295, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 2822, "sentence_text": "This model of acute monarticular arthritis is particularly suitable for further investigations into cell - mediated immunity in arthritis and the role of IL - 1 .", "sentence_char_start_global": 468416, "sentence_char_end_global": 468578, "entities": [{"text": "IL - 1", "type": "ENTITY", "char_start": 154, "char_end": 160, "token_start": 23, "token_end": 25}], "entities_global": [{"text": "IL - 1", "type": "ENTITY", "char_start": 468570, "char_end": 468576, "token_start": 23, "token_end": 25, "note": null}]}
+{"sentence_id": 2823, "sentence_text": "Positive and negative regulation of granulopoiesis by endogenous RARalpha .", "sentence_char_start_global": 468579, "sentence_char_end_global": 468654, "entities": [{"text": "endogenous RARalpha", "type": "ENTITY", "char_start": 54, "char_end": 73, "token_start": 7, "token_end": 8}], "entities_global": [{"text": "endogenous RARalpha", "type": "ENTITY", "char_start": 468633, "char_end": 468652, "token_start": 7, "token_end": 8, "note": null}]}
+{"sentence_id": 2824, "sentence_text": "Acute promyelocytic leukemia ( APL ) is always associated with chromosomal translocations that disrupt the retinoic acid receptor alpha ( RARalpha ) gene .", "sentence_char_start_global": 468655, "sentence_char_end_global": 468810, "entities": [{"text": "retinoic acid receptor alpha ( RARalpha ) gene", "type": "ENTITY", "char_start": 107, "char_end": 153, "token_start": 15, "token_end": 22}], "entities_global": [{"text": "retinoic acid receptor alpha ( RARalpha ) gene", "type": "ENTITY", "char_start": 468762, "char_end": 468808, "token_start": 15, "token_end": 22, "note": null}]}
+{"sentence_id": 2825, "sentence_text": "Whether these translocations relate to a role for endogenous RARalpha in normal granulopoiesis remains uncertain because most studies addressing this question have used non - physiological overexpression systems .", "sentence_char_start_global": 468811, "sentence_char_end_global": 469024, "entities": [{"text": "endogenous RARalpha", "type": "ENTITY", "char_start": 50, "char_end": 69, "token_start": 8, "token_end": 9}], "entities_global": [{"text": "endogenous RARalpha", "type": "ENTITY", "char_start": 468861, "char_end": 468880, "token_start": 8, "token_end": 9, "note": null}]}
+{"sentence_id": 2826, "sentence_text": "Granulocyte differentiation in cells derived from RARalpha - deficient ( RARalpha ( - / - ) ) mice was studied and evaluated in the context of agonist - bound and ligand - free RARalpha .", "sentence_char_start_global": 469025, "sentence_char_end_global": 469212, "entities": [{"text": "agonist - bound and ligand - free RARalpha", "type": "ENTITY", "char_start": 143, "char_end": 185, "token_start": 26, "token_end": 33}], "entities_global": [{"text": "agonist - bound and ligand - free RARalpha", "type": "ENTITY", "char_start": 469168, "char_end": 469210, "token_start": 26, "token_end": 33, "note": null}]}
+{"sentence_id": 2827, "sentence_text": "Our results demonstrate that RARalpha is dispensable for granulopoiesis , as RARalpha ( - / - ) mice have a normal granulocyte population despite an impaired ability to respond to retinoids .", "sentence_char_start_global": 469213, "sentence_char_end_global": 469404, "entities": [{"text": "RARalpha", "type": "ENTITY", "char_start": 29, "char_end": 37, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "RARalpha", "type": "ENTITY", "char_start": 469242, "char_end": 469250, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 2828, "sentence_text": "However , although it is not absolutely required , RARalpha can bidirectionally modulate granulopoiesis .", "sentence_char_start_global": 469405, "sentence_char_end_global": 469510, "entities": [{"text": "RARalpha", "type": "ENTITY", "char_start": 51, "char_end": 59, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "RARalpha", "type": "ENTITY", "char_start": 469456, "char_end": 469464, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 2829, "sentence_text": "RARalpha stimulates differentiation in response to exogenous retinoic acid .", "sentence_char_start_global": 469511, "sentence_char_end_global": 469587, "entities": [{"text": "RARalpha", "type": "ENTITY", "char_start": 0, "char_end": 8, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "RARalpha", "type": "ENTITY", "char_start": 469511, "char_end": 469519, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 2830, "sentence_text": "Furthermore , endogenous retinoids control granulopoiesis in vivo , as either vitamin A - deficient mice or animals treated with an RAR antagonist accumulate more immature granulocytes in their bone marrow .", "sentence_char_start_global": 469588, "sentence_char_end_global": 469795, "entities": [], "entities_global": []}
+{"sentence_id": 2831, "sentence_text": "Conversely , RARalpha acts to limit differentiation in the absence of ligand because granulocyte precursors from RARalpha ( - / - ) mice differentiate earlier in culture .", "sentence_char_start_global": 469796, "sentence_char_end_global": 469967, "entities": [{"text": "RARalpha", "type": "ENTITY", "char_start": 13, "char_end": 21, "token_start": 2, "token_end": 2}, {"text": "ligand", "type": "ENTITY", "char_start": 70, "char_end": 76, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "RARalpha", "type": "ENTITY", "char_start": 469809, "char_end": 469817, "token_start": 2, "token_end": 2, "note": null}, {"text": "ligand", "type": "ENTITY", "char_start": 469866, "char_end": 469872, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 2832, "sentence_text": "Thus , the block in granulopoiesis exerted by RARalpha fusion proteins expressed in APL cells may correspond to an amplification of a normal function of unliganded RARalpha .", "sentence_char_start_global": 469968, "sentence_char_end_global": 470142, "entities": [{"text": "RARalpha", "type": "ENTITY", "char_start": 46, "char_end": 54, "token_start": 8, "token_end": 8}, {"text": "fusion proteins", "type": "ENTITY", "char_start": 55, "char_end": 70, "token_start": 9, "token_end": 10}, {"text": "unliganded RARalpha", "type": "ENTITY", "char_start": 153, "char_end": 172, "token_start": 25, "token_end": 26}], "entities_global": [{"text": "RARalpha", "type": "ENTITY", "char_start": 470014, "char_end": 470022, "token_start": 8, "token_end": 8, "note": null}, {"text": "fusion proteins", "type": "ENTITY", "char_start": 470023, "char_end": 470038, "token_start": 9, "token_end": 10, "note": null}, {"text": "unliganded RARalpha", "type": "ENTITY", "char_start": 470121, "char_end": 470140, "token_start": 25, "token_end": 26, "note": null}]}
+{"sentence_id": 2833, "sentence_text": "Expression and function of a stem cell promoter for the murine CBFalpha2 gene : distinct roles and regulation in natural killer and T cell development .", "sentence_char_start_global": 470143, "sentence_char_end_global": 470295, "entities": [{"text": "stem cell promoter", "type": "ENTITY", "char_start": 29, "char_end": 47, "token_start": 5, "token_end": 7}, {"text": "murine CBFalpha2 gene", "type": "ENTITY", "char_start": 56, "char_end": 77, "token_start": 10, "token_end": 12}], "entities_global": [{"text": "stem cell promoter", "type": "ENTITY", "char_start": 470172, "char_end": 470190, "token_start": 5, "token_end": 7, "note": null}, {"text": "murine CBFalpha2 gene", "type": "ENTITY", "char_start": 470199, "char_end": 470220, "token_start": 10, "token_end": 12, "note": null}]}
+{"sentence_id": 2834, "sentence_text": "The Runt family transcription factor CBFalpha2 ( AML1 , PEBP2alphaB , or Runx1 ) is required by hematopoietic stem cells and expressed at high levels in T - lineage cells .", "sentence_char_start_global": 470296, "sentence_char_end_global": 470468, "entities": [{"text": "Runt family transcription factor", "type": "ENTITY", "char_start": 4, "char_end": 36, "token_start": 1, "token_end": 4}, {"text": "CBFalpha2", "type": "ENTITY", "char_start": 37, "char_end": 46, "token_start": 5, "token_end": 5}, {"text": "AML1", "type": "ENTITY", "char_start": 49, "char_end": 53, "token_start": 7, "token_end": 7}, {"text": "PEBP2alphaB", "type": "ENTITY", "char_start": 56, "char_end": 67, "token_start": 9, "token_end": 9}, {"text": "Runx1", "type": "ENTITY", "char_start": 73, "char_end": 78, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "Runt family transcription factor", "type": "ENTITY", "char_start": 470300, "char_end": 470332, "token_start": 1, "token_end": 4, "note": null}, {"text": "CBFalpha2", "type": "ENTITY", "char_start": 470333, "char_end": 470342, "token_start": 5, "token_end": 5, "note": null}, {"text": "AML1", "type": "ENTITY", "char_start": 470345, "char_end": 470349, "token_start": 7, "token_end": 7, "note": null}, {"text": "PEBP2alphaB", "type": "ENTITY", "char_start": 470352, "char_end": 470363, "token_start": 9, "token_end": 9, "note": null}, {"text": "Runx1", "type": "ENTITY", "char_start": 470369, "char_end": 470374, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 2835, "sentence_text": "In human T cells CBFalpha2 is usually transcribed from a different promoter ( distal promoter ) than in myeloid cells ( proximal promoter ) , but the developmental and functional significance of this promoter switch has not been known .", "sentence_char_start_global": 470469, "sentence_char_end_global": 470705, "entities": [{"text": "CBFalpha2", "type": "ENTITY", "char_start": 17, "char_end": 26, "token_start": 4, "token_end": 4}, {"text": "different promoter", "type": "ENTITY", "char_start": 57, "char_end": 75, "token_start": 10, "token_end": 11}, {"text": "distal promoter", "type": "ENTITY", "char_start": 78, "char_end": 93, "token_start": 13, "token_end": 14}, {"text": "proximal promoter", "type": "ENTITY", "char_start": 120, "char_end": 137, "token_start": 21, "token_end": 22}], "entities_global": [{"text": "CBFalpha2", "type": "ENTITY", "char_start": 470486, "char_end": 470495, "token_start": 4, "token_end": 4, "note": null}, {"text": "different promoter", "type": "ENTITY", "char_start": 470526, "char_end": 470544, "token_start": 10, "token_end": 11, "note": null}, {"text": "distal promoter", "type": "ENTITY", "char_start": 470547, "char_end": 470562, "token_start": 13, "token_end": 14, "note": null}, {"text": "proximal promoter", "type": "ENTITY", "char_start": 470589, "char_end": 470606, "token_start": 21, "token_end": 22, "note": null}]}
+{"sentence_id": 2836, "sentence_text": "Here , we report that both coding and noncoding sequences of the distal 5 ' end are highly conserved between the human and the murine genes , and the distal promoter is responsible for the overwhelming majority of CBFalpha2 expression in murine hematopoietic stem cells as well as in T cells .", "sentence_char_start_global": 470706, "sentence_char_end_global": 470999, "entities": [{"text": "coding and noncoding sequences", "type": "ENTITY", "char_start": 27, "char_end": 57, "token_start": 6, "token_end": 9}, {"text": "distal 5 ' end", "type": "ENTITY", "char_start": 65, "char_end": 79, "token_start": 12, "token_end": 15}, {"text": "human and the murine genes", "type": "ENTITY", "char_start": 113, "char_end": 139, "token_start": 21, "token_end": 25}, {"text": "distal promoter", "type": "ENTITY", "char_start": 150, "char_end": 165, "token_start": 29, "token_end": 30}], "entities_global": [{"text": "coding and noncoding sequences", "type": "ENTITY", "char_start": 470733, "char_end": 470763, "token_start": 6, "token_end": 9, "note": null}, {"text": "distal 5 ' end", "type": "ENTITY", "char_start": 470771, "char_end": 470785, "token_start": 12, "token_end": 15, "note": null}, {"text": "human and the murine genes", "type": "ENTITY", "char_start": 470819, "char_end": 470845, "token_start": 21, "token_end": 25, "note": null}, {"text": "distal promoter", "type": "ENTITY", "char_start": 470856, "char_end": 470871, "token_start": 29, "token_end": 30, "note": null}]}
+{"sentence_id": 2837, "sentence_text": "Distal promoter activity is maintained throughout T cell development and at lower levels in B cell development , but downregulated in natural killer cell development .", "sentence_char_start_global": 471000, "sentence_char_end_global": 471167, "entities": [], "entities_global": []}
+{"sentence_id": 2838, "sentence_text": "The distal N - terminal isoform binds to functionally important regulatory sites from known target genes with two - to threefold higher affinity than the proximal N - terminal isoform .", "sentence_char_start_global": 471168, "sentence_char_end_global": 471353, "entities": [{"text": "distal N - terminal isoform", "type": "ENTITY", "char_start": 4, "char_end": 31, "token_start": 1, "token_end": 5}, {"text": "regulatory sites", "type": "ENTITY", "char_start": 64, "char_end": 80, "token_start": 10, "token_end": 11}, {"text": "target genes", "type": "ENTITY", "char_start": 92, "char_end": 104, "token_start": 14, "token_end": 15}, {"text": "proximal N - terminal isoform", "type": "ENTITY", "char_start": 154, "char_end": 183, "token_start": 25, "token_end": 29}], "entities_global": [{"text": "distal N - terminal isoform", "type": "ENTITY", "char_start": 471172, "char_end": 471199, "token_start": 1, "token_end": 5, "note": null}, {"text": "regulatory sites", "type": "ENTITY", "char_start": 471232, "char_end": 471248, "token_start": 10, "token_end": 11, "note": null}, {"text": "target genes", "type": "ENTITY", "char_start": 471260, "char_end": 471272, "token_start": 14, "token_end": 15, "note": null}, {"text": "proximal N - terminal isoform", "type": "ENTITY", "char_start": 471322, "char_end": 471351, "token_start": 25, "token_end": 29, "note": null}]}
+{"sentence_id": 2839, "sentence_text": "Neither full - length isoform alters growth of a myeloid cell line under nondifferentiating conditions , but the proximal isoform selectively delays mitotic arrest of the cell line under differentiating conditions , resulting in the generation of greater numbers of neutrophils .", "sentence_char_start_global": 471354, "sentence_char_end_global": 471633, "entities": [{"text": "full - length isoform", "type": "ENTITY", "char_start": 8, "char_end": 29, "token_start": 1, "token_end": 4}, {"text": "proximal isoform", "type": "ENTITY", "char_start": 113, "char_end": 129, "token_start": 18, "token_end": 19}], "entities_global": [{"text": "full - length isoform", "type": "ENTITY", "char_start": 471362, "char_end": 471383, "token_start": 1, "token_end": 4, "note": null}, {"text": "proximal isoform", "type": "ENTITY", "char_start": 471467, "char_end": 471483, "token_start": 18, "token_end": 19, "note": null}]}
+{"sentence_id": 2840, "sentence_text": "Constitutive PI3 - K activity is essential for proliferation , but not survival , of Theileria parva - transformed B cells .", "sentence_char_start_global": 471634, "sentence_char_end_global": 471758, "entities": [], "entities_global": []}
+{"sentence_id": 2841, "sentence_text": "Theileria is an intracellular parasite that causes lymphoproliferative disorders in cattle , and infection of leucocytes induces a transformed phenotype similar to tumour cells , but the mechanisms by which the parasite induces this phenotype are not understood .", "sentence_char_start_global": 471759, "sentence_char_end_global": 472022, "entities": [], "entities_global": []}
+{"sentence_id": 2842, "sentence_text": "Here , we show that infected B lymphocytes display constitutive phosphoinositide 3 - kinase ( PI3 - K ) activity , which appears to be necessary for proliferation , but not survival .", "sentence_char_start_global": 472023, "sentence_char_end_global": 472206, "entities": [], "entities_global": []}
+{"sentence_id": 2843, "sentence_text": "Importantly , we demonstrate that one mechanism by which PI3 - K mediates the proliferation of infected B lymphocytes is through the induction of a granulocyte - monocyte colony - stimulating factor ( GM - CSF ) - dependent autocrine loop .", "sentence_char_start_global": 472207, "sentence_char_end_global": 472447, "entities": [{"text": "PI3 - K", "type": "ENTITY", "char_start": 57, "char_end": 64, "token_start": 9, "token_end": 11}, {"text": "granulocyte - monocyte colony - stimulating factor", "type": "ENTITY", "char_start": 148, "char_end": 198, "token_start": 25, "token_end": 31}, {"text": "GM - CSF", "type": "ENTITY", "char_start": 201, "char_end": 209, "token_start": 33, "token_end": 35}], "entities_global": [{"text": "PI3 - K", "type": "ENTITY", "char_start": 472264, "char_end": 472271, "token_start": 9, "token_end": 11, "note": null}, {"text": "granulocyte - monocyte colony - stimulating factor", "type": "ENTITY", "char_start": 472355, "char_end": 472405, "token_start": 25, "token_end": 31, "note": null}, {"text": "GM - CSF", "type": "ENTITY", "char_start": 472408, "char_end": 472416, "token_start": 33, "token_end": 35, "note": null}]}
+{"sentence_id": 2844, "sentence_text": "PI3 - K induction of GM - CSF appears to be at the transcriptional level and , consistently , we demonstrate that PI3 - K is also involved in the constitutive induction of AP - 1 and NF - kappaB , which characterizes Theileria - infected leucocytes .", "sentence_char_start_global": 472448, "sentence_char_end_global": 472698, "entities": [{"text": "PI3 - K", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 2}, {"text": "GM - CSF", "type": "ENTITY", "char_start": 21, "char_end": 29, "token_start": 5, "token_end": 7}, {"text": "PI3 - K", "type": "ENTITY", "char_start": 114, "char_end": 121, "token_start": 22, "token_end": 24}, {"text": "AP - 1", "type": "ENTITY", "char_start": 172, "char_end": 178, "token_start": 33, "token_end": 35}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 183, "char_end": 194, "token_start": 37, "token_end": 39}], "entities_global": [{"text": "PI3 - K", "type": "ENTITY", "char_start": 472448, "char_end": 472455, "token_start": 0, "token_end": 2, "note": null}, {"text": "GM - CSF", "type": "ENTITY", "char_start": 472469, "char_end": 472477, "token_start": 5, "token_end": 7, "note": null}, {"text": "PI3 - K", "type": "ENTITY", "char_start": 472562, "char_end": 472569, "token_start": 22, "token_end": 24, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 472620, "char_end": 472626, "token_start": 33, "token_end": 35, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 472631, "char_end": 472642, "token_start": 37, "token_end": 39, "note": null}]}
+{"sentence_id": 2845, "sentence_text": "Taken together , our results highlight a novel strategy exploited by the intracellular parasite Theileria to induce continued proliferation of its host leucocyte .", "sentence_char_start_global": 472699, "sentence_char_end_global": 472862, "entities": [], "entities_global": []}
+{"sentence_id": 2846, "sentence_text": "Lymphokine dependence of STAT3 activation produced by surface immunoglobulin cross - linking and by phorbol ester plus calcium ionophore treatment in B cells .", "sentence_char_start_global": 472863, "sentence_char_end_global": 473022, "entities": [{"text": "Lymphokine", "type": "ENTITY", "char_start": 0, "char_end": 10, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "Lymphokine", "type": "ENTITY", "char_start": 472863, "char_end": 472873, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 2847, "sentence_text": "Stimulation of B cells by surface immunoglobulin ( sIg ) triggering , or through the mitogenic combination of phorbol ester and calcium ionophore , is accompanied by activation of STAT transcription factors .", "sentence_char_start_global": 473023, "sentence_char_end_global": 473231, "entities": [{"text": "surface immunoglobulin", "type": "ENTITY", "char_start": 26, "char_end": 48, "token_start": 5, "token_end": 6}, {"text": "sIg", "type": "ENTITY", "char_start": 51, "char_end": 54, "token_start": 8, "token_end": 8}, {"text": "STAT transcription factors", "type": "ENTITY", "char_start": 180, "char_end": 206, "token_start": 29, "token_end": 31}], "entities_global": [{"text": "surface immunoglobulin", "type": "ENTITY", "char_start": 473049, "char_end": 473071, "token_start": 5, "token_end": 6, "note": null}, {"text": "sIg", "type": "ENTITY", "char_start": 473074, "char_end": 473077, "token_start": 8, "token_end": 8, "note": null}, {"text": "STAT transcription factors", "type": "ENTITY", "char_start": 473203, "char_end": 473229, "token_start": 29, "token_end": 31, "note": null}]}
+{"sentence_id": 2848, "sentence_text": "The mechanism responsible for the delayed nuclear accumulation of phosphorylated STAT3 was examined in detail , focusing on the role of B cell - derived lymphokines .", "sentence_char_start_global": 473232, "sentence_char_end_global": 473398, "entities": [{"text": "phosphorylated STAT3", "type": "ENTITY", "char_start": 66, "char_end": 86, "token_start": 9, "token_end": 10}, {"text": "B cell - derived lymphokines", "type": "ENTITY", "char_start": 136, "char_end": 164, "token_start": 21, "token_end": 25}], "entities_global": [{"text": "phosphorylated STAT3", "type": "ENTITY", "char_start": 473298, "char_end": 473318, "token_start": 9, "token_end": 10, "note": null}, {"text": "B cell - derived lymphokines", "type": "ENTITY", "char_start": 473368, "char_end": 473396, "token_start": 21, "token_end": 25, "note": null}]}
+{"sentence_id": 2849, "sentence_text": "sIg - induced activation of STAT3 was partially inhibited in B cells obtained from IL - 6 - or IL - 10 - deficient mice , and was partially blocked by neutralizing antibodies directed against either of these lymphokines .", "sentence_char_start_global": 473399, "sentence_char_end_global": 473620, "entities": [{"text": "sIg", "type": "ENTITY", "char_start": 0, "char_end": 3, "token_start": 0, "token_end": 0}, {"text": "STAT3", "type": "ENTITY", "char_start": 28, "char_end": 33, "token_start": 5, "token_end": 5}, {"text": "neutralizing antibodies", "type": "ENTITY", "char_start": 151, "char_end": 174, "token_start": 31, "token_end": 32}, {"text": "lymphokines", "type": "ENTITY", "char_start": 208, "char_end": 219, "token_start": 38, "token_end": 38}], "entities_global": [{"text": "sIg", "type": "ENTITY", "char_start": 473399, "char_end": 473402, "token_start": 0, "token_end": 0, "note": null}, {"text": "STAT3", "type": "ENTITY", "char_start": 473427, "char_end": 473432, "token_start": 5, "token_end": 5, "note": null}, {"text": "neutralizing antibodies", "type": "ENTITY", "char_start": 473550, "char_end": 473573, "token_start": 31, "token_end": 32, "note": null}, {"text": "lymphokines", "type": "ENTITY", "char_start": 473607, "char_end": 473618, "token_start": 38, "token_end": 38, "note": null}]}
+{"sentence_id": 2850, "sentence_text": "sIg - induced STAT3 activation was completely inhibited by combining IL - 6 - and IL - 10 - specific neutralizing antibodies , or by adding individual neutralizing antibodies to B cells obtained from lymphokine - deficient animals .", "sentence_char_start_global": 473621, "sentence_char_end_global": 473853, "entities": [{"text": "sIg", "type": "ENTITY", "char_start": 0, "char_end": 3, "token_start": 0, "token_end": 0}, {"text": "IL - 6 - and IL - 10 - specific neutralizing antibodies", "type": "ENTITY", "char_start": 69, "char_end": 124, "token_start": 10, "token_end": 21}, {"text": "neutralizing antibodies", "type": "ENTITY", "char_start": 151, "char_end": 174, "token_start": 27, "token_end": 28}], "entities_global": [{"text": "sIg", "type": "ENTITY", "char_start": 473621, "char_end": 473624, "token_start": 0, "token_end": 0, "note": null}, {"text": "IL - 6 - and IL - 10 - specific neutralizing antibodies", "type": "ENTITY", "char_start": 473690, "char_end": 473745, "token_start": 10, "token_end": 21, "note": null}, {"text": "neutralizing antibodies", "type": "ENTITY", "char_start": 473772, "char_end": 473795, "token_start": 27, "token_end": 28, "note": null}]}
+{"sentence_id": 2851, "sentence_text": "In contrast , IL - 10 alone appeared to account for STAT3 activation resulting from B cell stimulation with phorbol ester and calcium ionophore .", "sentence_char_start_global": 473854, "sentence_char_end_global": 473999, "entities": [{"text": "IL - 10", "type": "ENTITY", "char_start": 14, "char_end": 21, "token_start": 3, "token_end": 5}], "entities_global": [{"text": "IL - 10", "type": "ENTITY", "char_start": 473868, "char_end": 473875, "token_start": 3, "token_end": 5, "note": null}]}
+{"sentence_id": 2852, "sentence_text": "In keeping with these results , soluble IL - 6 and IL - 10 were found in supernatant fluid obtained from stimulated B cells .", "sentence_char_start_global": 474000, "sentence_char_end_global": 474125, "entities": [{"text": "IL - 6", "type": "ENTITY", "char_start": 40, "char_end": 46, "token_start": 7, "token_end": 9}, {"text": "IL - 10", "type": "ENTITY", "char_start": 51, "char_end": 58, "token_start": 11, "token_end": 13}], "entities_global": [{"text": "IL - 6", "type": "ENTITY", "char_start": 474040, "char_end": 474046, "token_start": 7, "token_end": 9, "note": null}, {"text": "IL - 10", "type": "ENTITY", "char_start": 474051, "char_end": 474058, "token_start": 11, "token_end": 13, "note": null}]}
+{"sentence_id": 2853, "sentence_text": "This work indicates that a lymphokine pathway is responsible for STAT3 activation that occurs late after B cell stimulation , and points out differences in B cell activation that result from stimulation through the antigen receptor and through pharmacological mimicry of signaling mediators .", "sentence_char_start_global": 474126, "sentence_char_end_global": 474418, "entities": [{"text": "antigen receptor", "type": "ENTITY", "char_start": 215, "char_end": 231, "token_start": 34, "token_end": 35}, {"text": "signaling mediators", "type": "ENTITY", "char_start": 271, "char_end": 290, "token_start": 41, "token_end": 42}], "entities_global": [{"text": "antigen receptor", "type": "ENTITY", "char_start": 474341, "char_end": 474357, "token_start": 34, "token_end": 35, "note": null}, {"text": "signaling mediators", "type": "ENTITY", "char_start": 474397, "char_end": 474416, "token_start": 41, "token_end": 42, "note": null}]}
+{"sentence_id": 2854, "sentence_text": "Transcription factor AP - 4 is a ligand for immunoglobulin - kappa promoter E - box elements .", "sentence_char_start_global": 474419, "sentence_char_end_global": 474513, "entities": [{"text": "Transcription factor AP - 4", "type": "ENTITY", "char_start": 0, "char_end": 27, "token_start": 0, "token_end": 4}, {"text": "ligand", "type": "ENTITY", "char_start": 33, "char_end": 39, "token_start": 7, "token_end": 7}, {"text": "immunoglobulin - kappa promoter E - box elements", "type": "ENTITY", "char_start": 44, "char_end": 92, "token_start": 9, "token_end": 16}], "entities_global": [{"text": "Transcription factor AP - 4", "type": "ENTITY", "char_start": 474419, "char_end": 474446, "token_start": 0, "token_end": 4, "note": null}, {"text": "ligand", "type": "ENTITY", "char_start": 474452, "char_end": 474458, "token_start": 7, "token_end": 7, "note": null}, {"text": "immunoglobulin - kappa promoter E - box elements", "type": "ENTITY", "char_start": 474463, "char_end": 474511, "token_start": 9, "token_end": 16, "note": null}]}
+{"sentence_id": 2855, "sentence_text": "Immunoglobulin ( Ig ) - kappa promoters from humans and mice share conserved sequences .", "sentence_char_start_global": 474514, "sentence_char_end_global": 474602, "entities": [{"text": "Immunoglobulin ( Ig ) - kappa promoters", "type": "ENTITY", "char_start": 0, "char_end": 39, "token_start": 0, "token_end": 6}, {"text": "conserved sequences", "type": "ENTITY", "char_start": 67, "char_end": 86, "token_start": 12, "token_end": 13}], "entities_global": [{"text": "Immunoglobulin ( Ig ) - kappa promoters", "type": "ENTITY", "char_start": 474514, "char_end": 474553, "token_start": 0, "token_end": 6, "note": null}, {"text": "conserved sequences", "type": "ENTITY", "char_start": 474581, "char_end": 474600, "token_start": 12, "token_end": 13, "note": null}]}
+{"sentence_id": 2856, "sentence_text": "The octamer element is common to all Ig promoters and pivotal for their function .", "sentence_char_start_global": 474603, "sentence_char_end_global": 474685, "entities": [{"text": "octamer element", "type": "ENTITY", "char_start": 4, "char_end": 19, "token_start": 1, "token_end": 2}, {"text": "Ig promoters", "type": "ENTITY", "char_start": 37, "char_end": 49, "token_start": 7, "token_end": 8}], "entities_global": [{"text": "octamer element", "type": "ENTITY", "char_start": 474607, "char_end": 474622, "token_start": 1, "token_end": 2, "note": null}, {"text": "Ig promoters", "type": "ENTITY", "char_start": 474640, "char_end": 474652, "token_start": 7, "token_end": 8, "note": null}]}
+{"sentence_id": 2857, "sentence_text": "However , other conserved sequence motifs , that differ between Ig variable gene families , are required for normal promoter function .", "sentence_char_start_global": 474686, "sentence_char_end_global": 474821, "entities": [{"text": "conserved sequence motifs", "type": "ENTITY", "char_start": 16, "char_end": 41, "token_start": 3, "token_end": 5}, {"text": "Ig variable gene families", "type": "ENTITY", "char_start": 64, "char_end": 89, "token_start": 10, "token_end": 13}], "entities_global": [{"text": "conserved sequence motifs", "type": "ENTITY", "char_start": 474702, "char_end": 474727, "token_start": 3, "token_end": 5, "note": null}, {"text": "Ig variable gene families", "type": "ENTITY", "char_start": 474750, "char_end": 474775, "token_start": 10, "token_end": 13, "note": null}]}
+{"sentence_id": 2858, "sentence_text": "These conserved motifs do not stimulate transcription in the absence of an octamer .", "sentence_char_start_global": 474822, "sentence_char_end_global": 474906, "entities": [{"text": "octamer", "type": "ENTITY", "char_start": 75, "char_end": 82, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "octamer", "type": "ENTITY", "char_start": 474897, "char_end": 474904, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 2859, "sentence_text": "One example is an E - box of the E47 / E12 type ( 5 ' - CAGCTG - 3 ' ) , which is found in all promoters of the human and murine Ig - kappa gene subgroups / families , with the exception of subgroups II and VI and their related murine families .", "sentence_char_start_global": 474907, "sentence_char_end_global": 475152, "entities": [{"text": "E - box", "type": "ENTITY", "char_start": 18, "char_end": 25, "token_start": 4, "token_end": 6}, {"text": "E47 / E12 type ( 5 ' - CAGCTG - 3 ' )", "type": "ENTITY", "char_start": 33, "char_end": 70, "token_start": 9, "token_end": 21}, {"text": "human and murine Ig - kappa gene subgroups / families", "type": "ENTITY", "char_start": 112, "char_end": 165, "token_start": 31, "token_end": 40}, {"text": "murine families", "type": "ENTITY", "char_start": 228, "char_end": 243, "token_start": 53, "token_end": 54}], "entities_global": [{"text": "E - box", "type": "ENTITY", "char_start": 474925, "char_end": 474932, "token_start": 4, "token_end": 6, "note": null}, {"text": "E47 / E12 type ( 5 ' - CAGCTG - 3 ' )", "type": "ENTITY", "char_start": 474940, "char_end": 474977, "token_start": 9, "token_end": 21, "note": null}, {"text": "human and murine Ig - kappa gene subgroups / families", "type": "ENTITY", "char_start": 475019, "char_end": 475072, "token_start": 31, "token_end": 40, "note": null}, {"text": "murine families", "type": "ENTITY", "char_start": 475135, "char_end": 475150, "token_start": 53, "token_end": 54, "note": null}]}
+{"sentence_id": 2860, "sentence_text": "In the present study we show that the ubiquitously expressed transcription factor AP - 4 , and not E47 , interacts specifically with the kappa promoter E - boxes when tested in electrophoretic mobility - shift assays using nuclear extracts derived from human and murine B - cell lines .", "sentence_char_start_global": 475153, "sentence_char_end_global": 475439, "entities": [{"text": "transcription factor AP - 4", "type": "ENTITY", "char_start": 61, "char_end": 88, "token_start": 10, "token_end": 14}, {"text": "E47", "type": "ENTITY", "char_start": 99, "char_end": 102, "token_start": 18, "token_end": 18}, {"text": "kappa promoter E - boxes", "type": "ENTITY", "char_start": 137, "char_end": 161, "token_start": 24, "token_end": 28}], "entities_global": [{"text": "transcription factor AP - 4", "type": "ENTITY", "char_start": 475214, "char_end": 475241, "token_start": 10, "token_end": 14, "note": null}, {"text": "E47", "type": "ENTITY", "char_start": 475252, "char_end": 475255, "token_start": 18, "token_end": 18, "note": null}, {"text": "kappa promoter E - boxes", "type": "ENTITY", "char_start": 475290, "char_end": 475314, "token_start": 24, "token_end": 28, "note": null}]}
+{"sentence_id": 2861, "sentence_text": "Furthermore , AP - 4 , unlike E47 , did not act as a transactivator , which is in agreement with previous studies on intact kappa promoters , showing that transcription is absent when the octamer element has been mutated .", "sentence_char_start_global": 475440, "sentence_char_end_global": 475662, "entities": [{"text": "AP - 4", "type": "ENTITY", "char_start": 14, "char_end": 20, "token_start": 2, "token_end": 4}, {"text": "E47", "type": "ENTITY", "char_start": 30, "char_end": 33, "token_start": 7, "token_end": 7}, {"text": "transactivator", "type": "ENTITY", "char_start": 53, "char_end": 67, "token_start": 14, "token_end": 14}, {"text": "kappa promoters", "type": "ENTITY", "char_start": 124, "char_end": 139, "token_start": 25, "token_end": 26}, {"text": "octamer element", "type": "ENTITY", "char_start": 188, "char_end": 203, "token_start": 35, "token_end": 36}], "entities_global": [{"text": "AP - 4", "type": "ENTITY", "char_start": 475454, "char_end": 475460, "token_start": 2, "token_end": 4, "note": null}, {"text": "E47", "type": "ENTITY", "char_start": 475470, "char_end": 475473, "token_start": 7, "token_end": 7, "note": null}, {"text": "transactivator", "type": "ENTITY", "char_start": 475493, "char_end": 475507, "token_start": 14, "token_end": 14, "note": null}, {"text": "kappa promoters", "type": "ENTITY", "char_start": 475564, "char_end": 475579, "token_start": 25, "token_end": 26, "note": null}, {"text": "octamer element", "type": "ENTITY", "char_start": 475628, "char_end": 475643, "token_start": 35, "token_end": 36, "note": null}]}
+{"sentence_id": 2862, "sentence_text": "Based on these data , and the conservation of the 5 ' - CAGCTG - 3 ' motif among human and murine kappa promoters , we propose that AP - 4 is the major ligand for Ig - kappa promoter E - boxes .", "sentence_char_start_global": 475663, "sentence_char_end_global": 475857, "entities": [{"text": "5 ' - CAGCTG - 3 ' motif", "type": "ENTITY", "char_start": 50, "char_end": 74, "token_start": 10, "token_end": 17}, {"text": "human and murine kappa promoters", "type": "ENTITY", "char_start": 81, "char_end": 113, "token_start": 19, "token_end": 23}, {"text": "AP - 4", "type": "ENTITY", "char_start": 132, "char_end": 138, "token_start": 28, "token_end": 30}, {"text": "major ligand", "type": "ENTITY", "char_start": 146, "char_end": 158, "token_start": 33, "token_end": 34}, {"text": "Ig - kappa promoter E - boxes", "type": "ENTITY", "char_start": 163, "char_end": 192, "token_start": 36, "token_end": 42}], "entities_global": [{"text": "5 ' - CAGCTG - 3 ' motif", "type": "ENTITY", "char_start": 475713, "char_end": 475737, "token_start": 10, "token_end": 17, "note": null}, {"text": "human and murine kappa promoters", "type": "ENTITY", "char_start": 475744, "char_end": 475776, "token_start": 19, "token_end": 23, "note": null}, {"text": "AP - 4", "type": "ENTITY", "char_start": 475795, "char_end": 475801, "token_start": 28, "token_end": 30, "note": null}, {"text": "major ligand", "type": "ENTITY", "char_start": 475809, "char_end": 475821, "token_start": 33, "token_end": 34, "note": null}, {"text": "Ig - kappa promoter E - boxes", "type": "ENTITY", "char_start": 475826, "char_end": 475855, "token_start": 36, "token_end": 42, "note": null}]}
+{"sentence_id": 2863, "sentence_text": "A 16 - mer peptide ( RQIKIWFQNRRMKWKK ) from antennapedia preferentially targets the Class I pathway .", "sentence_char_start_global": 475858, "sentence_char_end_global": 475960, "entities": [], "entities_global": []}
+{"sentence_id": 2864, "sentence_text": "Translocation of antigenic peptides into the cytosol of antigen presenting cells facilitates proteosomal processing and loading into Class I molecules for MHC presentation on the cell surface .", "sentence_char_start_global": 475961, "sentence_char_end_global": 476154, "entities": [{"text": "Class I molecules", "type": "ENTITY", "char_start": 133, "char_end": 150, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "Class I molecules", "type": "ENTITY", "char_start": 476094, "char_end": 476111, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 2865, "sentence_text": "The DNA binding domain of the Drosophila transcription factor ( Antennapedia ) , a 60 amino acid protein , is rapidly taken up by cells and has been fused to selected antigens to enhance their immunogenicity .", "sentence_char_start_global": 476155, "sentence_char_end_global": 476364, "entities": [{"text": "DNA binding domain", "type": "ENTITY", "char_start": 4, "char_end": 22, "token_start": 1, "token_end": 3}, {"text": "Drosophila transcription factor", "type": "ENTITY", "char_start": 30, "char_end": 61, "token_start": 6, "token_end": 8}, {"text": "Antennapedia", "type": "ENTITY", "char_start": 64, "char_end": 76, "token_start": 10, "token_end": 10}, {"text": "60 amino acid protein", "type": "ENTITY", "char_start": 83, "char_end": 104, "token_start": 14, "token_end": 17}, {"text": "antigens", "type": "ENTITY", "char_start": 167, "char_end": 175, "token_start": 31, "token_end": 31}], "entities_global": [{"text": "DNA binding domain", "type": "ENTITY", "char_start": 476159, "char_end": 476177, "token_start": 1, "token_end": 3, "note": null}, {"text": "Drosophila transcription factor", "type": "ENTITY", "char_start": 476185, "char_end": 476216, "token_start": 6, "token_end": 8, "note": null}, {"text": "Antennapedia", "type": "ENTITY", "char_start": 476219, "char_end": 476231, "token_start": 10, "token_end": 10, "note": null}, {"text": "60 amino acid protein", "type": "ENTITY", "char_start": 476238, "char_end": 476259, "token_start": 14, "token_end": 17, "note": null}, {"text": "antigens", "type": "ENTITY", "char_start": 476322, "char_end": 476330, "token_start": 31, "token_end": 31, "note": null}]}
+{"sentence_id": 2866, "sentence_text": "We now demonstrate that a 16 amino acid peptide from antennapedia can facilitate the cytoplasmic uptake of CTL epitope 9 - mer peptides .", "sentence_char_start_global": 476365, "sentence_char_end_global": 476502, "entities": [], "entities_global": []}
+{"sentence_id": 2867, "sentence_text": "Synthetic peptides were made containing the 16 - mer antennapedia peptide linked in tandem to the ovalbumin SIINFEKL CTL peptide .", "sentence_char_start_global": 476503, "sentence_char_end_global": 476633, "entities": [], "entities_global": []}
+{"sentence_id": 2868, "sentence_text": "The peptide complex was shown to rapidly internalise into APCs by confocal microscopy .", "sentence_char_start_global": 476634, "sentence_char_end_global": 476721, "entities": [], "entities_global": []}
+{"sentence_id": 2869, "sentence_text": "This peptide induced CTL in C57BL / 6 mice and protected them against growth of an ovalbumin expressing tumour cell line ( E . G7 - OVA ) .", "sentence_char_start_global": 476722, "sentence_char_end_global": 476861, "entities": [], "entities_global": []}
+{"sentence_id": 2870, "sentence_text": "The ability of the hybrid peptide to be processed and presented by APCs was similar , whether the SIINFEKL sequence was appended at the C - terminus or N - terminus of the Antennapedia peptide .", "sentence_char_start_global": 476862, "sentence_char_end_global": 477056, "entities": [{"text": "C - terminus", "type": "ENTITY", "char_start": 136, "char_end": 148, "token_start": 24, "token_end": 26}, {"text": "N - terminus", "type": "ENTITY", "char_start": 152, "char_end": 164, "token_start": 28, "token_end": 30}], "entities_global": [{"text": "C - terminus", "type": "ENTITY", "char_start": 476998, "char_end": 477010, "token_start": 24, "token_end": 26, "note": null}, {"text": "N - terminus", "type": "ENTITY", "char_start": 477014, "char_end": 477026, "token_start": 28, "token_end": 30, "note": null}]}
+{"sentence_id": 2871, "sentence_text": "The production of synthetic peptides containing other CTL peptide epitopes may be useful for priming CTLs in vitro and in vivo", "sentence_char_start_global": 477057, "sentence_char_end_global": 477183, "entities": [], "entities_global": []}
+{"sentence_id": 2872, "sentence_text": "Bone marrow cells promote TH2 polarization and inhibit virus - specific CTL generation .", "sentence_char_start_global": 477184, "sentence_char_end_global": 477272, "entities": [], "entities_global": []}
+{"sentence_id": 2873, "sentence_text": "This laboratory recently reported that human bone marrow cells ( BMC ) inhibit the generation of virus - specific CTL in culture .", "sentence_char_start_global": 477273, "sentence_char_end_global": 477403, "entities": [], "entities_global": []}
+{"sentence_id": 2874, "sentence_text": "The culture supernatants contained increased levels of prostaglandin E ( 2 ) ( PGE ( 2 ) ) ( shown to favor TH2 cell development ) and also inhibited EBV - CTL effector cell development .", "sentence_char_start_global": 477404, "sentence_char_end_global": 477591, "entities": [{"text": "prostaglandin E ( 2 ) ( PGE ( 2 ) )", "type": "ENTITY", "char_start": 55, "char_end": 90, "token_start": 7, "token_end": 17}], "entities_global": [{"text": "prostaglandin E ( 2 ) ( PGE ( 2 ) )", "type": "ENTITY", "char_start": 477459, "char_end": 477494, "token_start": 7, "token_end": 17, "note": null}]}
+{"sentence_id": 2875, "sentence_text": "In this study , we obtained PBL from Epstein - Barr virus ( EBV ) IgG antibody positive kidney transplant recipients ( R ) and their living - related donors ( LRD ) one year after renal transplantation .", "sentence_char_start_global": 477592, "sentence_char_end_global": 477795, "entities": [{"text": "IgG antibody", "type": "ENTITY", "char_start": 66, "char_end": 78, "token_start": 15, "token_end": 16}], "entities_global": [{"text": "IgG antibody", "type": "ENTITY", "char_start": 477658, "char_end": 477670, "token_start": 15, "token_end": 16, "note": null}]}
+{"sentence_id": 2876, "sentence_text": "EBV - specific CTL were then generated in vitro by stimulating PBL with autologous EBV - transformed B cells ( EBV - B ) in the presence or absence of autologous BMC .", "sentence_char_start_global": 477796, "sentence_char_end_global": 477963, "entities": [], "entities_global": []}
+{"sentence_id": 2877, "sentence_text": "The addition of BMC to the EBV - CTL generation cultures increased the intracellular expression in CD3 + cells of IL - 4 , - 5 , - 6 , - 10 , and - 13 .", "sentence_char_start_global": 477964, "sentence_char_end_global": 478116, "entities": [{"text": "IL - 4 , - 5 , - 6 , - 10 , and - 13", "type": "ENTITY", "char_start": 114, "char_end": 150, "token_start": 20, "token_end": 35}], "entities_global": [{"text": "IL - 4 , - 5 , - 6 , - 10 , and - 13", "type": "ENTITY", "char_start": 478078, "char_end": 478114, "token_start": 20, "token_end": 35, "note": null}]}
+{"sentence_id": 2878, "sentence_text": "These CD3 + cells also expressed increased levels of the TH2 associated receptor CCR3 .", "sentence_char_start_global": 478117, "sentence_char_end_global": 478204, "entities": [{"text": "TH2 associated receptor CCR3", "type": "ENTITY", "char_start": 57, "char_end": 85, "token_start": 10, "token_end": 13}], "entities_global": [{"text": "TH2 associated receptor CCR3", "type": "ENTITY", "char_start": 478174, "char_end": 478202, "token_start": 10, "token_end": 13, "note": null}]}
+{"sentence_id": 2879, "sentence_text": "Inhibition was even observed by preparing EBV - CTL generating cultures in trans - wells that separated the autologous BMC from the PBL + EBV - B .", "sentence_char_start_global": 478205, "sentence_char_end_global": 478352, "entities": [], "entities_global": []}
+{"sentence_id": 2880, "sentence_text": "It was then observed that CD3 + cells obtained after 7 days of culture in the presence of autologous BMC could be used as inhibitors of EBV - CTL generation .", "sentence_char_start_global": 478353, "sentence_char_end_global": 478511, "entities": [], "entities_global": []}
+{"sentence_id": 2881, "sentence_text": "Protein Kinase A ( PKA ) , a cAMP kinase that is involved in the upregulation of TH2 cytokine activity , was increased in EBV - CTL cultures by the presence of BMC .", "sentence_char_start_global": 478512, "sentence_char_end_global": 478677, "entities": [{"text": "Protein Kinase A", "type": "ENTITY", "char_start": 0, "char_end": 16, "token_start": 0, "token_end": 2}, {"text": "PKA", "type": "ENTITY", "char_start": 19, "char_end": 22, "token_start": 4, "token_end": 4}, {"text": "cAMP kinase", "type": "ENTITY", "char_start": 29, "char_end": 40, "token_start": 8, "token_end": 9}, {"text": "TH2 cytokine", "type": "ENTITY", "char_start": 81, "char_end": 93, "token_start": 17, "token_end": 18}], "entities_global": [{"text": "Protein Kinase A", "type": "ENTITY", "char_start": 478512, "char_end": 478528, "token_start": 0, "token_end": 2, "note": null}, {"text": "PKA", "type": "ENTITY", "char_start": 478531, "char_end": 478534, "token_start": 4, "token_end": 4, "note": null}, {"text": "cAMP kinase", "type": "ENTITY", "char_start": 478541, "char_end": 478552, "token_start": 8, "token_end": 9, "note": null}, {"text": "TH2 cytokine", "type": "ENTITY", "char_start": 478593, "char_end": 478605, "token_start": 17, "token_end": 18, "note": null}]}
+{"sentence_id": 2882, "sentence_text": "Additionally , IL - 4 - mediated signal transduction and activation of transcription ( STAT - 6 ) phosphorylation was slightly increased .", "sentence_char_start_global": 478678, "sentence_char_end_global": 478816, "entities": [{"text": "STAT - 6", "type": "ENTITY", "char_start": 87, "char_end": 95, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "STAT - 6", "type": "ENTITY", "char_start": 478765, "char_end": 478773, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 2883, "sentence_text": "These results show that the BMC inhibition is mediated by soluble factors ( cytokines ) and that cell - cell contact in this autologous system is not required , so that BMC ( at least partially , via cytokine production ) promote TH2 polarization in culture .", "sentence_char_start_global": 478817, "sentence_char_end_global": 479076, "entities": [{"text": "soluble factors", "type": "ENTITY", "char_start": 58, "char_end": 73, "token_start": 10, "token_end": 11}, {"text": "cytokines", "type": "ENTITY", "char_start": 76, "char_end": 85, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "soluble factors", "type": "ENTITY", "char_start": 478875, "char_end": 478890, "token_start": 10, "token_end": 11, "note": null}, {"text": "cytokines", "type": "ENTITY", "char_start": 478893, "char_end": 478902, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 2884, "sentence_text": "Moreover , TH2 cells induced by culturing with autologous BMC directly inhibit EBV - CTL generation , and TH2 associated PKA , CCR3 , and STAT - 6 phosphorylation are enhanced by BMC .", "sentence_char_start_global": 479077, "sentence_char_end_global": 479261, "entities": [{"text": "TH2", "type": "ENTITY", "char_start": 106, "char_end": 109, "token_start": 18, "token_end": 18}, {"text": "PKA", "type": "ENTITY", "char_start": 121, "char_end": 124, "token_start": 20, "token_end": 20}, {"text": "CCR3", "type": "ENTITY", "char_start": 127, "char_end": 131, "token_start": 22, "token_end": 22}, {"text": "STAT - 6", "type": "ENTITY", "char_start": 138, "char_end": 146, "token_start": 25, "token_end": 27}], "entities_global": [{"text": "TH2", "type": "ENTITY", "char_start": 479183, "char_end": 479186, "token_start": 18, "token_end": 18, "note": null}, {"text": "PKA", "type": "ENTITY", "char_start": 479198, "char_end": 479201, "token_start": 20, "token_end": 20, "note": null}, {"text": "CCR3", "type": "ENTITY", "char_start": 479204, "char_end": 479208, "token_start": 22, "token_end": 22, "note": null}, {"text": "STAT - 6", "type": "ENTITY", "char_start": 479215, "char_end": 479223, "token_start": 25, "token_end": 27, "note": null}]}
+{"sentence_id": 2885, "sentence_text": "Reduction in DNA binding activity of the transcription factor Pax - 5a in B lymphocytes of aged mice .", "sentence_char_start_global": 479262, "sentence_char_end_global": 479364, "entities": [{"text": "transcription factor", "type": "ENTITY", "char_start": 41, "char_end": 61, "token_start": 7, "token_end": 8}, {"text": "Pax - 5a", "type": "ENTITY", "char_start": 62, "char_end": 70, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "transcription factor", "type": "ENTITY", "char_start": 479303, "char_end": 479323, "token_start": 7, "token_end": 8, "note": null}, {"text": "Pax - 5a", "type": "ENTITY", "char_start": 479324, "char_end": 479332, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 2886, "sentence_text": "Aging has been associated with intrinsic changes of the humoral immune response , which may lead to an increased occurrence of autoimmune disorders and pathogenic susceptibility .", "sentence_char_start_global": 479365, "sentence_char_end_global": 479544, "entities": [], "entities_global": []}
+{"sentence_id": 2887, "sentence_text": "The transcription factor Pax - 5 is a key regulator of B cell development .", "sentence_char_start_global": 479545, "sentence_char_end_global": 479620, "entities": [{"text": "transcription factor", "type": "ENTITY", "char_start": 4, "char_end": 24, "token_start": 1, "token_end": 2}, {"text": "Pax - 5", "type": "ENTITY", "char_start": 25, "char_end": 32, "token_start": 3, "token_end": 5}], "entities_global": [{"text": "transcription factor", "type": "ENTITY", "char_start": 479549, "char_end": 479569, "token_start": 1, "token_end": 2, "note": null}, {"text": "Pax - 5", "type": "ENTITY", "char_start": 479570, "char_end": 479577, "token_start": 3, "token_end": 5, "note": null}]}
+{"sentence_id": 2888, "sentence_text": "Pax - 5a / B cell - specific activator protein and an alternatively spliced isoform , Pax - 5d , may have opposing functions in transcriptional regulation due to the lack of a transactivation domain in Pax - 5d .", "sentence_char_start_global": 479621, "sentence_char_end_global": 479833, "entities": [{"text": "Pax - 5a / B cell - specific activator protein", "type": "ENTITY", "char_start": 0, "char_end": 46, "token_start": 0, "token_end": 9}, {"text": "alternatively spliced isoform , Pax - 5d", "type": "ENTITY", "char_start": 54, "char_end": 94, "token_start": 12, "token_end": 18}, {"text": "transactivation domain", "type": "ENTITY", "char_start": 176, "char_end": 198, "token_start": 33, "token_end": 34}, {"text": "Pax - 5d", "type": "ENTITY", "char_start": 202, "char_end": 210, "token_start": 36, "token_end": 38}], "entities_global": [{"text": "Pax - 5a / B cell - specific activator protein", "type": "ENTITY", "char_start": 479621, "char_end": 479667, "token_start": 0, "token_end": 9, "note": null}, {"text": "alternatively spliced isoform , Pax - 5d", "type": "ENTITY", "char_start": 479675, "char_end": 479715, "token_start": 12, "token_end": 18, "note": null}, {"text": "transactivation domain", "type": "ENTITY", "char_start": 479797, "char_end": 479819, "token_start": 33, "token_end": 34, "note": null}, {"text": "Pax - 5d", "type": "ENTITY", "char_start": 479823, "char_end": 479831, "token_start": 36, "token_end": 38, "note": null}]}
+{"sentence_id": 2889, "sentence_text": "To study B cell - specific changes that occur during the aging process , we investigated expression patterns of Pax - 5a and 5d in mature B cells of young and aged mice .", "sentence_char_start_global": 479834, "sentence_char_end_global": 480004, "entities": [{"text": "Pax - 5a and 5d", "type": "ENTITY", "char_start": 112, "char_end": 127, "token_start": 19, "token_end": 23}], "entities_global": [{"text": "Pax - 5a and 5d", "type": "ENTITY", "char_start": 479946, "char_end": 479961, "token_start": 19, "token_end": 23, "note": null}]}
+{"sentence_id": 2890, "sentence_text": "RNase protection assays showed a similar transcriptional pattern for both age groups that indicates that aging has no affect on transcription initiation or alternative splicing for either isoform .", "sentence_char_start_global": 480005, "sentence_char_end_global": 480202, "entities": [{"text": "isoform", "type": "ENTITY", "char_start": 188, "char_end": 195, "token_start": 27, "token_end": 27}], "entities_global": [{"text": "isoform", "type": "ENTITY", "char_start": 480193, "char_end": 480200, "token_start": 27, "token_end": 27, "note": null}]}
+{"sentence_id": 2891, "sentence_text": "In contrast , a significant reduction in the DNA binding activity of Pax - 5a but not Pax - 5d protein was observed in aged B cells in vitro , while Western blot analyses showed that similar levels of Pax - 5a and 5d proteins were present in both age groups .", "sentence_char_start_global": 480203, "sentence_char_end_global": 480462, "entities": [{"text": "Pax - 5a", "type": "ENTITY", "char_start": 69, "char_end": 77, "token_start": 12, "token_end": 14}, {"text": "Pax - 5d", "type": "ENTITY", "char_start": 86, "char_end": 94, "token_start": 17, "token_end": 19}, {"text": "Pax - 5a and 5d", "type": "ENTITY", "char_start": 201, "char_end": 216, "token_start": 39, "token_end": 43}], "entities_global": [{"text": "Pax - 5a", "type": "ENTITY", "char_start": 480272, "char_end": 480280, "token_start": 12, "token_end": 14, "note": null}, {"text": "Pax - 5d", "type": "ENTITY", "char_start": 480289, "char_end": 480297, "token_start": 17, "token_end": 19, "note": null}, {"text": "Pax - 5a and 5d", "type": "ENTITY", "char_start": 480404, "char_end": 480419, "token_start": 39, "token_end": 43, "note": null}]}
+{"sentence_id": 2892, "sentence_text": "The observed decrease in Pax - 5a binding activity correlated with changes in expression of two Pax - 5 target genes in aged B cells .", "sentence_char_start_global": 480463, "sentence_char_end_global": 480597, "entities": [{"text": "Pax - 5a", "type": "ENTITY", "char_start": 25, "char_end": 33, "token_start": 4, "token_end": 6}, {"text": "Pax - 5 target genes", "type": "ENTITY", "char_start": 96, "char_end": 116, "token_start": 16, "token_end": 20}], "entities_global": [{"text": "Pax - 5a", "type": "ENTITY", "char_start": 480488, "char_end": 480496, "token_start": 4, "token_end": 6, "note": null}, {"text": "Pax - 5 target genes", "type": "ENTITY", "char_start": 480559, "char_end": 480579, "token_start": 16, "token_end": 20, "note": null}]}
+{"sentence_id": 2893, "sentence_text": "Expression of the Ig J chain and the secreted form of Ig mu , which are both known to be suppressed by Pax - 5a in mature B cells , were increased in B cells of aged mice .", "sentence_char_start_global": 480598, "sentence_char_end_global": 480770, "entities": [{"text": "Ig J chain", "type": "ENTITY", "char_start": 18, "char_end": 28, "token_start": 3, "token_end": 5}, {"text": "Ig mu", "type": "ENTITY", "char_start": 54, "char_end": 59, "token_start": 11, "token_end": 12}, {"text": "Pax - 5a", "type": "ENTITY", "char_start": 103, "char_end": 111, "token_start": 22, "token_end": 24}], "entities_global": [{"text": "Ig J chain", "type": "ENTITY", "char_start": 480616, "char_end": 480626, "token_start": 3, "token_end": 5, "note": null}, {"text": "Ig mu", "type": "ENTITY", "char_start": 480652, "char_end": 480657, "token_start": 11, "token_end": 12, "note": null}, {"text": "Pax - 5a", "type": "ENTITY", "char_start": 480701, "char_end": 480709, "token_start": 22, "token_end": 24, "note": null}]}
+{"sentence_id": 2894, "sentence_text": "Together , our studies suggest that changes associated with the aging phenotype cause posttranslational modification ( s ) of Pax - 5a but not Pax - 5d , which may lead to an abnormal B cell phenotype in aged mice , associated with elevated levels of J chain , and secretion of IgM", "sentence_char_start_global": 480771, "sentence_char_end_global": 481052, "entities": [{"text": "Pax - 5a", "type": "ENTITY", "char_start": 126, "char_end": 134, "token_start": 19, "token_end": 21}, {"text": "Pax - 5d", "type": "ENTITY", "char_start": 143, "char_end": 151, "token_start": 24, "token_end": 26}, {"text": "J chain", "type": "ENTITY", "char_start": 251, "char_end": 258, "token_start": 46, "token_end": 47}, {"text": "IgM", "type": "ENTITY", "char_start": 278, "char_end": 281, "token_start": 52, "token_end": 52}], "entities_global": [{"text": "Pax - 5a", "type": "ENTITY", "char_start": 480897, "char_end": 480905, "token_start": 19, "token_end": 21, "note": null}, {"text": "Pax - 5d", "type": "ENTITY", "char_start": 480914, "char_end": 480922, "token_start": 24, "token_end": 26, "note": null}, {"text": "J chain", "type": "ENTITY", "char_start": 481022, "char_end": 481029, "token_start": 46, "token_end": 47, "note": null}, {"text": "IgM", "type": "ENTITY", "char_start": 481049, "char_end": 481052, "token_start": 52, "token_end": 52, "note": null}]}
+{"sentence_id": 2895, "sentence_text": "NF - kappa B / Rel participation in the lymphokine - dependent proliferation of T lymphoid cells .", "sentence_char_start_global": 481053, "sentence_char_end_global": 481151, "entities": [{"text": "NF - kappa B / Rel", "type": "ENTITY", "char_start": 0, "char_end": 18, "token_start": 0, "token_end": 5}], "entities_global": [{"text": "NF - kappa B / Rel", "type": "ENTITY", "char_start": 481053, "char_end": 481071, "token_start": 0, "token_end": 5, "note": null}]}
+{"sentence_id": 2896, "sentence_text": "Proliferative responses of lymphoid cells to IL - 2 and IL - 4 depend on activation of the cells , but the mechanism ( s ) by which activation enhances cellular competence to respond to cytokines is not fully understood .", "sentence_char_start_global": 481152, "sentence_char_end_global": 481373, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 45, "char_end": 51, "token_start": 6, "token_end": 8}, {"text": "IL - 4", "type": "ENTITY", "char_start": 56, "char_end": 62, "token_start": 10, "token_end": 12}, {"text": "cytokines", "type": "ENTITY", "char_start": 186, "char_end": 195, "token_start": 35, "token_end": 35}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 481197, "char_end": 481203, "token_start": 6, "token_end": 8, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 481208, "char_end": 481214, "token_start": 10, "token_end": 12, "note": null}, {"text": "cytokines", "type": "ENTITY", "char_start": 481338, "char_end": 481347, "token_start": 35, "token_end": 35, "note": null}]}
+{"sentence_id": 2897, "sentence_text": "The NF - kappaB / Rel family represents one signal transduction pathway induced during such activation .", "sentence_char_start_global": 481374, "sentence_char_end_global": 481478, "entities": [{"text": "NF - kappaB / Rel family", "type": "ENTITY", "char_start": 4, "char_end": 28, "token_start": 1, "token_end": 6}], "entities_global": [{"text": "NF - kappaB / Rel family", "type": "ENTITY", "char_start": 481378, "char_end": 481402, "token_start": 1, "token_end": 6, "note": null}]}
+{"sentence_id": 2898, "sentence_text": "We show in this study that inhibition of NF - kappaB through the expression of an IkappaBalpha ( inhibitory protein that dissociates from NF - kappaB ) mutant refractory to signal - induced degradation ( IkappaBalpha ( DeltaN ) ) interfered with the acquisition of competence to proliferate in response to IL - 4 as well as IL - 2 .", "sentence_char_start_global": 481479, "sentence_char_end_global": 481811, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 41, "char_end": 52, "token_start": 8, "token_end": 10}, {"text": "IkappaBalpha", "type": "ENTITY", "char_start": 82, "char_end": 94, "token_start": 16, "token_end": 16}, {"text": "inhibitory protein", "type": "ENTITY", "char_start": 97, "char_end": 115, "token_start": 18, "token_end": 19}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 138, "char_end": 149, "token_start": 23, "token_end": 25}, {"text": "IkappaBalpha ( DeltaN )", "type": "ENTITY", "char_start": 204, "char_end": 227, "token_start": 35, "token_end": 38}, {"text": "IL - 4", "type": "ENTITY", "char_start": 306, "char_end": 312, "token_start": 51, "token_end": 53}, {"text": "IL - 2", "type": "ENTITY", "char_start": 324, "char_end": 330, "token_start": 57, "token_end": 59}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 481520, "char_end": 481531, "token_start": 8, "token_end": 10, "note": null}, {"text": "IkappaBalpha", "type": "ENTITY", "char_start": 481561, "char_end": 481573, "token_start": 16, "token_end": 16, "note": null}, {"text": "inhibitory protein", "type": "ENTITY", "char_start": 481576, "char_end": 481594, "token_start": 18, "token_end": 19, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 481617, "char_end": 481628, "token_start": 23, "token_end": 25, "note": null}, {"text": "IkappaBalpha ( DeltaN )", "type": "ENTITY", "char_start": 481683, "char_end": 481706, "token_start": 35, "token_end": 38, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 481785, "char_end": 481791, "token_start": 51, "token_end": 53, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 481803, "char_end": 481809, "token_start": 57, "token_end": 59, "note": null}]}
+{"sentence_id": 2899, "sentence_text": "Thymocytes and T cells from IkappaBalpha ( DeltaN ) transgenic mice expressed normal levels of IL - 2R subunits .", "sentence_char_start_global": 481812, "sentence_char_end_global": 481925, "entities": [{"text": "IkappaBalpha ( DeltaN )", "type": "ENTITY", "char_start": 28, "char_end": 51, "token_start": 5, "token_end": 8}, {"text": "IL - 2R subunits", "type": "ENTITY", "char_start": 95, "char_end": 111, "token_start": 15, "token_end": 18}], "entities_global": [{"text": "IkappaBalpha ( DeltaN )", "type": "ENTITY", "char_start": 481840, "char_end": 481863, "token_start": 5, "token_end": 8, "note": null}, {"text": "IL - 2R subunits", "type": "ENTITY", "char_start": 481907, "char_end": 481923, "token_start": 15, "token_end": 18, "note": null}]}
+{"sentence_id": 2900, "sentence_text": "However , transgenic cells exhibited a dramatic defect in Stat5A activation treatment with IL - 2 , and a similar defect was observed for IL - 4 - induced Stat5 .", "sentence_char_start_global": 481926, "sentence_char_end_global": 482088, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 91, "char_end": 97, "token_start": 13, "token_end": 15}, {"text": "IL - 4", "type": "ENTITY", "char_start": 138, "char_end": 144, "token_start": 24, "token_end": 26}, {"text": "Stat5", "type": "ENTITY", "char_start": 155, "char_end": 160, "token_start": 29, "token_end": 29}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 482017, "char_end": 482023, "token_start": 13, "token_end": 15, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 482064, "char_end": 482070, "token_start": 24, "token_end": 26, "note": null}, {"text": "Stat5", "type": "ENTITY", "char_start": 482081, "char_end": 482086, "token_start": 29, "token_end": 29, "note": null}]}
+{"sentence_id": 2901, "sentence_text": "In contrast , T lymphoid cells with inhibition of NF - kappaB showed normal insulin receptor substrate - 2 phosphorylation and only a modest decrease in Stat6 activation and insulin receptor substrate - 1 phosphorylation after IL - 4 stimulation .", "sentence_char_start_global": 482089, "sentence_char_end_global": 482336, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 50, "char_end": 61, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 482139, "char_end": 482150, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 2902, "sentence_text": "These results indicate that the NF - kappaB / Rel / IkappaBalpha system can regulate cytokine receptor capacitation through effects on the induction of downstream signaling by the Stat transcription factor family .", "sentence_char_start_global": 482337, "sentence_char_end_global": 482551, "entities": [{"text": "cytokine receptor", "type": "ENTITY", "char_start": 85, "char_end": 102, "token_start": 15, "token_end": 16}, {"text": "Stat transcription factor family", "type": "ENTITY", "char_start": 180, "char_end": 212, "token_start": 28, "token_end": 31}], "entities_global": [{"text": "cytokine receptor", "type": "ENTITY", "char_start": 482422, "char_end": 482439, "token_start": 15, "token_end": 16, "note": null}, {"text": "Stat transcription factor family", "type": "ENTITY", "char_start": 482517, "char_end": 482549, "token_start": 28, "token_end": 31, "note": null}]}
+{"sentence_id": 2903, "sentence_text": "BMS - 189453 , a novel retinoid receptor antagonist , is a potent testicular toxin .", "sentence_char_start_global": 482552, "sentence_char_end_global": 482636, "entities": [], "entities_global": []}
+{"sentence_id": 2904, "sentence_text": "BMS - 189453 is a synthetic retinoid that acts as an antagonist at retinoic acid receptors alpha , beta , and gamma .", "sentence_char_start_global": 482637, "sentence_char_end_global": 482754, "entities": [{"text": "retinoic acid receptors alpha , beta , and gamma", "type": "ENTITY", "char_start": 67, "char_end": 115, "token_start": 13, "token_end": 21}], "entities_global": [{"text": "retinoic acid receptors alpha , beta , and gamma", "type": "ENTITY", "char_start": 482704, "char_end": 482752, "token_start": 13, "token_end": 21, "note": null}]}
+{"sentence_id": 2905, "sentence_text": "In Sprague Dawley rats at daily oral doses of 15 , 60 , or 240 mg / kg for 1 month , BMS - 189453 produced increases in leukocyte counts , alkaline phosphatase and alanine aminotransferase levels , and marked testicular degeneration and atrophy at all doses .", "sentence_char_start_global": 482755, "sentence_char_end_global": 483014, "entities": [{"text": "alkaline phosphatase", "type": "ENTITY", "char_start": 139, "char_end": 159, "token_start": 31, "token_end": 32}, {"text": "alanine aminotransferase", "type": "ENTITY", "char_start": 164, "char_end": 188, "token_start": 34, "token_end": 35}], "entities_global": [{"text": "alkaline phosphatase", "type": "ENTITY", "char_start": 482894, "char_end": 482914, "token_start": 31, "token_end": 32, "note": null}, {"text": "alanine aminotransferase", "type": "ENTITY", "char_start": 482919, "char_end": 482943, "token_start": 34, "token_end": 35, "note": null}]}
+{"sentence_id": 2906, "sentence_text": "Significant overt signs of toxicity and deaths occurred at 240 mg / kg , whereas body - weight and food - consumption decreases occurred at 60 and 240 mg / kg .", "sentence_char_start_global": 483015, "sentence_char_end_global": 483175, "entities": [], "entities_global": []}
+{"sentence_id": 2907, "sentence_text": "When BMS - 189453 was administered to male rats at daily doses ranging from 12 . 5 to 100 mg / kg for 1 week , only minimal testicular changes occurred at all doses , shortly after the dosing period .", "sentence_char_start_global": 483176, "sentence_char_end_global": 483376, "entities": [], "entities_global": []}
+{"sentence_id": 2908, "sentence_text": "However , after a 1 - month drug - free observation period , marked testicular atrophy was evident at all doses .", "sentence_char_start_global": 483377, "sentence_char_end_global": 483490, "entities": [], "entities_global": []}
+{"sentence_id": 2909, "sentence_text": "BMS - 189453 was then administered at doses of 2 , 10 , or 50 mg / kg to male rats for 1 , 3 , or 7 consecutive days .", "sentence_char_start_global": 483491, "sentence_char_end_global": 483609, "entities": [], "entities_global": []}
+{"sentence_id": 2910, "sentence_text": "Dose - and duration - dependent testicular toxicity that occurred after a 1 - month observation period did not recover , and , in some cases , was more severe 4 months after the last dose .", "sentence_char_start_global": 483610, "sentence_char_end_global": 483799, "entities": [], "entities_global": []}
+{"sentence_id": 2911, "sentence_text": "In rabbits administered BMS - 189453 at oral doses of 2 , 10 , or 50 mg / kg for 1 week , testicular degeneration and atrophy were evident in the high - dose group at 1 month following treatment .", "sentence_char_start_global": 483800, "sentence_char_end_global": 483996, "entities": [], "entities_global": []}
+{"sentence_id": 2912, "sentence_text": "These studies indicate that retinoid antagonists can selectively produce progressive and prolonged testicular toxicity after single or repeated oral doses that are otherwise well tolerated .", "sentence_char_start_global": 483997, "sentence_char_end_global": 484187, "entities": [], "entities_global": []}
+{"sentence_id": 2913, "sentence_text": "Sequential involvement of NFAT and Egr transcription factors in FasL regulation .", "sentence_char_start_global": 484188, "sentence_char_end_global": 484269, "entities": [{"text": "NFAT", "type": "ENTITY", "char_start": 26, "char_end": 30, "token_start": 3, "token_end": 3}, {"text": "Egr", "type": "ENTITY", "char_start": 35, "char_end": 38, "token_start": 5, "token_end": 5}, {"text": "transcription factors", "type": "ENTITY", "char_start": 39, "char_end": 60, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "NFAT", "type": "ENTITY", "char_start": 484214, "char_end": 484218, "token_start": 3, "token_end": 3, "note": null}, {"text": "Egr", "type": "ENTITY", "char_start": 484223, "char_end": 484226, "token_start": 5, "token_end": 5, "note": null}, {"text": "transcription factors", "type": "ENTITY", "char_start": 484227, "char_end": 484248, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 2914, "sentence_text": "The critical function of NFAT proteins in maintaining lymphoid homeostasis was revealed in mice lacking both NFATp and NFAT4 ( DKO ) .", "sentence_char_start_global": 484270, "sentence_char_end_global": 484404, "entities": [{"text": "NFAT proteins", "type": "ENTITY", "char_start": 25, "char_end": 38, "token_start": 4, "token_end": 5}, {"text": "NFATp", "type": "ENTITY", "char_start": 109, "char_end": 114, "token_start": 16, "token_end": 16}, {"text": "NFAT4", "type": "ENTITY", "char_start": 119, "char_end": 124, "token_start": 18, "token_end": 18}], "entities_global": [{"text": "NFAT proteins", "type": "ENTITY", "char_start": 484295, "char_end": 484308, "token_start": 4, "token_end": 5, "note": null}, {"text": "NFATp", "type": "ENTITY", "char_start": 484379, "char_end": 484384, "token_start": 16, "token_end": 16, "note": null}, {"text": "NFAT4", "type": "ENTITY", "char_start": 484389, "char_end": 484394, "token_start": 18, "token_end": 18, "note": null}]}
+{"sentence_id": 2915, "sentence_text": "DKO mice exhibit increased lymphoproliferation , decreased activation - induced cell death , and impaired induction of FasL .", "sentence_char_start_global": 484405, "sentence_char_end_global": 484530, "entities": [{"text": "FasL", "type": "ENTITY", "char_start": 119, "char_end": 123, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "FasL", "type": "ENTITY", "char_start": 484524, "char_end": 484528, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 2916, "sentence_text": "The transcription factors Egr2 and Egr3 are potent activators of FasL expression .", "sentence_char_start_global": 484531, "sentence_char_end_global": 484613, "entities": [{"text": "transcription factors", "type": "ENTITY", "char_start": 4, "char_end": 25, "token_start": 1, "token_end": 2}, {"text": "Egr2", "type": "ENTITY", "char_start": 26, "char_end": 30, "token_start": 3, "token_end": 3}, {"text": "Egr3", "type": "ENTITY", "char_start": 35, "char_end": 39, "token_start": 5, "token_end": 5}], "entities_global": [{"text": "transcription factors", "type": "ENTITY", "char_start": 484535, "char_end": 484556, "token_start": 1, "token_end": 2, "note": null}, {"text": "Egr2", "type": "ENTITY", "char_start": 484557, "char_end": 484561, "token_start": 3, "token_end": 3, "note": null}, {"text": "Egr3", "type": "ENTITY", "char_start": 484566, "char_end": 484570, "token_start": 5, "token_end": 5, "note": null}]}
+{"sentence_id": 2917, "sentence_text": "Here we find that Egr2 and Egr3 are NFAT target genes .", "sentence_char_start_global": 484614, "sentence_char_end_global": 484669, "entities": [{"text": "Egr2", "type": "ENTITY", "char_start": 18, "char_end": 22, "token_start": 4, "token_end": 4}, {"text": "Egr3", "type": "ENTITY", "char_start": 27, "char_end": 31, "token_start": 6, "token_end": 6}, {"text": "NFAT target genes", "type": "ENTITY", "char_start": 36, "char_end": 53, "token_start": 8, "token_end": 10}], "entities_global": [{"text": "Egr2", "type": "ENTITY", "char_start": 484632, "char_end": 484636, "token_start": 4, "token_end": 4, "note": null}, {"text": "Egr3", "type": "ENTITY", "char_start": 484641, "char_end": 484645, "token_start": 6, "token_end": 6, "note": null}, {"text": "NFAT target genes", "type": "ENTITY", "char_start": 484650, "char_end": 484667, "token_start": 8, "token_end": 10, "note": null}]}
+{"sentence_id": 2918, "sentence_text": "Activation of FasL occurs via the NFAT - dependent induction of Egr3 , as demonstrated by the ability of exogenously provided NFATp to restore Egr - dependent FasL promoter activity in DKO lymph node cells .", "sentence_char_start_global": 484670, "sentence_char_end_global": 484877, "entities": [{"text": "FasL", "type": "ENTITY", "char_start": 14, "char_end": 18, "token_start": 2, "token_end": 2}, {"text": "NFAT", "type": "ENTITY", "char_start": 34, "char_end": 38, "token_start": 6, "token_end": 6}, {"text": "Egr3", "type": "ENTITY", "char_start": 64, "char_end": 68, "token_start": 11, "token_end": 11}, {"text": "NFATp", "type": "ENTITY", "char_start": 126, "char_end": 131, "token_start": 21, "token_end": 21}, {"text": "Egr", "type": "ENTITY", "char_start": 143, "char_end": 146, "token_start": 24, "token_end": 24}], "entities_global": [{"text": "FasL", "type": "ENTITY", "char_start": 484684, "char_end": 484688, "token_start": 2, "token_end": 2, "note": null}, {"text": "NFAT", "type": "ENTITY", "char_start": 484704, "char_end": 484708, "token_start": 6, "token_end": 6, "note": null}, {"text": "Egr3", "type": "ENTITY", "char_start": 484734, "char_end": 484738, "token_start": 11, "token_end": 11, "note": null}, {"text": "NFATp", "type": "ENTITY", "char_start": 484796, "char_end": 484801, "token_start": 21, "token_end": 21, "note": null}, {"text": "Egr", "type": "ENTITY", "char_start": 484813, "char_end": 484816, "token_start": 24, "token_end": 24, "note": null}]}
+{"sentence_id": 2919, "sentence_text": "Further , Egr3 expression is enriched in Th1 cells , suggesting a molecular basis for the known preferential expression of FasL in the Th1 versus Th2 subset .", "sentence_char_start_global": 484878, "sentence_char_end_global": 485036, "entities": [{"text": "Egr3", "type": "ENTITY", "char_start": 10, "char_end": 14, "token_start": 2, "token_end": 2}, {"text": "FasL", "type": "ENTITY", "char_start": 123, "char_end": 127, "token_start": 20, "token_end": 20}], "entities_global": [{"text": "Egr3", "type": "ENTITY", "char_start": 484888, "char_end": 484892, "token_start": 2, "token_end": 2, "note": null}, {"text": "FasL", "type": "ENTITY", "char_start": 485001, "char_end": 485005, "token_start": 20, "token_end": 20, "note": null}]}
+{"sentence_id": 2920, "sentence_text": "Mechanisms and clinical relevance of nongenomic glucocorticoid actions .", "sentence_char_start_global": 485037, "sentence_char_end_global": 485109, "entities": [], "entities_global": []}
+{"sentence_id": 2921, "sentence_text": "Glucocorticoids have profound anti - inflammatory and immunosuppressive actions when used therapeutically .", "sentence_char_start_global": 485110, "sentence_char_end_global": 485217, "entities": [], "entities_global": []}
+{"sentence_id": 2922, "sentence_text": "The therapeutic dose is quite variable and depends on the disease , but ranges from very low to extremely high .", "sentence_char_start_global": 485218, "sentence_char_end_global": 485330, "entities": [], "entities_global": []}
+{"sentence_id": 2923, "sentence_text": "The rationale for the use of various dosage regimens for specific clinical indications is the existence of three distinct , therapeutically relevant effects : genomic , specific nongenomic and unspecific nongenomic .", "sentence_char_start_global": 485331, "sentence_char_end_global": 485547, "entities": [], "entities_global": []}
+{"sentence_id": 2924, "sentence_text": "Genomic effects are mediated by cytosolic receptors that alter expression of specific genes .", "sentence_char_start_global": 485548, "sentence_char_end_global": 485641, "entities": [{"text": "cytosolic receptors", "type": "ENTITY", "char_start": 32, "char_end": 51, "token_start": 5, "token_end": 6}], "entities_global": [{"text": "cytosolic receptors", "type": "ENTITY", "char_start": 485580, "char_end": 485599, "token_start": 5, "token_end": 6, "note": null}]}
+{"sentence_id": 2925, "sentence_text": "Specific nongenomic effects occur within a few minutes and are mediated by steroid - selective membrane receptors .", "sentence_char_start_global": 485642, "sentence_char_end_global": 485757, "entities": [{"text": "steroid - selective membrane receptors", "type": "ENTITY", "char_start": 75, "char_end": 113, "token_start": 12, "token_end": 16}], "entities_global": [{"text": "steroid - selective membrane receptors", "type": "ENTITY", "char_start": 485717, "char_end": 485755, "token_start": 12, "token_end": 16, "note": null}]}
+{"sentence_id": 2926, "sentence_text": "Unspecific nongenomic effects occur within seconds , but only at high glucocorticoid dosages , and seem to result from direct interactions with biological membranes .", "sentence_char_start_global": 485758, "sentence_char_end_global": 485924, "entities": [], "entities_global": []}
+{"sentence_id": 2927, "sentence_text": "For unspecific nongenomic effects , methylprednisolone and other glucocorticoids have been shown to inhibit cation cycling across the plasma membrane , but to have little effect on protein synthesis .", "sentence_char_start_global": 485925, "sentence_char_end_global": 486125, "entities": [], "entities_global": []}
+{"sentence_id": 2928, "sentence_text": "Thus , glucocorticoids could diminish or prevent the acute immune response by interfering with processes such as the rise in intracellular Ca2 + concentration .", "sentence_char_start_global": 486126, "sentence_char_end_global": 486286, "entities": [], "entities_global": []}
+{"sentence_id": 2929, "sentence_text": "It is proposed that the additional therapeutic benefit of higher doses is obtained via these nongenomic effects .", "sentence_char_start_global": 486287, "sentence_char_end_global": 486400, "entities": [], "entities_global": []}
+{"sentence_id": 2930, "sentence_text": "High glucose - induced intercellular adhesion molecule - 1 ( ICAM - 1 ) expression through an osmotic effect in rat mesangial cells is PKC - NF - kappa B - dependent .", "sentence_char_start_global": 486401, "sentence_char_end_global": 486568, "entities": [{"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 23, "char_end": 58, "token_start": 4, "token_end": 8}, {"text": "ICAM - 1", "type": "ENTITY", "char_start": 61, "char_end": 69, "token_start": 10, "token_end": 12}], "entities_global": [{"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 486424, "char_end": 486459, "token_start": 4, "token_end": 8, "note": null}, {"text": "ICAM - 1", "type": "ENTITY", "char_start": 486462, "char_end": 486470, "token_start": 10, "token_end": 12, "note": null}]}
+{"sentence_id": 2931, "sentence_text": "AIMS / HYPOTHESIS : Infiltration of mononuclear cells and glomerular enlargement accompanied by glomerular cell proliferation are very early characteristics of the pathophysiology of diabetes .", "sentence_char_start_global": 486569, "sentence_char_end_global": 486762, "entities": [], "entities_global": []}
+{"sentence_id": 2932, "sentence_text": "To clarify the mechanism of early diabetic nephropathy , we measured [ 3H ] - thymidine incorporation and cell numbers to show the influence of a high ambient glucose concentration and the osmotic effect on rat mesangial cell proliferation .", "sentence_char_start_global": 486763, "sentence_char_end_global": 487004, "entities": [], "entities_global": []}
+{"sentence_id": 2933, "sentence_text": "We also measured the effect of high glucose on the expression of intercellular adhesion molecule - 1 and vascular adhesion molecule - 1 by flow cytometry and semiquantitative RT - PCR in mesangial cells and the adhesion of leukocytes to mesangial cells .", "sentence_char_start_global": 487005, "sentence_char_end_global": 487259, "entities": [{"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 65, "char_end": 100, "token_start": 12, "token_end": 16}, {"text": "vascular adhesion molecule - 1", "type": "ENTITY", "char_start": 105, "char_end": 135, "token_start": 18, "token_end": 22}], "entities_global": [{"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 487070, "char_end": 487105, "token_start": 12, "token_end": 16, "note": null}, {"text": "vascular adhesion molecule - 1", "type": "ENTITY", "char_start": 487110, "char_end": 487140, "token_start": 18, "token_end": 22, "note": null}]}
+{"sentence_id": 2934, "sentence_text": "METHODS / RESULTS : Cells exposed to high D - glucose ( 30 mmol / l ) caused an increase in [ 3H ] - thymidine incorporation and cell numbers at 24 and 48 h and normalized at 72 h ( p < 0 . 05 ) , whereas these changes were not found in high mannitol ( 30 mmol / l ) , IL - 1 beta , or TNF alpha - stimulated mesangial cells .", "sentence_char_start_global": 487260, "sentence_char_end_global": 487586, "entities": [{"text": "IL - 1 beta", "type": "ENTITY", "char_start": 269, "char_end": 280, "token_start": 64, "token_end": 67}, {"text": "TNF alpha", "type": "ENTITY", "char_start": 286, "char_end": 295, "token_start": 70, "token_end": 71}], "entities_global": [{"text": "IL - 1 beta", "type": "ENTITY", "char_start": 487529, "char_end": 487540, "token_start": 64, "token_end": 67, "note": null}, {"text": "TNF alpha", "type": "ENTITY", "char_start": 487546, "char_end": 487555, "token_start": 70, "token_end": 71, "note": null}]}
+{"sentence_id": 2935, "sentence_text": "Cells exposed to high - glucose ( 15 , 30 , or 60 mmol / l ) or osmotic agents ( L - glucose , raffinose and mannitol ) showed that intercellular adhesion molecule - 1 expression began to increase after 24 h , reached its maximum at 24 and 48 h and gradually decreased afterwards .", "sentence_char_start_global": 487587, "sentence_char_end_global": 487868, "entities": [{"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 132, "char_end": 167, "token_start": 31, "token_end": 35}], "entities_global": [{"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 487719, "char_end": 487754, "token_start": 31, "token_end": 35, "note": null}]}
+{"sentence_id": 2936, "sentence_text": "The stimulatory effects of high glucose and high mannitol on mRNA expression were observed as early as 6 h and reached its maximum at 12 h .", "sentence_char_start_global": 487869, "sentence_char_end_global": 488009, "entities": [], "entities_global": []}
+{"sentence_id": 2937, "sentence_text": "Up - regulation of ICAM - 1 protein and mRNA was also found in IL - 1 - beta and TNF - alpha - stimulated mesangial cells .", "sentence_char_start_global": 488010, "sentence_char_end_global": 488133, "entities": [{"text": "ICAM - 1", "type": "ENTITY", "char_start": 19, "char_end": 27, "token_start": 4, "token_end": 6}, {"text": "IL - 1 - beta", "type": "ENTITY", "char_start": 63, "char_end": 76, "token_start": 14, "token_end": 18}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 81, "char_end": 92, "token_start": 20, "token_end": 22}], "entities_global": [{"text": "ICAM - 1", "type": "ENTITY", "char_start": 488029, "char_end": 488037, "token_start": 4, "token_end": 6, "note": null}, {"text": "IL - 1 - beta", "type": "ENTITY", "char_start": 488073, "char_end": 488086, "token_start": 14, "token_end": 18, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 488091, "char_end": 488102, "token_start": 20, "token_end": 22, "note": null}]}
+{"sentence_id": 2938, "sentence_text": "Neither vascular adhesion molecule - 1 protein nor mRNA expression was , however , affected by high glucose and high mannitol .", "sentence_char_start_global": 488134, "sentence_char_end_global": 488261, "entities": [{"text": "vascular adhesion molecule - 1", "type": "ENTITY", "char_start": 8, "char_end": 38, "token_start": 1, "token_end": 5}], "entities_global": [{"text": "vascular adhesion molecule - 1", "type": "ENTITY", "char_start": 488142, "char_end": 488172, "token_start": 1, "token_end": 5, "note": null}]}
+{"sentence_id": 2939, "sentence_text": "Notably , the protein kinase C inhibitors calphostin C and staurosporine reduced high glucose - or high mannitol - induced intercellular adhesion molecule - 1 mRNA expression and high glucose - induced proliferation .", "sentence_char_start_global": 488262, "sentence_char_end_global": 488479, "entities": [{"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 123, "char_end": 158, "token_start": 20, "token_end": 24}], "entities_global": [{"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 488385, "char_end": 488420, "token_start": 20, "token_end": 24, "note": null}]}
+{"sentence_id": 2940, "sentence_text": "Furthermore , the NF - kappa B inhibitor N - tosyl - L - phenylalanine chloromethyl ketone reduced high glucose - or high mannitol - induced intercellular adhesion molecule - 1 mRNA expression and high glucose - induced proliferation .", "sentence_char_start_global": 488480, "sentence_char_end_global": 488715, "entities": [{"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 141, "char_end": 176, "token_start": 26, "token_end": 30}], "entities_global": [{"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 488621, "char_end": 488656, "token_start": 26, "token_end": 30, "note": null}]}
+{"sentence_id": 2941, "sentence_text": "Results showed that high glucose ( 15 , 30 mmol / l ) or high concentrations of osmotic agents remarkably increased the number of adherent leukocytes to mesangial cells ( p < 0 . 01 ) compared with control cells ( 5 mmol / l D - glucose ) .", "sentence_char_start_global": 488716, "sentence_char_end_global": 488956, "entities": [], "entities_global": []}
+{"sentence_id": 2942, "sentence_text": "Functional blocking of intercellular adhesion molecule - 1 on mesangial cells with rat intercellular adhesion molecule - 1 monoclonal antibody , calphostin C , staurosporine , or N - tosyl - L - phenylalanine chloromethyl ketone significantly inhibited high glucose - or high mannitol - induced increase in leukocyte adhesion ( p < < 0 . 05 ) .", "sentence_char_start_global": 488957, "sentence_char_end_global": 489301, "entities": [{"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 23, "char_end": 58, "token_start": 3, "token_end": 7}, {"text": "rat intercellular adhesion molecule - 1 monoclonal antibody", "type": "ENTITY", "char_start": 83, "char_end": 142, "token_start": 12, "token_end": 19}], "entities_global": [{"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 488980, "char_end": 489015, "token_start": 3, "token_end": 7, "note": null}, {"text": "rat intercellular adhesion molecule - 1 monoclonal antibody", "type": "ENTITY", "char_start": 489040, "char_end": 489099, "token_start": 12, "token_end": 19, "note": null}]}
+{"sentence_id": 2943, "sentence_text": "CONCLUSION / INTERPRETATION : These results suggest that high glucose can upregulate intercellular adhesion molecule - 1 protein and mRNA expression but not vascular adhesion molecule - 1 expression in mesangial cells and promote leukocyte adhesion through up - regulation of intercellular adhesion molecule - 1 through osmotic effect , possibly depending on the protein kinase C nuclear factor - kappa B ( PKC - NF - kappa B ) pathway .", "sentence_char_start_global": 489302, "sentence_char_end_global": 489739, "entities": [{"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 85, "char_end": 120, "token_start": 12, "token_end": 16}, {"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 276, "char_end": 311, "token_start": 41, "token_end": 45}, {"text": "protein kinase C", "type": "ENTITY", "char_start": 363, "char_end": 379, "token_start": 54, "token_end": 56}, {"text": "nuclear factor - kappa B", "type": "ENTITY", "char_start": 380, "char_end": 404, "token_start": 57, "token_end": 61}, {"text": "PKC", "type": "ENTITY", "char_start": 407, "char_end": 410, "token_start": 63, "token_end": 63}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 413, "char_end": 425, "token_start": 65, "token_end": 68}], "entities_global": [{"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 489387, "char_end": 489422, "token_start": 12, "token_end": 16, "note": null}, {"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 489578, "char_end": 489613, "token_start": 41, "token_end": 45, "note": null}, {"text": "protein kinase C", "type": "ENTITY", "char_start": 489665, "char_end": 489681, "token_start": 54, "token_end": 56, "note": null}, {"text": "nuclear factor - kappa B", "type": "ENTITY", "char_start": 489682, "char_end": 489706, "token_start": 57, "token_end": 61, "note": null}, {"text": "PKC", "type": "ENTITY", "char_start": 489709, "char_end": 489712, "token_start": 63, "token_end": 63, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 489715, "char_end": 489727, "token_start": 65, "token_end": 68, "note": null}]}
+{"sentence_id": 2944, "sentence_text": "High glucose itself can also promote mesangial cell proliferation through the PKC - NF - kappa B pathways .", "sentence_char_start_global": 489740, "sentence_char_end_global": 489847, "entities": [], "entities_global": []}
+{"sentence_id": 2945, "sentence_text": "We conclude that hyperglycaemia in itself seems to be an important factor in the development of early diabetic nephropathy .", "sentence_char_start_global": 489848, "sentence_char_end_global": 489972, "entities": [], "entities_global": []}
+{"sentence_id": 2946, "sentence_text": "Combined corticosteroid / granulocyte colony - stimulating factor ( G - CSF ) therapy in the treatment of severe congenital neutropenia unresponsive to G - CSF : Activated glucocorticoid receptors synergize with G - CSF signals .", "sentence_char_start_global": 489973, "sentence_char_end_global": 490202, "entities": [{"text": "granulocyte colony - stimulating factor", "type": "ENTITY", "char_start": 26, "char_end": 65, "token_start": 3, "token_end": 7}, {"text": "G - CSF", "type": "ENTITY", "char_start": 68, "char_end": 75, "token_start": 9, "token_end": 11}, {"text": "G - CSF", "type": "ENTITY", "char_start": 152, "char_end": 159, "token_start": 23, "token_end": 25}, {"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 172, "char_end": 196, "token_start": 28, "token_end": 29}, {"text": "G - CSF", "type": "ENTITY", "char_start": 212, "char_end": 219, "token_start": 32, "token_end": 34}], "entities_global": [{"text": "granulocyte colony - stimulating factor", "type": "ENTITY", "char_start": 489999, "char_end": 490038, "token_start": 3, "token_end": 7, "note": null}, {"text": "G - CSF", "type": "ENTITY", "char_start": 490041, "char_end": 490048, "token_start": 9, "token_end": 11, "note": null}, {"text": "G - CSF", "type": "ENTITY", "char_start": 490125, "char_end": 490132, "token_start": 23, "token_end": 25, "note": null}, {"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 490145, "char_end": 490169, "token_start": 28, "token_end": 29, "note": null}, {"text": "G - CSF", "type": "ENTITY", "char_start": 490185, "char_end": 490192, "token_start": 32, "token_end": 34, "note": null}]}
+{"sentence_id": 2947, "sentence_text": "More than 90 % of patients with severe congenital neutropenia ( SCN ) respond to granulocyte colony - stimulating factor ( G - CSF ) therapy .", "sentence_char_start_global": 490203, "sentence_char_end_global": 490345, "entities": [{"text": "granulocyte colony - stimulating factor", "type": "ENTITY", "char_start": 81, "char_end": 120, "token_start": 15, "token_end": 19}, {"text": "G - CSF", "type": "ENTITY", "char_start": 123, "char_end": 130, "token_start": 21, "token_end": 23}], "entities_global": [{"text": "granulocyte colony - stimulating factor", "type": "ENTITY", "char_start": 490284, "char_end": 490323, "token_start": 15, "token_end": 19, "note": null}, {"text": "G - CSF", "type": "ENTITY", "char_start": 490326, "char_end": 490333, "token_start": 21, "token_end": 23, "note": null}]}
+{"sentence_id": 2948, "sentence_text": "The basis for the refractory state in the remaining patients is unknown .", "sentence_char_start_global": 490346, "sentence_char_end_global": 490419, "entities": [], "entities_global": []}
+{"sentence_id": 2949, "sentence_text": "To address this issue , we studied a child with SCN who was totally unresponsive to G - CSF and had a novel point mutation in the extracellular domain of the G - CSF receptor ( GCSF - R ) .", "sentence_char_start_global": 490420, "sentence_char_end_global": 490609, "entities": [{"text": "G - CSF", "type": "ENTITY", "char_start": 84, "char_end": 91, "token_start": 16, "token_end": 18}, {"text": "extracellular domain", "type": "ENTITY", "char_start": 130, "char_end": 150, "token_start": 27, "token_end": 28}, {"text": "G - CSF receptor", "type": "ENTITY", "char_start": 158, "char_end": 174, "token_start": 31, "token_end": 34}, {"text": "GCSF - R", "type": "ENTITY", "char_start": 177, "char_end": 185, "token_start": 36, "token_end": 38}], "entities_global": [{"text": "G - CSF", "type": "ENTITY", "char_start": 490504, "char_end": 490511, "token_start": 16, "token_end": 18, "note": null}, {"text": "extracellular domain", "type": "ENTITY", "char_start": 490550, "char_end": 490570, "token_start": 27, "token_end": 28, "note": null}, {"text": "G - CSF receptor", "type": "ENTITY", "char_start": 490578, "char_end": 490594, "token_start": 31, "token_end": 34, "note": null}, {"text": "GCSF - R", "type": "ENTITY", "char_start": 490597, "char_end": 490605, "token_start": 36, "token_end": 38, "note": null}]}
+{"sentence_id": 2950, "sentence_text": "Marrow stromal support of granulopoiesis was evaluated by plating CD34 ( + ) cells on preformed stromal layers .", "sentence_char_start_global": 490610, "sentence_char_end_global": 490722, "entities": [], "entities_global": []}
+{"sentence_id": 2951, "sentence_text": "Nonadherent cells were harvested and assayed in clonogenic assays for granulocytic colony production .", "sentence_char_start_global": 490723, "sentence_char_end_global": 490825, "entities": [], "entities_global": []}
+{"sentence_id": 2952, "sentence_text": "The in vitro effect of G - CSF and corticosteroids on granulopoiesis was evaluated in clonogenic assays of marrow mononuclear cells , by proliferation studies of the murine myeloid cell line 32D expressing the patient ' s mutated G - CSFR , and by measuring STAT5 activation in nuclear extracts from stimulated cells .", "sentence_char_start_global": 490826, "sentence_char_end_global": 491144, "entities": [{"text": "G - CSF", "type": "ENTITY", "char_start": 23, "char_end": 30, "token_start": 5, "token_end": 7}, {"text": "mutated G - CSFR", "type": "ENTITY", "char_start": 222, "char_end": 238, "token_start": 37, "token_end": 40}], "entities_global": [{"text": "G - CSF", "type": "ENTITY", "char_start": 490849, "char_end": 490856, "token_start": 5, "token_end": 7, "note": null}, {"text": "mutated G - CSFR", "type": "ENTITY", "char_start": 491048, "char_end": 491064, "token_start": 37, "token_end": 40, "note": null}]}
+{"sentence_id": 2953, "sentence_text": "Patient ' s stroma supported granulopoiesis derived from control marrow CD34 ( + ) cells in a normal manner .", "sentence_char_start_global": 491145, "sentence_char_end_global": 491254, "entities": [], "entities_global": []}
+{"sentence_id": 2954, "sentence_text": "Normal stroma , however , failed to induce granulopoiesis from patient ' s CD34 ( + ) cells .", "sentence_char_start_global": 491255, "sentence_char_end_global": 491348, "entities": [], "entities_global": []}
+{"sentence_id": 2955, "sentence_text": "Clonogenic assays of the patient ' s marrow mononuclear cells incorporating either G - CSF or hydrocortisone produced little neutrophil growth .", "sentence_char_start_global": 491349, "sentence_char_end_global": 491493, "entities": [{"text": "G - CSF", "type": "ENTITY", "char_start": 83, "char_end": 90, "token_start": 12, "token_end": 14}], "entities_global": [{"text": "G - CSF", "type": "ENTITY", "char_start": 491432, "char_end": 491439, "token_start": 12, "token_end": 14, "note": null}]}
+{"sentence_id": 2956, "sentence_text": "In contrast , inclusion of both G - CSF and hydrocortisone in the cytokine ` ` cocktail ' ' markedly increased the neutrophil numbers .", "sentence_char_start_global": 491494, "sentence_char_end_global": 491629, "entities": [{"text": "G - CSF", "type": "ENTITY", "char_start": 32, "char_end": 39, "token_start": 6, "token_end": 8}, {"text": "cytokine ` ` cocktail ' '", "type": "ENTITY", "char_start": 66, "char_end": 91, "token_start": 13, "token_end": 18}], "entities_global": [{"text": "G - CSF", "type": "ENTITY", "char_start": 491526, "char_end": 491533, "token_start": 6, "token_end": 8, "note": null}, {"text": "cytokine ` ` cocktail ' '", "type": "ENTITY", "char_start": 491560, "char_end": 491585, "token_start": 13, "token_end": 18, "note": null}]}
+{"sentence_id": 2957, "sentence_text": "Proliferation of 32D cells expressing the mutated receptor and STAT5 activation were improved by a combination of G - CSF and dexamethasone .", "sentence_char_start_global": 491630, "sentence_char_end_global": 491771, "entities": [{"text": "mutated receptor", "type": "ENTITY", "char_start": 42, "char_end": 58, "token_start": 6, "token_end": 7}, {"text": "G - CSF", "type": "ENTITY", "char_start": 114, "char_end": 121, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "mutated receptor", "type": "ENTITY", "char_start": 491672, "char_end": 491688, "token_start": 6, "token_end": 7, "note": null}, {"text": "G - CSF", "type": "ENTITY", "char_start": 491744, "char_end": 491751, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 2958, "sentence_text": "When small daily doses of oral prednisone were then administered to the patient with conventional doses of subcutaneous G - CSF , the patient responded with increased neutrophil numbers and with a complete reversal of the infectious problems .", "sentence_char_start_global": 491772, "sentence_char_end_global": 492015, "entities": [{"text": "subcutaneous G - CSF", "type": "ENTITY", "char_start": 107, "char_end": 127, "token_start": 17, "token_end": 20}], "entities_global": [{"text": "subcutaneous G - CSF", "type": "ENTITY", "char_start": 491879, "char_end": 491899, "token_start": 17, "token_end": 20, "note": null}]}
+{"sentence_id": 2959, "sentence_text": "These data provide insight into SCN unresponsive to standard G - CSF treatment and to the potential corrective action of combined treatment with G - CSF and corticosteroids through synergistic activation of STAT5 .", "sentence_char_start_global": 492016, "sentence_char_end_global": 492230, "entities": [{"text": "G - CSF", "type": "ENTITY", "char_start": 61, "char_end": 68, "token_start": 9, "token_end": 11}, {"text": "G - CSF", "type": "ENTITY", "char_start": 145, "char_end": 152, "token_start": 23, "token_end": 25}, {"text": "STAT5", "type": "ENTITY", "char_start": 207, "char_end": 212, "token_start": 32, "token_end": 32}], "entities_global": [{"text": "G - CSF", "type": "ENTITY", "char_start": 492077, "char_end": 492084, "token_start": 9, "token_end": 11, "note": null}, {"text": "G - CSF", "type": "ENTITY", "char_start": 492161, "char_end": 492168, "token_start": 23, "token_end": 25, "note": null}, {"text": "STAT5", "type": "ENTITY", "char_start": 492223, "char_end": 492228, "token_start": 32, "token_end": 32, "note": null}]}
+{"sentence_id": 2960, "sentence_text": "Human renal mesangial cells are a target for the anti - inflammatory action of 9 - cis retinoic acid .", "sentence_char_start_global": 492231, "sentence_char_end_global": 492333, "entities": [], "entities_global": []}
+{"sentence_id": 2961, "sentence_text": "Mesangial cells play an active role in the inflammatory response to glomerular injury .", "sentence_char_start_global": 492334, "sentence_char_end_global": 492421, "entities": [], "entities_global": []}
+{"sentence_id": 2962, "sentence_text": "We have studied in cultured human mesangial cells ( CHMC ) several effects of 9 - cis retinoic acid ( 9 - cRA ) , an activator of both retinoic acid receptors ( RARs ) and retinoid X receptors ( RXRs ) .", "sentence_char_start_global": 492422, "sentence_char_end_global": 492625, "entities": [{"text": "retinoic acid receptors", "type": "ENTITY", "char_start": 135, "char_end": 158, "token_start": 29, "token_end": 31}, {"text": "RARs", "type": "ENTITY", "char_start": 161, "char_end": 165, "token_start": 33, "token_end": 33}, {"text": "retinoid X receptors", "type": "ENTITY", "char_start": 172, "char_end": 192, "token_start": 36, "token_end": 38}, {"text": "RXRs", "type": "ENTITY", "char_start": 195, "char_end": 199, "token_start": 40, "token_end": 40}], "entities_global": [{"text": "retinoic acid receptors", "type": "ENTITY", "char_start": 492557, "char_end": 492580, "token_start": 29, "token_end": 31, "note": null}, {"text": "RARs", "type": "ENTITY", "char_start": 492583, "char_end": 492587, "token_start": 33, "token_end": 33, "note": null}, {"text": "retinoid X receptors", "type": "ENTITY", "char_start": 492594, "char_end": 492614, "token_start": 36, "token_end": 38, "note": null}, {"text": "RXRs", "type": "ENTITY", "char_start": 492617, "char_end": 492621, "token_start": 40, "token_end": 40, "note": null}]}
+{"sentence_id": 2963, "sentence_text": "9 - cRA inhibited foetal calf serum - induced CHMC proliferation .", "sentence_char_start_global": 492626, "sentence_char_end_global": 492692, "entities": [], "entities_global": []}
+{"sentence_id": 2964, "sentence_text": "It also prevented CHMC death induced by the inflammatory mediator H ( 2 ) O ( 2 ) .", "sentence_char_start_global": 492693, "sentence_char_end_global": 492776, "entities": [], "entities_global": []}
+{"sentence_id": 2965, "sentence_text": "This preventive effect was not due to any increase in H ( 2 ) O ( 2 ) catabolism and it persisted even when both catalase and glutathione synthesis were inhibited .", "sentence_char_start_global": 492777, "sentence_char_end_global": 492941, "entities": [], "entities_global": []}
+{"sentence_id": 2966, "sentence_text": "Finally , 9 - cRA diminished monocyte adhesion to FCS - stimulated CHMC .", "sentence_char_start_global": 492942, "sentence_char_end_global": 493015, "entities": [], "entities_global": []}
+{"sentence_id": 2967, "sentence_text": "Interestingly , the retinoid also inhibited in FCS - stimulated cells the protein expression of two mesangial adhesion molecules , fibronectin and osteopontin , but it did not modify the protein expression of intercellular adhesion molecule - 1 and vascular adhesion molecule - 1 .", "sentence_char_start_global": 493016, "sentence_char_end_global": 493297, "entities": [{"text": "mesangial adhesion molecules", "type": "ENTITY", "char_start": 100, "char_end": 128, "token_start": 16, "token_end": 18}, {"text": "fibronectin", "type": "ENTITY", "char_start": 131, "char_end": 142, "token_start": 20, "token_end": 20}, {"text": "osteopontin", "type": "ENTITY", "char_start": 147, "char_end": 158, "token_start": 22, "token_end": 22}, {"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 209, "char_end": 244, "token_start": 33, "token_end": 37}, {"text": "vascular adhesion molecule - 1", "type": "ENTITY", "char_start": 249, "char_end": 279, "token_start": 39, "token_end": 43}], "entities_global": [{"text": "mesangial adhesion molecules", "type": "ENTITY", "char_start": 493116, "char_end": 493144, "token_start": 16, "token_end": 18, "note": null}, {"text": "fibronectin", "type": "ENTITY", "char_start": 493147, "char_end": 493158, "token_start": 20, "token_end": 20, "note": null}, {"text": "osteopontin", "type": "ENTITY", "char_start": 493163, "char_end": 493174, "token_start": 22, "token_end": 22, "note": null}, {"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 493225, "char_end": 493260, "token_start": 33, "token_end": 37, "note": null}, {"text": "vascular adhesion molecule - 1", "type": "ENTITY", "char_start": 493265, "char_end": 493295, "token_start": 39, "token_end": 43, "note": null}]}
+{"sentence_id": 2968, "sentence_text": "All major RARs and RXRs isotypes were expressed in CHMC regardless of the presence or absence of 9 - cRA .", "sentence_char_start_global": 493298, "sentence_char_end_global": 493404, "entities": [{"text": "RARs and RXRs isotypes", "type": "ENTITY", "char_start": 10, "char_end": 32, "token_start": 2, "token_end": 5}], "entities_global": [{"text": "RARs and RXRs isotypes", "type": "ENTITY", "char_start": 493308, "char_end": 493330, "token_start": 2, "token_end": 5, "note": null}]}
+{"sentence_id": 2969, "sentence_text": "Transcripts to RAR - alpha , RAR - beta and RXR - alpha increased after incubation with 9 - cRA whereas RXR - gamma was inhibited , suggesting a major role for RARs and RXRs in 9 - cRA - anti - inflammatory effects .", "sentence_char_start_global": 493405, "sentence_char_end_global": 493621, "entities": [{"text": "RAR - alpha", "type": "ENTITY", "char_start": 15, "char_end": 26, "token_start": 2, "token_end": 4}, {"text": "RAR - beta", "type": "ENTITY", "char_start": 29, "char_end": 39, "token_start": 6, "token_end": 8}, {"text": "RXR - alpha", "type": "ENTITY", "char_start": 44, "char_end": 55, "token_start": 10, "token_end": 12}, {"text": "RXR - gamma", "type": "ENTITY", "char_start": 104, "char_end": 115, "token_start": 21, "token_end": 23}, {"text": "RARs", "type": "ENTITY", "char_start": 160, "char_end": 164, "token_start": 32, "token_end": 32}, {"text": "RXRs", "type": "ENTITY", "char_start": 169, "char_end": 173, "token_start": 34, "token_end": 34}], "entities_global": [{"text": "RAR - alpha", "type": "ENTITY", "char_start": 493420, "char_end": 493431, "token_start": 2, "token_end": 4, "note": null}, {"text": "RAR - beta", "type": "ENTITY", "char_start": 493434, "char_end": 493444, "token_start": 6, "token_end": 8, "note": null}, {"text": "RXR - alpha", "type": "ENTITY", "char_start": 493449, "char_end": 493460, "token_start": 10, "token_end": 12, "note": null}, {"text": "RXR - gamma", "type": "ENTITY", "char_start": 493509, "char_end": 493520, "token_start": 21, "token_end": 23, "note": null}, {"text": "RARs", "type": "ENTITY", "char_start": 493565, "char_end": 493569, "token_start": 32, "token_end": 32, "note": null}, {"text": "RXRs", "type": "ENTITY", "char_start": 493574, "char_end": 493578, "token_start": 34, "token_end": 34, "note": null}]}
+{"sentence_id": 2970, "sentence_text": "9 - cRA was toxic only at 50 microM ( a concentration 50 - 5000 times higher than required for the effects above ) .", "sentence_char_start_global": 493622, "sentence_char_end_global": 493738, "entities": [], "entities_global": []}
+{"sentence_id": 2971, "sentence_text": "Cell death occurred by apoptosis , whose onset was associated with a pronounced increase in catalase activity and reduced glutathione content , being more effectively induced by all - trans retinoic acid .", "sentence_char_start_global": 493739, "sentence_char_end_global": 493944, "entities": [], "entities_global": []}
+{"sentence_id": 2972, "sentence_text": "Modulation of the oxidant / antioxidant balance failed to inhibit apoptosis .", "sentence_char_start_global": 493945, "sentence_char_end_global": 494022, "entities": [], "entities_global": []}
+{"sentence_id": 2973, "sentence_text": "We conclude that mesangial cells might be a target for the treatment of inflammatory glomerulopathies with 9 - cRA .", "sentence_char_start_global": 494023, "sentence_char_end_global": 494139, "entities": [], "entities_global": []}
+{"sentence_id": 2974, "sentence_text": "Expression of mammalian defensin genes .", "sentence_char_start_global": 494140, "sentence_char_end_global": 494180, "entities": [{"text": "mammalian defensin genes", "type": "ENTITY", "char_start": 14, "char_end": 38, "token_start": 2, "token_end": 4}], "entities_global": [{"text": "mammalian defensin genes", "type": "ENTITY", "char_start": 494154, "char_end": 494178, "token_start": 2, "token_end": 4, "note": null}]}
+{"sentence_id": 2975, "sentence_text": "Antimicrobial peptides are a prevalent mechanism of host defense found throughout nature .", "sentence_char_start_global": 494181, "sentence_char_end_global": 494271, "entities": [], "entities_global": []}
+{"sentence_id": 2976, "sentence_text": "In mammals , defensins are among the most abundant of these broad - spectrum antibiotics , and are expressed in epithelial and hematopoietic cells .", "sentence_char_start_global": 494272, "sentence_char_end_global": 494420, "entities": [{"text": "defensins", "type": "ENTITY", "char_start": 13, "char_end": 22, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "defensins", "type": "ENTITY", "char_start": 494285, "char_end": 494294, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 2977, "sentence_text": "The defensin peptides are especially abundant in neutrophils ; however , gene expression is limited to the promyelocyte stage .", "sentence_char_start_global": 494421, "sentence_char_end_global": 494548, "entities": [], "entities_global": []}
+{"sentence_id": 2978, "sentence_text": "In epithelial cells , defensin genes are found as both constitutively expressed and inducible .", "sentence_char_start_global": 494549, "sentence_char_end_global": 494644, "entities": [{"text": "defensin genes", "type": "ENTITY", "char_start": 22, "char_end": 36, "token_start": 4, "token_end": 5}], "entities_global": [{"text": "defensin genes", "type": "ENTITY", "char_start": 494571, "char_end": 494585, "token_start": 4, "token_end": 5, "note": null}]}
+{"sentence_id": 2979, "sentence_text": "Induction has been observed in vitro by stimulation with bacterial lipopolysaccharide as well as inflammatory mediators .", "sentence_char_start_global": 494645, "sentence_char_end_global": 494766, "entities": [], "entities_global": []}
+{"sentence_id": 2980, "sentence_text": "In vivo , up - regulation of several defensin genes occurs in both infectious and inflammatory states .", "sentence_char_start_global": 494767, "sentence_char_end_global": 494870, "entities": [{"text": "defensin genes", "type": "ENTITY", "char_start": 37, "char_end": 51, "token_start": 8, "token_end": 9}], "entities_global": [{"text": "defensin genes", "type": "ENTITY", "char_start": 494804, "char_end": 494818, "token_start": 8, "token_end": 9, "note": null}]}
+{"sentence_id": 2981, "sentence_text": "Gene regulation occurs via signal transduction pathways common to other innate immune responses , utilizing transcription factors such as nuclear factor ( NF ) - kappaB and NF interleukin - 6 .", "sentence_char_start_global": 494871, "sentence_char_end_global": 495064, "entities": [{"text": "transcription factors", "type": "ENTITY", "char_start": 108, "char_end": 129, "token_start": 15, "token_end": 16}, {"text": "nuclear factor ( NF ) - kappaB", "type": "ENTITY", "char_start": 138, "char_end": 168, "token_start": 19, "token_end": 25}, {"text": "NF interleukin - 6", "type": "ENTITY", "char_start": 173, "char_end": 191, "token_start": 27, "token_end": 30}], "entities_global": [{"text": "transcription factors", "type": "ENTITY", "char_start": 494979, "char_end": 495000, "token_start": 15, "token_end": 16, "note": null}, {"text": "nuclear factor ( NF ) - kappaB", "type": "ENTITY", "char_start": 495009, "char_end": 495039, "token_start": 19, "token_end": 25, "note": null}, {"text": "NF interleukin - 6", "type": "ENTITY", "char_start": 495044, "char_end": 495062, "token_start": 27, "token_end": 30, "note": null}]}
+{"sentence_id": 2982, "sentence_text": "Together , the data suggest a broad - based innate host defense whereby potent antimicrobial peptides are present to prevent initial colonization by pathogenic microorganisms .", "sentence_char_start_global": 495065, "sentence_char_end_global": 495241, "entities": [], "entities_global": []}
+{"sentence_id": 2983, "sentence_text": "In addition , the recognition of bacteria coupled with a nascent inflammatory response can bolster this defense by a coordinated up - regulation of the peptides .", "sentence_char_start_global": 495242, "sentence_char_end_global": 495404, "entities": [], "entities_global": []}
+{"sentence_id": 2984, "sentence_text": "Multiple signals required for cyclic AMP - responsive element binding protein ( CREB ) binding protein interaction induced by CD3 / CD28 costimulation .", "sentence_char_start_global": 495405, "sentence_char_end_global": 495557, "entities": [{"text": "cyclic AMP - responsive element binding protein", "type": "ENTITY", "char_start": 30, "char_end": 77, "token_start": 4, "token_end": 10}, {"text": "CREB", "type": "ENTITY", "char_start": 80, "char_end": 84, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "cyclic AMP - responsive element binding protein", "type": "ENTITY", "char_start": 495435, "char_end": 495482, "token_start": 4, "token_end": 10, "note": null}, {"text": "CREB", "type": "ENTITY", "char_start": 495485, "char_end": 495489, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 2985, "sentence_text": "The optimal activation of cAMP - responsive element binding protein ( CREB ) , similar to the full activation of T lymphocytes , requires the stimulation of both CD3 and CD28 .", "sentence_char_start_global": 495558, "sentence_char_end_global": 495734, "entities": [{"text": "cAMP - responsive element binding protein", "type": "ENTITY", "char_start": 26, "char_end": 67, "token_start": 4, "token_end": 9}, {"text": "CREB", "type": "ENTITY", "char_start": 70, "char_end": 74, "token_start": 11, "token_end": 11}, {"text": "CD3", "type": "ENTITY", "char_start": 162, "char_end": 165, "token_start": 28, "token_end": 28}, {"text": "CD28", "type": "ENTITY", "char_start": 170, "char_end": 174, "token_start": 30, "token_end": 30}], "entities_global": [{"text": "cAMP - responsive element binding protein", "type": "ENTITY", "char_start": 495584, "char_end": 495625, "token_start": 4, "token_end": 9, "note": null}, {"text": "CREB", "type": "ENTITY", "char_start": 495628, "char_end": 495632, "token_start": 11, "token_end": 11, "note": null}, {"text": "CD3", "type": "ENTITY", "char_start": 495720, "char_end": 495723, "token_start": 28, "token_end": 28, "note": null}, {"text": "CD28", "type": "ENTITY", "char_start": 495728, "char_end": 495732, "token_start": 30, "token_end": 30, "note": null}]}
+{"sentence_id": 2986, "sentence_text": "Using a reporter system to detect interaction of CREB and CREB - binding protein ( CBP ) , in this study we found that CREB binds to CBP only by engagement of both CD3 and CD28 .", "sentence_char_start_global": 495735, "sentence_char_end_global": 495913, "entities": [{"text": "CREB", "type": "ENTITY", "char_start": 49, "char_end": 53, "token_start": 8, "token_end": 8}, {"text": "CREB - binding protein", "type": "ENTITY", "char_start": 58, "char_end": 80, "token_start": 10, "token_end": 13}, {"text": "CBP", "type": "ENTITY", "char_start": 83, "char_end": 86, "token_start": 15, "token_end": 15}, {"text": "CREB", "type": "ENTITY", "char_start": 119, "char_end": 123, "token_start": 24, "token_end": 24}, {"text": "CBP", "type": "ENTITY", "char_start": 133, "char_end": 136, "token_start": 27, "token_end": 27}, {"text": "CD3", "type": "ENTITY", "char_start": 164, "char_end": 167, "token_start": 33, "token_end": 33}, {"text": "CD28", "type": "ENTITY", "char_start": 172, "char_end": 176, "token_start": 35, "token_end": 35}], "entities_global": [{"text": "CREB", "type": "ENTITY", "char_start": 495784, "char_end": 495788, "token_start": 8, "token_end": 8, "note": null}, {"text": "CREB - binding protein", "type": "ENTITY", "char_start": 495793, "char_end": 495815, "token_start": 10, "token_end": 13, "note": null}, {"text": "CBP", "type": "ENTITY", "char_start": 495818, "char_end": 495821, "token_start": 15, "token_end": 15, "note": null}, {"text": "CREB", "type": "ENTITY", "char_start": 495854, "char_end": 495858, "token_start": 24, "token_end": 24, "note": null}, {"text": "CBP", "type": "ENTITY", "char_start": 495868, "char_end": 495871, "token_start": 27, "token_end": 27, "note": null}, {"text": "CD3", "type": "ENTITY", "char_start": 495899, "char_end": 495902, "token_start": 33, "token_end": 33, "note": null}, {"text": "CD28", "type": "ENTITY", "char_start": 495907, "char_end": 495911, "token_start": 35, "token_end": 35, "note": null}]}
+{"sentence_id": 2987, "sentence_text": "CD3 / CD28 - promoted CREB - CBP interaction was dependent on p38 mitogen - activated protein kinase ( MAPK ) and calcium / calmodulin - dependent protein kinase ( CaMK ) IV in addition to the previously identified extracellular signal - regulated kinase pathway .", "sentence_char_start_global": 495914, "sentence_char_end_global": 496178, "entities": [{"text": "CD3 / CD28", "type": "ENTITY", "char_start": 0, "char_end": 10, "token_start": 0, "token_end": 2}, {"text": "CREB", "type": "ENTITY", "char_start": 22, "char_end": 26, "token_start": 5, "token_end": 5}, {"text": "CBP", "type": "ENTITY", "char_start": 29, "char_end": 32, "token_start": 7, "token_end": 7}, {"text": "p38 mitogen - activated protein kinase", "type": "ENTITY", "char_start": 62, "char_end": 100, "token_start": 12, "token_end": 17}, {"text": "MAPK", "type": "ENTITY", "char_start": 103, "char_end": 107, "token_start": 19, "token_end": 19}, {"text": "calcium / calmodulin - dependent protein kinase ( CaMK ) IV", "type": "ENTITY", "char_start": 114, "char_end": 173, "token_start": 22, "token_end": 32}], "entities_global": [{"text": "CD3 / CD28", "type": "ENTITY", "char_start": 495914, "char_end": 495924, "token_start": 0, "token_end": 2, "note": null}, {"text": "CREB", "type": "ENTITY", "char_start": 495936, "char_end": 495940, "token_start": 5, "token_end": 5, "note": null}, {"text": "CBP", "type": "ENTITY", "char_start": 495943, "char_end": 495946, "token_start": 7, "token_end": 7, "note": null}, {"text": "p38 mitogen - activated protein kinase", "type": "ENTITY", "char_start": 495976, "char_end": 496014, "token_start": 12, "token_end": 17, "note": null}, {"text": "MAPK", "type": "ENTITY", "char_start": 496017, "char_end": 496021, "token_start": 19, "token_end": 19, "note": null}, {"text": "calcium / calmodulin - dependent protein kinase ( CaMK ) IV", "type": "ENTITY", "char_start": 496028, "char_end": 496087, "token_start": 22, "token_end": 32, "note": null}]}
+{"sentence_id": 2988, "sentence_text": "Extracellular signal - regulated kinase , CaMKIV , and p38 MAPK were also the kinases involved in CREB Ser ( 133 ) phosphorylation induced by CD3 / CD28 .", "sentence_char_start_global": 496179, "sentence_char_end_global": 496333, "entities": [{"text": "Extracellular signal - regulated kinase , CaMKIV", "type": "ENTITY", "char_start": 0, "char_end": 48, "token_start": 0, "token_end": 6}, {"text": "p38 MAPK", "type": "ENTITY", "char_start": 55, "char_end": 63, "token_start": 9, "token_end": 10}, {"text": "CREB", "type": "ENTITY", "char_start": 98, "char_end": 102, "token_start": 17, "token_end": 17}, {"text": "CD3 / CD28", "type": "ENTITY", "char_start": 142, "char_end": 152, "token_start": 25, "token_end": 27}], "entities_global": [{"text": "Extracellular signal - regulated kinase , CaMKIV", "type": "ENTITY", "char_start": 496179, "char_end": 496227, "token_start": 0, "token_end": 6, "note": null}, {"text": "p38 MAPK", "type": "ENTITY", "char_start": 496234, "char_end": 496242, "token_start": 9, "token_end": 10, "note": null}, {"text": "CREB", "type": "ENTITY", "char_start": 496277, "char_end": 496281, "token_start": 17, "token_end": 17, "note": null}, {"text": "CD3 / CD28", "type": "ENTITY", "char_start": 496321, "char_end": 496331, "token_start": 25, "token_end": 27, "note": null}]}
+{"sentence_id": 2989, "sentence_text": "A reconstitution experiment illustrated that optimum CREB - CBP interaction and CREB trans - activation were attained when these three kinase pathways were simultaneously activated in T cells .", "sentence_char_start_global": 496334, "sentence_char_end_global": 496527, "entities": [{"text": "CREB", "type": "ENTITY", "char_start": 53, "char_end": 57, "token_start": 6, "token_end": 6}, {"text": "CBP", "type": "ENTITY", "char_start": 60, "char_end": 63, "token_start": 8, "token_end": 8}, {"text": "CREB", "type": "ENTITY", "char_start": 80, "char_end": 84, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "CREB", "type": "ENTITY", "char_start": 496387, "char_end": 496391, "token_start": 6, "token_end": 6, "note": null}, {"text": "CBP", "type": "ENTITY", "char_start": 496394, "char_end": 496397, "token_start": 8, "token_end": 8, "note": null}, {"text": "CREB", "type": "ENTITY", "char_start": 496414, "char_end": 496418, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 2990, "sentence_text": "Our results demonstrate that coordinated activation of different kinases leads to full activation of CREB .", "sentence_char_start_global": 496528, "sentence_char_end_global": 496635, "entities": [{"text": "kinases", "type": "ENTITY", "char_start": 65, "char_end": 72, "token_start": 8, "token_end": 8}, {"text": "CREB", "type": "ENTITY", "char_start": 101, "char_end": 105, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "kinases", "type": "ENTITY", "char_start": 496593, "char_end": 496600, "token_start": 8, "token_end": 8, "note": null}, {"text": "CREB", "type": "ENTITY", "char_start": 496629, "char_end": 496633, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 2991, "sentence_text": "Notably , CD28 ligation activated p38 MAPK and CaMKIV , the kinases stimulated by CD3 engagement , suggesting that CD28 acts by increasing the activation extent of p38 MAPK and CaMKIV .", "sentence_char_start_global": 496636, "sentence_char_end_global": 496821, "entities": [{"text": "p38 MAPK", "type": "ENTITY", "char_start": 34, "char_end": 42, "token_start": 5, "token_end": 6}, {"text": "CaMKIV", "type": "ENTITY", "char_start": 47, "char_end": 53, "token_start": 8, "token_end": 8}, {"text": "kinases", "type": "ENTITY", "char_start": 60, "char_end": 67, "token_start": 11, "token_end": 11}, {"text": "CD28", "type": "ENTITY", "char_start": 115, "char_end": 119, "token_start": 19, "token_end": 19}, {"text": "p38 MAPK", "type": "ENTITY", "char_start": 164, "char_end": 172, "token_start": 27, "token_end": 28}, {"text": "CaMKIV", "type": "ENTITY", "char_start": 177, "char_end": 183, "token_start": 30, "token_end": 30}], "entities_global": [{"text": "p38 MAPK", "type": "ENTITY", "char_start": 496670, "char_end": 496678, "token_start": 5, "token_end": 6, "note": null}, {"text": "CaMKIV", "type": "ENTITY", "char_start": 496683, "char_end": 496689, "token_start": 8, "token_end": 8, "note": null}, {"text": "kinases", "type": "ENTITY", "char_start": 496696, "char_end": 496703, "token_start": 11, "token_end": 11, "note": null}, {"text": "CD28", "type": "ENTITY", "char_start": 496751, "char_end": 496755, "token_start": 19, "token_end": 19, "note": null}, {"text": "p38 MAPK", "type": "ENTITY", "char_start": 496800, "char_end": 496808, "token_start": 27, "token_end": 28, "note": null}, {"text": "CaMKIV", "type": "ENTITY", "char_start": 496813, "char_end": 496819, "token_start": 30, "token_end": 30, "note": null}]}
+{"sentence_id": 2992, "sentence_text": "These results support the model of a minimum activation threshold for CREB - CBP interaction that can be reached only when both CD3 and CD28 are stimulated .", "sentence_char_start_global": 496822, "sentence_char_end_global": 496979, "entities": [{"text": "CREB", "type": "ENTITY", "char_start": 70, "char_end": 74, "token_start": 11, "token_end": 11}, {"text": "CBP", "type": "ENTITY", "char_start": 77, "char_end": 80, "token_start": 13, "token_end": 13}, {"text": "CD3", "type": "ENTITY", "char_start": 128, "char_end": 131, "token_start": 22, "token_end": 22}, {"text": "CD28", "type": "ENTITY", "char_start": 136, "char_end": 140, "token_start": 24, "token_end": 24}], "entities_global": [{"text": "CREB", "type": "ENTITY", "char_start": 496892, "char_end": 496896, "token_start": 11, "token_end": 11, "note": null}, {"text": "CBP", "type": "ENTITY", "char_start": 496899, "char_end": 496902, "token_start": 13, "token_end": 13, "note": null}, {"text": "CD3", "type": "ENTITY", "char_start": 496950, "char_end": 496953, "token_start": 22, "token_end": 22, "note": null}, {"text": "CD28", "type": "ENTITY", "char_start": 496958, "char_end": 496962, "token_start": 24, "token_end": 24, "note": null}]}
+{"sentence_id": 2993, "sentence_text": "The murine IL - 2 promoter contains distal regulatory elements responsive to the Ah receptor , a member of the evolutionarily conserved bHLH - PAS transcription factor family .", "sentence_char_start_global": 496980, "sentence_char_end_global": 497156, "entities": [{"text": "murine IL - 2 promoter", "type": "ENTITY", "char_start": 4, "char_end": 26, "token_start": 1, "token_end": 5}, {"text": "distal regulatory elements", "type": "ENTITY", "char_start": 36, "char_end": 62, "token_start": 7, "token_end": 9}, {"text": "Ah receptor", "type": "ENTITY", "char_start": 81, "char_end": 92, "token_start": 13, "token_end": 14}, {"text": "bHLH - PAS transcription factor family", "type": "ENTITY", "char_start": 136, "char_end": 174, "token_start": 22, "token_end": 27}], "entities_global": [{"text": "murine IL - 2 promoter", "type": "ENTITY", "char_start": 496984, "char_end": 497006, "token_start": 1, "token_end": 5, "note": null}, {"text": "distal regulatory elements", "type": "ENTITY", "char_start": 497016, "char_end": 497042, "token_start": 7, "token_end": 9, "note": null}, {"text": "Ah receptor", "type": "ENTITY", "char_start": 497061, "char_end": 497072, "token_start": 13, "token_end": 14, "note": null}, {"text": "bHLH - PAS transcription factor family", "type": "ENTITY", "char_start": 497116, "char_end": 497154, "token_start": 22, "token_end": 27, "note": null}]}
+{"sentence_id": 2994, "sentence_text": "Signaling through the TCR and costimulatory signals primarily control transcription of the IL - 2 gene in naive T cells .", "sentence_char_start_global": 497157, "sentence_char_end_global": 497278, "entities": [{"text": "TCR", "type": "ENTITY", "char_start": 22, "char_end": 25, "token_start": 3, "token_end": 3}, {"text": "IL - 2 gene", "type": "ENTITY", "char_start": 91, "char_end": 102, "token_start": 12, "token_end": 15}], "entities_global": [{"text": "TCR", "type": "ENTITY", "char_start": 497179, "char_end": 497182, "token_start": 3, "token_end": 3, "note": null}, {"text": "IL - 2 gene", "type": "ENTITY", "char_start": 497248, "char_end": 497259, "token_start": 12, "token_end": 15, "note": null}]}
+{"sentence_id": 2995, "sentence_text": "The minimal promoter necessary for this expression lies proximal , between - 300 and the transcription start site .", "sentence_char_start_global": 497279, "sentence_char_end_global": 497394, "entities": [{"text": "minimal promoter", "type": "ENTITY", "char_start": 4, "char_end": 20, "token_start": 1, "token_end": 2}, {"text": "transcription start site", "type": "ENTITY", "char_start": 89, "char_end": 113, "token_start": 15, "token_end": 17}], "entities_global": [{"text": "minimal promoter", "type": "ENTITY", "char_start": 497283, "char_end": 497299, "token_start": 1, "token_end": 2, "note": null}, {"text": "transcription start site", "type": "ENTITY", "char_start": 497368, "char_end": 497392, "token_start": 15, "token_end": 17, "note": null}]}
+{"sentence_id": 2996, "sentence_text": "We had previously shown that activation of the arylhydrocarbon receptor ( AHR ) , a member of the bHLH - PAS family of transcription factors , leads to increased mRNA expression of IL - 2 in murine fetal thymocytes .", "sentence_char_start_global": 497395, "sentence_char_end_global": 497611, "entities": [{"text": "arylhydrocarbon receptor", "type": "ENTITY", "char_start": 47, "char_end": 71, "token_start": 8, "token_end": 9}, {"text": "AHR", "type": "ENTITY", "char_start": 74, "char_end": 77, "token_start": 11, "token_end": 11}, {"text": "bHLH - PAS family of transcription factors", "type": "ENTITY", "char_start": 98, "char_end": 140, "token_start": 18, "token_end": 24}, {"text": "IL - 2", "type": "ENTITY", "char_start": 181, "char_end": 187, "token_start": 32, "token_end": 34}], "entities_global": [{"text": "arylhydrocarbon receptor", "type": "ENTITY", "char_start": 497442, "char_end": 497466, "token_start": 8, "token_end": 9, "note": null}, {"text": "AHR", "type": "ENTITY", "char_start": 497469, "char_end": 497472, "token_start": 11, "token_end": 11, "note": null}, {"text": "bHLH - PAS family of transcription factors", "type": "ENTITY", "char_start": 497493, "char_end": 497535, "token_start": 18, "token_end": 24, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 497576, "char_end": 497582, "token_start": 32, "token_end": 34, "note": null}]}
+{"sentence_id": 2997, "sentence_text": "The AHR is abundant in the thymus and may play a role for the development of the immune system .", "sentence_char_start_global": 497612, "sentence_char_end_global": 497708, "entities": [{"text": "AHR", "type": "ENTITY", "char_start": 4, "char_end": 7, "token_start": 1, "token_end": 1}], "entities_global": [{"text": "AHR", "type": "ENTITY", "char_start": 497616, "char_end": 497619, "token_start": 1, "token_end": 1, "note": null}]}
+{"sentence_id": 2998, "sentence_text": "Moreover , its overactivation by chemicals such as dioxins leads to immunosuppression and thymic involution .", "sentence_char_start_global": 497709, "sentence_char_end_global": 497818, "entities": [], "entities_global": []}
+{"sentence_id": 2999, "sentence_text": "Binding motifs for the liganded AHR can be identified in the distal region - 1300 to - 800 of the mouse IL - 2 promoter .", "sentence_char_start_global": 497819, "sentence_char_end_global": 497940, "entities": [{"text": "liganded AHR", "type": "ENTITY", "char_start": 23, "char_end": 35, "token_start": 4, "token_end": 5}, {"text": "distal region - 1300 to - 800", "type": "ENTITY", "char_start": 61, "char_end": 90, "token_start": 11, "token_end": 17}, {"text": "mouse IL - 2 promoter", "type": "ENTITY", "char_start": 98, "char_end": 119, "token_start": 20, "token_end": 24}], "entities_global": [{"text": "liganded AHR", "type": "ENTITY", "char_start": 497842, "char_end": 497854, "token_start": 4, "token_end": 5, "note": null}, {"text": "distal region - 1300 to - 800", "type": "ENTITY", "char_start": 497880, "char_end": 497909, "token_start": 11, "token_end": 17, "note": null}, {"text": "mouse IL - 2 promoter", "type": "ENTITY", "char_start": 497917, "char_end": 497938, "token_start": 20, "token_end": 24, "note": null}]}
+{"sentence_id": 3000, "sentence_text": "We show here that these DNA motifs , the so - called dioxin response elements , after binding to the liganded AHR are sufficient to transactivate luciferase expression in a reporter gene system .", "sentence_char_start_global": 497941, "sentence_char_end_global": 498136, "entities": [{"text": "DNA motifs", "type": "ENTITY", "char_start": 24, "char_end": 34, "token_start": 5, "token_end": 6}, {"text": "dioxin response elements", "type": "ENTITY", "char_start": 53, "char_end": 77, "token_start": 12, "token_end": 14}, {"text": "liganded AHR", "type": "ENTITY", "char_start": 101, "char_end": 113, "token_start": 20, "token_end": 21}], "entities_global": [{"text": "DNA motifs", "type": "ENTITY", "char_start": 497965, "char_end": 497975, "token_start": 5, "token_end": 6, "note": null}, {"text": "dioxin response elements", "type": "ENTITY", "char_start": 497994, "char_end": 498018, "token_start": 12, "token_end": 14, "note": null}, {"text": "liganded AHR", "type": "ENTITY", "char_start": 498042, "char_end": 498054, "token_start": 20, "token_end": 21, "note": null}]}
+{"sentence_id": 3001, "sentence_text": "The IL - 2 gene can be induced by the AHR also in thymocytes in vivo after injection of 2 , 3 , 7 , 8 - tetrachlorodibenzo - p - dioxin , a potent ligand of the AHR .", "sentence_char_start_global": 498137, "sentence_char_end_global": 498303, "entities": [{"text": "IL - 2 gene", "type": "ENTITY", "char_start": 4, "char_end": 15, "token_start": 1, "token_end": 4}, {"text": "AHR", "type": "ENTITY", "char_start": 38, "char_end": 41, "token_start": 10, "token_end": 10}, {"text": "AHR", "type": "ENTITY", "char_start": 161, "char_end": 164, "token_start": 38, "token_end": 38}], "entities_global": [{"text": "IL - 2 gene", "type": "ENTITY", "char_start": 498141, "char_end": 498152, "token_start": 1, "token_end": 4, "note": null}, {"text": "AHR", "type": "ENTITY", "char_start": 498175, "char_end": 498178, "token_start": 10, "token_end": 10, "note": null}, {"text": "AHR", "type": "ENTITY", "char_start": 498298, "char_end": 498301, "token_start": 38, "token_end": 38, "note": null}]}
+{"sentence_id": 3002, "sentence_text": "The AHR mediates the IL - 2 induction as shown with AHR - deficient mice .", "sentence_char_start_global": 498304, "sentence_char_end_global": 498378, "entities": [{"text": "AHR", "type": "ENTITY", "char_start": 4, "char_end": 7, "token_start": 1, "token_end": 1}, {"text": "AHR", "type": "ENTITY", "char_start": 52, "char_end": 55, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "AHR", "type": "ENTITY", "char_start": 498308, "char_end": 498311, "token_start": 1, "token_end": 1, "note": null}, {"text": "AHR", "type": "ENTITY", "char_start": 498356, "char_end": 498359, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 3003, "sentence_text": "However , in spleen cells in vitro costimulation via the TCR is necessary for optimal IL - 2 gene induction .", "sentence_char_start_global": 498379, "sentence_char_end_global": 498488, "entities": [{"text": "TCR", "type": "ENTITY", "char_start": 57, "char_end": 60, "token_start": 10, "token_end": 10}, {"text": "IL - 2 gene", "type": "ENTITY", "char_start": 86, "char_end": 97, "token_start": 15, "token_end": 18}], "entities_global": [{"text": "TCR", "type": "ENTITY", "char_start": 498436, "char_end": 498439, "token_start": 10, "token_end": 10, "note": null}, {"text": "IL - 2 gene", "type": "ENTITY", "char_start": 498465, "char_end": 498476, "token_start": 15, "token_end": 18, "note": null}]}
+{"sentence_id": 3004, "sentence_text": "Thus , the IL - 2 promoter region contains novel distal regulatory elements that can be addressed by the AHR to induce IL - 2 and can cooperate with the proximal promoter", "sentence_char_start_global": 498489, "sentence_char_end_global": 498659, "entities": [{"text": "IL - 2 promoter region", "type": "ENTITY", "char_start": 11, "char_end": 33, "token_start": 3, "token_end": 7}, {"text": "distal regulatory elements", "type": "ENTITY", "char_start": 49, "char_end": 75, "token_start": 10, "token_end": 12}, {"text": "AHR", "type": "ENTITY", "char_start": 105, "char_end": 108, "token_start": 19, "token_end": 19}, {"text": "IL - 2", "type": "ENTITY", "char_start": 119, "char_end": 125, "token_start": 22, "token_end": 24}, {"text": "proximal promoter", "type": "ENTITY", "char_start": 153, "char_end": 170, "token_start": 30, "token_end": 31}], "entities_global": [{"text": "IL - 2 promoter region", "type": "ENTITY", "char_start": 498500, "char_end": 498522, "token_start": 3, "token_end": 7, "note": null}, {"text": "distal regulatory elements", "type": "ENTITY", "char_start": 498538, "char_end": 498564, "token_start": 10, "token_end": 12, "note": null}, {"text": "AHR", "type": "ENTITY", "char_start": 498594, "char_end": 498597, "token_start": 19, "token_end": 19, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 498608, "char_end": 498614, "token_start": 22, "token_end": 24, "note": null}, {"text": "proximal promoter", "type": "ENTITY", "char_start": 498642, "char_end": 498659, "token_start": 30, "token_end": 31, "note": null}]}
+{"sentence_id": 3005, "sentence_text": "Visualization of Syk - antigen receptor interactions using green fluorescent protein : differential roles for Syk and Lyn in the regulation of receptor capping and internalization .", "sentence_char_start_global": 498660, "sentence_char_end_global": 498841, "entities": [{"text": "Syk - antigen receptor", "type": "ENTITY", "char_start": 17, "char_end": 39, "token_start": 2, "token_end": 5}, {"text": "green fluorescent protein", "type": "ENTITY", "char_start": 59, "char_end": 84, "token_start": 8, "token_end": 10}, {"text": "Syk", "type": "ENTITY", "char_start": 110, "char_end": 113, "token_start": 15, "token_end": 15}, {"text": "Lyn", "type": "ENTITY", "char_start": 118, "char_end": 121, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "Syk - antigen receptor", "type": "ENTITY", "char_start": 498677, "char_end": 498699, "token_start": 2, "token_end": 5, "note": null}, {"text": "green fluorescent protein", "type": "ENTITY", "char_start": 498719, "char_end": 498744, "token_start": 8, "token_end": 10, "note": null}, {"text": "Syk", "type": "ENTITY", "char_start": 498770, "char_end": 498773, "token_start": 15, "token_end": 15, "note": null}, {"text": "Lyn", "type": "ENTITY", "char_start": 498778, "char_end": 498781, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 3006, "sentence_text": "The cross - linking of the B cell Ag receptor ( BCR ) is coupled to the stimulation of multiple intracellular signal transduction cascades via receptor - associated , protein tyrosine kinases of both the Src and Syk families .", "sentence_char_start_global": 498842, "sentence_char_end_global": 499068, "entities": [{"text": "B cell Ag receptor", "type": "ENTITY", "char_start": 27, "char_end": 45, "token_start": 6, "token_end": 9}, {"text": "BCR", "type": "ENTITY", "char_start": 48, "char_end": 51, "token_start": 11, "token_end": 11}, {"text": "protein tyrosine kinases", "type": "ENTITY", "char_start": 167, "char_end": 191, "token_start": 29, "token_end": 31}, {"text": "Src and Syk families", "type": "ENTITY", "char_start": 204, "char_end": 224, "token_start": 35, "token_end": 38}], "entities_global": [{"text": "B cell Ag receptor", "type": "ENTITY", "char_start": 498869, "char_end": 498887, "token_start": 6, "token_end": 9, "note": null}, {"text": "BCR", "type": "ENTITY", "char_start": 498890, "char_end": 498893, "token_start": 11, "token_end": 11, "note": null}, {"text": "protein tyrosine kinases", "type": "ENTITY", "char_start": 499009, "char_end": 499033, "token_start": 29, "token_end": 31, "note": null}, {"text": "Src and Syk families", "type": "ENTITY", "char_start": 499046, "char_end": 499066, "token_start": 35, "token_end": 38, "note": null}]}
+{"sentence_id": 3007, "sentence_text": "To monitor changes in the subcellular distribution of Syk in B cells responding to BCR cross - linking , we expressed in Syk - deficient DT40 B cells a fusion protein consisting of Syk coupled to green fluorescent protein .", "sentence_char_start_global": 499069, "sentence_char_end_global": 499292, "entities": [{"text": "Syk", "type": "ENTITY", "char_start": 54, "char_end": 57, "token_start": 8, "token_end": 8}, {"text": "BCR", "type": "ENTITY", "char_start": 83, "char_end": 86, "token_start": 14, "token_end": 14}, {"text": "Syk", "type": "ENTITY", "char_start": 121, "char_end": 124, "token_start": 22, "token_end": 22}, {"text": "fusion protein", "type": "ENTITY", "char_start": 152, "char_end": 166, "token_start": 29, "token_end": 30}, {"text": "Syk", "type": "ENTITY", "char_start": 181, "char_end": 184, "token_start": 33, "token_end": 33}, {"text": "green fluorescent protein", "type": "ENTITY", "char_start": 196, "char_end": 221, "token_start": 36, "token_end": 38}], "entities_global": [{"text": "Syk", "type": "ENTITY", "char_start": 499123, "char_end": 499126, "token_start": 8, "token_end": 8, "note": null}, {"text": "BCR", "type": "ENTITY", "char_start": 499152, "char_end": 499155, "token_start": 14, "token_end": 14, "note": null}, {"text": "Syk", "type": "ENTITY", "char_start": 499190, "char_end": 499193, "token_start": 22, "token_end": 22, "note": null}, {"text": "fusion protein", "type": "ENTITY", "char_start": 499221, "char_end": 499235, "token_start": 29, "token_end": 30, "note": null}, {"text": "Syk", "type": "ENTITY", "char_start": 499250, "char_end": 499253, "token_start": 33, "token_end": 33, "note": null}, {"text": "green fluorescent protein", "type": "ENTITY", "char_start": 499265, "char_end": 499290, "token_start": 36, "token_end": 38, "note": null}]}
+{"sentence_id": 3008, "sentence_text": "Treatment of these cells with anti - IgM Abs leads to the recruitment of the kinase from cytoplasmic and nuclear compartments to the site of the cross - linked receptor at the plasma membrane .", "sentence_char_start_global": 499293, "sentence_char_end_global": 499486, "entities": [{"text": "anti - IgM Abs", "type": "ENTITY", "char_start": 30, "char_end": 44, "token_start": 5, "token_end": 8}, {"text": "kinase", "type": "ENTITY", "char_start": 77, "char_end": 83, "token_start": 15, "token_end": 15}, {"text": "cross - linked receptor", "type": "ENTITY", "char_start": 145, "char_end": 168, "token_start": 26, "token_end": 29}], "entities_global": [{"text": "anti - IgM Abs", "type": "ENTITY", "char_start": 499323, "char_end": 499337, "token_start": 5, "token_end": 8, "note": null}, {"text": "kinase", "type": "ENTITY", "char_start": 499370, "char_end": 499376, "token_start": 15, "token_end": 15, "note": null}, {"text": "cross - linked receptor", "type": "ENTITY", "char_start": 499438, "char_end": 499461, "token_start": 26, "token_end": 29, "note": null}]}
+{"sentence_id": 3009, "sentence_text": "The Syk - receptor complexes aggregate into membrane patches that redistribute to form a cap at one pole of the cell .", "sentence_char_start_global": 499487, "sentence_char_end_global": 499605, "entities": [{"text": "Syk - receptor complexes", "type": "ENTITY", "char_start": 4, "char_end": 28, "token_start": 1, "token_end": 4}], "entities_global": [{"text": "Syk - receptor complexes", "type": "ENTITY", "char_start": 499491, "char_end": 499515, "token_start": 1, "token_end": 4, "note": null}]}
+{"sentence_id": 3010, "sentence_text": "Syk is not demonstrably associated with the internalized receptor .", "sentence_char_start_global": 499606, "sentence_char_end_global": 499673, "entities": [{"text": "Syk", "type": "ENTITY", "char_start": 0, "char_end": 3, "token_start": 0, "token_end": 0}, {"text": "internalized receptor", "type": "ENTITY", "char_start": 44, "char_end": 65, "token_start": 7, "token_end": 8}], "entities_global": [{"text": "Syk", "type": "ENTITY", "char_start": 499606, "char_end": 499609, "token_start": 0, "token_end": 0, "note": null}, {"text": "internalized receptor", "type": "ENTITY", "char_start": 499650, "char_end": 499671, "token_start": 7, "token_end": 8, "note": null}]}
+{"sentence_id": 3011, "sentence_text": "Catalytically active Syk promotes and stabilizes the formation of tightly capped BCR complexes at the plasma membrane .", "sentence_char_start_global": 499674, "sentence_char_end_global": 499793, "entities": [{"text": "Syk", "type": "ENTITY", "char_start": 21, "char_end": 24, "token_start": 2, "token_end": 2}, {"text": "tightly capped BCR complexes", "type": "ENTITY", "char_start": 66, "char_end": 94, "token_start": 9, "token_end": 12}], "entities_global": [{"text": "Syk", "type": "ENTITY", "char_start": 499695, "char_end": 499698, "token_start": 2, "token_end": 2, "note": null}, {"text": "tightly capped BCR complexes", "type": "ENTITY", "char_start": 499740, "char_end": 499768, "token_start": 9, "token_end": 12, "note": null}]}
+{"sentence_id": 3012, "sentence_text": "Lyn is not required for the recruitment of Syk to the cross - linked receptor , but is required for the internalization of the clustered BCR complexes .", "sentence_char_start_global": 499794, "sentence_char_end_global": 499946, "entities": [{"text": "Lyn", "type": "ENTITY", "char_start": 0, "char_end": 3, "token_start": 0, "token_end": 0}, {"text": "Syk", "type": "ENTITY", "char_start": 43, "char_end": 46, "token_start": 8, "token_end": 8}, {"text": "cross - linked receptor", "type": "ENTITY", "char_start": 54, "char_end": 77, "token_start": 11, "token_end": 14}, {"text": "BCR complexes", "type": "ENTITY", "char_start": 137, "char_end": 150, "token_start": 25, "token_end": 26}], "entities_global": [{"text": "Lyn", "type": "ENTITY", "char_start": 499794, "char_end": 499797, "token_start": 0, "token_end": 0, "note": null}, {"text": "Syk", "type": "ENTITY", "char_start": 499837, "char_end": 499840, "token_start": 8, "token_end": 8, "note": null}, {"text": "cross - linked receptor", "type": "ENTITY", "char_start": 499848, "char_end": 499871, "token_start": 11, "token_end": 14, "note": null}, {"text": "BCR complexes", "type": "ENTITY", "char_start": 499931, "char_end": 499944, "token_start": 25, "token_end": 26, "note": null}]}
+{"sentence_id": 3013, "sentence_text": "In the absence of Lyn , receptor - Syk complexes at the plasma membrane are long lived , and the receptor - mediated activation of the NF - AT transcription factor is enhanced .", "sentence_char_start_global": 499947, "sentence_char_end_global": 500124, "entities": [{"text": "Lyn", "type": "ENTITY", "char_start": 18, "char_end": 21, "token_start": 4, "token_end": 4}, {"text": "receptor - Syk complexes", "type": "ENTITY", "char_start": 24, "char_end": 48, "token_start": 6, "token_end": 9}, {"text": "NF - AT transcription factor", "type": "ENTITY", "char_start": 135, "char_end": 163, "token_start": 26, "token_end": 30}], "entities_global": [{"text": "Lyn", "type": "ENTITY", "char_start": 499965, "char_end": 499968, "token_start": 4, "token_end": 4, "note": null}, {"text": "receptor - Syk complexes", "type": "ENTITY", "char_start": 499971, "char_end": 499995, "token_start": 6, "token_end": 9, "note": null}, {"text": "NF - AT transcription factor", "type": "ENTITY", "char_start": 500082, "char_end": 500110, "token_start": 26, "token_end": 30, "note": null}]}
+{"sentence_id": 3014, "sentence_text": "Thus , Lyn appears to function to negatively regulate aspects of BCR - dependent signaling by stimulating receptor internalization and down - regulation .", "sentence_char_start_global": 500125, "sentence_char_end_global": 500279, "entities": [{"text": "Lyn", "type": "ENTITY", "char_start": 7, "char_end": 10, "token_start": 2, "token_end": 2}, {"text": "BCR", "type": "ENTITY", "char_start": 65, "char_end": 68, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "Lyn", "type": "ENTITY", "char_start": 500132, "char_end": 500135, "token_start": 2, "token_end": 2, "note": null}, {"text": "BCR", "type": "ENTITY", "char_start": 500190, "char_end": 500193, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 3015, "sentence_text": "Renal interstitial fibrosis is reduced in angiotensin II type 1a receptor - deficient mice .", "sentence_char_start_global": 500280, "sentence_char_end_global": 500372, "entities": [{"text": "angiotensin II type 1a receptor", "type": "ENTITY", "char_start": 42, "char_end": 73, "token_start": 6, "token_end": 10}], "entities_global": [{"text": "angiotensin II type 1a receptor", "type": "ENTITY", "char_start": 500322, "char_end": 500353, "token_start": 6, "token_end": 10, "note": null}]}
+{"sentence_id": 3016, "sentence_text": "Unilateral ureteral obstruction ( UUO ) results in tubulointerstitial fibrosis of the affected kidney by stimulating the renin - angiotensin system .", "sentence_char_start_global": 500373, "sentence_char_end_global": 500522, "entities": [], "entities_global": []}
+{"sentence_id": 3017, "sentence_text": "This study established a UUO model in angiotensin type 1a receptor ( AT1a ) deficient ( mutant ) mice to elucidate the role of angiotensin II through AT1a on the fibrosis of the obstructed kidney ( OBK ) .", "sentence_char_start_global": 500523, "sentence_char_end_global": 500728, "entities": [{"text": "angiotensin type 1a receptor", "type": "ENTITY", "char_start": 38, "char_end": 66, "token_start": 7, "token_end": 10}, {"text": "AT1a", "type": "ENTITY", "char_start": 69, "char_end": 73, "token_start": 12, "token_end": 12}, {"text": "angiotensin II", "type": "ENTITY", "char_start": 127, "char_end": 141, "token_start": 24, "token_end": 25}, {"text": "AT1a", "type": "ENTITY", "char_start": 150, "char_end": 154, "token_start": 27, "token_end": 27}], "entities_global": [{"text": "angiotensin type 1a receptor", "type": "ENTITY", "char_start": 500561, "char_end": 500589, "token_start": 7, "token_end": 10, "note": null}, {"text": "AT1a", "type": "ENTITY", "char_start": 500592, "char_end": 500596, "token_start": 12, "token_end": 12, "note": null}, {"text": "angiotensin II", "type": "ENTITY", "char_start": 500650, "char_end": 500664, "token_start": 24, "token_end": 25, "note": null}, {"text": "AT1a", "type": "ENTITY", "char_start": 500673, "char_end": 500677, "token_start": 27, "token_end": 27, "note": null}]}
+{"sentence_id": 3018, "sentence_text": "The relative volume of the tubulointerstitium was measured by an image analyzer ; deposition of collagen types III and IV and monocyte / macrophage infiltration were histologically examined using specific antibodies .", "sentence_char_start_global": 500729, "sentence_char_end_global": 500946, "entities": [{"text": "collagen types III and IV", "type": "ENTITY", "char_start": 96, "char_end": 121, "token_start": 15, "token_end": 19}, {"text": "specific antibodies", "type": "ENTITY", "char_start": 196, "char_end": 215, "token_start": 29, "token_end": 30}], "entities_global": [{"text": "collagen types III and IV", "type": "ENTITY", "char_start": 500825, "char_end": 500850, "token_start": 15, "token_end": 19, "note": null}, {"text": "specific antibodies", "type": "ENTITY", "char_start": 500925, "char_end": 500944, "token_start": 29, "token_end": 30, "note": null}]}
+{"sentence_id": 3019, "sentence_text": "Also determined were the mRNA levels of transforming growth factor - beta by Northern blot analysis .", "sentence_char_start_global": 500947, "sentence_char_end_global": 501048, "entities": [{"text": "transforming growth factor - beta", "type": "ENTITY", "char_start": 40, "char_end": 73, "token_start": 7, "token_end": 11}], "entities_global": [{"text": "transforming growth factor - beta", "type": "ENTITY", "char_start": 500987, "char_end": 501020, "token_start": 7, "token_end": 11, "note": null}]}
+{"sentence_id": 3020, "sentence_text": "Nuclear factor - kappaB activity was assessed by gel shift assay .", "sentence_char_start_global": 501049, "sentence_char_end_global": 501115, "entities": [{"text": "Nuclear factor - kappaB", "type": "ENTITY", "char_start": 0, "char_end": 23, "token_start": 0, "token_end": 3}], "entities_global": [{"text": "Nuclear factor - kappaB", "type": "ENTITY", "char_start": 501049, "char_end": 501072, "token_start": 0, "token_end": 3, "note": null}]}
+{"sentence_id": 3021, "sentence_text": "UUO in wild mice resulted in a marked expansion of relative volume of the tubulointerstitium , together with increased deposition of collagen types III and IV and number of infiltrated monocytes / macrophages in the interstitium , relative to sham - operated mice .", "sentence_char_start_global": 501116, "sentence_char_end_global": 501381, "entities": [{"text": "collagen types III and IV", "type": "ENTITY", "char_start": 133, "char_end": 158, "token_start": 21, "token_end": 25}], "entities_global": [{"text": "collagen types III and IV", "type": "ENTITY", "char_start": 501249, "char_end": 501274, "token_start": 21, "token_end": 25, "note": null}]}
+{"sentence_id": 3022, "sentence_text": "In comparison , these changes were significantly lower in mutant mice with UUO .", "sentence_char_start_global": 501382, "sentence_char_end_global": 501462, "entities": [], "entities_global": []}
+{"sentence_id": 3023, "sentence_text": "The mRNA level of transforming growth factor - beta was significantly higher in the OBK of wild mice with UUO compared with sham - operated mice .", "sentence_char_start_global": 501463, "sentence_char_end_global": 501609, "entities": [{"text": "transforming growth factor - beta", "type": "ENTITY", "char_start": 18, "char_end": 51, "token_start": 4, "token_end": 8}], "entities_global": [{"text": "transforming growth factor - beta", "type": "ENTITY", "char_start": 501481, "char_end": 501514, "token_start": 4, "token_end": 8, "note": null}]}
+{"sentence_id": 3024, "sentence_text": "In contrast , the increase in mRNA level in the OBK of mutant mice was significantly less than in wild mice .", "sentence_char_start_global": 501610, "sentence_char_end_global": 501719, "entities": [], "entities_global": []}
+{"sentence_id": 3025, "sentence_text": "Finally , UUO resulted in activation of nuclear factor - kappaB in wild mice but was inhibited in the OBK of mutant mice .", "sentence_char_start_global": 501720, "sentence_char_end_global": 501842, "entities": [{"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 40, "char_end": 63, "token_start": 7, "token_end": 10}], "entities_global": [{"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 501760, "char_end": 501783, "token_start": 7, "token_end": 10, "note": null}]}
+{"sentence_id": 3026, "sentence_text": "The results provide direct evidence that angiotensin II acting via the AT1a plays a pivotal role in the development of tubulointerstitial fibrosis in UUO .", "sentence_char_start_global": 501843, "sentence_char_end_global": 501998, "entities": [{"text": "angiotensin II", "type": "ENTITY", "char_start": 41, "char_end": 55, "token_start": 6, "token_end": 7}, {"text": "AT1a", "type": "ENTITY", "char_start": 71, "char_end": 75, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "angiotensin II", "type": "ENTITY", "char_start": 501884, "char_end": 501898, "token_start": 6, "token_end": 7, "note": null}, {"text": "AT1a", "type": "ENTITY", "char_start": 501914, "char_end": 501918, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 3027, "sentence_text": "HLA - DQ tetramers identify epitope - specific T cells in peripheral blood of herpes simplex virus type 2 - infected individuals : direct detection of immunodominant antigen - responsive cells .", "sentence_char_start_global": 501999, "sentence_char_end_global": 502193, "entities": [{"text": "HLA - DQ tetramers", "type": "ENTITY", "char_start": 0, "char_end": 18, "token_start": 0, "token_end": 3}], "entities_global": [{"text": "HLA - DQ tetramers", "type": "ENTITY", "char_start": 501999, "char_end": 502017, "token_start": 0, "token_end": 3, "note": null}]}
+{"sentence_id": 3028, "sentence_text": "Ag - specific CD4 + T cells are present in peripheral blood in low frequency , where they undergo recruitment and expansion during immune responses and in the pathogenesis of numerous autoimmune diseases .", "sentence_char_start_global": 502194, "sentence_char_end_global": 502399, "entities": [], "entities_global": []}
+{"sentence_id": 3029, "sentence_text": "MHC tetramers , which constitute a labeled MHC - peptide ligand suitable for binding to the Ag - specific receptor on T cells , provide a novel approach for the detection and characterization of such rare cells .", "sentence_char_start_global": 502400, "sentence_char_end_global": 502612, "entities": [{"text": "MHC tetramers", "type": "ENTITY", "char_start": 0, "char_end": 13, "token_start": 0, "token_end": 1}, {"text": "labeled MHC - peptide ligand", "type": "ENTITY", "char_start": 35, "char_end": 63, "token_start": 6, "token_end": 10}, {"text": "Ag - specific receptor", "type": "ENTITY", "char_start": 92, "char_end": 114, "token_start": 16, "token_end": 19}], "entities_global": [{"text": "MHC tetramers", "type": "ENTITY", "char_start": 502400, "char_end": 502413, "token_start": 0, "token_end": 1, "note": null}, {"text": "labeled MHC - peptide ligand", "type": "ENTITY", "char_start": 502435, "char_end": 502463, "token_start": 6, "token_end": 10, "note": null}, {"text": "Ag - specific receptor", "type": "ENTITY", "char_start": 502492, "char_end": 502514, "token_start": 16, "token_end": 19, "note": null}]}
+{"sentence_id": 3030, "sentence_text": "In this study , we utilized this technology to identify HLA DQ - restricted Ag - specific T cells in the peripheral blood of human subjects and to identify immunodominant epitopes associated with viral infection .", "sentence_char_start_global": 502613, "sentence_char_end_global": 502826, "entities": [{"text": "HLA DQ", "type": "ENTITY", "char_start": 56, "char_end": 62, "token_start": 10, "token_end": 11}], "entities_global": [{"text": "HLA DQ", "type": "ENTITY", "char_start": 502669, "char_end": 502675, "token_start": 10, "token_end": 11, "note": null}]}
+{"sentence_id": 3031, "sentence_text": "Peptides representing potential epitope regions of the VP16 protein from HSV - 2 were loaded onto recombinant DQ0602 molecules to generate a panel of Ag - specific DQ0602 tetramers .", "sentence_char_start_global": 502827, "sentence_char_end_global": 503009, "entities": [{"text": "epitope regions", "type": "ENTITY", "char_start": 32, "char_end": 47, "token_start": 3, "token_end": 4}, {"text": "VP16 protein", "type": "ENTITY", "char_start": 55, "char_end": 67, "token_start": 7, "token_end": 8}, {"text": "recombinant DQ0602 molecules", "type": "ENTITY", "char_start": 98, "char_end": 126, "token_start": 16, "token_end": 18}, {"text": "Ag - specific DQ0602 tetramers", "type": "ENTITY", "char_start": 150, "char_end": 180, "token_start": 24, "token_end": 28}], "entities_global": [{"text": "epitope regions", "type": "ENTITY", "char_start": 502859, "char_end": 502874, "token_start": 3, "token_end": 4, "note": null}, {"text": "VP16 protein", "type": "ENTITY", "char_start": 502882, "char_end": 502894, "token_start": 7, "token_end": 8, "note": null}, {"text": "recombinant DQ0602 molecules", "type": "ENTITY", "char_start": 502925, "char_end": 502953, "token_start": 16, "token_end": 18, "note": null}, {"text": "Ag - specific DQ0602 tetramers", "type": "ENTITY", "char_start": 502977, "char_end": 503007, "token_start": 24, "token_end": 28, "note": null}]}
+{"sentence_id": 3032, "sentence_text": "VP16 Ag - specific DQ - restricted T cells were identified and expanded from the peripheral blood of HSV - 2 - infected individuals , representing two predominant epitope specificities .", "sentence_char_start_global": 503010, "sentence_char_end_global": 503196, "entities": [{"text": "VP16 Ag", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "VP16 Ag", "type": "ENTITY", "char_start": 503010, "char_end": 503017, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 3033, "sentence_text": "Although the VP16 369 - 380 peptide has a lower binding affinity for DQ0602 molecules than the VP16 33 - 52 peptide , T cells that recognized the VP16 369 - 380 peptide occurred at a much higher frequency than those that were specific for the VP16 33 - 52 peptide .", "sentence_char_start_global": 503197, "sentence_char_end_global": 503462, "entities": [{"text": "DQ0602 molecules", "type": "ENTITY", "char_start": 69, "char_end": 85, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "DQ0602 molecules", "type": "ENTITY", "char_start": 503266, "char_end": 503282, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 3034, "sentence_text": "Down - regulation of BOB . 1 / OBF . 1 and Oct2 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription .", "sentence_char_start_global": 503463, "sentence_char_end_global": 503636, "entities": [{"text": "BOB . 1 / OBF . 1", "type": "ENTITY", "char_start": 21, "char_end": 38, "token_start": 4, "token_end": 10}, {"text": "Oct2", "type": "ENTITY", "char_start": 43, "char_end": 47, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "BOB . 1 / OBF . 1", "type": "ENTITY", "char_start": 503484, "char_end": 503501, "token_start": 4, "token_end": 10, "note": null}, {"text": "Oct2", "type": "ENTITY", "char_start": 503506, "char_end": 503510, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 3035, "sentence_text": "In contrast to the tumor cells ( L & H cells ) of lymphocyte predominant Hodgkin disease ( LPHD ) , Hodgkin and Reed - Sternberg ( HRS ) cells of classical Hodgkin disease ( cHD ) are unable to transcribe immunoglobulin , despite the presence of rearranged immunoglobulin genes .", "sentence_char_start_global": 503637, "sentence_char_end_global": 503916, "entities": [{"text": "immunoglobulin", "type": "ENTITY", "char_start": 205, "char_end": 219, "token_start": 41, "token_end": 41}, {"text": "rearranged immunoglobulin genes", "type": "ENTITY", "char_start": 246, "char_end": 277, "token_start": 47, "token_end": 49}], "entities_global": [{"text": "immunoglobulin", "type": "ENTITY", "char_start": 503842, "char_end": 503856, "token_start": 41, "token_end": 41, "note": null}, {"text": "rearranged immunoglobulin genes", "type": "ENTITY", "char_start": 503883, "char_end": 503914, "token_start": 47, "token_end": 49, "note": null}]}
+{"sentence_id": 3036, "sentence_text": "Although initial studies have suggested crippling immunoglobulin gene mutations to be the cause of absent immunoglobulin expression in cHD , recent work of our group has demonstrated an impaired activation of the immunoglobulin promoter as a superior mechanism .", "sentence_char_start_global": 503917, "sentence_char_end_global": 504179, "entities": [{"text": "immunoglobulin promoter", "type": "ENTITY", "char_start": 213, "char_end": 236, "token_start": 32, "token_end": 33}], "entities_global": [{"text": "immunoglobulin promoter", "type": "ENTITY", "char_start": 504130, "char_end": 504153, "token_start": 32, "token_end": 33, "note": null}]}
+{"sentence_id": 3037, "sentence_text": "As immunoglobulin transcription is mainly regulated by the B - cell transcription factors Oct2 and BOB . 1 / OBF . 1 , we analyzed 35 cases of LPHD , 32 cases of cHD , and 2 Hodgkin disease cell lines for the expression of these transcription factors and also in parallel for immunoglobulin expression .", "sentence_char_start_global": 504180, "sentence_char_end_global": 504483, "entities": [{"text": "B - cell transcription factors", "type": "ENTITY", "char_start": 59, "char_end": 89, "token_start": 8, "token_end": 12}, {"text": "Oct2", "type": "ENTITY", "char_start": 90, "char_end": 94, "token_start": 13, "token_end": 13}, {"text": "BOB . 1 / OBF . 1", "type": "ENTITY", "char_start": 99, "char_end": 116, "token_start": 15, "token_end": 21}, {"text": "transcription factors", "type": "ENTITY", "char_start": 229, "char_end": 250, "token_start": 46, "token_end": 47}], "entities_global": [{"text": "B - cell transcription factors", "type": "ENTITY", "char_start": 504239, "char_end": 504269, "token_start": 8, "token_end": 12, "note": null}, {"text": "Oct2", "type": "ENTITY", "char_start": 504270, "char_end": 504274, "token_start": 13, "token_end": 13, "note": null}, {"text": "BOB . 1 / OBF . 1", "type": "ENTITY", "char_start": 504279, "char_end": 504296, "token_start": 15, "token_end": 21, "note": null}, {"text": "transcription factors", "type": "ENTITY", "char_start": 504409, "char_end": 504430, "token_start": 46, "token_end": 47, "note": null}]}
+{"sentence_id": 3038, "sentence_text": "Our results demonstrate an absence of Oct2 and / or BOB . 1 / OBF . 1 in cHD and a striking overexpression of Oct2 in LPHD .", "sentence_char_start_global": 504484, "sentence_char_end_global": 504608, "entities": [{"text": "Oct2", "type": "ENTITY", "char_start": 38, "char_end": 42, "token_start": 6, "token_end": 6}, {"text": "BOB . 1 / OBF . 1", "type": "ENTITY", "char_start": 52, "char_end": 69, "token_start": 10, "token_end": 16}, {"text": "Oct2", "type": "ENTITY", "char_start": 110, "char_end": 114, "token_start": 24, "token_end": 24}], "entities_global": [{"text": "Oct2", "type": "ENTITY", "char_start": 504522, "char_end": 504526, "token_start": 6, "token_end": 6, "note": null}, {"text": "BOB . 1 / OBF . 1", "type": "ENTITY", "char_start": 504536, "char_end": 504553, "token_start": 10, "token_end": 16, "note": null}, {"text": "Oct2", "type": "ENTITY", "char_start": 504594, "char_end": 504598, "token_start": 24, "token_end": 24, "note": null}]}
+{"sentence_id": 3039, "sentence_text": "Immunoglobulin expression was lacking in cHD but present in LPHD .", "sentence_char_start_global": 504609, "sentence_char_end_global": 504675, "entities": [], "entities_global": []}
+{"sentence_id": 3040, "sentence_text": "Furthermore , the reintroduction of BOB . 1 / OBF . 1 and Oct2 into cultured HRS cells restored the activity of cotransduced immunoglobulin promoter constructs .", "sentence_char_start_global": 504676, "sentence_char_end_global": 504837, "entities": [{"text": "BOB . 1 / OBF . 1", "type": "ENTITY", "char_start": 36, "char_end": 53, "token_start": 5, "token_end": 11}, {"text": "Oct2", "type": "ENTITY", "char_start": 58, "char_end": 62, "token_start": 13, "token_end": 13}, {"text": "immunoglobulin promoter constructs", "type": "ENTITY", "char_start": 125, "char_end": 159, "token_start": 23, "token_end": 25}], "entities_global": [{"text": "BOB . 1 / OBF . 1", "type": "ENTITY", "char_start": 504712, "char_end": 504729, "token_start": 5, "token_end": 11, "note": null}, {"text": "Oct2", "type": "ENTITY", "char_start": 504734, "char_end": 504738, "token_start": 13, "token_end": 13, "note": null}, {"text": "immunoglobulin promoter constructs", "type": "ENTITY", "char_start": 504801, "char_end": 504835, "token_start": 23, "token_end": 25, "note": null}]}
+{"sentence_id": 3041, "sentence_text": "Our findings dismiss the concept that the different immunoglobulin expression in cHD and LPHD is due to disrupting mutations of immunoglobulin V genes in cHD but is most likely due to a down - regulation of Oct2 and / or BOB . 1 / OBF . 1 .", "sentence_char_start_global": 504838, "sentence_char_end_global": 505078, "entities": [{"text": "immunoglobulin V genes", "type": "ENTITY", "char_start": 128, "char_end": 150, "token_start": 20, "token_end": 22}, {"text": "Oct2", "type": "ENTITY", "char_start": 207, "char_end": 211, "token_start": 36, "token_end": 36}, {"text": "BOB . 1 / OBF . 1", "type": "ENTITY", "char_start": 221, "char_end": 238, "token_start": 40, "token_end": 46}], "entities_global": [{"text": "immunoglobulin V genes", "type": "ENTITY", "char_start": 504966, "char_end": 504988, "token_start": 20, "token_end": 22, "note": null}, {"text": "Oct2", "type": "ENTITY", "char_start": 505045, "char_end": 505049, "token_start": 36, "token_end": 36, "note": null}, {"text": "BOB . 1 / OBF . 1", "type": "ENTITY", "char_start": 505059, "char_end": 505076, "token_start": 40, "token_end": 46, "note": null}]}
+{"sentence_id": 3042, "sentence_text": "This study further revealed Oct2 as a new and valuable marker for the identification of L & H cells and their distinction from HRS cells .", "sentence_char_start_global": 505079, "sentence_char_end_global": 505217, "entities": [{"text": "Oct2", "type": "ENTITY", "char_start": 28, "char_end": 32, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "Oct2", "type": "ENTITY", "char_start": 505107, "char_end": 505111, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 3043, "sentence_text": "The impairment of immunoglobulin transcription with a down - regulated synthesis of Oct2 and BOB . 1 / OBF . 1 is the first established general recurrent defect found in HRS cells .", "sentence_char_start_global": 505218, "sentence_char_end_global": 505399, "entities": [{"text": "Oct2", "type": "ENTITY", "char_start": 84, "char_end": 88, "token_start": 12, "token_end": 12}, {"text": "BOB . 1 / OBF . 1", "type": "ENTITY", "char_start": 93, "char_end": 110, "token_start": 14, "token_end": 20}], "entities_global": [{"text": "Oct2", "type": "ENTITY", "char_start": 505302, "char_end": 505306, "token_start": 12, "token_end": 12, "note": null}, {"text": "BOB . 1 / OBF . 1", "type": "ENTITY", "char_start": 505311, "char_end": 505328, "token_start": 14, "token_end": 20, "note": null}]}
+{"sentence_id": 3044, "sentence_text": "Constitutive expression of NF - kappa B is a characteristic feature of mycosis fungoides : implications for apoptosis resistance and pathogenesis .", "sentence_char_start_global": 505400, "sentence_char_end_global": 505547, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 27, "char_end": 39, "token_start": 3, "token_end": 6}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 505427, "char_end": 505439, "token_start": 3, "token_end": 6, "note": null}]}
+{"sentence_id": 3045, "sentence_text": "The NF - kappa B family of transcription factors is an important regulator of genes expressed during inflammatory responses , immunoglobulin ( Ig ) class switching , cellular differentiation , and apoptosis .", "sentence_char_start_global": 505548, "sentence_char_end_global": 505756, "entities": [{"text": "NF - kappa B family of transcription factors", "type": "ENTITY", "char_start": 4, "char_end": 48, "token_start": 1, "token_end": 8}], "entities_global": [{"text": "NF - kappa B family of transcription factors", "type": "ENTITY", "char_start": 505552, "char_end": 505596, "token_start": 1, "token_end": 8, "note": null}]}
+{"sentence_id": 3046, "sentence_text": "Recently , members of the NF - kappaB family , including p65 ( Rel A ) , have been implicated in promoting survival of various hematopoeitic neoplasms , including T cell malignancies such as adult T cell leukemia - lymphoma .", "sentence_char_start_global": 505757, "sentence_char_end_global": 505982, "entities": [{"text": "NF - kappaB family", "type": "ENTITY", "char_start": 26, "char_end": 44, "token_start": 5, "token_end": 8}, {"text": "p65 ( Rel A )", "type": "ENTITY", "char_start": 57, "char_end": 70, "token_start": 11, "token_end": 15}], "entities_global": [{"text": "NF - kappaB family", "type": "ENTITY", "char_start": 505783, "char_end": 505801, "token_start": 5, "token_end": 8, "note": null}, {"text": "p65 ( Rel A )", "type": "ENTITY", "char_start": 505814, "char_end": 505827, "token_start": 11, "token_end": 15, "note": null}]}
+{"sentence_id": 3047, "sentence_text": "We investigated the expression of active NF - kappa B p65 ( Rel A ) in cases of mycosis fungoides ( MF ) and the effect of chemical inhibitors of NF - kappa B on apoptosis in cutaneous T cell lymphoma ( CTCL ) cell lines .", "sentence_char_start_global": 505983, "sentence_char_end_global": 506205, "entities": [{"text": "active NF - kappa B p65 ( Rel A )", "type": "ENTITY", "char_start": 34, "char_end": 67, "token_start": 5, "token_end": 14}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 146, "char_end": 158, "token_start": 30, "token_end": 33}], "entities_global": [{"text": "active NF - kappa B p65 ( Rel A )", "type": "ENTITY", "char_start": 506017, "char_end": 506050, "token_start": 5, "token_end": 14, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 506129, "char_end": 506141, "token_start": 30, "token_end": 33, "note": null}]}
+{"sentence_id": 3048, "sentence_text": "Paraffin - embedded tissues from 23 cutaneous lesions and a single lymph node biopsy from patients diagnosed with MF were evaluated for p65 ( Rel A ) expression by using a monoclonal mouse antibody that detects the activated form of p65 ( Rel A ) .", "sentence_char_start_global": 506206, "sentence_char_end_global": 506454, "entities": [{"text": "monoclonal mouse antibody", "type": "ENTITY", "char_start": 172, "char_end": 197, "token_start": 31, "token_end": 33}, {"text": "p65 ( Rel A )", "type": "ENTITY", "char_start": 233, "char_end": 246, "token_start": 40, "token_end": 44}], "entities_global": [{"text": "monoclonal mouse antibody", "type": "ENTITY", "char_start": 506378, "char_end": 506403, "token_start": 31, "token_end": 33, "note": null}, {"text": "p65 ( Rel A )", "type": "ENTITY", "char_start": 506439, "char_end": 506452, "token_start": 40, "token_end": 44, "note": null}]}
+{"sentence_id": 3049, "sentence_text": "Apoptosis after treatment with the NF - kappa B inhibitors gliotoxin , MG132 , BAY 11 - 7082 , and BAY 11 - 7085 was quantitatively measured in the CTCL cell lines HuT - 78 and HH by propidium iodide ( PI ) / cell cycle analysis for detection of a hypodiploid ( sub - G ( 0 ) ) population and by determination of increased Annexin V / 7 - amino - actinomycin D ( 7 - AAD ) expression .", "sentence_char_start_global": 506455, "sentence_char_end_global": 506840, "entities": [], "entities_global": []}
+{"sentence_id": 3050, "sentence_text": "Nuclear extracts from CTCL cells before and after chemical inhibition were analyzed for NF - kappa B nuclear DNA - binding activity by electrophoretic mobility shift assay ( EMSA ) with quantitative densitometry .", "sentence_char_start_global": 506841, "sentence_char_end_global": 507054, "entities": [], "entities_global": []}
+{"sentence_id": 3051, "sentence_text": "Nuclear expression of p65 ( Rel A ) before and after treatment with the various inhibitory compounds was measured by immunofluorescence staining in each CTCL cell line .", "sentence_char_start_global": 507055, "sentence_char_end_global": 507224, "entities": [{"text": "p65 ( Rel A )", "type": "ENTITY", "char_start": 22, "char_end": 35, "token_start": 3, "token_end": 7}], "entities_global": [{"text": "p65 ( Rel A )", "type": "ENTITY", "char_start": 507077, "char_end": 507090, "token_start": 3, "token_end": 7, "note": null}]}
+{"sentence_id": 3052, "sentence_text": "Neoplastic T lymphocytes from 22 of 24 cases of MF showed strong nuclear and cytoplasmic expression of active p65 ( Rel A ) .", "sentence_char_start_global": 507225, "sentence_char_end_global": 507350, "entities": [{"text": "active p65 ( Rel A )", "type": "ENTITY", "char_start": 103, "char_end": 123, "token_start": 17, "token_end": 22}], "entities_global": [{"text": "active p65 ( Rel A )", "type": "ENTITY", "char_start": 507328, "char_end": 507348, "token_start": 17, "token_end": 22, "note": null}]}
+{"sentence_id": 3053, "sentence_text": "Compared with untreated control cells , a marked increase in apoptosis , a significant decrease in NF - kappa B DNA - binding activity , and a marked decrease in nuclear p65 ( Rel A ) expression were seen in cells from both CTCL cell lines after chemical NF - kappa B inhibition .", "sentence_char_start_global": 507351, "sentence_char_end_global": 507631, "entities": [], "entities_global": []}
+{"sentence_id": 3054, "sentence_text": "These data show that the active form of NF - kappa B p65 ( Rel A ) is commonly expressed in neoplastic T lymphocytes in patients with MF .", "sentence_char_start_global": 507632, "sentence_char_end_global": 507770, "entities": [{"text": "NF - kappa B p65 ( Rel A )", "type": "ENTITY", "char_start": 40, "char_end": 66, "token_start": 8, "token_end": 16}], "entities_global": [{"text": "NF - kappa B p65 ( Rel A )", "type": "ENTITY", "char_start": 507672, "char_end": 507698, "token_start": 8, "token_end": 16, "note": null}]}
+{"sentence_id": 3055, "sentence_text": "In CTCL cell lines , the significant decrease in nuclear NF - kappa B expression and the marked increase in spontaneous apoptosis caused by chemical NF - kappa B inhibition suggest a critical role for NF - kappa B in the pathogenesis and tumor cell maintenance of CTCLs .", "sentence_char_start_global": 507771, "sentence_char_end_global": 508042, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 201, "char_end": 213, "token_start": 35, "token_end": 38}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 507972, "char_end": 507984, "token_start": 35, "token_end": 38, "note": null}]}
+{"sentence_id": 3056, "sentence_text": "HUM PATHOL 31 : 1482 - 1490 .", "sentence_char_start_global": 508043, "sentence_char_end_global": 508072, "entities": [], "entities_global": []}
+{"sentence_id": 3057, "sentence_text": "Human T - cell leukemia virus type 1 tax protein activates transcription through AP - 1 site by inducing DNA binding activity in T cells .", "sentence_char_start_global": 508073, "sentence_char_end_global": 508211, "entities": [{"text": "tax protein", "type": "ENTITY", "char_start": 37, "char_end": 48, "token_start": 8, "token_end": 9}, {"text": "AP - 1 site", "type": "ENTITY", "char_start": 81, "char_end": 92, "token_start": 13, "token_end": 16}], "entities_global": [{"text": "tax protein", "type": "ENTITY", "char_start": 508110, "char_end": 508121, "token_start": 8, "token_end": 9, "note": null}, {"text": "AP - 1 site", "type": "ENTITY", "char_start": 508154, "char_end": 508165, "token_start": 13, "token_end": 16, "note": null}]}
+{"sentence_id": 3058, "sentence_text": "Human T - cell leukemia virus type 1 ( HTLV - 1 ) Tax protein induces the expression of various family members of the transcription factor AP - 1 , such as c - Jun , JunD , c - Fos , and Fra - 1 , at the level of RNA expression in T cells .", "sentence_char_start_global": 508212, "sentence_char_end_global": 508452, "entities": [{"text": "Tax protein", "type": "ENTITY", "char_start": 50, "char_end": 61, "token_start": 13, "token_end": 14}, {"text": "transcription factor AP - 1", "type": "ENTITY", "char_start": 118, "char_end": 145, "token_start": 24, "token_end": 28}, {"text": "c - Jun", "type": "ENTITY", "char_start": 156, "char_end": 163, "token_start": 32, "token_end": 34}, {"text": "JunD", "type": "ENTITY", "char_start": 166, "char_end": 170, "token_start": 36, "token_end": 36}, {"text": "c - Fos", "type": "ENTITY", "char_start": 173, "char_end": 180, "token_start": 38, "token_end": 40}, {"text": "Fra - 1", "type": "ENTITY", "char_start": 187, "char_end": 194, "token_start": 43, "token_end": 45}], "entities_global": [{"text": "Tax protein", "type": "ENTITY", "char_start": 508262, "char_end": 508273, "token_start": 13, "token_end": 14, "note": null}, {"text": "transcription factor AP - 1", "type": "ENTITY", "char_start": 508330, "char_end": 508357, "token_start": 24, "token_end": 28, "note": null}, {"text": "c - Jun", "type": "ENTITY", "char_start": 508368, "char_end": 508375, "token_start": 32, "token_end": 34, "note": null}, {"text": "JunD", "type": "ENTITY", "char_start": 508378, "char_end": 508382, "token_start": 36, "token_end": 36, "note": null}, {"text": "c - Fos", "type": "ENTITY", "char_start": 508385, "char_end": 508392, "token_start": 38, "token_end": 40, "note": null}, {"text": "Fra - 1", "type": "ENTITY", "char_start": 508399, "char_end": 508406, "token_start": 43, "token_end": 45, "note": null}]}
+{"sentence_id": 3059, "sentence_text": "We examined the activity of Tax in transcription through AP - 1 - binding sites ( AP - 1 site ) in T cells .", "sentence_char_start_global": 508453, "sentence_char_end_global": 508561, "entities": [{"text": "Tax", "type": "ENTITY", "char_start": 28, "char_end": 31, "token_start": 5, "token_end": 5}, {"text": "AP - 1 - binding sites", "type": "ENTITY", "char_start": 57, "char_end": 79, "token_start": 9, "token_end": 14}, {"text": "AP - 1 site", "type": "ENTITY", "char_start": 82, "char_end": 93, "token_start": 16, "token_end": 19}], "entities_global": [{"text": "Tax", "type": "ENTITY", "char_start": 508481, "char_end": 508484, "token_start": 5, "token_end": 5, "note": null}, {"text": "AP - 1 - binding sites", "type": "ENTITY", "char_start": 508510, "char_end": 508532, "token_start": 9, "token_end": 14, "note": null}, {"text": "AP - 1 site", "type": "ENTITY", "char_start": 508535, "char_end": 508546, "token_start": 16, "token_end": 19, "note": null}]}
+{"sentence_id": 3060, "sentence_text": "Transient transfection studies showed that Tax activated the expression of a luciferase gene regulated by two copies of an AP - 1 site in the human Jurkat T - cell line .", "sentence_char_start_global": 508562, "sentence_char_end_global": 508732, "entities": [{"text": "Tax", "type": "ENTITY", "char_start": 43, "char_end": 46, "token_start": 5, "token_end": 5}, {"text": "luciferase gene", "type": "ENTITY", "char_start": 77, "char_end": 92, "token_start": 11, "token_end": 12}, {"text": "AP - 1 site", "type": "ENTITY", "char_start": 123, "char_end": 134, "token_start": 19, "token_end": 22}], "entities_global": [{"text": "Tax", "type": "ENTITY", "char_start": 508605, "char_end": 508608, "token_start": 5, "token_end": 5, "note": null}, {"text": "luciferase gene", "type": "ENTITY", "char_start": 508639, "char_end": 508654, "token_start": 11, "token_end": 12, "note": null}, {"text": "AP - 1 site", "type": "ENTITY", "char_start": 508685, "char_end": 508696, "token_start": 19, "token_end": 22, "note": null}]}
+{"sentence_id": 3061, "sentence_text": "Tax activates the expression of viral and cellular genes through two different enhancers : a cAMP - responsive ( CRE ) - like element and a kappaB element .", "sentence_char_start_global": 508733, "sentence_char_end_global": 508889, "entities": [{"text": "Tax", "type": "ENTITY", "char_start": 0, "char_end": 3, "token_start": 0, "token_end": 0}, {"text": "viral and cellular genes", "type": "ENTITY", "char_start": 32, "char_end": 56, "token_start": 5, "token_end": 8}, {"text": "cAMP - responsive ( CRE ) - like element", "type": "ENTITY", "char_start": 93, "char_end": 133, "token_start": 15, "token_end": 23}, {"text": "kappaB element", "type": "ENTITY", "char_start": 140, "char_end": 154, "token_start": 26, "token_end": 27}], "entities_global": [{"text": "Tax", "type": "ENTITY", "char_start": 508733, "char_end": 508736, "token_start": 0, "token_end": 0, "note": null}, {"text": "viral and cellular genes", "type": "ENTITY", "char_start": 508765, "char_end": 508789, "token_start": 5, "token_end": 8, "note": null}, {"text": "cAMP - responsive ( CRE ) - like element", "type": "ENTITY", "char_start": 508826, "char_end": 508866, "token_start": 15, "token_end": 23, "note": null}, {"text": "kappaB element", "type": "ENTITY", "char_start": 508873, "char_end": 508887, "token_start": 26, "token_end": 27, "note": null}]}
+{"sentence_id": 3062, "sentence_text": "Two Tax mutants differentially activated expression of these two elements .", "sentence_char_start_global": 508890, "sentence_char_end_global": 508965, "entities": [{"text": "Tax mutants", "type": "ENTITY", "char_start": 4, "char_end": 15, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "Tax mutants", "type": "ENTITY", "char_start": 508894, "char_end": 508905, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 3063, "sentence_text": "Tax703 preferentially activated the kappaB element but not the CRE - like one , whereas TaxM22 showed the reverse .", "sentence_char_start_global": 508966, "sentence_char_end_global": 509081, "entities": [{"text": "Tax703", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 0}, {"text": "kappaB element", "type": "ENTITY", "char_start": 36, "char_end": 50, "token_start": 4, "token_end": 5}, {"text": "TaxM22", "type": "ENTITY", "char_start": 88, "char_end": 94, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "Tax703", "type": "ENTITY", "char_start": 508966, "char_end": 508972, "token_start": 0, "token_end": 0, "note": null}, {"text": "kappaB element", "type": "ENTITY", "char_start": 509002, "char_end": 509016, "token_start": 4, "token_end": 5, "note": null}, {"text": "TaxM22", "type": "ENTITY", "char_start": 509054, "char_end": 509060, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 3064, "sentence_text": "In addition , Tax703 and Tax , but not TaxM22 , converted cell growth of a mouse T - cell line from being interleukin ( IL ) - 2 - dependent to being IL - 2 - independent .", "sentence_char_start_global": 509082, "sentence_char_end_global": 509254, "entities": [{"text": "Tax703", "type": "ENTITY", "char_start": 14, "char_end": 20, "token_start": 3, "token_end": 3}, {"text": "Tax", "type": "ENTITY", "char_start": 25, "char_end": 28, "token_start": 5, "token_end": 5}, {"text": "TaxM22", "type": "ENTITY", "char_start": 39, "char_end": 45, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "Tax703", "type": "ENTITY", "char_start": 509096, "char_end": 509102, "token_start": 3, "token_end": 3, "note": null}, {"text": "Tax", "type": "ENTITY", "char_start": 509107, "char_end": 509110, "token_start": 5, "token_end": 5, "note": null}, {"text": "TaxM22", "type": "ENTITY", "char_start": 509121, "char_end": 509127, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 3065, "sentence_text": "Unlike the wild - type Tax , Tax703 and TaxM22 only weakly activated the AP - 1 site in the T - cell line .", "sentence_char_start_global": 509255, "sentence_char_end_global": 509362, "entities": [{"text": "wild - type Tax", "type": "ENTITY", "char_start": 11, "char_end": 26, "token_start": 2, "token_end": 5}, {"text": "Tax703", "type": "ENTITY", "char_start": 29, "char_end": 35, "token_start": 7, "token_end": 7}, {"text": "TaxM22", "type": "ENTITY", "char_start": 40, "char_end": 46, "token_start": 9, "token_end": 9}, {"text": "AP - 1 site", "type": "ENTITY", "char_start": 73, "char_end": 84, "token_start": 14, "token_end": 17}], "entities_global": [{"text": "wild - type Tax", "type": "ENTITY", "char_start": 509266, "char_end": 509281, "token_start": 2, "token_end": 5, "note": null}, {"text": "Tax703", "type": "ENTITY", "char_start": 509284, "char_end": 509290, "token_start": 7, "token_end": 7, "note": null}, {"text": "TaxM22", "type": "ENTITY", "char_start": 509295, "char_end": 509301, "token_start": 9, "token_end": 9, "note": null}, {"text": "AP - 1 site", "type": "ENTITY", "char_start": 509328, "char_end": 509339, "token_start": 14, "token_end": 17, "note": null}]}
+{"sentence_id": 3066, "sentence_text": "Thus , Tax seems to activate the AP - 1 site via mechanisms distinct from those of kappaB or CRE - like elements , and the activation of the AP - 1 site is dispensable for IL - 2 - independent growth of CTLL - 2 .", "sentence_char_start_global": 509363, "sentence_char_end_global": 509576, "entities": [{"text": "Tax", "type": "ENTITY", "char_start": 7, "char_end": 10, "token_start": 2, "token_end": 2}, {"text": "AP - 1 site", "type": "ENTITY", "char_start": 33, "char_end": 44, "token_start": 7, "token_end": 10}, {"text": "kappaB or CRE - like elements", "type": "ENTITY", "char_start": 83, "char_end": 112, "token_start": 17, "token_end": 22}, {"text": "AP - 1 site", "type": "ENTITY", "char_start": 141, "char_end": 152, "token_start": 29, "token_end": 32}], "entities_global": [{"text": "Tax", "type": "ENTITY", "char_start": 509370, "char_end": 509373, "token_start": 2, "token_end": 2, "note": null}, {"text": "AP - 1 site", "type": "ENTITY", "char_start": 509396, "char_end": 509407, "token_start": 7, "token_end": 10, "note": null}, {"text": "kappaB or CRE - like elements", "type": "ENTITY", "char_start": 509446, "char_end": 509475, "token_start": 17, "token_end": 22, "note": null}, {"text": "AP - 1 site", "type": "ENTITY", "char_start": 509504, "char_end": 509515, "token_start": 29, "token_end": 32, "note": null}]}
+{"sentence_id": 3067, "sentence_text": "Electrophoretic mobility shift assays showed that Tax induced strong binding activity to an AP - 1 site in CTLL - 2 , whereas Tax703 did not , indicating that the induction of binding activity to the AP - 1 site is essential for the transcriptional activation by Tax .", "sentence_char_start_global": 509577, "sentence_char_end_global": 509845, "entities": [{"text": "Tax", "type": "ENTITY", "char_start": 50, "char_end": 53, "token_start": 6, "token_end": 6}, {"text": "AP - 1 site", "type": "ENTITY", "char_start": 92, "char_end": 103, "token_start": 13, "token_end": 16}, {"text": "Tax703", "type": "ENTITY", "char_start": 126, "char_end": 132, "token_start": 23, "token_end": 23}, {"text": "AP - 1 site", "type": "ENTITY", "char_start": 200, "char_end": 211, "token_start": 36, "token_end": 39}, {"text": "Tax", "type": "ENTITY", "char_start": 263, "char_end": 266, "token_start": 47, "token_end": 47}], "entities_global": [{"text": "Tax", "type": "ENTITY", "char_start": 509627, "char_end": 509630, "token_start": 6, "token_end": 6, "note": null}, {"text": "AP - 1 site", "type": "ENTITY", "char_start": 509669, "char_end": 509680, "token_start": 13, "token_end": 16, "note": null}, {"text": "Tax703", "type": "ENTITY", "char_start": 509703, "char_end": 509709, "token_start": 23, "token_end": 23, "note": null}, {"text": "AP - 1 site", "type": "ENTITY", "char_start": 509777, "char_end": 509788, "token_start": 36, "token_end": 39, "note": null}, {"text": "Tax", "type": "ENTITY", "char_start": 509840, "char_end": 509843, "token_start": 47, "token_end": 47, "note": null}]}
+{"sentence_id": 3068, "sentence_text": "The binding complex induced by Tax in CTLL - 2 contained JunD and Fra - 2 .", "sentence_char_start_global": 509846, "sentence_char_end_global": 509921, "entities": [{"text": "binding complex", "type": "ENTITY", "char_start": 4, "char_end": 19, "token_start": 1, "token_end": 2}, {"text": "Tax", "type": "ENTITY", "char_start": 31, "char_end": 34, "token_start": 5, "token_end": 5}, {"text": "JunD", "type": "ENTITY", "char_start": 57, "char_end": 61, "token_start": 11, "token_end": 11}, {"text": "Fra - 2", "type": "ENTITY", "char_start": 66, "char_end": 73, "token_start": 13, "token_end": 15}], "entities_global": [{"text": "binding complex", "type": "ENTITY", "char_start": 509850, "char_end": 509865, "token_start": 1, "token_end": 2, "note": null}, {"text": "Tax", "type": "ENTITY", "char_start": 509877, "char_end": 509880, "token_start": 5, "token_end": 5, "note": null}, {"text": "JunD", "type": "ENTITY", "char_start": 509903, "char_end": 509907, "token_start": 11, "token_end": 11, "note": null}, {"text": "Fra - 2", "type": "ENTITY", "char_start": 509912, "char_end": 509919, "token_start": 13, "token_end": 15, "note": null}]}
+{"sentence_id": 3069, "sentence_text": "Other AP - 1 proteins were undetectable .", "sentence_char_start_global": 509922, "sentence_char_end_global": 509963, "entities": [{"text": "AP - 1 proteins", "type": "ENTITY", "char_start": 6, "char_end": 21, "token_start": 1, "token_end": 4}], "entities_global": [{"text": "AP - 1 proteins", "type": "ENTITY", "char_start": 509928, "char_end": 509943, "token_start": 1, "token_end": 4, "note": null}]}
+{"sentence_id": 3070, "sentence_text": "Activation of transcription through the AP - 1 site in Jurkat cells by JunD and / or Fra - 2 was weak .", "sentence_char_start_global": 509964, "sentence_char_end_global": 510067, "entities": [{"text": "AP - 1 site", "type": "ENTITY", "char_start": 40, "char_end": 51, "token_start": 5, "token_end": 8}, {"text": "JunD", "type": "ENTITY", "char_start": 71, "char_end": 75, "token_start": 13, "token_end": 13}, {"text": "Fra - 2", "type": "ENTITY", "char_start": 85, "char_end": 92, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "AP - 1 site", "type": "ENTITY", "char_start": 510004, "char_end": 510015, "token_start": 5, "token_end": 8, "note": null}, {"text": "JunD", "type": "ENTITY", "char_start": 510035, "char_end": 510039, "token_start": 13, "token_end": 13, "note": null}, {"text": "Fra - 2", "type": "ENTITY", "char_start": 510049, "char_end": 510056, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 3071, "sentence_text": "c - Jun , JunB , and c - Fos activation was greater , although the level was still less than that with Tax .", "sentence_char_start_global": 510068, "sentence_char_end_global": 510176, "entities": [{"text": "c - Jun", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 2}, {"text": "JunB", "type": "ENTITY", "char_start": 10, "char_end": 14, "token_start": 4, "token_end": 4}, {"text": "c - Fos", "type": "ENTITY", "char_start": 21, "char_end": 28, "token_start": 7, "token_end": 9}, {"text": "Tax", "type": "ENTITY", "char_start": 103, "char_end": 106, "token_start": 23, "token_end": 23}], "entities_global": [{"text": "c - Jun", "type": "ENTITY", "char_start": 510068, "char_end": 510075, "token_start": 0, "token_end": 2, "note": null}, {"text": "JunB", "type": "ENTITY", "char_start": 510078, "char_end": 510082, "token_start": 4, "token_end": 4, "note": null}, {"text": "c - Fos", "type": "ENTITY", "char_start": 510089, "char_end": 510096, "token_start": 7, "token_end": 9, "note": null}, {"text": "Tax", "type": "ENTITY", "char_start": 510171, "char_end": 510174, "token_start": 23, "token_end": 23, "note": null}]}
+{"sentence_id": 3072, "sentence_text": "Thus , the induction of AP - 1 mRNA by Tax may not be sufficient for a complete activation of AP - 1 site by Tax .", "sentence_char_start_global": 510177, "sentence_char_end_global": 510291, "entities": [{"text": "AP - 1 mRNA", "type": "ENTITY", "char_start": 24, "char_end": 35, "token_start": 5, "token_end": 8}, {"text": "Tax", "type": "ENTITY", "char_start": 39, "char_end": 42, "token_start": 10, "token_end": 10}, {"text": "AP - 1 site", "type": "ENTITY", "char_start": 94, "char_end": 105, "token_start": 20, "token_end": 23}, {"text": "Tax", "type": "ENTITY", "char_start": 109, "char_end": 112, "token_start": 25, "token_end": 25}], "entities_global": [{"text": "AP - 1 mRNA", "type": "ENTITY", "char_start": 510201, "char_end": 510212, "token_start": 5, "token_end": 8, "note": null}, {"text": "Tax", "type": "ENTITY", "char_start": 510216, "char_end": 510219, "token_start": 10, "token_end": 10, "note": null}, {"text": "AP - 1 site", "type": "ENTITY", "char_start": 510271, "char_end": 510282, "token_start": 20, "token_end": 23, "note": null}, {"text": "Tax", "type": "ENTITY", "char_start": 510286, "char_end": 510289, "token_start": 25, "token_end": 25, "note": null}]}
+{"sentence_id": 3073, "sentence_text": "Our results suggest that Tax activates the transcription of cellular genes with AP - 1 sites by inducing the DNA - binding activity of AP - 1 proteins in T cells , a mechanism distinct from those of CRE - like and kappaB elements .", "sentence_char_start_global": 510292, "sentence_char_end_global": 510523, "entities": [{"text": "Tax", "type": "ENTITY", "char_start": 25, "char_end": 28, "token_start": 4, "token_end": 4}, {"text": "cellular genes", "type": "ENTITY", "char_start": 60, "char_end": 74, "token_start": 9, "token_end": 10}, {"text": "AP - 1 sites", "type": "ENTITY", "char_start": 80, "char_end": 92, "token_start": 12, "token_end": 15}, {"text": "AP - 1 proteins", "type": "ENTITY", "char_start": 135, "char_end": 150, "token_start": 24, "token_end": 27}, {"text": "CRE - like and kappaB elements", "type": "ENTITY", "char_start": 199, "char_end": 229, "token_start": 38, "token_end": 43}], "entities_global": [{"text": "Tax", "type": "ENTITY", "char_start": 510317, "char_end": 510320, "token_start": 4, "token_end": 4, "note": null}, {"text": "cellular genes", "type": "ENTITY", "char_start": 510352, "char_end": 510366, "token_start": 9, "token_end": 10, "note": null}, {"text": "AP - 1 sites", "type": "ENTITY", "char_start": 510372, "char_end": 510384, "token_start": 12, "token_end": 15, "note": null}, {"text": "AP - 1 proteins", "type": "ENTITY", "char_start": 510427, "char_end": 510442, "token_start": 24, "token_end": 27, "note": null}, {"text": "CRE - like and kappaB elements", "type": "ENTITY", "char_start": 510491, "char_end": 510521, "token_start": 38, "token_end": 43, "note": null}]}
+{"sentence_id": 3074, "sentence_text": "Copyright 2001 Academic Press .", "sentence_char_start_global": 510524, "sentence_char_end_global": 510555, "entities": [], "entities_global": []}
+{"sentence_id": 3075, "sentence_text": "Strict control of human immunodeficiency virus type 1 replication by a genetic switch : Tet for Tat .", "sentence_char_start_global": 510556, "sentence_char_end_global": 510657, "entities": [], "entities_global": []}
+{"sentence_id": 3076, "sentence_text": "Live - attenuated human immunodeficiency virus type 1 ( HIV - 1 ) variants have shown great promise as AIDS vaccines , but continued replication can lead to the selection of faster - replicating variants that are pathogenic .", "sentence_char_start_global": 510658, "sentence_char_end_global": 510883, "entities": [], "entities_global": []}
+{"sentence_id": 3077, "sentence_text": "We therefore designed HIV - 1 genomes that replicate exclusively upon addition of the nontoxic effector doxycycline ( dox ) .", "sentence_char_start_global": 510884, "sentence_char_end_global": 511009, "entities": [{"text": "HIV - 1 genomes", "type": "ENTITY", "char_start": 22, "char_end": 37, "token_start": 3, "token_end": 6}], "entities_global": [{"text": "HIV - 1 genomes", "type": "ENTITY", "char_start": 510906, "char_end": 510921, "token_start": 3, "token_end": 6, "note": null}]}
+{"sentence_id": 3078, "sentence_text": "This was achieved by replacement of the viral TAR - Tat system for transcriptional activation by the Escherichia coli - derived Tet system for inducible gene expression .", "sentence_char_start_global": 511010, "sentence_char_end_global": 511180, "entities": [], "entities_global": []}
+{"sentence_id": 3079, "sentence_text": "These designer ` ` HIV - rtTA ' ' viruses replicate in a strictly dox - dependent manner both in a T - cell line and in primary blood cells , and the rate of replication can be fine - tuned by simple variation of the dox concentration .", "sentence_char_start_global": 511181, "sentence_char_end_global": 511417, "entities": [], "entities_global": []}
+{"sentence_id": 3080, "sentence_text": "These HIV - rtTA viruses provide a tool to perform genetics , e . g . , selection and optimization experiments , with the E . coli - derived Tet reagents in a eukaryotic background .", "sentence_char_start_global": 511418, "sentence_char_end_global": 511600, "entities": [], "entities_global": []}
+{"sentence_id": 3081, "sentence_text": "Furthermore , such viruses may represent improved vaccine candidates because their replication can be turned on and off at will .", "sentence_char_start_global": 511601, "sentence_char_end_global": 511730, "entities": [], "entities_global": []}
+{"sentence_id": 3082, "sentence_text": "Synovial fluid induced nuclear factor - kappaB DNA binding in a monocytic cell line .", "sentence_char_start_global": 511731, "sentence_char_end_global": 511816, "entities": [{"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 23, "char_end": 46, "token_start": 3, "token_end": 6}], "entities_global": [{"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 511754, "char_end": 511777, "token_start": 3, "token_end": 6, "note": null}]}
+{"sentence_id": 3083, "sentence_text": "OBJECTIVE : To determine the effects of synovial fluids ( SF ) on DNA binding activity of transcription factor nuclear factor - kappaB ( NF - kappaB ) in the Mono Mac 6 monocytic / macrophage cell line as a model for the interaction between SF and synovial tissue macrophages in arthritis .", "sentence_char_start_global": 511817, "sentence_char_end_global": 512107, "entities": [{"text": "transcription factor", "type": "ENTITY", "char_start": 90, "char_end": 110, "token_start": 17, "token_end": 18}, {"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 111, "char_end": 134, "token_start": 19, "token_end": 22}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 137, "char_end": 148, "token_start": 24, "token_end": 26}], "entities_global": [{"text": "transcription factor", "type": "ENTITY", "char_start": 511907, "char_end": 511927, "token_start": 17, "token_end": 18, "note": null}, {"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 511928, "char_end": 511951, "token_start": 19, "token_end": 22, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 511954, "char_end": 511965, "token_start": 24, "token_end": 26, "note": null}]}
+{"sentence_id": 3084, "sentence_text": "METHODS : Mono Mac 6 cells were incubated with SF from the knee joints of human subjects with rheumatoid arthritis ( RA ) , undifferentiated seronegative oligoarthritis , and osteoarthritis ( OA ) .", "sentence_char_start_global": 512108, "sentence_char_end_global": 512306, "entities": [], "entities_global": []}
+{"sentence_id": 3085, "sentence_text": "Nuclear extracts prepared from the Mono Mac 6 cells and RA synovial tissue were analyzed by electrophoretic mobility shift analysis ( EMSA ) for NF - kappaB DNA binding proteins .", "sentence_char_start_global": 512307, "sentence_char_end_global": 512486, "entities": [{"text": "NF - kappaB DNA binding proteins", "type": "ENTITY", "char_start": 145, "char_end": 177, "token_start": 24, "token_end": 29}], "entities_global": [{"text": "NF - kappaB DNA binding proteins", "type": "ENTITY", "char_start": 512452, "char_end": 512484, "token_start": 24, "token_end": 29, "note": null}]}
+{"sentence_id": 3086, "sentence_text": "RESULTS : Induction of NF - kappaB DNA binding by the p65 ( RelA ) / p50 heterodimer was observed in response to incubation of Mono Mac 6 cells with SF ( 20 % in culture medium ) from 5 of 8 subjects with RA , 4 of 5 with OA , and none of 3 with undifferentiated seronegative oligoarthritis .", "sentence_char_start_global": 512487, "sentence_char_end_global": 512779, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 23, "char_end": 34, "token_start": 4, "token_end": 6}, {"text": "p65 ( RelA ) / p50 heterodimer", "type": "ENTITY", "char_start": 54, "char_end": 84, "token_start": 11, "token_end": 17}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 512510, "char_end": 512521, "token_start": 4, "token_end": 6, "note": null}, {"text": "p65 ( RelA ) / p50 heterodimer", "type": "ENTITY", "char_start": 512541, "char_end": 512571, "token_start": 11, "token_end": 17, "note": null}]}
+{"sentence_id": 3087, "sentence_text": "Incubation of SF with neutralizing antibodies against tumor necrosis factor - alpha ( TNF - alpha ) , but not antibodies against interleukin 6 ( IL - 6 ) , significantly reduced the induction of p65 / p50 binding activity in SF from subjects with RA and OA .", "sentence_char_start_global": 512780, "sentence_char_end_global": 513038, "entities": [{"text": "neutralizing antibodies", "type": "ENTITY", "char_start": 22, "char_end": 45, "token_start": 4, "token_end": 5}, {"text": "tumor necrosis factor - alpha ( TNF - alpha )", "type": "ENTITY", "char_start": 54, "char_end": 99, "token_start": 7, "token_end": 16}, {"text": "antibodies", "type": "ENTITY", "char_start": 110, "char_end": 120, "token_start": 20, "token_end": 20}, {"text": "interleukin 6 ( IL - 6 )", "type": "ENTITY", "char_start": 129, "char_end": 153, "token_start": 22, "token_end": 28}], "entities_global": [{"text": "neutralizing antibodies", "type": "ENTITY", "char_start": 512802, "char_end": 512825, "token_start": 4, "token_end": 5, "note": null}, {"text": "tumor necrosis factor - alpha ( TNF - alpha )", "type": "ENTITY", "char_start": 512834, "char_end": 512879, "token_start": 7, "token_end": 16, "note": null}, {"text": "antibodies", "type": "ENTITY", "char_start": 512890, "char_end": 512900, "token_start": 20, "token_end": 20, "note": null}, {"text": "interleukin 6 ( IL - 6 )", "type": "ENTITY", "char_start": 512909, "char_end": 512933, "token_start": 22, "token_end": 28, "note": null}]}
+{"sentence_id": 3088, "sentence_text": "Unexpectedly , a slowly migrating SF inducible NF - kappaB - binding complex was observed in EMSA of Mono Mac 6 cells after incubation with SF from 5 of 8 RA and 2 of 5 OA subjects .", "sentence_char_start_global": 513039, "sentence_char_end_global": 513221, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 47, "char_end": 58, "token_start": 7, "token_end": 9}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 513086, "char_end": 513097, "token_start": 7, "token_end": 9, "note": null}]}
+{"sentence_id": 3089, "sentence_text": "The induction of this complex by SF was not affected by neutralization of TNF - alpha or IL - 6 in SF , and the complex was not inducible by TNF - alpha , IL - 1beta , TNF - alpha / IL - 1beta , IL - 6 , platelet derived growth factor , lipopolysaccharide , or tetradecanoyl phorbol acetate .", "sentence_char_start_global": 513222, "sentence_char_end_global": 513514, "entities": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 74, "char_end": 85, "token_start": 13, "token_end": 15}, {"text": "IL - 6", "type": "ENTITY", "char_start": 89, "char_end": 95, "token_start": 17, "token_end": 19}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 141, "char_end": 152, "token_start": 30, "token_end": 32}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 168, "char_end": 179, "token_start": 38, "token_end": 40}, {"text": "IL - 1beta", "type": "ENTITY", "char_start": 182, "char_end": 192, "token_start": 42, "token_end": 44}, {"text": "IL - 6", "type": "ENTITY", "char_start": 195, "char_end": 201, "token_start": 46, "token_end": 48}, {"text": "platelet derived growth factor", "type": "ENTITY", "char_start": 204, "char_end": 234, "token_start": 50, "token_end": 53}], "entities_global": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 513296, "char_end": 513307, "token_start": 13, "token_end": 15, "note": null}, {"text": "IL - 6", "type": "ENTITY", "char_start": 513311, "char_end": 513317, "token_start": 17, "token_end": 19, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 513363, "char_end": 513374, "token_start": 30, "token_end": 32, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 513390, "char_end": 513401, "token_start": 38, "token_end": 40, "note": null}, {"text": "IL - 1beta", "type": "ENTITY", "char_start": 513404, "char_end": 513414, "token_start": 42, "token_end": 44, "note": null}, {"text": "IL - 6", "type": "ENTITY", "char_start": 513417, "char_end": 513423, "token_start": 46, "token_end": 48, "note": null}, {"text": "platelet derived growth factor", "type": "ENTITY", "char_start": 513426, "char_end": 513456, "token_start": 50, "token_end": 53, "note": null}]}
+{"sentence_id": 3090, "sentence_text": "The slowly migrating complex could not be supershifted with antibodies against NF - kappaB , Jun , or the transcriptional coactivators p300 or CBP .", "sentence_char_start_global": 513515, "sentence_char_end_global": 513663, "entities": [{"text": "migrating complex", "type": "ENTITY", "char_start": 11, "char_end": 28, "token_start": 2, "token_end": 3}, {"text": "antibodies", "type": "ENTITY", "char_start": 60, "char_end": 70, "token_start": 9, "token_end": 9}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 79, "char_end": 90, "token_start": 11, "token_end": 13}, {"text": "Jun", "type": "ENTITY", "char_start": 93, "char_end": 96, "token_start": 15, "token_end": 15}, {"text": "p300", "type": "ENTITY", "char_start": 135, "char_end": 139, "token_start": 21, "token_end": 21}, {"text": "CBP", "type": "ENTITY", "char_start": 143, "char_end": 146, "token_start": 23, "token_end": 23}], "entities_global": [{"text": "migrating complex", "type": "ENTITY", "char_start": 513526, "char_end": 513543, "token_start": 2, "token_end": 3, "note": null}, {"text": "antibodies", "type": "ENTITY", "char_start": 513575, "char_end": 513585, "token_start": 9, "token_end": 9, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 513594, "char_end": 513605, "token_start": 11, "token_end": 13, "note": null}, {"text": "Jun", "type": "ENTITY", "char_start": 513608, "char_end": 513611, "token_start": 15, "token_end": 15, "note": null}, {"text": "p300", "type": "ENTITY", "char_start": 513650, "char_end": 513654, "token_start": 21, "token_end": 21, "note": null}, {"text": "CBP", "type": "ENTITY", "char_start": 513658, "char_end": 513661, "token_start": 23, "token_end": 23, "note": null}]}
+{"sentence_id": 3091, "sentence_text": "A NF - kappaB - binding complex with similar slow mobility was observed in nuclear extracts prepared from fresh human RA synovial tissue .", "sentence_char_start_global": 513664, "sentence_char_end_global": 513802, "entities": [{"text": "NF - kappaB - binding complex", "type": "ENTITY", "char_start": 2, "char_end": 31, "token_start": 1, "token_end": 6}], "entities_global": [{"text": "NF - kappaB - binding complex", "type": "ENTITY", "char_start": 513666, "char_end": 513695, "token_start": 1, "token_end": 6, "note": null}]}
+{"sentence_id": 3092, "sentence_text": "CONCLUSION : Biological activity of TNF - alpha in SF from RA and OA subjects is capable of inducing p65 / p50 NF - kappaB DNA binding activity in macrophages .", "sentence_char_start_global": 513803, "sentence_char_end_global": 513963, "entities": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 36, "char_end": 47, "token_start": 5, "token_end": 7}, {"text": "p65 / p50 NF - kappaB", "type": "ENTITY", "char_start": 101, "char_end": 122, "token_start": 19, "token_end": 24}], "entities_global": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 513839, "char_end": 513850, "token_start": 5, "token_end": 7, "note": null}, {"text": "p65 / p50 NF - kappaB", "type": "ENTITY", "char_start": 513904, "char_end": 513925, "token_start": 19, "token_end": 24, "note": null}]}
+{"sentence_id": 3093, "sentence_text": "A property of SF that is independent of TNF - alpha and other cytokines is responsible for the induction of a novel slowly migrating NF - kappaB - binding complex .", "sentence_char_start_global": 513964, "sentence_char_end_global": 514128, "entities": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 40, "char_end": 51, "token_start": 8, "token_end": 10}, {"text": "cytokines", "type": "ENTITY", "char_start": 62, "char_end": 71, "token_start": 13, "token_end": 13}, {"text": "NF - kappaB - binding complex", "type": "ENTITY", "char_start": 133, "char_end": 162, "token_start": 24, "token_end": 29}], "entities_global": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 514004, "char_end": 514015, "token_start": 8, "token_end": 10, "note": null}, {"text": "cytokines", "type": "ENTITY", "char_start": 514026, "char_end": 514035, "token_start": 13, "token_end": 13, "note": null}, {"text": "NF - kappaB - binding complex", "type": "ENTITY", "char_start": 514097, "char_end": 514126, "token_start": 24, "token_end": 29, "note": null}]}
+{"sentence_id": 3094, "sentence_text": "Soluble mediators in SF of subjects with RA and OA can therefore modulate binding of nuclear proteins to the NF - kappaB binding site in macrophages and may play a role in inflammatory gene expression in arthritis .", "sentence_char_start_global": 514129, "sentence_char_end_global": 514344, "entities": [{"text": "nuclear proteins", "type": "ENTITY", "char_start": 85, "char_end": 101, "token_start": 15, "token_end": 16}, {"text": "NF - kappaB binding site", "type": "ENTITY", "char_start": 109, "char_end": 133, "token_start": 19, "token_end": 23}], "entities_global": [{"text": "nuclear proteins", "type": "ENTITY", "char_start": 514214, "char_end": 514230, "token_start": 15, "token_end": 16, "note": null}, {"text": "NF - kappaB binding site", "type": "ENTITY", "char_start": 514238, "char_end": 514262, "token_start": 19, "token_end": 23, "note": null}]}
+{"sentence_id": 3095, "sentence_text": "Peroxisome proliferator activator receptor - gamma agonists and 15 - deoxy - Delta ( 12 , 14 ) ( 12 , 14 ) - PGJ ( 2 ) induce apoptosis in normal and malignant B - lineage cells .", "sentence_char_start_global": 514345, "sentence_char_end_global": 514524, "entities": [{"text": "Peroxisome proliferator activator receptor - gamma", "type": "ENTITY", "char_start": 0, "char_end": 50, "token_start": 0, "token_end": 5}], "entities_global": [{"text": "Peroxisome proliferator activator receptor - gamma", "type": "ENTITY", "char_start": 514345, "char_end": 514395, "token_start": 0, "token_end": 5, "note": null}]}
+{"sentence_id": 3096, "sentence_text": "The research described herein evaluates the expression and functional significance of peroxisome proliferator activator receptor - gamma ( PPAR - gamma ) on B - lineage cells .", "sentence_char_start_global": 514525, "sentence_char_end_global": 514701, "entities": [{"text": "peroxisome proliferator activator receptor - gamma ( PPAR - gamma )", "type": "ENTITY", "char_start": 86, "char_end": 153, "token_start": 11, "token_end": 21}], "entities_global": [{"text": "peroxisome proliferator activator receptor - gamma ( PPAR - gamma )", "type": "ENTITY", "char_start": 514611, "char_end": 514678, "token_start": 11, "token_end": 21, "note": null}]}
+{"sentence_id": 3097, "sentence_text": "Normal mouse B cells and a variety of B lymphoma cells reflective of stages of B cell differentiation ( e . g . , 70Z / 3 , CH31 , WEHI - 231 , CH12 , and J558 ) express PPAR - gamma mRNA and , by Western blot analysis , the 67 - kDa PPAR - gamma protein .", "sentence_char_start_global": 514702, "sentence_char_end_global": 514958, "entities": [{"text": "PPAR - gamma mRNA", "type": "ENTITY", "char_start": 170, "char_end": 187, "token_start": 40, "token_end": 43}, {"text": "67 - kDa PPAR - gamma protein", "type": "ENTITY", "char_start": 225, "char_end": 254, "token_start": 52, "token_end": 58}], "entities_global": [{"text": "PPAR - gamma mRNA", "type": "ENTITY", "char_start": 514872, "char_end": 514889, "token_start": 40, "token_end": 43, "note": null}, {"text": "67 - kDa PPAR - gamma protein", "type": "ENTITY", "char_start": 514927, "char_end": 514956, "token_start": 52, "token_end": 58, "note": null}]}
+{"sentence_id": 3098, "sentence_text": "15 - Deoxy - Delta ( 12 , 14 ) - PGJ ( 2 ) ( 15d - PGJ ( 2 ) ) , a PPAR - gamma agonist , has a dose - dependent antiproliferative and cytotoxic effect on normal and malignant B cells as shown by [ ( 3 ) H ] thymidine and 3 - [ 4 , 5 - dimethylthiazol - 2 - yl ] - 2 , 5 - diphenyltetrazolium bromide assays .", "sentence_char_start_global": 514959, "sentence_char_end_global": 515268, "entities": [], "entities_global": []}
+{"sentence_id": 3099, "sentence_text": "Only PPAR - gamma agonists ( thiazolidinediones ) , and not PPAR - alpha agonists , mimicked the effect of 15d - PGJ ( 2 ) on B - lineage cells , indicating that the mechanism by which 15d - PGJ ( 2 ) negatively affects B - lineage cells involves in part PPAR - gamma .", "sentence_char_start_global": 515269, "sentence_char_end_global": 515538, "entities": [{"text": "PPAR - gamma", "type": "ENTITY", "char_start": 255, "char_end": 267, "token_start": 53, "token_end": 55}], "entities_global": [{"text": "PPAR - gamma", "type": "ENTITY", "char_start": 515524, "char_end": 515536, "token_start": 53, "token_end": 55, "note": null}]}
+{"sentence_id": 3100, "sentence_text": "The mechanism by which PPAR - gamma agonists induce cytotoxicity is via apoptosis , as shown by annexin V staining and as confirmed by DNA fragmentation detected using the TUNEL assay .", "sentence_char_start_global": 515539, "sentence_char_end_global": 515724, "entities": [], "entities_global": []}
+{"sentence_id": 3101, "sentence_text": "Interestingly , addition of PGF ( 2alpha ) , which was not known to affect lymphocytes , dramatically attenuated the deleterious effects of PPAR - gamma agonists on B lymphomas .", "sentence_char_start_global": 515725, "sentence_char_end_global": 515903, "entities": [], "entities_global": []}
+{"sentence_id": 3102, "sentence_text": "Surprisingly , 15d - PGJ ( 2 ) induced a massive increase in nuclear mitogen - activated protein kinase activation , and pretreatment with PGF ( 2alpha ) blunted the mitogen - activated protein kinase activation .", "sentence_char_start_global": 515904, "sentence_char_end_global": 516117, "entities": [], "entities_global": []}
+{"sentence_id": 3103, "sentence_text": "This is the first study evaluating PPAR - gamma expression and its significance on B lymphocytes .", "sentence_char_start_global": 516118, "sentence_char_end_global": 516216, "entities": [], "entities_global": []}
+{"sentence_id": 3104, "sentence_text": "PPAR - gamma agonists may serve as a counterbalance to the stimulating effects of other PGs , namely PGE ( 2 ) , which promotes B cell differentiation .", "sentence_char_start_global": 516217, "sentence_char_end_global": 516369, "entities": [], "entities_global": []}
+{"sentence_id": 3105, "sentence_text": "Finally , the use of PGs , such as 15d - PGJ ( 2 ) , and synthetic PPAR - gamma agonists to induce apoptosis in B - lineage cells may lead to the development of novel therapies for fatal B lymphomas", "sentence_char_start_global": 516370, "sentence_char_end_global": 516568, "entities": [], "entities_global": []}
+{"sentence_id": 3106, "sentence_text": "Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl - 1 expression .", "sentence_char_start_global": 516569, "sentence_char_end_global": 516691, "entities": [], "entities_global": []}
+{"sentence_id": 3107, "sentence_text": "Large granular lymphocyte ( LGL ) leukemia is characterized by the expansion of antigen - activated cytotoxic T lymphocytes .", "sentence_char_start_global": 516692, "sentence_char_end_global": 516817, "entities": [], "entities_global": []}
+{"sentence_id": 3108, "sentence_text": "These leukemic cells are resistant to Fas - mediated apoptosis despite expressing high levels of Fas .", "sentence_char_start_global": 516818, "sentence_char_end_global": 516920, "entities": [{"text": "Fas", "type": "ENTITY", "char_start": 97, "char_end": 100, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "Fas", "type": "ENTITY", "char_start": 516915, "char_end": 516918, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 3109, "sentence_text": "We found that leukemic LGL from 19 patients displayed high levels of activated STAT3 .", "sentence_char_start_global": 516921, "sentence_char_end_global": 517007, "entities": [{"text": "activated STAT3", "type": "ENTITY", "char_start": 69, "char_end": 84, "token_start": 12, "token_end": 13}], "entities_global": [{"text": "activated STAT3", "type": "ENTITY", "char_start": 516990, "char_end": 517005, "token_start": 12, "token_end": 13, "note": null}]}
+{"sentence_id": 3110, "sentence_text": "Treatment of leukemic LGL with the JAK - selective tyrosine kinase inhibitor AG - 490 induced apoptosis with a corresponding decrease in STAT - DNA binding activity .", "sentence_char_start_global": 517008, "sentence_char_end_global": 517174, "entities": [{"text": "STAT", "type": "ENTITY", "char_start": 137, "char_end": 141, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "STAT", "type": "ENTITY", "char_start": 517145, "char_end": 517149, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 3111, "sentence_text": "Moreover , using an antisense oligonucleotide approach to diminish STAT3 expression , we found that Fas sensitivity was restored in leukemic LGL .", "sentence_char_start_global": 517175, "sentence_char_end_global": 517321, "entities": [], "entities_global": []}
+{"sentence_id": 3112, "sentence_text": "AG - 490 - induced apoptosis in leukemic LGL was independent of Bcl - xL or Bcl - 2 expression .", "sentence_char_start_global": 517322, "sentence_char_end_global": 517418, "entities": [], "entities_global": []}
+{"sentence_id": 3113, "sentence_text": "However , we found that the Bcl - 2 - family protein Mcl - 1 was significantly reduced by AG - 490 treatment .", "sentence_char_start_global": 517419, "sentence_char_end_global": 517529, "entities": [{"text": "Bcl - 2 - family protein Mcl - 1", "type": "ENTITY", "char_start": 28, "char_end": 60, "token_start": 6, "token_end": 14}], "entities_global": [{"text": "Bcl - 2 - family protein Mcl - 1", "type": "ENTITY", "char_start": 517447, "char_end": 517479, "token_start": 6, "token_end": 14, "note": null}]}
+{"sentence_id": 3114, "sentence_text": "Activated STAT3 was shown to bind an SIE - related element in the murine mcl - 1 promoter .", "sentence_char_start_global": 517530, "sentence_char_end_global": 517621, "entities": [{"text": "Activated STAT3", "type": "ENTITY", "char_start": 0, "char_end": 15, "token_start": 0, "token_end": 1}, {"text": "SIE - related element", "type": "ENTITY", "char_start": 37, "char_end": 58, "token_start": 7, "token_end": 10}, {"text": "murine mcl - 1 promoter", "type": "ENTITY", "char_start": 66, "char_end": 89, "token_start": 13, "token_end": 17}], "entities_global": [{"text": "Activated STAT3", "type": "ENTITY", "char_start": 517530, "char_end": 517545, "token_start": 0, "token_end": 1, "note": null}, {"text": "SIE - related element", "type": "ENTITY", "char_start": 517567, "char_end": 517588, "token_start": 7, "token_end": 10, "note": null}, {"text": "murine mcl - 1 promoter", "type": "ENTITY", "char_start": 517596, "char_end": 517619, "token_start": 13, "token_end": 17, "note": null}]}
+{"sentence_id": 3115, "sentence_text": "Using a luciferase reporter assay , we demonstrated that v - src overexpression in NIH3T3 induced STAT3 - dependent transcriptional activity from the mcl - 1 promoter and increased endogenous Mcl - 1 protein levels .", "sentence_char_start_global": 517622, "sentence_char_end_global": 517838, "entities": [{"text": "STAT3", "type": "ENTITY", "char_start": 98, "char_end": 103, "token_start": 16, "token_end": 16}, {"text": "mcl - 1 promoter", "type": "ENTITY", "char_start": 150, "char_end": 166, "token_start": 23, "token_end": 26}], "entities_global": [{"text": "STAT3", "type": "ENTITY", "char_start": 517720, "char_end": 517725, "token_start": 16, "token_end": 16, "note": null}, {"text": "mcl - 1 promoter", "type": "ENTITY", "char_start": 517772, "char_end": 517788, "token_start": 23, "token_end": 26, "note": null}]}
+{"sentence_id": 3116, "sentence_text": "We conclude that STAT3 activation contributed to accumulation of the leukemic LGL clones .", "sentence_char_start_global": 517839, "sentence_char_end_global": 517929, "entities": [{"text": "STAT3", "type": "ENTITY", "char_start": 17, "char_end": 22, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "STAT3", "type": "ENTITY", "char_start": 517856, "char_end": 517861, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 3117, "sentence_text": "These findings suggest that investigation should focus on novel strategies targeting STAT3 in the treatment of LGL leukemia .", "sentence_char_start_global": 517930, "sentence_char_end_global": 518055, "entities": [{"text": "STAT3", "type": "ENTITY", "char_start": 85, "char_end": 90, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "STAT3", "type": "ENTITY", "char_start": 518015, "char_end": 518020, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 3118, "sentence_text": "Decreased immediate inflammatory gene induction in activating transcription factor - 2 mutant mice .", "sentence_char_start_global": 518056, "sentence_char_end_global": 518156, "entities": [{"text": "inflammatory gene", "type": "ENTITY", "char_start": 20, "char_end": 37, "token_start": 2, "token_end": 3}, {"text": "activating transcription factor - 2", "type": "ENTITY", "char_start": 51, "char_end": 86, "token_start": 6, "token_end": 10}], "entities_global": [{"text": "inflammatory gene", "type": "ENTITY", "char_start": 518076, "char_end": 518093, "token_start": 2, "token_end": 3, "note": null}, {"text": "activating transcription factor - 2", "type": "ENTITY", "char_start": 518107, "char_end": 518142, "token_start": 6, "token_end": 10, "note": null}]}
+{"sentence_id": 3119, "sentence_text": "Transcription factor activating transcription factor ( ATF ) - 2 is activated by inflammatory signals transduced by the JNK and p38 MAP kinase pathways .", "sentence_char_start_global": 518157, "sentence_char_end_global": 518310, "entities": [{"text": "Transcription factor activating transcription factor ( ATF ) - 2", "type": "ENTITY", "char_start": 0, "char_end": 64, "token_start": 0, "token_end": 9}], "entities_global": [{"text": "Transcription factor activating transcription factor ( ATF ) - 2", "type": "ENTITY", "char_start": 518157, "char_end": 518221, "token_start": 0, "token_end": 9, "note": null}]}
+{"sentence_id": 3120, "sentence_text": "To better define the role of ATF - 2 in inflammation , adult mice expressing small amounts of a mutant ATF - 2 protein were challenged with lipopolysaccharide ( LPS ) , anti - CD3 antibody or virus .", "sentence_char_start_global": 518311, "sentence_char_end_global": 518510, "entities": [{"text": "ATF - 2", "type": "ENTITY", "char_start": 29, "char_end": 36, "token_start": 6, "token_end": 8}, {"text": "mutant ATF - 2 protein", "type": "ENTITY", "char_start": 96, "char_end": 118, "token_start": 19, "token_end": 23}, {"text": "anti - CD3 antibody", "type": "ENTITY", "char_start": 169, "char_end": 188, "token_start": 32, "token_end": 35}], "entities_global": [{"text": "ATF - 2", "type": "ENTITY", "char_start": 518340, "char_end": 518347, "token_start": 6, "token_end": 8, "note": null}, {"text": "mutant ATF - 2 protein", "type": "ENTITY", "char_start": 518407, "char_end": 518429, "token_start": 19, "token_end": 23, "note": null}, {"text": "anti - CD3 antibody", "type": "ENTITY", "char_start": 518480, "char_end": 518499, "token_start": 32, "token_end": 35, "note": null}]}
+{"sentence_id": 3121, "sentence_text": "Within 3 h of challenge by LPS , ATF - 2 mutant mice had decreased induction of the adhesion molecules E - selectin , P - selectin and VCAM - 1 as well as the cytokines tumor necrosis factor - alpha , IL - 1beta and IL - 6 compared with control mice .", "sentence_char_start_global": 518511, "sentence_char_end_global": 518762, "entities": [{"text": "adhesion molecules", "type": "ENTITY", "char_start": 84, "char_end": 102, "token_start": 18, "token_end": 19}, {"text": "E - selectin", "type": "ENTITY", "char_start": 103, "char_end": 115, "token_start": 20, "token_end": 22}, {"text": "P - selectin", "type": "ENTITY", "char_start": 118, "char_end": 130, "token_start": 24, "token_end": 26}, {"text": "VCAM - 1", "type": "ENTITY", "char_start": 135, "char_end": 143, "token_start": 28, "token_end": 30}, {"text": "cytokines", "type": "ENTITY", "char_start": 159, "char_end": 168, "token_start": 35, "token_end": 35}, {"text": "tumor necrosis factor - alpha", "type": "ENTITY", "char_start": 169, "char_end": 198, "token_start": 36, "token_end": 40}, {"text": "IL - 1beta", "type": "ENTITY", "char_start": 201, "char_end": 211, "token_start": 42, "token_end": 44}, {"text": "IL - 6", "type": "ENTITY", "char_start": 216, "char_end": 222, "token_start": 46, "token_end": 48}], "entities_global": [{"text": "adhesion molecules", "type": "ENTITY", "char_start": 518595, "char_end": 518613, "token_start": 18, "token_end": 19, "note": null}, {"text": "E - selectin", "type": "ENTITY", "char_start": 518614, "char_end": 518626, "token_start": 20, "token_end": 22, "note": null}, {"text": "P - selectin", "type": "ENTITY", "char_start": 518629, "char_end": 518641, "token_start": 24, "token_end": 26, "note": null}, {"text": "VCAM - 1", "type": "ENTITY", "char_start": 518646, "char_end": 518654, "token_start": 28, "token_end": 30, "note": null}, {"text": "cytokines", "type": "ENTITY", "char_start": 518670, "char_end": 518679, "token_start": 35, "token_end": 35, "note": null}, {"text": "tumor necrosis factor - alpha", "type": "ENTITY", "char_start": 518680, "char_end": 518709, "token_start": 36, "token_end": 40, "note": null}, {"text": "IL - 1beta", "type": "ENTITY", "char_start": 518712, "char_end": 518722, "token_start": 42, "token_end": 44, "note": null}, {"text": "IL - 6", "type": "ENTITY", "char_start": 518727, "char_end": 518733, "token_start": 46, "token_end": 48, "note": null}]}
+{"sentence_id": 3122, "sentence_text": "Stimulation of T lymphocytes by anti - CD3 antibody also showed less induction of IL - 1 and IL - 6 in ATF - 2 mutant tissues .", "sentence_char_start_global": 518763, "sentence_char_end_global": 518890, "entities": [{"text": "anti - CD3 antibody", "type": "ENTITY", "char_start": 32, "char_end": 51, "token_start": 5, "token_end": 8}, {"text": "IL - 1", "type": "ENTITY", "char_start": 82, "char_end": 88, "token_start": 14, "token_end": 16}, {"text": "IL - 6", "type": "ENTITY", "char_start": 93, "char_end": 99, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "anti - CD3 antibody", "type": "ENTITY", "char_start": 518795, "char_end": 518814, "token_start": 5, "token_end": 8, "note": null}, {"text": "IL - 1", "type": "ENTITY", "char_start": 518845, "char_end": 518851, "token_start": 14, "token_end": 16, "note": null}, {"text": "IL - 6", "type": "ENTITY", "char_start": 518856, "char_end": 518862, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 3123, "sentence_text": "ATF - 2 mutant thymocytes treated with anti - CD3 antibody in vitro demonstrated reduced induction of c - Jun , JunB , JunD and Fra - 2 .", "sentence_char_start_global": 518891, "sentence_char_end_global": 519028, "entities": [{"text": "anti - CD3 antibody", "type": "ENTITY", "char_start": 39, "char_end": 58, "token_start": 7, "token_end": 10}, {"text": "c - Jun", "type": "ENTITY", "char_start": 102, "char_end": 109, "token_start": 17, "token_end": 19}, {"text": "JunB", "type": "ENTITY", "char_start": 112, "char_end": 116, "token_start": 21, "token_end": 21}, {"text": "JunD", "type": "ENTITY", "char_start": 119, "char_end": 123, "token_start": 23, "token_end": 23}, {"text": "Fra - 2", "type": "ENTITY", "char_start": 128, "char_end": 135, "token_start": 25, "token_end": 27}], "entities_global": [{"text": "anti - CD3 antibody", "type": "ENTITY", "char_start": 518930, "char_end": 518949, "token_start": 7, "token_end": 10, "note": null}, {"text": "c - Jun", "type": "ENTITY", "char_start": 518993, "char_end": 519000, "token_start": 17, "token_end": 19, "note": null}, {"text": "JunB", "type": "ENTITY", "char_start": 519003, "char_end": 519007, "token_start": 21, "token_end": 21, "note": null}, {"text": "JunD", "type": "ENTITY", "char_start": 519010, "char_end": 519014, "token_start": 23, "token_end": 23, "note": null}, {"text": "Fra - 2", "type": "ENTITY", "char_start": 519019, "char_end": 519026, "token_start": 25, "token_end": 27, "note": null}]}
+{"sentence_id": 3124, "sentence_text": "However , similar to what was observed after p38 kinase inhibition in normal mice , relative ATF - 2 deficiency did not prevent the development of a mononuclear cell infiltrate in the week following an inflammatory stimulus .", "sentence_char_start_global": 519029, "sentence_char_end_global": 519254, "entities": [], "entities_global": []}
+{"sentence_id": 3125, "sentence_text": "ATF - 2 mutant mice proved more susceptible to death than control mice from LPS plus D - galactosamine injection or Coxsackievirus B3 infection and had a higher incidence of mononuclear pulmonary infiltrates after exposure to Herpes simplex virus - 1 .", "sentence_char_start_global": 519255, "sentence_char_end_global": 519507, "entities": [], "entities_global": []}
+{"sentence_id": 3126, "sentence_text": "ATF - 2 is essential for maximal immediate induction of adhesion molecules and cytokine genes , but at later time points may even protect against overactive immune responses .", "sentence_char_start_global": 519508, "sentence_char_end_global": 519683, "entities": [{"text": "ATF - 2", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 2}, {"text": "adhesion molecules", "type": "ENTITY", "char_start": 56, "char_end": 74, "token_start": 10, "token_end": 11}, {"text": "cytokine genes", "type": "ENTITY", "char_start": 79, "char_end": 93, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "ATF - 2", "type": "ENTITY", "char_start": 519508, "char_end": 519515, "token_start": 0, "token_end": 2, "note": null}, {"text": "adhesion molecules", "type": "ENTITY", "char_start": 519564, "char_end": 519582, "token_start": 10, "token_end": 11, "note": null}, {"text": "cytokine genes", "type": "ENTITY", "char_start": 519587, "char_end": 519601, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 3127, "sentence_text": "LIGHT , a TNF - like molecule , costimulates T cell proliferation and is required for dendritic cell - mediated allogeneic T cell response .", "sentence_char_start_global": 519684, "sentence_char_end_global": 519824, "entities": [{"text": "LIGHT", "type": "ENTITY", "char_start": 0, "char_end": 5, "token_start": 0, "token_end": 0}, {"text": "TNF - like molecule", "type": "ENTITY", "char_start": 10, "char_end": 29, "token_start": 3, "token_end": 6}], "entities_global": [{"text": "LIGHT", "type": "ENTITY", "char_start": 519684, "char_end": 519689, "token_start": 0, "token_end": 0, "note": null}, {"text": "TNF - like molecule", "type": "ENTITY", "char_start": 519694, "char_end": 519713, "token_start": 3, "token_end": 6, "note": null}]}
+{"sentence_id": 3128, "sentence_text": "LIGHT is a recently identified member of the TNF superfamily and its receptors , herpesvirus entry mediator and lymphotoxin beta receptor , are found in T cells and stromal cells .", "sentence_char_start_global": 519825, "sentence_char_end_global": 520005, "entities": [{"text": "LIGHT", "type": "ENTITY", "char_start": 0, "char_end": 5, "token_start": 0, "token_end": 0}, {"text": "TNF superfamily", "type": "ENTITY", "char_start": 45, "char_end": 60, "token_start": 8, "token_end": 9}, {"text": "herpesvirus entry mediator", "type": "ENTITY", "char_start": 81, "char_end": 107, "token_start": 14, "token_end": 16}, {"text": "lymphotoxin beta receptor", "type": "ENTITY", "char_start": 112, "char_end": 137, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "LIGHT", "type": "ENTITY", "char_start": 519825, "char_end": 519830, "token_start": 0, "token_end": 0, "note": null}, {"text": "TNF superfamily", "type": "ENTITY", "char_start": 519870, "char_end": 519885, "token_start": 8, "token_end": 9, "note": null}, {"text": "herpesvirus entry mediator", "type": "ENTITY", "char_start": 519906, "char_end": 519932, "token_start": 14, "token_end": 16, "note": null}, {"text": "lymphotoxin beta receptor", "type": "ENTITY", "char_start": 519937, "char_end": 519962, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 3129, "sentence_text": "In this study , we demonstrate that LIGHT is selectively expressed on immature dendritic cells ( DCs ) generated from human PBMCs .", "sentence_char_start_global": 520006, "sentence_char_end_global": 520137, "entities": [{"text": "LIGHT", "type": "ENTITY", "char_start": 36, "char_end": 41, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "LIGHT", "type": "ENTITY", "char_start": 520042, "char_end": 520047, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 3130, "sentence_text": "In contrast , LIGHT is not detectable in DCs either freshly isolated from PBMCs or rendered mature in vitro by LPS treatment .", "sentence_char_start_global": 520138, "sentence_char_end_global": 520264, "entities": [{"text": "LIGHT", "type": "ENTITY", "char_start": 14, "char_end": 19, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "LIGHT", "type": "ENTITY", "char_start": 520152, "char_end": 520157, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 3131, "sentence_text": "Blockade of LIGHT by its soluble receptors , lymphotoxin beta receptor - Ig or HVEM - Ig , inhibits the induction of DC - mediated primary allogeneic T cell response .", "sentence_char_start_global": 520265, "sentence_char_end_global": 520432, "entities": [{"text": "LIGHT", "type": "ENTITY", "char_start": 12, "char_end": 17, "token_start": 2, "token_end": 2}, {"text": "soluble receptors", "type": "ENTITY", "char_start": 25, "char_end": 42, "token_start": 5, "token_end": 6}, {"text": "lymphotoxin beta receptor - Ig", "type": "ENTITY", "char_start": 45, "char_end": 75, "token_start": 8, "token_end": 12}, {"text": "HVEM - Ig", "type": "ENTITY", "char_start": 79, "char_end": 88, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "LIGHT", "type": "ENTITY", "char_start": 520277, "char_end": 520282, "token_start": 2, "token_end": 2, "note": null}, {"text": "soluble receptors", "type": "ENTITY", "char_start": 520290, "char_end": 520307, "token_start": 5, "token_end": 6, "note": null}, {"text": "lymphotoxin beta receptor - Ig", "type": "ENTITY", "char_start": 520310, "char_end": 520340, "token_start": 8, "token_end": 12, "note": null}, {"text": "HVEM - Ig", "type": "ENTITY", "char_start": 520344, "char_end": 520353, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 3132, "sentence_text": "Furthermore , engagement of LIGHT costimulates human T cell proliferation , amplifies the NF - kappaB signaling pathway , and preferentially induces the production of IFN - gamma , but not IL - 4 , in the presence of an antigenic signal .", "sentence_char_start_global": 520433, "sentence_char_end_global": 520671, "entities": [{"text": "LIGHT", "type": "ENTITY", "char_start": 28, "char_end": 33, "token_start": 4, "token_end": 4}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 167, "char_end": 178, "token_start": 25, "token_end": 27}, {"text": "IL - 4", "type": "ENTITY", "char_start": 189, "char_end": 195, "token_start": 31, "token_end": 33}], "entities_global": [{"text": "LIGHT", "type": "ENTITY", "char_start": 520461, "char_end": 520466, "token_start": 4, "token_end": 4, "note": null}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 520600, "char_end": 520611, "token_start": 25, "token_end": 27, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 520622, "char_end": 520628, "token_start": 31, "token_end": 33, "note": null}]}
+{"sentence_id": 3133, "sentence_text": "Our results suggest that LIGHT is a costimulatory molecule involved in DC - mediated cellular immune responses .", "sentence_char_start_global": 520672, "sentence_char_end_global": 520784, "entities": [{"text": "LIGHT", "type": "ENTITY", "char_start": 25, "char_end": 30, "token_start": 4, "token_end": 4}, {"text": "costimulatory molecule", "type": "ENTITY", "char_start": 36, "char_end": 58, "token_start": 7, "token_end": 8}], "entities_global": [{"text": "LIGHT", "type": "ENTITY", "char_start": 520697, "char_end": 520702, "token_start": 4, "token_end": 4, "note": null}, {"text": "costimulatory molecule", "type": "ENTITY", "char_start": 520708, "char_end": 520730, "token_start": 7, "token_end": 8, "note": null}]}
+{"sentence_id": 3134, "sentence_text": "Suppression of HIV type 1 replication by a dominant - negative Ets - 1 mutant .", "sentence_char_start_global": 520785, "sentence_char_end_global": 520864, "entities": [{"text": "dominant - negative Ets - 1 mutant", "type": "ENTITY", "char_start": 43, "char_end": 77, "token_start": 8, "token_end": 14}], "entities_global": [{"text": "dominant - negative Ets - 1 mutant", "type": "ENTITY", "char_start": 520828, "char_end": 520862, "token_start": 8, "token_end": 14, "note": null}]}
+{"sentence_id": 3135, "sentence_text": "Activity of the distal region of the human immunodeficiency virus ( HIV - 1 ) long terminal repeat ( LTR ) , which contains binding sites for the Ets - 1 and USF - 1 proteins , is integral for HIV - 1 replication .", "sentence_char_start_global": 520865, "sentence_char_end_global": 521079, "entities": [{"text": "distal region", "type": "ENTITY", "char_start": 16, "char_end": 29, "token_start": 3, "token_end": 4}, {"text": "long terminal repeat", "type": "ENTITY", "char_start": 78, "char_end": 98, "token_start": 15, "token_end": 17}, {"text": "LTR", "type": "ENTITY", "char_start": 101, "char_end": 104, "token_start": 19, "token_end": 19}, {"text": "binding sites", "type": "ENTITY", "char_start": 124, "char_end": 137, "token_start": 24, "token_end": 25}, {"text": "Ets - 1 and USF - 1 proteins", "type": "ENTITY", "char_start": 146, "char_end": 174, "token_start": 28, "token_end": 35}], "entities_global": [{"text": "distal region", "type": "ENTITY", "char_start": 520881, "char_end": 520894, "token_start": 3, "token_end": 4, "note": null}, {"text": "long terminal repeat", "type": "ENTITY", "char_start": 520943, "char_end": 520963, "token_start": 15, "token_end": 17, "note": null}, {"text": "LTR", "type": "ENTITY", "char_start": 520966, "char_end": 520969, "token_start": 19, "token_end": 19, "note": null}, {"text": "binding sites", "type": "ENTITY", "char_start": 520989, "char_end": 521002, "token_start": 24, "token_end": 25, "note": null}, {"text": "Ets - 1 and USF - 1 proteins", "type": "ENTITY", "char_start": 521011, "char_end": 521039, "token_start": 28, "token_end": 35, "note": null}]}
+{"sentence_id": 3136, "sentence_text": "The Ets - 1 and USF - 1 proteins play a critical role in the activity of the HIV - 1 LTR distal enhancer region , as indicated by the potent dominant negative effect of a mutant Ets - 1 lacking trans - activation domains on the transcriptional activity of the LTR .", "sentence_char_start_global": 521080, "sentence_char_end_global": 521345, "entities": [{"text": "Ets - 1 and USF - 1 proteins", "type": "ENTITY", "char_start": 4, "char_end": 32, "token_start": 1, "token_end": 8}, {"text": "HIV - 1 LTR distal enhancer region", "type": "ENTITY", "char_start": 77, "char_end": 111, "token_start": 18, "token_end": 24}, {"text": "mutant Ets - 1 lacking trans - activation domains", "type": "ENTITY", "char_start": 171, "char_end": 220, "token_start": 36, "token_end": 44}, {"text": "LTR", "type": "ENTITY", "char_start": 260, "char_end": 263, "token_start": 51, "token_end": 51}], "entities_global": [{"text": "Ets - 1 and USF - 1 proteins", "type": "ENTITY", "char_start": 521084, "char_end": 521112, "token_start": 1, "token_end": 8, "note": null}, {"text": "HIV - 1 LTR distal enhancer region", "type": "ENTITY", "char_start": 521157, "char_end": 521191, "token_start": 18, "token_end": 24, "note": null}, {"text": "mutant Ets - 1 lacking trans - activation domains", "type": "ENTITY", "char_start": 521251, "char_end": 521300, "token_start": 36, "token_end": 44, "note": null}, {"text": "LTR", "type": "ENTITY", "char_start": 521340, "char_end": 521343, "token_start": 51, "token_end": 51, "note": null}]}
+{"sentence_id": 3137, "sentence_text": "To determine the biological relevance of the Ets - 1 and USF - 1 proteins in HIV - 1 replication , we examined the effect of expression of the dominant - negative mutant of Ets - 1 ( dnEts - 1 ) on HIV - 1 infection of T cells .", "sentence_char_start_global": 521346, "sentence_char_end_global": 521574, "entities": [{"text": "Ets - 1 and USF - 1 proteins", "type": "ENTITY", "char_start": 45, "char_end": 73, "token_start": 7, "token_end": 14}, {"text": "Ets - 1", "type": "ENTITY", "char_start": 173, "char_end": 180, "token_start": 34, "token_end": 36}, {"text": "dnEts - 1", "type": "ENTITY", "char_start": 183, "char_end": 192, "token_start": 38, "token_end": 40}], "entities_global": [{"text": "Ets - 1 and USF - 1 proteins", "type": "ENTITY", "char_start": 521391, "char_end": 521419, "token_start": 7, "token_end": 14, "note": null}, {"text": "Ets - 1", "type": "ENTITY", "char_start": 521519, "char_end": 521526, "token_start": 34, "token_end": 36, "note": null}, {"text": "dnEts - 1", "type": "ENTITY", "char_start": 521529, "char_end": 521538, "token_start": 38, "token_end": 40, "note": null}]}
+{"sentence_id": 3138, "sentence_text": "We demonstrated that expression of dnEts markedly suppressed HIV - 1 infection of a T cell line .", "sentence_char_start_global": 521575, "sentence_char_end_global": 521672, "entities": [{"text": "dnEts", "type": "ENTITY", "char_start": 35, "char_end": 40, "token_start": 5, "token_end": 5}], "entities_global": [{"text": "dnEts", "type": "ENTITY", "char_start": 521610, "char_end": 521615, "token_start": 5, "token_end": 5, "note": null}]}
+{"sentence_id": 3139, "sentence_text": "This finding indicates that formation of a transcriptionaly active USF - 1 / Ets - 1 complex is important in the productive infection of cells by HIV - 1 , and suggests that inhibition of the interaction between USF - 1 and Ets - 1 with the HIV - 1 LTR may provide a new target for anti - HIV - 1 gene therapy .", "sentence_char_start_global": 521673, "sentence_char_end_global": 521984, "entities": [{"text": "transcriptionaly active USF - 1 / Ets - 1 complex", "type": "ENTITY", "char_start": 43, "char_end": 92, "token_start": 7, "token_end": 16}, {"text": "USF - 1", "type": "ENTITY", "char_start": 212, "char_end": 219, "token_start": 38, "token_end": 40}, {"text": "Ets - 1", "type": "ENTITY", "char_start": 224, "char_end": 231, "token_start": 42, "token_end": 44}, {"text": "HIV - 1 LTR", "type": "ENTITY", "char_start": 241, "char_end": 252, "token_start": 47, "token_end": 50}], "entities_global": [{"text": "transcriptionaly active USF - 1 / Ets - 1 complex", "type": "ENTITY", "char_start": 521716, "char_end": 521765, "token_start": 7, "token_end": 16, "note": null}, {"text": "USF - 1", "type": "ENTITY", "char_start": 521885, "char_end": 521892, "token_start": 38, "token_end": 40, "note": null}, {"text": "Ets - 1", "type": "ENTITY", "char_start": 521897, "char_end": 521904, "token_start": 42, "token_end": 44, "note": null}, {"text": "HIV - 1 LTR", "type": "ENTITY", "char_start": 521914, "char_end": 521925, "token_start": 47, "token_end": 50, "note": null}]}
+{"sentence_id": 3140, "sentence_text": "Human eosinophils constitutively express nuclear factor of activated T cells p and c .", "sentence_char_start_global": 521985, "sentence_char_end_global": 522071, "entities": [{"text": "nuclear factor of activated T cells p and c", "type": "ENTITY", "char_start": 41, "char_end": 84, "token_start": 4, "token_end": 12}], "entities_global": [{"text": "nuclear factor of activated T cells p and c", "type": "ENTITY", "char_start": 522026, "char_end": 522069, "token_start": 4, "token_end": 12, "note": null}]}
+{"sentence_id": 3141, "sentence_text": "BACKGROUND : Eosinophils are now known to produce a variety of proinflammatory cytokines , although the molecular factors that regulate their production are poorly understood .", "sentence_char_start_global": 522072, "sentence_char_end_global": 522248, "entities": [{"text": "proinflammatory cytokines", "type": "ENTITY", "char_start": 63, "char_end": 88, "token_start": 11, "token_end": 12}], "entities_global": [{"text": "proinflammatory cytokines", "type": "ENTITY", "char_start": 522135, "char_end": 522160, "token_start": 11, "token_end": 12, "note": null}]}
+{"sentence_id": 3142, "sentence_text": "The expression of almost all of the cytokines produced by eosinophils , including the proallergic cytokine IL - 4 , is now known to be regulated at the level of transcription by members of the nuclear factor of activated T cells ( NFAT ) family of transcription factors .", "sentence_char_start_global": 522249, "sentence_char_end_global": 522520, "entities": [{"text": "cytokines", "type": "ENTITY", "char_start": 36, "char_end": 45, "token_start": 7, "token_end": 7}, {"text": "proallergic cytokine IL - 4", "type": "ENTITY", "char_start": 86, "char_end": 113, "token_start": 14, "token_end": 18}, {"text": "nuclear factor of activated T cells", "type": "ENTITY", "char_start": 193, "char_end": 228, "token_start": 35, "token_end": 40}, {"text": "NFAT", "type": "ENTITY", "char_start": 231, "char_end": 235, "token_start": 42, "token_end": 42}], "entities_global": [{"text": "cytokines", "type": "ENTITY", "char_start": 522285, "char_end": 522294, "token_start": 7, "token_end": 7, "note": null}, {"text": "proallergic cytokine IL - 4", "type": "ENTITY", "char_start": 522335, "char_end": 522362, "token_start": 14, "token_end": 18, "note": null}, {"text": "nuclear factor of activated T cells", "type": "ENTITY", "char_start": 522442, "char_end": 522477, "token_start": 35, "token_end": 40, "note": null}, {"text": "NFAT", "type": "ENTITY", "char_start": 522480, "char_end": 522484, "token_start": 42, "token_end": 42, "note": null}]}
+{"sentence_id": 3143, "sentence_text": "OBJECTIVE : We sought to characterize the expression of different NFAT proteins in resting and activated eosinophils .", "sentence_char_start_global": 522521, "sentence_char_end_global": 522639, "entities": [{"text": "NFAT proteins", "type": "ENTITY", "char_start": 66, "char_end": 79, "token_start": 10, "token_end": 11}], "entities_global": [{"text": "NFAT proteins", "type": "ENTITY", "char_start": 522587, "char_end": 522600, "token_start": 10, "token_end": 11, "note": null}]}
+{"sentence_id": 3144, "sentence_text": "METHODS : Nuclear and whole cell extracts were obtained from both peripheral blood eosinophils and those obtained from bronchoalveolar lavage fluid of asthmatic subjects after endobronchial allergen challenge .", "sentence_char_start_global": 522640, "sentence_char_end_global": 522850, "entities": [], "entities_global": []}
+{"sentence_id": 3145, "sentence_text": "NFAT expression was determined by using immunoprecipitation and Western blot analysis , DNA - binding assays , and RT - PCR analysis of eosinophil mRNA .", "sentence_char_start_global": 522851, "sentence_char_end_global": 523004, "entities": [{"text": "NFAT", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}, {"text": "eosinophil mRNA", "type": "ENTITY", "char_start": 136, "char_end": 151, "token_start": 23, "token_end": 24}], "entities_global": [{"text": "NFAT", "type": "ENTITY", "char_start": 522851, "char_end": 522855, "token_start": 0, "token_end": 0, "note": null}, {"text": "eosinophil mRNA", "type": "ENTITY", "char_start": 522987, "char_end": 523002, "token_start": 23, "token_end": 24, "note": null}]}
+{"sentence_id": 3146, "sentence_text": "RESULTS : Both peripheral blood and bronchoalveolar lavage fluid eosinophils expressed NFATp and NFATc protein .", "sentence_char_start_global": 523005, "sentence_char_end_global": 523117, "entities": [{"text": "NFATp and NFATc protein", "type": "ENTITY", "char_start": 87, "char_end": 110, "token_start": 11, "token_end": 14}], "entities_global": [{"text": "NFATp and NFATc protein", "type": "ENTITY", "char_start": 523092, "char_end": 523115, "token_start": 11, "token_end": 14, "note": null}]}
+{"sentence_id": 3147, "sentence_text": "Unlike activated T cells , which express multiple NFATc isoforms , eosinophils preferentially express the approximately 85 - kd isoform .", "sentence_char_start_global": 523118, "sentence_char_end_global": 523255, "entities": [], "entities_global": []}
+{"sentence_id": 3148, "sentence_text": "In addition , eosinophils were found to constitutively express NFATc mRNA .", "sentence_char_start_global": 523256, "sentence_char_end_global": 523331, "entities": [{"text": "NFATc mRNA", "type": "ENTITY", "char_start": 63, "char_end": 73, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "NFATc mRNA", "type": "ENTITY", "char_start": 523319, "char_end": 523329, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 3149, "sentence_text": "A brief incubation with the T ( H ) 2 cytokines IL - 4 and IL - 5 was sufficient to induce the nuclear translocation of NFATc .", "sentence_char_start_global": 523332, "sentence_char_end_global": 523459, "entities": [{"text": "T ( H ) 2 cytokines", "type": "ENTITY", "char_start": 28, "char_end": 47, "token_start": 5, "token_end": 10}, {"text": "IL - 4", "type": "ENTITY", "char_start": 48, "char_end": 54, "token_start": 11, "token_end": 13}, {"text": "IL - 5", "type": "ENTITY", "char_start": 59, "char_end": 65, "token_start": 15, "token_end": 17}, {"text": "NFATc", "type": "ENTITY", "char_start": 120, "char_end": 125, "token_start": 26, "token_end": 26}], "entities_global": [{"text": "T ( H ) 2 cytokines", "type": "ENTITY", "char_start": 523360, "char_end": 523379, "token_start": 5, "token_end": 10, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 523380, "char_end": 523386, "token_start": 11, "token_end": 13, "note": null}, {"text": "IL - 5", "type": "ENTITY", "char_start": 523391, "char_end": 523397, "token_start": 15, "token_end": 17, "note": null}, {"text": "NFATc", "type": "ENTITY", "char_start": 523452, "char_end": 523457, "token_start": 26, "token_end": 26, "note": null}]}
+{"sentence_id": 3150, "sentence_text": "Eosinophil nuclear extracts contain multiple factors that can specifically recognize the IL - 4 promoter P1 NFAT site in DNA - binding assays , including NFATp .", "sentence_char_start_global": 523460, "sentence_char_end_global": 523621, "entities": [{"text": "IL - 4 promoter P1 NFAT site", "type": "ENTITY", "char_start": 89, "char_end": 117, "token_start": 11, "token_end": 17}, {"text": "NFATp", "type": "ENTITY", "char_start": 154, "char_end": 159, "token_start": 25, "token_end": 25}], "entities_global": [{"text": "IL - 4 promoter P1 NFAT site", "type": "ENTITY", "char_start": 523549, "char_end": 523577, "token_start": 11, "token_end": 17, "note": null}, {"text": "NFATp", "type": "ENTITY", "char_start": 523614, "char_end": 523619, "token_start": 25, "token_end": 25, "note": null}]}
+{"sentence_id": 3151, "sentence_text": "CONCLUSION : NFATp and NFATc can regulate the expression of cytokines and other genes in eosinophils but appear to be regulated by a novel signal transduction mechanism in these cells .", "sentence_char_start_global": 523622, "sentence_char_end_global": 523807, "entities": [{"text": "NFATp", "type": "ENTITY", "char_start": 13, "char_end": 18, "token_start": 2, "token_end": 2}, {"text": "NFATc", "type": "ENTITY", "char_start": 23, "char_end": 28, "token_start": 4, "token_end": 4}, {"text": "cytokines", "type": "ENTITY", "char_start": 60, "char_end": 69, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "NFATp", "type": "ENTITY", "char_start": 523635, "char_end": 523640, "token_start": 2, "token_end": 2, "note": null}, {"text": "NFATc", "type": "ENTITY", "char_start": 523645, "char_end": 523650, "token_start": 4, "token_end": 4, "note": null}, {"text": "cytokines", "type": "ENTITY", "char_start": 523682, "char_end": 523691, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 3152, "sentence_text": "BLyS BINDS TO B CELLS WITH HIGH AFFINITY AND INDUCES ACTIVATION OF THE TRANSCRIPTION FACTORS NF - kappaB AND ELF - 1 .", "sentence_char_start_global": 523808, "sentence_char_end_global": 523926, "entities": [{"text": "BLyS", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}, {"text": "TRANSCRIPTION FACTORS", "type": "ENTITY", "char_start": 71, "char_end": 92, "token_start": 13, "token_end": 14}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 93, "char_end": 104, "token_start": 15, "token_end": 17}, {"text": "ELF - 1", "type": "ENTITY", "char_start": 109, "char_end": 116, "token_start": 19, "token_end": 21}], "entities_global": [{"text": "BLyS", "type": "ENTITY", "char_start": 523808, "char_end": 523812, "token_start": 0, "token_end": 0, "note": null}, {"text": "TRANSCRIPTION FACTORS", "type": "ENTITY", "char_start": 523879, "char_end": 523900, "token_start": 13, "token_end": 14, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 523901, "char_end": 523912, "token_start": 15, "token_end": 17, "note": null}, {"text": "ELF - 1", "type": "ENTITY", "char_start": 523917, "char_end": 523924, "token_start": 19, "token_end": 21, "note": null}]}
+{"sentence_id": 3153, "sentence_text": "B lymphocyte stimulator ( BLyS ) is a novel member of the TNF family of proteins expressed by myeloid cells as membrane - bound and soluble forms .", "sentence_char_start_global": 523927, "sentence_char_end_global": 524074, "entities": [{"text": "B lymphocyte stimulator", "type": "ENTITY", "char_start": 0, "char_end": 23, "token_start": 0, "token_end": 2}, {"text": "BLyS", "type": "ENTITY", "char_start": 26, "char_end": 30, "token_start": 4, "token_end": 4}, {"text": "TNF family of proteins", "type": "ENTITY", "char_start": 58, "char_end": 80, "token_start": 12, "token_end": 15}], "entities_global": [{"text": "B lymphocyte stimulator", "type": "ENTITY", "char_start": 523927, "char_end": 523950, "token_start": 0, "token_end": 2, "note": null}, {"text": "BLyS", "type": "ENTITY", "char_start": 523953, "char_end": 523957, "token_start": 4, "token_end": 4, "note": null}, {"text": "TNF family of proteins", "type": "ENTITY", "char_start": 523985, "char_end": 524007, "token_start": 12, "token_end": 15, "note": null}]}
+{"sentence_id": 3154, "sentence_text": "BLyS was shown to act specifically on B cells , inducing proliferation and immunoglobulin production both in vitro and in vivo .", "sentence_char_start_global": 524075, "sentence_char_end_global": 524203, "entities": [{"text": "BLyS", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "BLyS", "type": "ENTITY", "char_start": 524075, "char_end": 524079, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 3155, "sentence_text": "The present study was undertaken to characterize binding of radiolabeled BLyS to its cognate receptor on human B lymphocytes and examine intracellular events initiated by BLyS binding .", "sentence_char_start_global": 524204, "sentence_char_end_global": 524389, "entities": [{"text": "radiolabeled BLyS", "type": "ENTITY", "char_start": 60, "char_end": 77, "token_start": 9, "token_end": 10}, {"text": "cognate receptor", "type": "ENTITY", "char_start": 85, "char_end": 101, "token_start": 13, "token_end": 14}, {"text": "BLyS", "type": "ENTITY", "char_start": 171, "char_end": 175, "token_start": 25, "token_end": 25}], "entities_global": [{"text": "radiolabeled BLyS", "type": "ENTITY", "char_start": 524264, "char_end": 524281, "token_start": 9, "token_end": 10, "note": null}, {"text": "cognate receptor", "type": "ENTITY", "char_start": 524289, "char_end": 524305, "token_start": 13, "token_end": 14, "note": null}, {"text": "BLyS", "type": "ENTITY", "char_start": 524375, "char_end": 524379, "token_start": 25, "token_end": 25, "note": null}]}
+{"sentence_id": 3156, "sentence_text": "Similar to other TNF family members , BLyS is present in solution as a homotrimer as determined by gel filtration chromatography and light scattering analysis .", "sentence_char_start_global": 524390, "sentence_char_end_global": 524550, "entities": [{"text": "TNF family members", "type": "ENTITY", "char_start": 17, "char_end": 35, "token_start": 3, "token_end": 5}, {"text": "BLyS", "type": "ENTITY", "char_start": 38, "char_end": 42, "token_start": 7, "token_end": 7}, {"text": "homotrimer", "type": "ENTITY", "char_start": 71, "char_end": 81, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "TNF family members", "type": "ENTITY", "char_start": 524407, "char_end": 524425, "token_start": 3, "token_end": 5, "note": null}, {"text": "BLyS", "type": "ENTITY", "char_start": 524428, "char_end": 524432, "token_start": 7, "token_end": 7, "note": null}, {"text": "homotrimer", "type": "ENTITY", "char_start": 524461, "char_end": 524471, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 3157, "sentence_text": "BLyS binding to B cells is specific as other TNF family members tested did not compete for ( 125 ) I - BLyS binding .", "sentence_char_start_global": 524551, "sentence_char_end_global": 524668, "entities": [{"text": "BLyS", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}, {"text": "TNF family members", "type": "ENTITY", "char_start": 45, "char_end": 63, "token_start": 9, "token_end": 11}, {"text": "BLyS", "type": "ENTITY", "char_start": 103, "char_end": 107, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "BLyS", "type": "ENTITY", "char_start": 524551, "char_end": 524555, "token_start": 0, "token_end": 0, "note": null}, {"text": "TNF family members", "type": "ENTITY", "char_start": 524596, "char_end": 524614, "token_start": 9, "token_end": 11, "note": null}, {"text": "BLyS", "type": "ENTITY", "char_start": 524654, "char_end": 524658, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 3158, "sentence_text": "Analysis of equilibrium binding of ( 125 ) I - labeled BLyS to purified human tonsillar B cells demonstrated saturable binding .", "sentence_char_start_global": 524669, "sentence_char_end_global": 524797, "entities": [{"text": "( 125 ) I - labeled BLyS", "type": "ENTITY", "char_start": 35, "char_end": 59, "token_start": 5, "token_end": 11}], "entities_global": [{"text": "( 125 ) I - labeled BLyS", "type": "ENTITY", "char_start": 524704, "char_end": 524728, "token_start": 5, "token_end": 11, "note": null}]}
+{"sentence_id": 3159, "sentence_text": "Scatchard analysis of the binding data revealed a single class of high - affinity binding on human B cells with approximately 2600 binding sites per cell and an apparent dissociation constant ( K ( D ) ) of about 0 . 1 nM .", "sentence_char_start_global": 524798, "sentence_char_end_global": 525021, "entities": [], "entities_global": []}
+{"sentence_id": 3160, "sentence_text": "In addition we report that BLyS binding to B cells results in the activation of NF - kappaB and the Ets family transcription factor , ELF - 1 , and in the induction of mRNA for Polo - like kinase ( PLK ) .", "sentence_char_start_global": 525022, "sentence_char_end_global": 525227, "entities": [{"text": "BLyS", "type": "ENTITY", "char_start": 27, "char_end": 31, "token_start": 5, "token_end": 5}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 80, "char_end": 91, "token_start": 15, "token_end": 17}, {"text": "Ets family transcription factor", "type": "ENTITY", "char_start": 100, "char_end": 131, "token_start": 20, "token_end": 23}, {"text": "ELF - 1", "type": "ENTITY", "char_start": 134, "char_end": 141, "token_start": 25, "token_end": 27}, {"text": "Polo - like kinase", "type": "ENTITY", "char_start": 177, "char_end": 195, "token_start": 36, "token_end": 39}, {"text": "PLK", "type": "ENTITY", "char_start": 198, "char_end": 201, "token_start": 41, "token_end": 41}], "entities_global": [{"text": "BLyS", "type": "ENTITY", "char_start": 525049, "char_end": 525053, "token_start": 5, "token_end": 5, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 525102, "char_end": 525113, "token_start": 15, "token_end": 17, "note": null}, {"text": "Ets family transcription factor", "type": "ENTITY", "char_start": 525122, "char_end": 525153, "token_start": 20, "token_end": 23, "note": null}, {"text": "ELF - 1", "type": "ENTITY", "char_start": 525156, "char_end": 525163, "token_start": 25, "token_end": 27, "note": null}, {"text": "Polo - like kinase", "type": "ENTITY", "char_start": 525199, "char_end": 525217, "token_start": 36, "token_end": 39, "note": null}, {"text": "PLK", "type": "ENTITY", "char_start": 525220, "char_end": 525223, "token_start": 41, "token_end": 41, "note": null}]}
+{"sentence_id": 3161, "sentence_text": "Copyright 2001 Academic Press .", "sentence_char_start_global": 525228, "sentence_char_end_global": 525259, "entities": [], "entities_global": []}
+{"sentence_id": 3162, "sentence_text": "Design and use of an inducibly activated human immunodeficiency virus type 1 Nef to study immune modulation .", "sentence_char_start_global": 525260, "sentence_char_end_global": 525369, "entities": [{"text": "Nef", "type": "ENTITY", "char_start": 77, "char_end": 80, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "Nef", "type": "ENTITY", "char_start": 525337, "char_end": 525340, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 3163, "sentence_text": "The Nef protein of the human immunodeficiency virus type 1 ( HIV - 1 ) has been shown to enhance the infectivity of virus particles , downmodulate cell surface proteins , and associate with many intracellular proteins that are thought to facilitate HIV infection .", "sentence_char_start_global": 525370, "sentence_char_end_global": 525634, "entities": [{"text": "Nef protein", "type": "ENTITY", "char_start": 4, "char_end": 15, "token_start": 1, "token_end": 2}, {"text": "cell surface proteins", "type": "ENTITY", "char_start": 147, "char_end": 168, "token_start": 27, "token_end": 29}, {"text": "intracellular proteins", "type": "ENTITY", "char_start": 195, "char_end": 217, "token_start": 35, "token_end": 36}], "entities_global": [{"text": "Nef protein", "type": "ENTITY", "char_start": 525374, "char_end": 525385, "token_start": 1, "token_end": 2, "note": null}, {"text": "cell surface proteins", "type": "ENTITY", "char_start": 525517, "char_end": 525538, "token_start": 27, "token_end": 29, "note": null}, {"text": "intracellular proteins", "type": "ENTITY", "char_start": 525565, "char_end": 525587, "token_start": 35, "token_end": 36, "note": null}]}
+{"sentence_id": 3164, "sentence_text": "One of the challenges in defining the molecular events regulated by Nef has been obtaining good expression of Nef protein in T cells .", "sentence_char_start_global": 525635, "sentence_char_end_global": 525769, "entities": [{"text": "Nef", "type": "ENTITY", "char_start": 68, "char_end": 71, "token_start": 11, "token_end": 11}, {"text": "Nef protein", "type": "ENTITY", "char_start": 110, "char_end": 121, "token_start": 18, "token_end": 19}], "entities_global": [{"text": "Nef", "type": "ENTITY", "char_start": 525703, "char_end": 525706, "token_start": 11, "token_end": 11, "note": null}, {"text": "Nef protein", "type": "ENTITY", "char_start": 525745, "char_end": 525756, "token_start": 18, "token_end": 19, "note": null}]}
+{"sentence_id": 3165, "sentence_text": "This has been attributed to effects of Nef on cell proliferation and apoptosis .", "sentence_char_start_global": 525770, "sentence_char_end_global": 525850, "entities": [{"text": "Nef", "type": "ENTITY", "char_start": 39, "char_end": 42, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "Nef", "type": "ENTITY", "char_start": 525809, "char_end": 525812, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 3166, "sentence_text": "We have designed a Nef protein that is readily expressed in T - cell lines and whose function is inducibly activated .", "sentence_char_start_global": 525851, "sentence_char_end_global": 525969, "entities": [{"text": "Nef protein", "type": "ENTITY", "char_start": 19, "char_end": 30, "token_start": 4, "token_end": 5}], "entities_global": [{"text": "Nef protein", "type": "ENTITY", "char_start": 525870, "char_end": 525881, "token_start": 4, "token_end": 5, "note": null}]}
+{"sentence_id": 3167, "sentence_text": "It is composed of a fusion between full - length Nef and the estrogen receptor hormone - binding domain ( Nef - ER ) .", "sentence_char_start_global": 525970, "sentence_char_end_global": 526088, "entities": [{"text": "full - length Nef", "type": "ENTITY", "char_start": 35, "char_end": 52, "token_start": 7, "token_end": 10}, {"text": "estrogen receptor hormone - binding domain", "type": "ENTITY", "char_start": 61, "char_end": 103, "token_start": 13, "token_end": 18}, {"text": "Nef - ER", "type": "ENTITY", "char_start": 106, "char_end": 114, "token_start": 20, "token_end": 22}], "entities_global": [{"text": "full - length Nef", "type": "ENTITY", "char_start": 526005, "char_end": 526022, "token_start": 7, "token_end": 10, "note": null}, {"text": "estrogen receptor hormone - binding domain", "type": "ENTITY", "char_start": 526031, "char_end": 526073, "token_start": 13, "token_end": 18, "note": null}, {"text": "Nef - ER", "type": "ENTITY", "char_start": 526076, "char_end": 526084, "token_start": 20, "token_end": 22, "note": null}]}
+{"sentence_id": 3168, "sentence_text": "The Nef - ER is kept in an inactive state due to steric hindrance , and addition of the membrane - permeable drug 4 - hydroxytamoxifen ( 4 - HT ) , which binds to the ER domain , leads to inducible activation of Nef - ER within cells .", "sentence_char_start_global": 526089, "sentence_char_end_global": 526324, "entities": [{"text": "Nef - ER", "type": "ENTITY", "char_start": 4, "char_end": 12, "token_start": 1, "token_end": 3}, {"text": "ER domain", "type": "ENTITY", "char_start": 167, "char_end": 176, "token_start": 36, "token_end": 37}, {"text": "Nef - ER", "type": "ENTITY", "char_start": 212, "char_end": 220, "token_start": 44, "token_end": 46}], "entities_global": [{"text": "Nef - ER", "type": "ENTITY", "char_start": 526093, "char_end": 526101, "token_start": 1, "token_end": 3, "note": null}, {"text": "ER domain", "type": "ENTITY", "char_start": 526256, "char_end": 526265, "token_start": 36, "token_end": 37, "note": null}, {"text": "Nef - ER", "type": "ENTITY", "char_start": 526301, "char_end": 526309, "token_start": 44, "token_end": 46, "note": null}]}
+{"sentence_id": 3169, "sentence_text": "We demonstrate that Nef - ER inducibly associates with the 62 - kDa Ser / Thr kinase and is localized to specific membrane microdomains ( lipid rafts ) only after activation .", "sentence_char_start_global": 526325, "sentence_char_end_global": 526500, "entities": [{"text": "Nef - ER", "type": "ENTITY", "char_start": 20, "char_end": 28, "token_start": 3, "token_end": 5}, {"text": "62 - kDa Ser / Thr kinase", "type": "ENTITY", "char_start": 59, "char_end": 84, "token_start": 10, "token_end": 16}], "entities_global": [{"text": "Nef - ER", "type": "ENTITY", "char_start": 526345, "char_end": 526353, "token_start": 3, "token_end": 5, "note": null}, {"text": "62 - kDa Ser / Thr kinase", "type": "ENTITY", "char_start": 526384, "char_end": 526409, "token_start": 10, "token_end": 16, "note": null}]}
+{"sentence_id": 3170, "sentence_text": "Using this inducible Nef , we also compared the specific requirements for CD4 and HLA - A2 downmodulation in a SupT1 T - cell line .", "sentence_char_start_global": 526501, "sentence_char_end_global": 526633, "entities": [{"text": "Nef", "type": "ENTITY", "char_start": 21, "char_end": 24, "token_start": 3, "token_end": 3}, {"text": "CD4", "type": "ENTITY", "char_start": 74, "char_end": 77, "token_start": 12, "token_end": 12}, {"text": "HLA - A2", "type": "ENTITY", "char_start": 82, "char_end": 90, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "Nef", "type": "ENTITY", "char_start": 526522, "char_end": 526525, "token_start": 3, "token_end": 3, "note": null}, {"text": "CD4", "type": "ENTITY", "char_start": 526575, "char_end": 526578, "token_start": 12, "token_end": 12, "note": null}, {"text": "HLA - A2", "type": "ENTITY", "char_start": 526583, "char_end": 526591, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 3171, "sentence_text": "Half - maximal downmodulation of cell surface CD4 required very little active Nef - ER and occurred as early as 4 h after addition of 4 - HT .", "sentence_char_start_global": 526634, "sentence_char_end_global": 526776, "entities": [{"text": "cell surface CD4", "type": "ENTITY", "char_start": 33, "char_end": 49, "token_start": 5, "token_end": 7}, {"text": "Nef - ER", "type": "ENTITY", "char_start": 78, "char_end": 86, "token_start": 12, "token_end": 14}], "entities_global": [{"text": "cell surface CD4", "type": "ENTITY", "char_start": 526667, "char_end": 526683, "token_start": 5, "token_end": 7, "note": null}, {"text": "Nef - ER", "type": "ENTITY", "char_start": 526712, "char_end": 526720, "token_start": 12, "token_end": 14, "note": null}]}
+{"sentence_id": 3172, "sentence_text": "In contrast , 50 % downmodulation of HLA - A2 by Nef required 16 to 24 h and about 50 - to 100 - fold - greater concentrations of 4 - HT .", "sentence_char_start_global": 526777, "sentence_char_end_global": 526915, "entities": [{"text": "HLA - A2", "type": "ENTITY", "char_start": 37, "char_end": 45, "token_start": 7, "token_end": 9}, {"text": "Nef", "type": "ENTITY", "char_start": 49, "char_end": 52, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "HLA - A2", "type": "ENTITY", "char_start": 526814, "char_end": 526822, "token_start": 7, "token_end": 9, "note": null}, {"text": "Nef", "type": "ENTITY", "char_start": 526826, "char_end": 526829, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 3173, "sentence_text": "These data suggest that HLA - A2 downmodulation may require certain threshold levels of active Nef .", "sentence_char_start_global": 526916, "sentence_char_end_global": 527016, "entities": [{"text": "HLA - A2", "type": "ENTITY", "char_start": 24, "char_end": 32, "token_start": 4, "token_end": 6}, {"text": "Nef", "type": "ENTITY", "char_start": 95, "char_end": 98, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "HLA - A2", "type": "ENTITY", "char_start": 526940, "char_end": 526948, "token_start": 4, "token_end": 6, "note": null}, {"text": "Nef", "type": "ENTITY", "char_start": 527011, "char_end": 527014, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 3174, "sentence_text": "The differential timing of CD4 and HLA - A2 downmodulation may have implications for HIV pathogenesis and immune evasion .", "sentence_char_start_global": 527017, "sentence_char_end_global": 527139, "entities": [{"text": "CD4", "type": "ENTITY", "char_start": 27, "char_end": 30, "token_start": 4, "token_end": 4}, {"text": "HLA - A2", "type": "ENTITY", "char_start": 35, "char_end": 43, "token_start": 6, "token_end": 8}], "entities_global": [{"text": "CD4", "type": "ENTITY", "char_start": 527044, "char_end": 527047, "token_start": 4, "token_end": 4, "note": null}, {"text": "HLA - A2", "type": "ENTITY", "char_start": 527052, "char_end": 527060, "token_start": 6, "token_end": 8, "note": null}]}
+{"sentence_id": 3175, "sentence_text": "Regulation of chemokine mRNA expression in a rat model of vanadium - induced pulmonary inflammation .", "sentence_char_start_global": 527140, "sentence_char_end_global": 527241, "entities": [], "entities_global": []}
+{"sentence_id": 3176, "sentence_text": "Environmental and occupational exposure to vanadium dusts results in toxic effects mainly confined to the respiratory system .", "sentence_char_start_global": 527242, "sentence_char_end_global": 527368, "entities": [], "entities_global": []}
+{"sentence_id": 3177, "sentence_text": "Using a rat model of acute lung inflammation induced by intratracheal instillation of sodium metavanadate ( NaVO3 ) at the dose of 200 microg V / kg , we investigated the relationship between the cytologic characterization of pulmonary inflammation and the expression of chemokine mRNA .", "sentence_char_start_global": 527369, "sentence_char_end_global": 527656, "entities": [{"text": "chemokine mRNA", "type": "ENTITY", "char_start": 271, "char_end": 285, "token_start": 43, "token_end": 44}], "entities_global": [{"text": "chemokine mRNA", "type": "ENTITY", "char_start": 527640, "char_end": 527654, "token_start": 43, "token_end": 44, "note": null}]}
+{"sentence_id": 3178, "sentence_text": "Significant polymorphonuclear leukocyte ( PMN ) influx ( P < 0 . 01 ) into the lung was noted 4 h after NaVO3 instillation , whereas alveolar macrophages ( AMs ) in bronchoalveolar lavage ( BAL ) cells appeared to decrease significantly .", "sentence_char_start_global": 527657, "sentence_char_end_global": 527895, "entities": [], "entities_global": []}
+{"sentence_id": 3179, "sentence_text": "In contrast , neither PMNs nor AMs changed substantially 1 h after NaVO3 instillation .", "sentence_char_start_global": 527896, "sentence_char_end_global": 527983, "entities": [], "entities_global": []}
+{"sentence_id": 3180, "sentence_text": "By Northern analysis , macrophage inflammatory protein ( MIP ) - 2 mRNA in BAL cells increased markedly 1 h after NaVO3 instillation and reduced a little bit at 4 h , whereas MIP - 1alpha mRNA in BAL cells was expressed relatively high 1 h after NaVO3 instillation , although a basal expression was detected in control group , and returned rapidly nearly to control level at 4 h .", "sentence_char_start_global": 527984, "sentence_char_end_global": 528364, "entities": [{"text": "macrophage inflammatory protein ( MIP ) - 2 mRNA", "type": "ENTITY", "char_start": 23, "char_end": 71, "token_start": 4, "token_end": 12}, {"text": "MIP - 1alpha mRNA", "type": "ENTITY", "char_start": 175, "char_end": 192, "token_start": 33, "token_end": 36}], "entities_global": [{"text": "macrophage inflammatory protein ( MIP ) - 2 mRNA", "type": "ENTITY", "char_start": 528007, "char_end": 528055, "token_start": 4, "token_end": 12, "note": null}, {"text": "MIP - 1alpha mRNA", "type": "ENTITY", "char_start": 528159, "char_end": 528176, "token_start": 33, "token_end": 36, "note": null}]}
+{"sentence_id": 3181, "sentence_text": "Since MIP - 2 is a potent PMN chemoattractant and MIP - 1alpha is a potent macrophage / monocyte chemoattractant has been well known .", "sentence_char_start_global": 528365, "sentence_char_end_global": 528499, "entities": [{"text": "MIP - 2", "type": "ENTITY", "char_start": 6, "char_end": 13, "token_start": 1, "token_end": 3}, {"text": "MIP - 1alpha", "type": "ENTITY", "char_start": 50, "char_end": 62, "token_start": 10, "token_end": 12}], "entities_global": [{"text": "MIP - 2", "type": "ENTITY", "char_start": 528371, "char_end": 528378, "token_start": 1, "token_end": 3, "note": null}, {"text": "MIP - 1alpha", "type": "ENTITY", "char_start": 528415, "char_end": 528427, "token_start": 10, "token_end": 12, "note": null}]}
+{"sentence_id": 3182, "sentence_text": "The facts that PMN influx was preceded by increased MIP - 2 mRNA expression , suggesting that MIP - 2 is involved in the development of NaVO3 - induced pulmonary inflammation , whereas increased MIP - 1alpha mRNA expression was followed by decreased AMs in BAL cells , suggesting AMs might be activated by MIP - 1alpha , adherent to the lining surface of the airways and then resistant to be washed out .", "sentence_char_start_global": 528500, "sentence_char_end_global": 528904, "entities": [{"text": "MIP - 2", "type": "ENTITY", "char_start": 94, "char_end": 101, "token_start": 17, "token_end": 19}, {"text": "MIP - 1alpha mRNA", "type": "ENTITY", "char_start": 195, "char_end": 212, "token_start": 34, "token_end": 37}, {"text": "MIP - 1alpha", "type": "ENTITY", "char_start": 306, "char_end": 318, "token_start": 54, "token_end": 56}], "entities_global": [{"text": "MIP - 2", "type": "ENTITY", "char_start": 528594, "char_end": 528601, "token_start": 17, "token_end": 19, "note": null}, {"text": "MIP - 1alpha mRNA", "type": "ENTITY", "char_start": 528695, "char_end": 528712, "token_start": 34, "token_end": 37, "note": null}, {"text": "MIP - 1alpha", "type": "ENTITY", "char_start": 528806, "char_end": 528818, "token_start": 54, "token_end": 56, "note": null}]}
+{"sentence_id": 3183, "sentence_text": "To delineate the mechanisms of transcriptional activation , we recently cloned the 5 ' - flanking region of the MIP - 2 gene .", "sentence_char_start_global": 528905, "sentence_char_end_global": 529031, "entities": [{"text": "5 ' - flanking region", "type": "ENTITY", "char_start": 83, "char_end": 104, "token_start": 12, "token_end": 16}, {"text": "MIP - 2 gene", "type": "ENTITY", "char_start": 112, "char_end": 124, "token_start": 19, "token_end": 22}], "entities_global": [{"text": "5 ' - flanking region", "type": "ENTITY", "char_start": 528988, "char_end": 529009, "token_start": 12, "token_end": 16, "note": null}, {"text": "MIP - 2 gene", "type": "ENTITY", "char_start": 529017, "char_end": 529029, "token_start": 19, "token_end": 22, "note": null}]}
+{"sentence_id": 3184, "sentence_text": "The promotor region contains consensus binding sites for transcription factor nuclear factor kappaB ( NF - kappaB ) and activator protein - 1 ( AP - 1 ) .", "sentence_char_start_global": 529032, "sentence_char_end_global": 529186, "entities": [{"text": "promotor region", "type": "ENTITY", "char_start": 4, "char_end": 19, "token_start": 1, "token_end": 2}, {"text": "consensus binding sites", "type": "ENTITY", "char_start": 29, "char_end": 52, "token_start": 4, "token_end": 6}, {"text": "transcription factor nuclear factor kappaB", "type": "ENTITY", "char_start": 57, "char_end": 99, "token_start": 8, "token_end": 12}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 102, "char_end": 113, "token_start": 14, "token_end": 16}, {"text": "activator protein - 1", "type": "ENTITY", "char_start": 120, "char_end": 141, "token_start": 19, "token_end": 22}, {"text": "AP - 1", "type": "ENTITY", "char_start": 144, "char_end": 150, "token_start": 24, "token_end": 26}], "entities_global": [{"text": "promotor region", "type": "ENTITY", "char_start": 529036, "char_end": 529051, "token_start": 1, "token_end": 2, "note": null}, {"text": "consensus binding sites", "type": "ENTITY", "char_start": 529061, "char_end": 529084, "token_start": 4, "token_end": 6, "note": null}, {"text": "transcription factor nuclear factor kappaB", "type": "ENTITY", "char_start": 529089, "char_end": 529131, "token_start": 8, "token_end": 12, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 529134, "char_end": 529145, "token_start": 14, "token_end": 16, "note": null}, {"text": "activator protein - 1", "type": "ENTITY", "char_start": 529152, "char_end": 529173, "token_start": 19, "token_end": 22, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 529176, "char_end": 529182, "token_start": 24, "token_end": 26, "note": null}]}
+{"sentence_id": 3185, "sentence_text": "Using electrophoretic mobility shift assay , increased nuclear NF - kappaB , not AP - 1 , binding activity was detected 1 h after NaVO3 instillation , which correlated with the induction of MIP - 2 mRNA .", "sentence_char_start_global": 529187, "sentence_char_end_global": 529391, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 63, "char_end": 74, "token_start": 8, "token_end": 10}, {"text": "AP - 1", "type": "ENTITY", "char_start": 81, "char_end": 87, "token_start": 13, "token_end": 15}, {"text": "MIP - 2 mRNA", "type": "ENTITY", "char_start": 190, "char_end": 202, "token_start": 33, "token_end": 36}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 529250, "char_end": 529261, "token_start": 8, "token_end": 10, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 529268, "char_end": 529274, "token_start": 13, "token_end": 15, "note": null}, {"text": "MIP - 2 mRNA", "type": "ENTITY", "char_start": 529377, "char_end": 529389, "token_start": 33, "token_end": 36, "note": null}]}
+{"sentence_id": 3186, "sentence_text": "p65 ( Rel A ) and p50 protein appears to be involved in MIP - 2 NF - kappaB binding .", "sentence_char_start_global": 529392, "sentence_char_end_global": 529477, "entities": [{"text": "p65 ( Rel A )", "type": "ENTITY", "char_start": 0, "char_end": 13, "token_start": 0, "token_end": 4}, {"text": "p50 protein", "type": "ENTITY", "char_start": 18, "char_end": 29, "token_start": 6, "token_end": 7}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 64, "char_end": 75, "token_start": 16, "token_end": 18}], "entities_global": [{"text": "p65 ( Rel A )", "type": "ENTITY", "char_start": 529392, "char_end": 529405, "token_start": 0, "token_end": 4, "note": null}, {"text": "p50 protein", "type": "ENTITY", "char_start": 529410, "char_end": 529421, "token_start": 6, "token_end": 7, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 529456, "char_end": 529467, "token_start": 16, "token_end": 18, "note": null}]}
+{"sentence_id": 3187, "sentence_text": "Taken together , our studies suggest that MIP - 2 is an important mediator of NaVO3 - induced pulmonary inflammation in the rat model .", "sentence_char_start_global": 529478, "sentence_char_end_global": 529613, "entities": [{"text": "MIP - 2", "type": "ENTITY", "char_start": 42, "char_end": 49, "token_start": 7, "token_end": 9}], "entities_global": [{"text": "MIP - 2", "type": "ENTITY", "char_start": 529520, "char_end": 529527, "token_start": 7, "token_end": 9, "note": null}]}
+{"sentence_id": 3188, "sentence_text": "In addition , elevated MIP - 2 mRNA levels are accompanied by increased NF - kappaB binding activity in BAL cells , suggesting possible MIP - 2 transcriptional regulation through NF - kappaB .", "sentence_char_start_global": 529614, "sentence_char_end_global": 529806, "entities": [{"text": "MIP - 2 mRNA", "type": "ENTITY", "char_start": 23, "char_end": 35, "token_start": 4, "token_end": 7}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 72, "char_end": 83, "token_start": 13, "token_end": 15}, {"text": "MIP - 2", "type": "ENTITY", "char_start": 136, "char_end": 143, "token_start": 24, "token_end": 26}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 179, "char_end": 190, "token_start": 30, "token_end": 32}], "entities_global": [{"text": "MIP - 2 mRNA", "type": "ENTITY", "char_start": 529637, "char_end": 529649, "token_start": 4, "token_end": 7, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 529686, "char_end": 529697, "token_start": 13, "token_end": 15, "note": null}, {"text": "MIP - 2", "type": "ENTITY", "char_start": 529750, "char_end": 529757, "token_start": 24, "token_end": 26, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 529793, "char_end": 529804, "token_start": 30, "token_end": 32, "note": null}]}
+{"sentence_id": 3189, "sentence_text": "Activation of signal transduction and apoptosis in healthy lymphomonocytes exposed to bystander HIV - 1 - infected cells .", "sentence_char_start_global": 529807, "sentence_char_end_global": 529929, "entities": [], "entities_global": []}
+{"sentence_id": 3190, "sentence_text": "Persistent activation of the immune system is one of the hallmarks of HIV - 1 infection .", "sentence_char_start_global": 529930, "sentence_char_end_global": 530019, "entities": [], "entities_global": []}
+{"sentence_id": 3191, "sentence_text": "In this study we analysed the induction of factors involved in cytokine signal transduction , such as STAT 1 proteins and IRF - 1 mRNA , in normal peripheral blood mononuclear cells ( PBMC ) exposed to HIV - infected cells , and the induction of apoptosis .", "sentence_char_start_global": 530020, "sentence_char_end_global": 530277, "entities": [{"text": "STAT 1 proteins", "type": "ENTITY", "char_start": 102, "char_end": 117, "token_start": 17, "token_end": 19}, {"text": "IRF - 1 mRNA", "type": "ENTITY", "char_start": 122, "char_end": 134, "token_start": 21, "token_end": 24}], "entities_global": [{"text": "STAT 1 proteins", "type": "ENTITY", "char_start": 530122, "char_end": 530137, "token_start": 17, "token_end": 19, "note": null}, {"text": "IRF - 1 mRNA", "type": "ENTITY", "char_start": 530142, "char_end": 530154, "token_start": 21, "token_end": 24, "note": null}]}
+{"sentence_id": 3192, "sentence_text": "Western blot analyses and reverse transcriptase - polymerase chain reaction results indicate that both cells infected with a X4 strain and cells infected with a R5 strain are able to increase intracellular levels of STAT 1alpha and beta proteins as well as IRF - 1 mRNA .", "sentence_char_start_global": 530278, "sentence_char_end_global": 530549, "entities": [{"text": "STAT 1alpha and beta", "type": "ENTITY", "char_start": 216, "char_end": 236, "token_start": 34, "token_end": 37}, {"text": "IRF - 1 mRNA", "type": "ENTITY", "char_start": 257, "char_end": 269, "token_start": 42, "token_end": 45}], "entities_global": [{"text": "STAT 1alpha and beta", "type": "ENTITY", "char_start": 530494, "char_end": 530514, "token_start": 34, "token_end": 37, "note": null}, {"text": "IRF - 1 mRNA", "type": "ENTITY", "char_start": 530535, "char_end": 530547, "token_start": 42, "token_end": 45, "note": null}]}
+{"sentence_id": 3193, "sentence_text": "This effect was prevented by neutralizing antibodies against interferon - alpha ( IFN - alpha ) .", "sentence_char_start_global": 530550, "sentence_char_end_global": 530647, "entities": [{"text": "interferon - alpha", "type": "ENTITY", "char_start": 61, "char_end": 79, "token_start": 8, "token_end": 10}, {"text": "IFN - alpha", "type": "ENTITY", "char_start": 82, "char_end": 93, "token_start": 12, "token_end": 14}], "entities_global": [{"text": "interferon - alpha", "type": "ENTITY", "char_start": 530611, "char_end": 530629, "token_start": 8, "token_end": 10, "note": null}, {"text": "IFN - alpha", "type": "ENTITY", "char_start": 530632, "char_end": 530643, "token_start": 12, "token_end": 14, "note": null}]}
+{"sentence_id": 3194, "sentence_text": "HIV - 1 - infected cells dose - dependently induced apoptotic commitment in normal PBMC , as revealed by DNA fragmentation analysis , but this was not accompanied by an increase of caspase - 3 activity , even if a slight up - regulation of IL - 1beta - converting enzyme mRNA was detected .", "sentence_char_start_global": 530648, "sentence_char_end_global": 530938, "entities": [{"text": "IL - 1beta - converting enzyme mRNA", "type": "ENTITY", "char_start": 240, "char_end": 275, "token_start": 45, "token_end": 51}], "entities_global": [{"text": "IL - 1beta - converting enzyme mRNA", "type": "ENTITY", "char_start": 530888, "char_end": 530923, "token_start": 45, "token_end": 51, "note": null}]}
+{"sentence_id": 3195, "sentence_text": "Apoptosis induction could be abrogated mainly by antibodies against tumour necrosis factor - alpha ( TNF - alpha ) and , to a lesser extent , by antibodies against IFN - gamma .", "sentence_char_start_global": 530939, "sentence_char_end_global": 531116, "entities": [{"text": "antibodies", "type": "ENTITY", "char_start": 49, "char_end": 59, "token_start": 7, "token_end": 7}, {"text": "tumour necrosis factor - alpha", "type": "ENTITY", "char_start": 68, "char_end": 98, "token_start": 9, "token_end": 13}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 101, "char_end": 112, "token_start": 15, "token_end": 17}, {"text": "antibodies", "type": "ENTITY", "char_start": 145, "char_end": 155, "token_start": 27, "token_end": 27}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 164, "char_end": 175, "token_start": 29, "token_end": 31}], "entities_global": [{"text": "antibodies", "type": "ENTITY", "char_start": 530988, "char_end": 530998, "token_start": 7, "token_end": 7, "note": null}, {"text": "tumour necrosis factor - alpha", "type": "ENTITY", "char_start": 531007, "char_end": 531037, "token_start": 9, "token_end": 13, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 531040, "char_end": 531051, "token_start": 15, "token_end": 17, "note": null}, {"text": "antibodies", "type": "ENTITY", "char_start": 531084, "char_end": 531094, "token_start": 27, "token_end": 27, "note": null}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 531103, "char_end": 531114, "token_start": 29, "token_end": 31, "note": null}]}
+{"sentence_id": 3196, "sentence_text": "All these findings suggest that uninfected PBMC can undergo activation of signal transduction and apoptosis after exposure to bystander HIV - infected cells , subsequent to the induction of cytokines such as IFNs and TNF - alpha .", "sentence_char_start_global": 531117, "sentence_char_end_global": 531347, "entities": [{"text": "cytokines", "type": "ENTITY", "char_start": 190, "char_end": 199, "token_start": 29, "token_end": 29}, {"text": "IFNs", "type": "ENTITY", "char_start": 208, "char_end": 212, "token_start": 32, "token_end": 32}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 217, "char_end": 228, "token_start": 34, "token_end": 36}], "entities_global": [{"text": "cytokines", "type": "ENTITY", "char_start": 531307, "char_end": 531316, "token_start": 29, "token_end": 29, "note": null}, {"text": "IFNs", "type": "ENTITY", "char_start": 531325, "char_end": 531329, "token_start": 32, "token_end": 32, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 531334, "char_end": 531345, "token_start": 34, "token_end": 36, "note": null}]}
+{"sentence_id": 3197, "sentence_text": "The physical association of protein kinase C theta with a lipid raft - associated inhibitor of kappa B factor kinase ( IKK ) complex plays a role in the activation of the NF - kappa B cascade by TCR and CD28 .", "sentence_char_start_global": 531348, "sentence_char_end_global": 531557, "entities": [{"text": "protein kinase C theta", "type": "ENTITY", "char_start": 28, "char_end": 50, "token_start": 4, "token_end": 7}, {"text": "kappa B factor kinase ( IKK ) complex", "type": "ENTITY", "char_start": 95, "char_end": 132, "token_start": 16, "token_end": 23}, {"text": "TCR", "type": "ENTITY", "char_start": 195, "char_end": 198, "token_start": 38, "token_end": 38}, {"text": "CD28", "type": "ENTITY", "char_start": 203, "char_end": 207, "token_start": 40, "token_end": 40}], "entities_global": [{"text": "protein kinase C theta", "type": "ENTITY", "char_start": 531376, "char_end": 531398, "token_start": 4, "token_end": 7, "note": null}, {"text": "kappa B factor kinase ( IKK ) complex", "type": "ENTITY", "char_start": 531443, "char_end": 531480, "token_start": 16, "token_end": 23, "note": null}, {"text": "TCR", "type": "ENTITY", "char_start": 531543, "char_end": 531546, "token_start": 38, "token_end": 38, "note": null}, {"text": "CD28", "type": "ENTITY", "char_start": 531551, "char_end": 531555, "token_start": 40, "token_end": 40, "note": null}]}
+{"sentence_id": 3198, "sentence_text": "We investigated the role of protein kinase C theta ( PKCtheta ) in the activation of the NF - kappaB cascade in primary human CD4 ( + ) lymphocytes .", "sentence_char_start_global": 531558, "sentence_char_end_global": 531707, "entities": [{"text": "protein kinase C theta", "type": "ENTITY", "char_start": 28, "char_end": 50, "token_start": 5, "token_end": 8}, {"text": "PKCtheta", "type": "ENTITY", "char_start": 53, "char_end": 61, "token_start": 10, "token_end": 10}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 89, "char_end": 100, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "protein kinase C theta", "type": "ENTITY", "char_start": 531586, "char_end": 531608, "token_start": 5, "token_end": 8, "note": null}, {"text": "PKCtheta", "type": "ENTITY", "char_start": 531611, "char_end": 531619, "token_start": 10, "token_end": 10, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 531647, "char_end": 531658, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 3199, "sentence_text": "Among six or so PKC isoforms expressed in T cells , only PKCtheta participates in the assembly of the supramolecular activation clusters at the contact site of the TCR with Ag .", "sentence_char_start_global": 531708, "sentence_char_end_global": 531885, "entities": [{"text": "PKC isoforms", "type": "ENTITY", "char_start": 16, "char_end": 28, "token_start": 4, "token_end": 5}, {"text": "PKCtheta", "type": "ENTITY", "char_start": 57, "char_end": 65, "token_start": 12, "token_end": 12}, {"text": "TCR", "type": "ENTITY", "char_start": 164, "char_end": 167, "token_start": 28, "token_end": 28}, {"text": "Ag", "type": "ENTITY", "char_start": 173, "char_end": 175, "token_start": 30, "token_end": 30}], "entities_global": [{"text": "PKC isoforms", "type": "ENTITY", "char_start": 531724, "char_end": 531736, "token_start": 4, "token_end": 5, "note": null}, {"text": "PKCtheta", "type": "ENTITY", "char_start": 531765, "char_end": 531773, "token_start": 12, "token_end": 12, "note": null}, {"text": "TCR", "type": "ENTITY", "char_start": 531872, "char_end": 531875, "token_start": 28, "token_end": 28, "note": null}, {"text": "Ag", "type": "ENTITY", "char_start": 531881, "char_end": 531883, "token_start": 30, "token_end": 30, "note": null}]}
+{"sentence_id": 3200, "sentence_text": "Signaling via both the TCR and CD28 is required for optimal activation of the multisubunit IkappaB kinase ( IKK ) complex in primary human T lymphocytes ; this activation could be inhibited by a Ca ( 2 + ) - independent PKC isoform inhibitor , rottlerin .", "sentence_char_start_global": 531886, "sentence_char_end_global": 532141, "entities": [{"text": "TCR", "type": "ENTITY", "char_start": 23, "char_end": 26, "token_start": 4, "token_end": 4}, {"text": "CD28", "type": "ENTITY", "char_start": 31, "char_end": 35, "token_start": 6, "token_end": 6}, {"text": "multisubunit IkappaB kinase ( IKK ) complex", "type": "ENTITY", "char_start": 78, "char_end": 121, "token_start": 14, "token_end": 20}], "entities_global": [{"text": "TCR", "type": "ENTITY", "char_start": 531909, "char_end": 531912, "token_start": 4, "token_end": 4, "note": null}, {"text": "CD28", "type": "ENTITY", "char_start": 531917, "char_end": 531921, "token_start": 6, "token_end": 6, "note": null}, {"text": "multisubunit IkappaB kinase ( IKK ) complex", "type": "ENTITY", "char_start": 531964, "char_end": 532007, "token_start": 14, "token_end": 20, "note": null}]}
+{"sentence_id": 3201, "sentence_text": "Moreover , endogenous PKCtheta physically associates with activated IKK complexes in CD3 / CD28 - costimulated primary CD4 ( + ) T cells .", "sentence_char_start_global": 532142, "sentence_char_end_global": 532280, "entities": [{"text": "PKCtheta", "type": "ENTITY", "char_start": 22, "char_end": 30, "token_start": 3, "token_end": 3}, {"text": "IKK complexes", "type": "ENTITY", "char_start": 68, "char_end": 81, "token_start": 8, "token_end": 9}], "entities_global": [{"text": "PKCtheta", "type": "ENTITY", "char_start": 532164, "char_end": 532172, "token_start": 3, "token_end": 3, "note": null}, {"text": "IKK complexes", "type": "ENTITY", "char_start": 532210, "char_end": 532223, "token_start": 8, "token_end": 9, "note": null}]}
+{"sentence_id": 3202, "sentence_text": "The same set of stimuli also induced relocation of endogenous PKCtheta and IKKs to a GM1 ganglioside - enriched , detergent - insoluble membrane compartment in primary T cells .", "sentence_char_start_global": 532281, "sentence_char_end_global": 532458, "entities": [{"text": "PKCtheta", "type": "ENTITY", "char_start": 62, "char_end": 70, "token_start": 10, "token_end": 10}, {"text": "IKKs", "type": "ENTITY", "char_start": 75, "char_end": 79, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "PKCtheta", "type": "ENTITY", "char_start": 532343, "char_end": 532351, "token_start": 10, "token_end": 10, "note": null}, {"text": "IKKs", "type": "ENTITY", "char_start": 532356, "char_end": 532360, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 3203, "sentence_text": "IKKs recruited to these lipid rafts were capable of phosphorylating a recombinant IkappaBalpha sustrate .", "sentence_char_start_global": 532459, "sentence_char_end_global": 532564, "entities": [{"text": "IKKs", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "IKKs", "type": "ENTITY", "char_start": 532459, "char_end": 532463, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 3204, "sentence_text": "Confocal microscopy further demonstrated that exogenously expressed PKCtheta and IKKss colocalize in the membrane of CD3 / CD28 - costimulated Jurkat T cells .", "sentence_char_start_global": 532565, "sentence_char_end_global": 532724, "entities": [{"text": "PKCtheta", "type": "ENTITY", "char_start": 68, "char_end": 76, "token_start": 7, "token_end": 7}, {"text": "IKKss", "type": "ENTITY", "char_start": 81, "char_end": 86, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "PKCtheta", "type": "ENTITY", "char_start": 532633, "char_end": 532641, "token_start": 7, "token_end": 7, "note": null}, {"text": "IKKss", "type": "ENTITY", "char_start": 532646, "char_end": 532651, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 3205, "sentence_text": "Constitutively active but not kinase - inactive PKCtheta activated IKKbeta in Jurkat T cells .", "sentence_char_start_global": 532725, "sentence_char_end_global": 532819, "entities": [{"text": "kinase - inactive PKCtheta", "type": "ENTITY", "char_start": 30, "char_end": 56, "token_start": 4, "token_end": 7}, {"text": "IKKbeta", "type": "ENTITY", "char_start": 67, "char_end": 74, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "kinase - inactive PKCtheta", "type": "ENTITY", "char_start": 532755, "char_end": 532781, "token_start": 4, "token_end": 7, "note": null}, {"text": "IKKbeta", "type": "ENTITY", "char_start": 532792, "char_end": 532799, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 3206, "sentence_text": "Expression of dominant - active PKCtheta also had stimulatory effects on the CD28 response element of the IL - 2 promoter .", "sentence_char_start_global": 532820, "sentence_char_end_global": 532943, "entities": [{"text": "dominant - active PKCtheta", "type": "ENTITY", "char_start": 14, "char_end": 40, "token_start": 2, "token_end": 5}, {"text": "CD28 response element", "type": "ENTITY", "char_start": 77, "char_end": 98, "token_start": 12, "token_end": 14}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 106, "char_end": 121, "token_start": 17, "token_end": 20}], "entities_global": [{"text": "dominant - active PKCtheta", "type": "ENTITY", "char_start": 532834, "char_end": 532860, "token_start": 2, "token_end": 5, "note": null}, {"text": "CD28 response element", "type": "ENTITY", "char_start": 532897, "char_end": 532918, "token_start": 12, "token_end": 14, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 532926, "char_end": 532941, "token_start": 17, "token_end": 20, "note": null}]}
+{"sentence_id": 3207, "sentence_text": "Taken together , these data show that the activation of PKCtheta by the TCR and CD28 plays an important role in the assembly and activation of IKK complexes in the T cell membrane", "sentence_char_start_global": 532944, "sentence_char_end_global": 533123, "entities": [{"text": "PKCtheta", "type": "ENTITY", "char_start": 56, "char_end": 64, "token_start": 10, "token_end": 10}, {"text": "TCR", "type": "ENTITY", "char_start": 72, "char_end": 75, "token_start": 13, "token_end": 13}, {"text": "CD28", "type": "ENTITY", "char_start": 80, "char_end": 84, "token_start": 15, "token_end": 15}, {"text": "IKK complexes", "type": "ENTITY", "char_start": 143, "char_end": 156, "token_start": 26, "token_end": 27}], "entities_global": [{"text": "PKCtheta", "type": "ENTITY", "char_start": 533000, "char_end": 533008, "token_start": 10, "token_end": 10, "note": null}, {"text": "TCR", "type": "ENTITY", "char_start": 533016, "char_end": 533019, "token_start": 13, "token_end": 13, "note": null}, {"text": "CD28", "type": "ENTITY", "char_start": 533024, "char_end": 533028, "token_start": 15, "token_end": 15, "note": null}, {"text": "IKK complexes", "type": "ENTITY", "char_start": 533087, "char_end": 533100, "token_start": 26, "token_end": 27, "note": null}]}
+{"sentence_id": 3208, "sentence_text": "T - cell - mediated regulation of osteoclastogenesis by signalling cross - talk between RANKL and IFN - gamma .", "sentence_char_start_global": 533124, "sentence_char_end_global": 533235, "entities": [{"text": "RANKL", "type": "ENTITY", "char_start": 88, "char_end": 93, "token_start": 14, "token_end": 14}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 98, "char_end": 109, "token_start": 16, "token_end": 18}], "entities_global": [{"text": "RANKL", "type": "ENTITY", "char_start": 533212, "char_end": 533217, "token_start": 14, "token_end": 14, "note": null}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 533222, "char_end": 533233, "token_start": 16, "token_end": 18, "note": null}]}
+{"sentence_id": 3209, "sentence_text": "Bone resorption is regulated by the immune system , where T - cell expression of RANKL ( receptor activator of nuclear factor ( NF ) - kappaB ligand ) , a member of the tumour - necrosis factor family that is essential for osteoclastogenesis , may contribute to pathological conditions , such as autoimmune arthritis .", "sentence_char_start_global": 533236, "sentence_char_end_global": 533554, "entities": [{"text": "RANKL", "type": "ENTITY", "char_start": 81, "char_end": 86, "token_start": 15, "token_end": 15}, {"text": "receptor activator of nuclear factor ( NF ) - kappaB ligand", "type": "ENTITY", "char_start": 89, "char_end": 148, "token_start": 17, "token_end": 27}, {"text": "tumour - necrosis factor family", "type": "ENTITY", "char_start": 169, "char_end": 200, "token_start": 34, "token_end": 38}], "entities_global": [{"text": "RANKL", "type": "ENTITY", "char_start": 533317, "char_end": 533322, "token_start": 15, "token_end": 15, "note": null}, {"text": "receptor activator of nuclear factor ( NF ) - kappaB ligand", "type": "ENTITY", "char_start": 533325, "char_end": 533384, "token_start": 17, "token_end": 27, "note": null}, {"text": "tumour - necrosis factor family", "type": "ENTITY", "char_start": 533405, "char_end": 533436, "token_start": 34, "token_end": 38, "note": null}]}
+{"sentence_id": 3210, "sentence_text": "However , whether activated T cells maintain bone homeostasis by counterbalancing the action of RANKL remains unknown .", "sentence_char_start_global": 533555, "sentence_char_end_global": 533674, "entities": [{"text": "RANKL", "type": "ENTITY", "char_start": 96, "char_end": 101, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "RANKL", "type": "ENTITY", "char_start": 533651, "char_end": 533656, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 3211, "sentence_text": "Here we show that T - cell production of interferon ( IFN ) - gamma strongly suppresses osteoclastogenesis by interfering with the RANKL - RANK signalling pathway .", "sentence_char_start_global": 533675, "sentence_char_end_global": 533839, "entities": [{"text": "interferon ( IFN ) - gamma", "type": "ENTITY", "char_start": 41, "char_end": 67, "token_start": 9, "token_end": 14}, {"text": "RANKL", "type": "ENTITY", "char_start": 131, "char_end": 136, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "interferon ( IFN ) - gamma", "type": "ENTITY", "char_start": 533716, "char_end": 533742, "token_start": 9, "token_end": 14, "note": null}, {"text": "RANKL", "type": "ENTITY", "char_start": 533806, "char_end": 533811, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 3212, "sentence_text": "IFN - gamma induces rapid degradation of the RANK adapter protein , TRAF6 ( tumour necrosis factor receptor - associated factor 6 ) , which results in strong inhibition of the RANKL - induced activation of the transcription factor NF - kappaB and JNK .", "sentence_char_start_global": 533840, "sentence_char_end_global": 534092, "entities": [{"text": "IFN - gamma", "type": "ENTITY", "char_start": 0, "char_end": 11, "token_start": 0, "token_end": 2}, {"text": "RANK adapter protein", "type": "ENTITY", "char_start": 45, "char_end": 65, "token_start": 8, "token_end": 10}, {"text": "TRAF6", "type": "ENTITY", "char_start": 68, "char_end": 73, "token_start": 12, "token_end": 12}, {"text": "tumour necrosis factor receptor - associated factor 6", "type": "ENTITY", "char_start": 76, "char_end": 129, "token_start": 14, "token_end": 21}, {"text": "RANKL", "type": "ENTITY", "char_start": 176, "char_end": 181, "token_start": 31, "token_end": 31}, {"text": "transcription factor", "type": "ENTITY", "char_start": 210, "char_end": 230, "token_start": 37, "token_end": 38}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 231, "char_end": 242, "token_start": 39, "token_end": 41}, {"text": "JNK", "type": "ENTITY", "char_start": 247, "char_end": 250, "token_start": 43, "token_end": 43}], "entities_global": [{"text": "IFN - gamma", "type": "ENTITY", "char_start": 533840, "char_end": 533851, "token_start": 0, "token_end": 2, "note": null}, {"text": "RANK adapter protein", "type": "ENTITY", "char_start": 533885, "char_end": 533905, "token_start": 8, "token_end": 10, "note": null}, {"text": "TRAF6", "type": "ENTITY", "char_start": 533908, "char_end": 533913, "token_start": 12, "token_end": 12, "note": null}, {"text": "tumour necrosis factor receptor - associated factor 6", "type": "ENTITY", "char_start": 533916, "char_end": 533969, "token_start": 14, "token_end": 21, "note": null}, {"text": "RANKL", "type": "ENTITY", "char_start": 534016, "char_end": 534021, "token_start": 31, "token_end": 31, "note": null}, {"text": "transcription factor", "type": "ENTITY", "char_start": 534050, "char_end": 534070, "token_start": 37, "token_end": 38, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 534071, "char_end": 534082, "token_start": 39, "token_end": 41, "note": null}, {"text": "JNK", "type": "ENTITY", "char_start": 534087, "char_end": 534090, "token_start": 43, "token_end": 43, "note": null}]}
+{"sentence_id": 3213, "sentence_text": "This inhibition of osteoclastogenesis is rescued by overexpressing TRAF6 in precursor cells , which indicates that TRAF6 is the target critical for the IFN - gamma action .", "sentence_char_start_global": 534093, "sentence_char_end_global": 534265, "entities": [{"text": "TRAF6", "type": "ENTITY", "char_start": 67, "char_end": 72, "token_start": 8, "token_end": 8}, {"text": "TRAF6", "type": "ENTITY", "char_start": 115, "char_end": 120, "token_start": 16, "token_end": 16}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 152, "char_end": 163, "token_start": 23, "token_end": 25}], "entities_global": [{"text": "TRAF6", "type": "ENTITY", "char_start": 534160, "char_end": 534165, "token_start": 8, "token_end": 8, "note": null}, {"text": "TRAF6", "type": "ENTITY", "char_start": 534208, "char_end": 534213, "token_start": 16, "token_end": 16, "note": null}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 534245, "char_end": 534256, "token_start": 23, "token_end": 25, "note": null}]}
+{"sentence_id": 3214, "sentence_text": "Furthermore , we provide evidence that the accelerated degradation of TRAF6 requires both its ubiquitination , which is initiated by RANKL , and IFN - gamma - induced activation of the ubiquitin - proteasome system .", "sentence_char_start_global": 534266, "sentence_char_end_global": 534482, "entities": [{"text": "TRAF6", "type": "ENTITY", "char_start": 70, "char_end": 75, "token_start": 10, "token_end": 10}, {"text": "RANKL", "type": "ENTITY", "char_start": 133, "char_end": 138, "token_start": 20, "token_end": 20}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 145, "char_end": 156, "token_start": 23, "token_end": 25}], "entities_global": [{"text": "TRAF6", "type": "ENTITY", "char_start": 534336, "char_end": 534341, "token_start": 10, "token_end": 10, "note": null}, {"text": "RANKL", "type": "ENTITY", "char_start": 534399, "char_end": 534404, "token_start": 20, "token_end": 20, "note": null}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 534411, "char_end": 534422, "token_start": 23, "token_end": 25, "note": null}]}
+{"sentence_id": 3215, "sentence_text": "Our study shows that there is cross - talk between the tumour necrosis factor and IFN families of cytokines , through which IFN - gamma provides a negative link between T - cell activation and bone resorption .", "sentence_char_start_global": 534483, "sentence_char_end_global": 534693, "entities": [{"text": "tumour necrosis factor", "type": "ENTITY", "char_start": 55, "char_end": 77, "token_start": 11, "token_end": 13}, {"text": "IFN families", "type": "ENTITY", "char_start": 82, "char_end": 94, "token_start": 15, "token_end": 16}, {"text": "cytokines", "type": "ENTITY", "char_start": 98, "char_end": 107, "token_start": 18, "token_end": 18}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 124, "char_end": 135, "token_start": 22, "token_end": 24}], "entities_global": [{"text": "tumour necrosis factor", "type": "ENTITY", "char_start": 534538, "char_end": 534560, "token_start": 11, "token_end": 13, "note": null}, {"text": "IFN families", "type": "ENTITY", "char_start": 534565, "char_end": 534577, "token_start": 15, "token_end": 16, "note": null}, {"text": "cytokines", "type": "ENTITY", "char_start": 534581, "char_end": 534590, "token_start": 18, "token_end": 18, "note": null}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 534607, "char_end": 534618, "token_start": 22, "token_end": 24, "note": null}]}
+{"sentence_id": 3216, "sentence_text": "Our results may offer a therapeutic approach to treat the inflammation - induced tissue breakdown .", "sentence_char_start_global": 534694, "sentence_char_end_global": 534793, "entities": [], "entities_global": []}
+{"sentence_id": 3217, "sentence_text": "Stromal - derived factor 1 and thrombopoietin regulate distinct aspects of human megakaryopoiesis .", "sentence_char_start_global": 534794, "sentence_char_end_global": 534893, "entities": [{"text": "Stromal - derived factor 1", "type": "ENTITY", "char_start": 0, "char_end": 26, "token_start": 0, "token_end": 4}, {"text": "thrombopoietin", "type": "ENTITY", "char_start": 31, "char_end": 45, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "Stromal - derived factor 1", "type": "ENTITY", "char_start": 534794, "char_end": 534820, "token_start": 0, "token_end": 4, "note": null}, {"text": "thrombopoietin", "type": "ENTITY", "char_start": 534825, "char_end": 534839, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 3218, "sentence_text": "The role of the chemokine binding stromal - derived factor 1 ( SDF - 1 ) in normal human megakaryopoiesis at the cellular and molecular levels and its comparison with that of thrombopoietin ( TPO ) have not been determined .", "sentence_char_start_global": 534894, "sentence_char_end_global": 535118, "entities": [{"text": "chemokine", "type": "ENTITY", "char_start": 16, "char_end": 25, "token_start": 4, "token_end": 4}, {"text": "stromal - derived factor 1", "type": "ENTITY", "char_start": 34, "char_end": 60, "token_start": 6, "token_end": 10}, {"text": "SDF - 1", "type": "ENTITY", "char_start": 63, "char_end": 70, "token_start": 12, "token_end": 14}, {"text": "thrombopoietin", "type": "ENTITY", "char_start": 175, "char_end": 189, "token_start": 32, "token_end": 32}, {"text": "TPO", "type": "ENTITY", "char_start": 192, "char_end": 195, "token_start": 34, "token_end": 34}], "entities_global": [{"text": "chemokine", "type": "ENTITY", "char_start": 534910, "char_end": 534919, "token_start": 4, "token_end": 4, "note": null}, {"text": "stromal - derived factor 1", "type": "ENTITY", "char_start": 534928, "char_end": 534954, "token_start": 6, "token_end": 10, "note": null}, {"text": "SDF - 1", "type": "ENTITY", "char_start": 534957, "char_end": 534964, "token_start": 12, "token_end": 14, "note": null}, {"text": "thrombopoietin", "type": "ENTITY", "char_start": 535069, "char_end": 535083, "token_start": 32, "token_end": 32, "note": null}, {"text": "TPO", "type": "ENTITY", "char_start": 535086, "char_end": 535089, "token_start": 34, "token_end": 34, "note": null}]}
+{"sentence_id": 3219, "sentence_text": "In this study it was found that SDF - 1 , unlike TPO , does not stimulate alpha ( IIb ) beta ( 3 ) ( + ) cell proliferation or differentiation or have an antiapoptotic effect .", "sentence_char_start_global": 535119, "sentence_char_end_global": 535295, "entities": [{"text": "SDF - 1", "type": "ENTITY", "char_start": 32, "char_end": 39, "token_start": 7, "token_end": 9}, {"text": "TPO", "type": "ENTITY", "char_start": 49, "char_end": 52, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "SDF - 1", "type": "ENTITY", "char_start": 535151, "char_end": 535158, "token_start": 7, "token_end": 9, "note": null}, {"text": "TPO", "type": "ENTITY", "char_start": 535168, "char_end": 535171, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 3220, "sentence_text": "However , it does induce chemotaxis , trans - Matrigel migration , and secretion of matrix metalloproteinase 9 ( MMP - 9 ) and vascular endothelial growth factor ( VEGF ) by these cells , and both SDF - 1 and TPO increase the adhesion of alpha ( IIb ) beta ( 3 ) ( + ) cells to fibrinogen and vitronectin .", "sentence_char_start_global": 535296, "sentence_char_end_global": 535602, "entities": [{"text": "metalloproteinase 9", "type": "ENTITY", "char_start": 91, "char_end": 110, "token_start": 16, "token_end": 17}, {"text": "MMP - 9", "type": "ENTITY", "char_start": 113, "char_end": 120, "token_start": 19, "token_end": 21}, {"text": "vascular endothelial growth factor", "type": "ENTITY", "char_start": 127, "char_end": 161, "token_start": 24, "token_end": 27}, {"text": "VEGF", "type": "ENTITY", "char_start": 164, "char_end": 168, "token_start": 29, "token_end": 29}, {"text": "SDF - 1", "type": "ENTITY", "char_start": 197, "char_end": 204, "token_start": 37, "token_end": 39}, {"text": "TPO", "type": "ENTITY", "char_start": 209, "char_end": 212, "token_start": 41, "token_end": 41}, {"text": "fibrinogen", "type": "ENTITY", "char_start": 278, "char_end": 288, "token_start": 59, "token_end": 59}, {"text": "vitronectin", "type": "ENTITY", "char_start": 293, "char_end": 304, "token_start": 61, "token_end": 61}], "entities_global": [{"text": "metalloproteinase 9", "type": "ENTITY", "char_start": 535387, "char_end": 535406, "token_start": 16, "token_end": 17, "note": null}, {"text": "MMP - 9", "type": "ENTITY", "char_start": 535409, "char_end": 535416, "token_start": 19, "token_end": 21, "note": null}, {"text": "vascular endothelial growth factor", "type": "ENTITY", "char_start": 535423, "char_end": 535457, "token_start": 24, "token_end": 27, "note": null}, {"text": "VEGF", "type": "ENTITY", "char_start": 535460, "char_end": 535464, "token_start": 29, "token_end": 29, "note": null}, {"text": "SDF - 1", "type": "ENTITY", "char_start": 535493, "char_end": 535500, "token_start": 37, "token_end": 39, "note": null}, {"text": "TPO", "type": "ENTITY", "char_start": 535505, "char_end": 535508, "token_start": 41, "token_end": 41, "note": null}, {"text": "fibrinogen", "type": "ENTITY", "char_start": 535574, "char_end": 535584, "token_start": 59, "token_end": 59, "note": null}, {"text": "vitronectin", "type": "ENTITY", "char_start": 535589, "char_end": 535600, "token_start": 61, "token_end": 61, "note": null}]}
+{"sentence_id": 3221, "sentence_text": "Investigating the intracellular signaling pathways induced by SDF - 1 and TPO revealed some overlapping patterns of protein phosphorylation / activation ( mitogen - activated protein kinase [ MAPK ] p42 / 44 , MAPK p38 , and AKT [ protein kinase B ] ) and some that were distinct for TPO ( eg , JAK - STAT ) and for SDF - 1 ( eg , NF - kappa B ) .", "sentence_char_start_global": 535603, "sentence_char_end_global": 535950, "entities": [{"text": "SDF - 1", "type": "ENTITY", "char_start": 62, "char_end": 69, "token_start": 7, "token_end": 9}, {"text": "TPO", "type": "ENTITY", "char_start": 74, "char_end": 77, "token_start": 11, "token_end": 11}, {"text": "mitogen - activated protein kinase [ MAPK ] p42 / 44", "type": "ENTITY", "char_start": 155, "char_end": 207, "token_start": 22, "token_end": 32}, {"text": "MAPK p38", "type": "ENTITY", "char_start": 210, "char_end": 218, "token_start": 34, "token_end": 35}, {"text": "AKT [ protein kinase B ]", "type": "ENTITY", "char_start": 225, "char_end": 249, "token_start": 38, "token_end": 43}, {"text": "TPO", "type": "ENTITY", "char_start": 284, "char_end": 287, "token_start": 51, "token_end": 51}, {"text": "JAK - STAT", "type": "ENTITY", "char_start": 295, "char_end": 305, "token_start": 55, "token_end": 57}, {"text": "SDF - 1", "type": "ENTITY", "char_start": 316, "char_end": 323, "token_start": 61, "token_end": 63}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 331, "char_end": 343, "token_start": 67, "token_end": 70}], "entities_global": [{"text": "SDF - 1", "type": "ENTITY", "char_start": 535665, "char_end": 535672, "token_start": 7, "token_end": 9, "note": null}, {"text": "TPO", "type": "ENTITY", "char_start": 535677, "char_end": 535680, "token_start": 11, "token_end": 11, "note": null}, {"text": "mitogen - activated protein kinase [ MAPK ] p42 / 44", "type": "ENTITY", "char_start": 535758, "char_end": 535810, "token_start": 22, "token_end": 32, "note": null}, {"text": "MAPK p38", "type": "ENTITY", "char_start": 535813, "char_end": 535821, "token_start": 34, "token_end": 35, "note": null}, {"text": "AKT [ protein kinase B ]", "type": "ENTITY", "char_start": 535828, "char_end": 535852, "token_start": 38, "token_end": 43, "note": null}, {"text": "TPO", "type": "ENTITY", "char_start": 535887, "char_end": 535890, "token_start": 51, "token_end": 51, "note": null}, {"text": "JAK - STAT", "type": "ENTITY", "char_start": 535898, "char_end": 535908, "token_start": 55, "token_end": 57, "note": null}, {"text": "SDF - 1", "type": "ENTITY", "char_start": 535919, "char_end": 535926, "token_start": 61, "token_end": 63, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 535934, "char_end": 535946, "token_start": 67, "token_end": 70, "note": null}]}
+{"sentence_id": 3222, "sentence_text": "It was also found that though inhibition of phosphatidyl - inositol 3 - kinase ( PI - 3K ) by LY294002 in alpha ( IIb ) beta ( 3 ) ( + ) cells induced apoptosis and inhibited chemotaxis adhesion and the secretion of MMP - 9 and VEGF , the inhibition of MAPK p42 / 44 ( by the MEK inhibitor U0126 ) had no effect on the survival , proliferation , and migration of these cells .", "sentence_char_start_global": 535951, "sentence_char_end_global": 536327, "entities": [{"text": "phosphatidyl - inositol 3 - kinase", "type": "ENTITY", "char_start": 44, "char_end": 78, "token_start": 8, "token_end": 13}, {"text": "PI - 3K", "type": "ENTITY", "char_start": 81, "char_end": 88, "token_start": 15, "token_end": 17}, {"text": "MMP - 9", "type": "ENTITY", "char_start": 216, "char_end": 223, "token_start": 44, "token_end": 46}, {"text": "VEGF", "type": "ENTITY", "char_start": 228, "char_end": 232, "token_start": 48, "token_end": 48}, {"text": "MAPK p42 / 44", "type": "ENTITY", "char_start": 253, "char_end": 266, "token_start": 53, "token_end": 56}], "entities_global": [{"text": "phosphatidyl - inositol 3 - kinase", "type": "ENTITY", "char_start": 535995, "char_end": 536029, "token_start": 8, "token_end": 13, "note": null}, {"text": "PI - 3K", "type": "ENTITY", "char_start": 536032, "char_end": 536039, "token_start": 15, "token_end": 17, "note": null}, {"text": "MMP - 9", "type": "ENTITY", "char_start": 536167, "char_end": 536174, "token_start": 44, "token_end": 46, "note": null}, {"text": "VEGF", "type": "ENTITY", "char_start": 536179, "char_end": 536183, "token_start": 48, "token_end": 48, "note": null}, {"text": "MAPK p42 / 44", "type": "ENTITY", "char_start": 536204, "char_end": 536217, "token_start": 53, "token_end": 56, "note": null}]}
+{"sentence_id": 3223, "sentence_text": "Hence , it is suggested that the proliferative effect of TPO is more related to activation of the JAK - STAT pathway ( unique to TPO ) , and the PI - 3K - AKT axis is differentially involved in TPO - and SDF - 1 - dependent signaling .", "sentence_char_start_global": 536328, "sentence_char_end_global": 536563, "entities": [{"text": "TPO", "type": "ENTITY", "char_start": 57, "char_end": 60, "token_start": 10, "token_end": 10}, {"text": "TPO", "type": "ENTITY", "char_start": 129, "char_end": 132, "token_start": 25, "token_end": 25}], "entities_global": [{"text": "TPO", "type": "ENTITY", "char_start": 536385, "char_end": 536388, "token_start": 10, "token_end": 10, "note": null}, {"text": "TPO", "type": "ENTITY", "char_start": 536457, "char_end": 536460, "token_start": 25, "token_end": 25, "note": null}]}
+{"sentence_id": 3224, "sentence_text": "Accordingly , PI - 3K is involved in TPO - mediated inhibition of apoptosis , TPO - and SDF - 1 - regulated adhesion to fibrinogen and vitronectin , and SDF - 1 - mediated migration .", "sentence_char_start_global": 536564, "sentence_char_end_global": 536747, "entities": [{"text": "PI - 3K", "type": "ENTITY", "char_start": 14, "char_end": 21, "token_start": 2, "token_end": 4}, {"text": "TPO", "type": "ENTITY", "char_start": 37, "char_end": 40, "token_start": 8, "token_end": 8}, {"text": "fibrinogen", "type": "ENTITY", "char_start": 120, "char_end": 130, "token_start": 25, "token_end": 25}, {"text": "vitronectin", "type": "ENTITY", "char_start": 135, "char_end": 146, "token_start": 27, "token_end": 27}, {"text": "SDF - 1", "type": "ENTITY", "char_start": 153, "char_end": 160, "token_start": 30, "token_end": 32}], "entities_global": [{"text": "PI - 3K", "type": "ENTITY", "char_start": 536578, "char_end": 536585, "token_start": 2, "token_end": 4, "note": null}, {"text": "TPO", "type": "ENTITY", "char_start": 536601, "char_end": 536604, "token_start": 8, "token_end": 8, "note": null}, {"text": "fibrinogen", "type": "ENTITY", "char_start": 536684, "char_end": 536694, "token_start": 25, "token_end": 25, "note": null}, {"text": "vitronectin", "type": "ENTITY", "char_start": 536699, "char_end": 536710, "token_start": 27, "token_end": 27, "note": null}, {"text": "SDF - 1", "type": "ENTITY", "char_start": 536717, "char_end": 536724, "token_start": 30, "token_end": 32, "note": null}]}
+{"sentence_id": 3225, "sentence_text": "This study expands the understanding of the role of SDF - 1 and TPO in normal human megakaryopoiesis and indicates the molecular basis of the observed differences in cellular responses .", "sentence_char_start_global": 536748, "sentence_char_end_global": 536934, "entities": [{"text": "SDF - 1", "type": "ENTITY", "char_start": 52, "char_end": 59, "token_start": 9, "token_end": 11}, {"text": "TPO", "type": "ENTITY", "char_start": 64, "char_end": 67, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "SDF - 1", "type": "ENTITY", "char_start": 536800, "char_end": 536807, "token_start": 9, "token_end": 11, "note": null}, {"text": "TPO", "type": "ENTITY", "char_start": 536812, "char_end": 536815, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 3226, "sentence_text": "( Blood . 2000 ; 96 : 4142 - 4151 )", "sentence_char_start_global": 536935, "sentence_char_end_global": 536970, "entities": [], "entities_global": []}
+{"sentence_id": 3227, "sentence_text": "Adhesion of immature and mature T cells induces in human thymic epithelial cells ( TEC ) activation of IL - 6 gene trascription factors ( NF - kappaB and NF - IL6 ) and IL - 6 gene expression : role of alpha3beta1 and alpha6beta4 integrins .", "sentence_char_start_global": 536971, "sentence_char_end_global": 537212, "entities": [{"text": "IL - 6 gene trascription factors", "type": "ENTITY", "char_start": 103, "char_end": 135, "token_start": 18, "token_end": 23}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 138, "char_end": 149, "token_start": 25, "token_end": 27}, {"text": "NF - IL6", "type": "ENTITY", "char_start": 154, "char_end": 162, "token_start": 29, "token_end": 31}, {"text": "alpha3beta1 and alpha6beta4 integrins", "type": "ENTITY", "char_start": 202, "char_end": 239, "token_start": 42, "token_end": 45}], "entities_global": [{"text": "IL - 6 gene trascription factors", "type": "ENTITY", "char_start": 537074, "char_end": 537106, "token_start": 18, "token_end": 23, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 537109, "char_end": 537120, "token_start": 25, "token_end": 27, "note": null}, {"text": "NF - IL6", "type": "ENTITY", "char_start": 537125, "char_end": 537133, "token_start": 29, "token_end": 31, "note": null}, {"text": "alpha3beta1 and alpha6beta4 integrins", "type": "ENTITY", "char_start": 537173, "char_end": 537210, "token_start": 42, "token_end": 45, "note": null}]}
+{"sentence_id": 3228, "sentence_text": "T cell precursors homed to thymus develop in close contact with stromal cells .", "sentence_char_start_global": 537213, "sentence_char_end_global": 537292, "entities": [], "entities_global": []}
+{"sentence_id": 3229, "sentence_text": "Among them , thymic epithelial cells ( TEC ) are known to exert dominant roles in their survival and functional shaping .", "sentence_char_start_global": 537293, "sentence_char_end_global": 537414, "entities": [], "entities_global": []}
+{"sentence_id": 3230, "sentence_text": "Key molecules mediating TEC / thymocytes interactions include cytokines and growth factors secreted by the two cell types and adhesion receptors mediating cell contact .", "sentence_char_start_global": 537415, "sentence_char_end_global": 537584, "entities": [{"text": "cytokines", "type": "ENTITY", "char_start": 62, "char_end": 71, "token_start": 8, "token_end": 8}, {"text": "growth factors", "type": "ENTITY", "char_start": 76, "char_end": 90, "token_start": 10, "token_end": 11}, {"text": "adhesion receptors", "type": "ENTITY", "char_start": 126, "char_end": 144, "token_start": 19, "token_end": 20}], "entities_global": [{"text": "cytokines", "type": "ENTITY", "char_start": 537477, "char_end": 537486, "token_start": 8, "token_end": 8, "note": null}, {"text": "growth factors", "type": "ENTITY", "char_start": 537491, "char_end": 537505, "token_start": 10, "token_end": 11, "note": null}, {"text": "adhesion receptors", "type": "ENTITY", "char_start": 537541, "char_end": 537559, "token_start": 19, "token_end": 20, "note": null}]}
+{"sentence_id": 3231, "sentence_text": "Signaling events triggered in thymocytes by adhesion to epithelial cells have been extensively investigated , whereas little is known on the opposite phenomenon .", "sentence_char_start_global": 537585, "sentence_char_end_global": 537747, "entities": [], "entities_global": []}
+{"sentence_id": 3232, "sentence_text": "We have previously investigated this issue in a co - culture system composed of TEC cultures derived from human normal thymus and heterologous thymocytes .", "sentence_char_start_global": 537748, "sentence_char_end_global": 537903, "entities": [], "entities_global": []}
+{"sentence_id": 3233, "sentence_text": "We demonstrated that thymocytes adhere to TEC involving beta1 and beta4 integrins and induce the clustering of alpha3beta1 and alpha6beta4 heterodimers at the TEC surface .", "sentence_char_start_global": 537904, "sentence_char_end_global": 538076, "entities": [{"text": "beta1 and beta4 integrins", "type": "ENTITY", "char_start": 56, "char_end": 81, "token_start": 8, "token_end": 11}, {"text": "alpha3beta1 and alpha6beta4 heterodimers", "type": "ENTITY", "char_start": 111, "char_end": 151, "token_start": 17, "token_end": 20}], "entities_global": [{"text": "beta1 and beta4 integrins", "type": "ENTITY", "char_start": 537960, "char_end": 537985, "token_start": 8, "token_end": 11, "note": null}, {"text": "alpha3beta1 and alpha6beta4 heterodimers", "type": "ENTITY", "char_start": 538015, "char_end": 538055, "token_start": 17, "token_end": 20, "note": null}]}
+{"sentence_id": 3234, "sentence_text": "In addition thymocyte adhesion was followed by activation of NF - kappaB and NF - IL6 gene transcription factors and enhanced IL - 6 production .", "sentence_char_start_global": 538077, "sentence_char_end_global": 538222, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 61, "char_end": 72, "token_start": 9, "token_end": 11}, {"text": "NF - IL6", "type": "ENTITY", "char_start": 77, "char_end": 85, "token_start": 13, "token_end": 15}, {"text": "gene transcription factors", "type": "ENTITY", "char_start": 86, "char_end": 112, "token_start": 16, "token_end": 18}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 538138, "char_end": 538149, "token_start": 9, "token_end": 11, "note": null}, {"text": "NF - IL6", "type": "ENTITY", "char_start": 538154, "char_end": 538162, "token_start": 13, "token_end": 15, "note": null}, {"text": "gene transcription factors", "type": "ENTITY", "char_start": 538163, "char_end": 538189, "token_start": 16, "token_end": 18, "note": null}]}
+{"sentence_id": 3235, "sentence_text": "The two latter phenomena were reproduced by the cross - linking of the alpha3 , alpha6 , beta1 and beta4 integrins , thus implying that the alpha3beta1 and alpha6beta4 heterodimers can signal during thymocyte adhesion .", "sentence_char_start_global": 538223, "sentence_char_end_global": 538442, "entities": [{"text": "alpha3", "type": "ENTITY", "char_start": 71, "char_end": 77, "token_start": 13, "token_end": 13}, {"text": "alpha6", "type": "ENTITY", "char_start": 80, "char_end": 86, "token_start": 15, "token_end": 15}, {"text": "beta1 and beta4 integrins", "type": "ENTITY", "char_start": 89, "char_end": 114, "token_start": 17, "token_end": 20}, {"text": "alpha3beta1 and alpha6beta4 heterodimers", "type": "ENTITY", "char_start": 140, "char_end": 180, "token_start": 26, "token_end": 29}], "entities_global": [{"text": "alpha3", "type": "ENTITY", "char_start": 538294, "char_end": 538300, "token_start": 13, "token_end": 13, "note": null}, {"text": "alpha6", "type": "ENTITY", "char_start": 538303, "char_end": 538309, "token_start": 15, "token_end": 15, "note": null}, {"text": "beta1 and beta4 integrins", "type": "ENTITY", "char_start": 538312, "char_end": 538337, "token_start": 17, "token_end": 20, "note": null}, {"text": "alpha3beta1 and alpha6beta4 heterodimers", "type": "ENTITY", "char_start": 538363, "char_end": 538403, "token_start": 26, "token_end": 29, "note": null}]}
+{"sentence_id": 3236, "sentence_text": "We have extended our previous work investigating in the same experimental setting the inducing activity of non stimulated or activated policlonal or clonal mature T cells as representative of the more mature thymocyte subset .", "sentence_char_start_global": 538443, "sentence_char_end_global": 538669, "entities": [], "entities_global": []}
+{"sentence_id": 3237, "sentence_text": "We found that adhesion of unstimulated T cell i ) involved beta1 , but not beta4 integrin functions at the surface ii ) induced the clustering of alpha3beta1 , but not alpha2beta1 heterodimers at the TEC surface and iii ) up - regulated the nuclear binding activity of NF - kappaB transcription factor and the IL - 6 secretion .", "sentence_char_start_global": 538670, "sentence_char_end_global": 538998, "entities": [{"text": "alpha3beta1", "type": "ENTITY", "char_start": 146, "char_end": 157, "token_start": 27, "token_end": 27}, {"text": "alpha2beta1 heterodimers", "type": "ENTITY", "char_start": 168, "char_end": 192, "token_start": 31, "token_end": 32}, {"text": "NF - kappaB transcription factor", "type": "ENTITY", "char_start": 269, "char_end": 301, "token_start": 48, "token_end": 52}], "entities_global": [{"text": "alpha3beta1", "type": "ENTITY", "char_start": 538816, "char_end": 538827, "token_start": 27, "token_end": 27, "note": null}, {"text": "alpha2beta1 heterodimers", "type": "ENTITY", "char_start": 538838, "char_end": 538862, "token_start": 31, "token_end": 32, "note": null}, {"text": "NF - kappaB transcription factor", "type": "ENTITY", "char_start": 538939, "char_end": 538971, "token_start": 48, "token_end": 52, "note": null}]}
+{"sentence_id": 3238, "sentence_text": "We propose that alpha3beta1 and alpha6beta4 heterodimers are induced to cluster at the TEC surface recognizing yet unknown cellular ligands differentially expressed during T cell development .", "sentence_char_start_global": 538999, "sentence_char_end_global": 539191, "entities": [{"text": "alpha3beta1 and alpha6beta4 heterodimers", "type": "ENTITY", "char_start": 16, "char_end": 56, "token_start": 3, "token_end": 6}, {"text": "cellular ligands", "type": "ENTITY", "char_start": 123, "char_end": 139, "token_start": 18, "token_end": 19}], "entities_global": [{"text": "alpha3beta1 and alpha6beta4 heterodimers", "type": "ENTITY", "char_start": 539015, "char_end": 539055, "token_start": 3, "token_end": 6, "note": null}, {"text": "cellular ligands", "type": "ENTITY", "char_start": 539122, "char_end": 539138, "token_start": 18, "token_end": 19, "note": null}]}
+{"sentence_id": 3239, "sentence_text": "Identification and characterization of SKAT - 2 , a novel Th2 - specific zinc finger gene .", "sentence_char_start_global": 539192, "sentence_char_end_global": 539283, "entities": [{"text": "SKAT - 2", "type": "ENTITY", "char_start": 39, "char_end": 47, "token_start": 4, "token_end": 6}, {"text": "Th2 - specific zinc finger gene", "type": "ENTITY", "char_start": 58, "char_end": 89, "token_start": 10, "token_end": 15}], "entities_global": [{"text": "SKAT - 2", "type": "ENTITY", "char_start": 539231, "char_end": 539239, "token_start": 4, "token_end": 6, "note": null}, {"text": "Th2 - specific zinc finger gene", "type": "ENTITY", "char_start": 539250, "char_end": 539281, "token_start": 10, "token_end": 15, "note": null}]}
+{"sentence_id": 3240, "sentence_text": "We have identified a novel Kruppel - type zinc finger ( ZF ) gene , SKAT - 2 , which is selectively expressed by murine Th2 cells .", "sentence_char_start_global": 539284, "sentence_char_end_global": 539415, "entities": [{"text": "Kruppel - type zinc finger ( ZF ) gene", "type": "ENTITY", "char_start": 27, "char_end": 65, "token_start": 5, "token_end": 13}, {"text": "SKAT - 2", "type": "ENTITY", "char_start": 68, "char_end": 76, "token_start": 15, "token_end": 17}], "entities_global": [{"text": "Kruppel - type zinc finger ( ZF ) gene", "type": "ENTITY", "char_start": 539311, "char_end": 539349, "token_start": 5, "token_end": 13, "note": null}, {"text": "SKAT - 2", "type": "ENTITY", "char_start": 539352, "char_end": 539360, "token_start": 15, "token_end": 17, "note": null}]}
+{"sentence_id": 3241, "sentence_text": "The protein encoded by this gene has 14 C2H2 - type ZF tandemly arrayed at its C terminus and N - terminal SCAN box and KRAB domains .", "sentence_char_start_global": 539416, "sentence_char_end_global": 539550, "entities": [{"text": "C terminus", "type": "ENTITY", "char_start": 79, "char_end": 89, "token_start": 16, "token_end": 17}, {"text": "N - terminal", "type": "ENTITY", "char_start": 94, "char_end": 106, "token_start": 19, "token_end": 21}, {"text": "SCAN box", "type": "ENTITY", "char_start": 107, "char_end": 115, "token_start": 22, "token_end": 23}, {"text": "KRAB domains", "type": "ENTITY", "char_start": 120, "char_end": 132, "token_start": 25, "token_end": 26}], "entities_global": [{"text": "C terminus", "type": "ENTITY", "char_start": 539495, "char_end": 539505, "token_start": 16, "token_end": 17, "note": null}, {"text": "N - terminal", "type": "ENTITY", "char_start": 539510, "char_end": 539522, "token_start": 19, "token_end": 21, "note": null}, {"text": "SCAN box", "type": "ENTITY", "char_start": 539523, "char_end": 539531, "token_start": 22, "token_end": 23, "note": null}, {"text": "KRAB domains", "type": "ENTITY", "char_start": 539536, "char_end": 539548, "token_start": 25, "token_end": 26, "note": null}]}
+{"sentence_id": 3242, "sentence_text": "SKAT - 2 is tissue restricted in expression at the RNA level , detectable only in brain and at low levels in kidney and spleen and few hematopoietic cell lines .", "sentence_char_start_global": 539551, "sentence_char_end_global": 539712, "entities": [{"text": "SKAT - 2", "type": "ENTITY", "char_start": 0, "char_end": 8, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "SKAT - 2", "type": "ENTITY", "char_start": 539551, "char_end": 539559, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 3243, "sentence_text": "By in situ hybridization , SKAT - 2 expression was found to peak in antigen - stimulated CD4 ( + ) T cells after 2 - 3 days of culture under Th2 but not Th1 biasing conditions .", "sentence_char_start_global": 539713, "sentence_char_end_global": 539890, "entities": [{"text": "SKAT - 2", "type": "ENTITY", "char_start": 27, "char_end": 35, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "SKAT - 2", "type": "ENTITY", "char_start": 539740, "char_end": 539748, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 3244, "sentence_text": "This pattern of expression closely mirrored that of GATA - 3 in the same cells .", "sentence_char_start_global": 539891, "sentence_char_end_global": 539971, "entities": [{"text": "GATA - 3", "type": "ENTITY", "char_start": 52, "char_end": 60, "token_start": 8, "token_end": 10}], "entities_global": [{"text": "GATA - 3", "type": "ENTITY", "char_start": 539943, "char_end": 539951, "token_start": 8, "token_end": 10, "note": null}]}
+{"sentence_id": 3245, "sentence_text": "In transient transfection experiments in phorbol 12 - myristate 13 - acetate / ionomycin - stimulated EL4 cells , SKAT - 2 was found to up - regulate the activity of the IL - 4 but not the IL - 5 promoter , contrasting with the ability of GATA - 3 to activate both promoters .", "sentence_char_start_global": 539972, "sentence_char_end_global": 540248, "entities": [{"text": "SKAT - 2", "type": "ENTITY", "char_start": 114, "char_end": 122, "token_start": 19, "token_end": 21}, {"text": "IL - 4 but not the IL - 5 promoter", "type": "ENTITY", "char_start": 170, "char_end": 204, "token_start": 32, "token_end": 41}, {"text": "GATA - 3", "type": "ENTITY", "char_start": 239, "char_end": 247, "token_start": 48, "token_end": 50}, {"text": "promoters", "type": "ENTITY", "char_start": 265, "char_end": 274, "token_start": 54, "token_end": 54}], "entities_global": [{"text": "SKAT - 2", "type": "ENTITY", "char_start": 540086, "char_end": 540094, "token_start": 19, "token_end": 21, "note": null}, {"text": "IL - 4 but not the IL - 5 promoter", "type": "ENTITY", "char_start": 540142, "char_end": 540176, "token_start": 32, "token_end": 41, "note": null}, {"text": "GATA - 3", "type": "ENTITY", "char_start": 540211, "char_end": 540219, "token_start": 48, "token_end": 50, "note": null}, {"text": "promoters", "type": "ENTITY", "char_start": 540237, "char_end": 540246, "token_start": 54, "token_end": 54, "note": null}]}
+{"sentence_id": 3246, "sentence_text": "This result was confirmed using clones of EL4 cells stably expressing an inducible form of SKAT - 2 , thus SKAT - 2 is a novel Th2 - specific gene that may play a role in selective regulation of cytokine genes in T cells .", "sentence_char_start_global": 540249, "sentence_char_end_global": 540471, "entities": [{"text": "SKAT - 2", "type": "ENTITY", "char_start": 91, "char_end": 99, "token_start": 15, "token_end": 17}, {"text": "SKAT - 2", "type": "ENTITY", "char_start": 107, "char_end": 115, "token_start": 20, "token_end": 22}, {"text": "Th2 - specific gene", "type": "ENTITY", "char_start": 127, "char_end": 146, "token_start": 26, "token_end": 29}, {"text": "cytokine genes", "type": "ENTITY", "char_start": 195, "char_end": 209, "token_start": 39, "token_end": 40}], "entities_global": [{"text": "SKAT - 2", "type": "ENTITY", "char_start": 540340, "char_end": 540348, "token_start": 15, "token_end": 17, "note": null}, {"text": "SKAT - 2", "type": "ENTITY", "char_start": 540356, "char_end": 540364, "token_start": 20, "token_end": 22, "note": null}, {"text": "Th2 - specific gene", "type": "ENTITY", "char_start": 540376, "char_end": 540395, "token_start": 26, "token_end": 29, "note": null}, {"text": "cytokine genes", "type": "ENTITY", "char_start": 540444, "char_end": 540458, "token_start": 39, "token_end": 40, "note": null}]}
+{"sentence_id": 3247, "sentence_text": "hsp70 interacting protein Hip does not affect glucocorticoid receptor folding by the hsp90 - based chaperone machinery except to oppose the effect of BAG - 1 .", "sentence_char_start_global": 540472, "sentence_char_end_global": 540631, "entities": [{"text": "hsp70 interacting protein Hip", "type": "ENTITY", "char_start": 0, "char_end": 29, "token_start": 0, "token_end": 3}, {"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 46, "char_end": 69, "token_start": 7, "token_end": 8}, {"text": "BAG - 1", "type": "ENTITY", "char_start": 150, "char_end": 157, "token_start": 23, "token_end": 25}], "entities_global": [{"text": "hsp70 interacting protein Hip", "type": "ENTITY", "char_start": 540472, "char_end": 540501, "token_start": 0, "token_end": 3, "note": null}, {"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 540518, "char_end": 540541, "token_start": 7, "token_end": 8, "note": null}, {"text": "BAG - 1", "type": "ENTITY", "char_start": 540622, "char_end": 540629, "token_start": 23, "token_end": 25, "note": null}]}
+{"sentence_id": 3248, "sentence_text": "Reticulocyte lysate contains a chaperone system that assembles glucocorticoid receptor ( GR ) . hsp90 heterocomplexes .", "sentence_char_start_global": 540632, "sentence_char_end_global": 540751, "entities": [{"text": "glucocorticoid receptor ( GR ) . hsp90 heterocomplexes", "type": "ENTITY", "char_start": 63, "char_end": 117, "token_start": 8, "token_end": 15}], "entities_global": [{"text": "glucocorticoid receptor ( GR ) . hsp90 heterocomplexes", "type": "ENTITY", "char_start": 540695, "char_end": 540749, "token_start": 8, "token_end": 15, "note": null}]}
+{"sentence_id": 3249, "sentence_text": "Using purified proteins , we have prepared a five - protein heterocomplex assembly system consisting of two proteins essential for heterocomplex assembly - hsp90 and hsp70 - and three proteins that act as co - chaperones to enhance assembly - Hop , hsp40 , p23 [ Morishima , Y . , Kanelakis , K . C . , Silverstein , A . M . , Dittmar , K . D . , Estrada , L . , and Pratt , W . B . ( 2000 ) J . Biol . Chem . 275 , 6894 - 6900 ] .", "sentence_char_start_global": 540752, "sentence_char_end_global": 541183, "entities": [{"text": "purified proteins", "type": "ENTITY", "char_start": 6, "char_end": 23, "token_start": 1, "token_end": 2}, {"text": "hsp90", "type": "ENTITY", "char_start": 156, "char_end": 161, "token_start": 23, "token_end": 23}, {"text": "hsp70", "type": "ENTITY", "char_start": 166, "char_end": 171, "token_start": 25, "token_end": 25}, {"text": "Hop", "type": "ENTITY", "char_start": 243, "char_end": 246, "token_start": 40, "token_end": 40}, {"text": "hsp40", "type": "ENTITY", "char_start": 249, "char_end": 254, "token_start": 42, "token_end": 42}, {"text": "p23", "type": "ENTITY", "char_start": 257, "char_end": 260, "token_start": 44, "token_end": 44}], "entities_global": [{"text": "purified proteins", "type": "ENTITY", "char_start": 540758, "char_end": 540775, "token_start": 1, "token_end": 2, "note": null}, {"text": "hsp90", "type": "ENTITY", "char_start": 540908, "char_end": 540913, "token_start": 23, "token_end": 23, "note": null}, {"text": "hsp70", "type": "ENTITY", "char_start": 540918, "char_end": 540923, "token_start": 25, "token_end": 25, "note": null}, {"text": "Hop", "type": "ENTITY", "char_start": 540995, "char_end": 540998, "token_start": 40, "token_end": 40, "note": null}, {"text": "hsp40", "type": "ENTITY", "char_start": 541001, "char_end": 541006, "token_start": 42, "token_end": 42, "note": null}, {"text": "p23", "type": "ENTITY", "char_start": 541009, "char_end": 541012, "token_start": 44, "token_end": 44, "note": null}]}
+{"sentence_id": 3250, "sentence_text": "The hsp70 co - chaperone Hip has been recovered in receptor . hsp90 heterocomplexes at an intermediate stage of assembly in reticulocyte lysate , and Hip is also thought to be an intrinsic component of the assembly machinery .", "sentence_char_start_global": 541184, "sentence_char_end_global": 541410, "entities": [{"text": "hsp70 co - chaperone Hip", "type": "ENTITY", "char_start": 4, "char_end": 28, "token_start": 1, "token_end": 5}, {"text": "receptor . hsp90 heterocomplexes", "type": "ENTITY", "char_start": 51, "char_end": 83, "token_start": 10, "token_end": 13}, {"text": "Hip", "type": "ENTITY", "char_start": 150, "char_end": 153, "token_start": 25, "token_end": 25}], "entities_global": [{"text": "hsp70 co - chaperone Hip", "type": "ENTITY", "char_start": 541188, "char_end": 541212, "token_start": 1, "token_end": 5, "note": null}, {"text": "receptor . hsp90 heterocomplexes", "type": "ENTITY", "char_start": 541235, "char_end": 541267, "token_start": 10, "token_end": 13, "note": null}, {"text": "Hip", "type": "ENTITY", "char_start": 541334, "char_end": 541337, "token_start": 25, "token_end": 25, "note": null}]}
+{"sentence_id": 3251, "sentence_text": "Here we show that immunodepletion of Hip from reticulocyte lysate or addition of high levels of Hip to the purified five - protein system does not affect GR . hsp90 heterocomplex assembly or the activation of steroid binding activity that occurs with assembly .", "sentence_char_start_global": 541411, "sentence_char_end_global": 541672, "entities": [{"text": "Hip", "type": "ENTITY", "char_start": 37, "char_end": 40, "token_start": 6, "token_end": 6}, {"text": "Hip", "type": "ENTITY", "char_start": 96, "char_end": 99, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "Hip", "type": "ENTITY", "char_start": 541448, "char_end": 541451, "token_start": 6, "token_end": 6, "note": null}, {"text": "Hip", "type": "ENTITY", "char_start": 541507, "char_end": 541510, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 3252, "sentence_text": "Despite the fact that Hip does not affect assembly , it is recovered in GR . hsp90 heterocomplexes assembled by both systems .", "sentence_char_start_global": 541673, "sentence_char_end_global": 541799, "entities": [{"text": "Hip", "type": "ENTITY", "char_start": 22, "char_end": 25, "token_start": 4, "token_end": 4}, {"text": "GR . hsp90 heterocomplexes", "type": "ENTITY", "char_start": 72, "char_end": 98, "token_start": 14, "token_end": 17}], "entities_global": [{"text": "Hip", "type": "ENTITY", "char_start": 541695, "char_end": 541698, "token_start": 4, "token_end": 4, "note": null}, {"text": "GR . hsp90 heterocomplexes", "type": "ENTITY", "char_start": 541745, "char_end": 541771, "token_start": 14, "token_end": 17, "note": null}]}
+{"sentence_id": 3253, "sentence_text": "In the five - protein system , Hip prevents inhibition of assembly by the hsp70 co - chaperone BAG - 1 , and cotransfection of Hip with BAG - 1 opposes BAG - 1 reduction of steroid binding activity in COS cells .", "sentence_char_start_global": 541800, "sentence_char_end_global": 542012, "entities": [{"text": "Hip", "type": "ENTITY", "char_start": 31, "char_end": 34, "token_start": 7, "token_end": 7}, {"text": "hsp70 co - chaperone BAG - 1", "type": "ENTITY", "char_start": 74, "char_end": 102, "token_start": 14, "token_end": 20}, {"text": "Hip", "type": "ENTITY", "char_start": 127, "char_end": 130, "token_start": 25, "token_end": 25}, {"text": "BAG - 1", "type": "ENTITY", "char_start": 136, "char_end": 143, "token_start": 27, "token_end": 29}, {"text": "BAG - 1", "type": "ENTITY", "char_start": 152, "char_end": 159, "token_start": 31, "token_end": 33}], "entities_global": [{"text": "Hip", "type": "ENTITY", "char_start": 541831, "char_end": 541834, "token_start": 7, "token_end": 7, "note": null}, {"text": "hsp70 co - chaperone BAG - 1", "type": "ENTITY", "char_start": 541874, "char_end": 541902, "token_start": 14, "token_end": 20, "note": null}, {"text": "Hip", "type": "ENTITY", "char_start": 541927, "char_end": 541930, "token_start": 25, "token_end": 25, "note": null}, {"text": "BAG - 1", "type": "ENTITY", "char_start": 541936, "char_end": 541943, "token_start": 27, "token_end": 29, "note": null}, {"text": "BAG - 1", "type": "ENTITY", "char_start": 541952, "char_end": 541959, "token_start": 31, "token_end": 33, "note": null}]}
+{"sentence_id": 3254, "sentence_text": "We conclude that Hip is not a component of the assembly machinery but that it could play a regulatory role in opposition to BAG - 1 .", "sentence_char_start_global": 542013, "sentence_char_end_global": 542146, "entities": [{"text": "Hip", "type": "ENTITY", "char_start": 17, "char_end": 20, "token_start": 3, "token_end": 3}, {"text": "BAG - 1", "type": "ENTITY", "char_start": 124, "char_end": 131, "token_start": 23, "token_end": 25}], "entities_global": [{"text": "Hip", "type": "ENTITY", "char_start": 542030, "char_end": 542033, "token_start": 3, "token_end": 3, "note": null}, {"text": "BAG - 1", "type": "ENTITY", "char_start": 542137, "char_end": 542144, "token_start": 23, "token_end": 25, "note": null}]}
+{"sentence_id": 3255, "sentence_text": "Cutting edge : STAT6 - deficient mice have enhanced tumor immunity to primary and metastatic mammary carcinoma .", "sentence_char_start_global": 542147, "sentence_char_end_global": 542259, "entities": [], "entities_global": []}
+{"sentence_id": 3256, "sentence_text": "STAT4 and STAT6 are essential for the development of CD4 ( + ) Th1 and Th2 development , respectively .", "sentence_char_start_global": 542260, "sentence_char_end_global": 542363, "entities": [{"text": "STAT4", "type": "ENTITY", "char_start": 0, "char_end": 5, "token_start": 0, "token_end": 0}, {"text": "STAT6", "type": "ENTITY", "char_start": 10, "char_end": 15, "token_start": 2, "token_end": 2}], "entities_global": [{"text": "STAT4", "type": "ENTITY", "char_start": 542260, "char_end": 542265, "token_start": 0, "token_end": 0, "note": null}, {"text": "STAT6", "type": "ENTITY", "char_start": 542270, "char_end": 542275, "token_start": 2, "token_end": 2, "note": null}]}
+{"sentence_id": 3257, "sentence_text": "Tumor immunologists have hypothesized that Th1 cells are critical in tumor immunity because they facilitate differentiation of CD8 ( + ) T cells , which are potent anti - tumor effectors .", "sentence_char_start_global": 542364, "sentence_char_end_global": 542552, "entities": [], "entities_global": []}
+{"sentence_id": 3258, "sentence_text": "We have used STAT4 ( - / - ) and STAT6 ( - / - ) mice to test this hypothesis .", "sentence_char_start_global": 542553, "sentence_char_end_global": 542632, "entities": [], "entities_global": []}
+{"sentence_id": 3259, "sentence_text": "BALB / c and knockout mice were challenged in the mammary gland with the highly malignant and spontaneously metastatic BALB / c - derived 4T1 mammary carcinoma .", "sentence_char_start_global": 542633, "sentence_char_end_global": 542794, "entities": [], "entities_global": []}
+{"sentence_id": 3260, "sentence_text": "Primary tumor growth and metastatic disease are reduced in STAT6 ( - / - ) mice relative to BALB / c and STAT4 ( - / - ) mice .", "sentence_char_start_global": 542795, "sentence_char_end_global": 542922, "entities": [], "entities_global": []}
+{"sentence_id": 3261, "sentence_text": "Ab depletions demonstrate that the effect is mediated by CD8 ( + ) T cells , and immunized STAT6 ( - / - ) mice have higher levels of 4T1 - specific CTL than BALB / c or STAT4 ( - / - ) mice .", "sentence_char_start_global": 542923, "sentence_char_end_global": 543115, "entities": [], "entities_global": []}
+{"sentence_id": 3262, "sentence_text": "Surprisingly , Th1 or Th2 cells are not involved , because CD4 depletion does not diminish the anti - tumor effect .", "sentence_char_start_global": 543116, "sentence_char_end_global": 543232, "entities": [], "entities_global": []}
+{"sentence_id": 3263, "sentence_text": "Therefore , deletion of the STAT6 gene facilitates development of potent anti - tumor immunity via a CD4 ( + ) - independent pathway .", "sentence_char_start_global": 543233, "sentence_char_end_global": 543367, "entities": [{"text": "STAT6 gene", "type": "ENTITY", "char_start": 28, "char_end": 38, "token_start": 5, "token_end": 6}], "entities_global": [{"text": "STAT6 gene", "type": "ENTITY", "char_start": 543261, "char_end": 543271, "token_start": 5, "token_end": 6, "note": null}]}
+{"sentence_id": 3264, "sentence_text": "Activation of oncogenic transcription factor AP - 1 in T cells infected with human T cell leukemia virus type 1 .", "sentence_char_start_global": 543368, "sentence_char_end_global": 543481, "entities": [{"text": "oncogenic transcription factor AP - 1", "type": "ENTITY", "char_start": 14, "char_end": 51, "token_start": 2, "token_end": 7}], "entities_global": [{"text": "oncogenic transcription factor AP - 1", "type": "ENTITY", "char_start": 543382, "char_end": 543419, "token_start": 2, "token_end": 7, "note": null}]}
+{"sentence_id": 3265, "sentence_text": "Human T cell leukemia virus type 1 ( HTLV - 1 ) Tax protein transforms primary human T cells in vitro .", "sentence_char_start_global": 543482, "sentence_char_end_global": 543585, "entities": [{"text": "Tax protein", "type": "ENTITY", "char_start": 48, "char_end": 59, "token_start": 12, "token_end": 13}], "entities_global": [{"text": "Tax protein", "type": "ENTITY", "char_start": 543530, "char_end": 543541, "token_start": 12, "token_end": 13, "note": null}]}
+{"sentence_id": 3266, "sentence_text": "We previously showed that Tax induces the expression of various family members of the transcription factor AP - 1 such as c - Jun , JunD , c - Fos , and Fra - 1 at the mRNA level in T cells .", "sentence_char_start_global": 543586, "sentence_char_end_global": 543777, "entities": [{"text": "Tax", "type": "ENTITY", "char_start": 26, "char_end": 29, "token_start": 4, "token_end": 4}, {"text": "transcription factor AP - 1", "type": "ENTITY", "char_start": 86, "char_end": 113, "token_start": 14, "token_end": 18}, {"text": "c - Jun", "type": "ENTITY", "char_start": 122, "char_end": 129, "token_start": 21, "token_end": 23}, {"text": "JunD", "type": "ENTITY", "char_start": 132, "char_end": 136, "token_start": 25, "token_end": 25}, {"text": "c - Fos", "type": "ENTITY", "char_start": 139, "char_end": 146, "token_start": 27, "token_end": 29}, {"text": "Fra - 1", "type": "ENTITY", "char_start": 153, "char_end": 160, "token_start": 32, "token_end": 34}], "entities_global": [{"text": "Tax", "type": "ENTITY", "char_start": 543612, "char_end": 543615, "token_start": 4, "token_end": 4, "note": null}, {"text": "transcription factor AP - 1", "type": "ENTITY", "char_start": 543672, "char_end": 543699, "token_start": 14, "token_end": 18, "note": null}, {"text": "c - Jun", "type": "ENTITY", "char_start": 543708, "char_end": 543715, "token_start": 21, "token_end": 23, "note": null}, {"text": "JunD", "type": "ENTITY", "char_start": 543718, "char_end": 543722, "token_start": 25, "token_end": 25, "note": null}, {"text": "c - Fos", "type": "ENTITY", "char_start": 543725, "char_end": 543732, "token_start": 27, "token_end": 29, "note": null}, {"text": "Fra - 1", "type": "ENTITY", "char_start": 543739, "char_end": 543746, "token_start": 32, "token_end": 34, "note": null}]}
+{"sentence_id": 3267, "sentence_text": "In this study , we have examined the ability of Tax to activate transcription through the AP - 1 - binding site ( AP - 1 site ) .", "sentence_char_start_global": 543778, "sentence_char_end_global": 543907, "entities": [{"text": "Tax", "type": "ENTITY", "char_start": 48, "char_end": 51, "token_start": 10, "token_end": 10}, {"text": "AP - 1 - binding site", "type": "ENTITY", "char_start": 90, "char_end": 111, "token_start": 16, "token_end": 21}, {"text": "AP - 1 site", "type": "ENTITY", "char_start": 114, "char_end": 125, "token_start": 23, "token_end": 26}], "entities_global": [{"text": "Tax", "type": "ENTITY", "char_start": 543826, "char_end": 543829, "token_start": 10, "token_end": 10, "note": null}, {"text": "AP - 1 - binding site", "type": "ENTITY", "char_start": 543868, "char_end": 543889, "token_start": 16, "token_end": 21, "note": null}, {"text": "AP - 1 site", "type": "ENTITY", "char_start": 543892, "char_end": 543903, "token_start": 23, "token_end": 26, "note": null}]}
+{"sentence_id": 3268, "sentence_text": "A transient transfection study showed that Tax can activate transcription through the AP - 1 - binding site in a human T cell line , whereas any combination of AP - 1 proteins did so much less than Tax , indicating that the activation of the AP - 1 site by Tax may require a mechanism other than the induction of AP - 1 mRNA .", "sentence_char_start_global": 543908, "sentence_char_end_global": 544234, "entities": [{"text": "Tax", "type": "ENTITY", "char_start": 43, "char_end": 46, "token_start": 6, "token_end": 6}, {"text": "AP - 1 - binding site", "type": "ENTITY", "char_start": 86, "char_end": 107, "token_start": 12, "token_end": 17}, {"text": "AP - 1 proteins", "type": "ENTITY", "char_start": 160, "char_end": 175, "token_start": 29, "token_end": 32}, {"text": "Tax", "type": "ENTITY", "char_start": 198, "char_end": 201, "token_start": 38, "token_end": 38}, {"text": "AP - 1 site", "type": "ENTITY", "char_start": 242, "char_end": 253, "token_start": 46, "token_end": 49}, {"text": "Tax", "type": "ENTITY", "char_start": 257, "char_end": 260, "token_start": 51, "token_end": 51}, {"text": "AP - 1 mRNA", "type": "ENTITY", "char_start": 313, "char_end": 324, "token_start": 61, "token_end": 64}], "entities_global": [{"text": "Tax", "type": "ENTITY", "char_start": 543951, "char_end": 543954, "token_start": 6, "token_end": 6, "note": null}, {"text": "AP - 1 - binding site", "type": "ENTITY", "char_start": 543994, "char_end": 544015, "token_start": 12, "token_end": 17, "note": null}, {"text": "AP - 1 proteins", "type": "ENTITY", "char_start": 544068, "char_end": 544083, "token_start": 29, "token_end": 32, "note": null}, {"text": "Tax", "type": "ENTITY", "char_start": 544106, "char_end": 544109, "token_start": 38, "token_end": 38, "note": null}, {"text": "AP - 1 site", "type": "ENTITY", "char_start": 544150, "char_end": 544161, "token_start": 46, "token_end": 49, "note": null}, {"text": "Tax", "type": "ENTITY", "char_start": 544165, "char_end": 544168, "token_start": 51, "token_end": 51, "note": null}, {"text": "AP - 1 mRNA", "type": "ENTITY", "char_start": 544221, "char_end": 544232, "token_start": 61, "token_end": 64, "note": null}]}
+{"sentence_id": 3269, "sentence_text": "Fresh peripheral blood leukemia cells of all surveyed ATL patients displayed constitutive AP - 1 DNA - binding activity , whereas no normal individuals did .", "sentence_char_start_global": 544235, "sentence_char_end_global": 544392, "entities": [], "entities_global": []}
+{"sentence_id": 3270, "sentence_text": "However , the HTLV - 1 genes , including tax , are not significantly expressed in fresh leukemia cells from ATL patients .", "sentence_char_start_global": 544393, "sentence_char_end_global": 544515, "entities": [{"text": "HTLV - 1 genes", "type": "ENTITY", "char_start": 14, "char_end": 28, "token_start": 3, "token_end": 6}, {"text": "tax", "type": "ENTITY", "char_start": 41, "char_end": 44, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "HTLV - 1 genes", "type": "ENTITY", "char_start": 544407, "char_end": 544421, "token_start": 3, "token_end": 6, "note": null}, {"text": "tax", "type": "ENTITY", "char_start": 544434, "char_end": 544437, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 3271, "sentence_text": "Our present results suggest that activation of AP - 1 occurs through Tax - dependent and - independent mechanisms in HTLV - 1 - infected T cells , which may play some roles in dysregulated phenotypes of HTLV - 1 - infected cells .", "sentence_char_start_global": 544516, "sentence_char_end_global": 544746, "entities": [{"text": "AP - 1", "type": "ENTITY", "char_start": 47, "char_end": 53, "token_start": 7, "token_end": 9}], "entities_global": [{"text": "AP - 1", "type": "ENTITY", "char_start": 544563, "char_end": 544569, "token_start": 7, "token_end": 9, "note": null}]}
+{"sentence_id": 3272, "sentence_text": "2 , 2 ' , 4 , 6 , 6 ' - pentachlorobiphenyl induces apoptosis in human monocytic cells .", "sentence_char_start_global": 544747, "sentence_char_end_global": 544835, "entities": [], "entities_global": []}
+{"sentence_id": 3273, "sentence_text": "Polychlorinatedbiphe ( PCBs ) are a group of persistent and widely dispersed environmental pollutants , some of which may be immunotoxic .", "sentence_char_start_global": 544836, "sentence_char_end_global": 544974, "entities": [], "entities_global": []}
+{"sentence_id": 3274, "sentence_text": "In the present study , we investigated the effect of PCBs on immune system by assessing apoptotic cell death in human monocytic U937 cells .", "sentence_char_start_global": 544975, "sentence_char_end_global": 545115, "entities": [], "entities_global": []}
+{"sentence_id": 3275, "sentence_text": "Among the various congeners tested , 2 , 2 ' , 4 , 6 , 6 ' - pentachlorobiphenyl ( PeCB ) , a highly ortho - substituted congener , specifically induced DNA fragmentation , a hallmark of apoptosis , while the other examined di - , tri - , tetra - , and pentachlorobiphenyls did not .", "sentence_char_start_global": 545116, "sentence_char_end_global": 545399, "entities": [], "entities_global": []}
+{"sentence_id": 3276, "sentence_text": "To further study the 2 , 2 ' , 4 , 6 , 6 ' - PeCB - induced cell death , various features of apoptosis were examined .", "sentence_char_start_global": 545400, "sentence_char_end_global": 545518, "entities": [], "entities_global": []}
+{"sentence_id": 3277, "sentence_text": "2 , 2 ' , 4 , 6 , 6 ' - PeCB caused a decrease in cell viability and induced cellular morphologic features characteristic of apoptosis such as chromatin aggregation and apoptotic bodies .", "sentence_char_start_global": 545519, "sentence_char_end_global": 545706, "entities": [], "entities_global": []}
+{"sentence_id": 3278, "sentence_text": "In addition , caspase - 3 , an executioner of apoptosis , was activated and its substrate , poly ( ADP - ribose ) polymerase ( PARP ) , was cleaved during 2 , 2 ' , 4 , 6 , 6 ' - PeCB - induced apoptosis .", "sentence_char_start_global": 545707, "sentence_char_end_global": 545912, "entities": [{"text": "caspase - 3", "type": "ENTITY", "char_start": 14, "char_end": 25, "token_start": 3, "token_end": 5}, {"text": "poly ( ADP - ribose ) polymerase", "type": "ENTITY", "char_start": 92, "char_end": 124, "token_start": 18, "token_end": 24}, {"text": "PARP", "type": "ENTITY", "char_start": 127, "char_end": 131, "token_start": 26, "token_end": 26}], "entities_global": [{"text": "caspase - 3", "type": "ENTITY", "char_start": 545721, "char_end": 545732, "token_start": 3, "token_end": 5, "note": null}, {"text": "poly ( ADP - ribose ) polymerase", "type": "ENTITY", "char_start": 545799, "char_end": 545831, "token_start": 18, "token_end": 24, "note": null}, {"text": "PARP", "type": "ENTITY", "char_start": 545834, "char_end": 545838, "token_start": 26, "token_end": 26, "note": null}]}
+{"sentence_id": 3279, "sentence_text": "In contrast , 3 , 3 ' , 4 , 4 ' , 5 - PeCB , a congener of coplanar structure , as well as 2 , 3 , 7 , 8 - TCDD did not induce apoptosis in these human monocytic cells , although they potently induced CYP 1A1 in human hepatoma Hep G2 cells .", "sentence_char_start_global": 545913, "sentence_char_end_global": 546154, "entities": [{"text": "CYP 1A1", "type": "ENTITY", "char_start": 201, "char_end": 208, "token_start": 49, "token_end": 50}], "entities_global": [{"text": "CYP 1A1", "type": "ENTITY", "char_start": 546114, "char_end": 546121, "token_start": 49, "token_end": 50, "note": null}]}
+{"sentence_id": 3280, "sentence_text": "Taken together , the data indicate that 2 , 2 ' , 4 , 6 , 6 ' - PeCB induces apoptosis in human monocytic cells through a mechanism that is independent of the arylhydrocarbon receptor .", "sentence_char_start_global": 546155, "sentence_char_end_global": 546340, "entities": [{"text": "arylhydrocarbon receptor", "type": "ENTITY", "char_start": 159, "char_end": 183, "token_start": 34, "token_end": 35}], "entities_global": [{"text": "arylhydrocarbon receptor", "type": "ENTITY", "char_start": 546314, "char_end": 546338, "token_start": 34, "token_end": 35, "note": null}]}
+{"sentence_id": 3281, "sentence_text": "This suggests a possibly separate mechanism by which PCBs cause immunosuppression .", "sentence_char_start_global": 546341, "sentence_char_end_global": 546424, "entities": [], "entities_global": []}
+{"sentence_id": 3282, "sentence_text": "Effects of deregulated Raf activation on integrin , cytokine - receptor expression and the induction of apoptosis in hematopoietic cells .", "sentence_char_start_global": 546425, "sentence_char_end_global": 546563, "entities": [{"text": "integrin", "type": "ENTITY", "char_start": 41, "char_end": 49, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "integrin", "type": "ENTITY", "char_start": 546466, "char_end": 546474, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 3283, "sentence_text": "The effects of deregulated Raf activation on the growth and differentiation of hematopoietic cells were investigated .", "sentence_char_start_global": 546564, "sentence_char_end_global": 546682, "entities": [], "entities_global": []}
+{"sentence_id": 3284, "sentence_text": "The cytokine - dependent murine myeloid FDC - P1 and human erythroleukemic TF - 1 cell lines were transformed to grow in response to deregulated Raf expression in the absence of exogenous cytokines .", "sentence_char_start_global": 546683, "sentence_char_end_global": 546882, "entities": [{"text": "exogenous cytokines", "type": "ENTITY", "char_start": 178, "char_end": 197, "token_start": 31, "token_end": 32}], "entities_global": [{"text": "exogenous cytokines", "type": "ENTITY", "char_start": 546861, "char_end": 546880, "token_start": 31, "token_end": 32, "note": null}]}
+{"sentence_id": 3285, "sentence_text": "The conditionally active Raf proteins were regulated by beta - estradiol as cDNAs containing the Raf catalytic , but lacking negative - regulatory domains , were ligated to the hormone binding domain of the estrogen receptor ( deltaRaf : ER ) .", "sentence_char_start_global": 546883, "sentence_char_end_global": 547127, "entities": [{"text": "Raf proteins", "type": "ENTITY", "char_start": 25, "char_end": 37, "token_start": 3, "token_end": 4}, {"text": "cDNAs", "type": "ENTITY", "char_start": 76, "char_end": 81, "token_start": 12, "token_end": 12}, {"text": "Raf catalytic", "type": "ENTITY", "char_start": 97, "char_end": 110, "token_start": 15, "token_end": 16}, {"text": "negative - regulatory domains", "type": "ENTITY", "char_start": 125, "char_end": 154, "token_start": 20, "token_end": 23}, {"text": "hormone binding domain", "type": "ENTITY", "char_start": 177, "char_end": 199, "token_start": 29, "token_end": 31}, {"text": "estrogen receptor", "type": "ENTITY", "char_start": 207, "char_end": 224, "token_start": 34, "token_end": 35}, {"text": "deltaRaf : ER", "type": "ENTITY", "char_start": 227, "char_end": 240, "token_start": 37, "token_end": 39}], "entities_global": [{"text": "Raf proteins", "type": "ENTITY", "char_start": 546908, "char_end": 546920, "token_start": 3, "token_end": 4, "note": null}, {"text": "cDNAs", "type": "ENTITY", "char_start": 546959, "char_end": 546964, "token_start": 12, "token_end": 12, "note": null}, {"text": "Raf catalytic", "type": "ENTITY", "char_start": 546980, "char_end": 546993, "token_start": 15, "token_end": 16, "note": null}, {"text": "negative - regulatory domains", "type": "ENTITY", "char_start": 547008, "char_end": 547037, "token_start": 20, "token_end": 23, "note": null}, {"text": "hormone binding domain", "type": "ENTITY", "char_start": 547060, "char_end": 547082, "token_start": 29, "token_end": 31, "note": null}, {"text": "estrogen receptor", "type": "ENTITY", "char_start": 547090, "char_end": 547107, "token_start": 34, "token_end": 35, "note": null}, {"text": "deltaRaf : ER", "type": "ENTITY", "char_start": 547110, "char_end": 547123, "token_start": 37, "token_end": 39, "note": null}]}
+{"sentence_id": 3286, "sentence_text": "Continuous deltaRaf expression prevented apoptosis in the absence of exogenous cytokines and altered the morphology of the FD / deltaRaf : ER cells as they grew in large aggregated masses ( > 100 cells ) whereas the parental cytokine - dependent FDC - P1 cells grew in smaller grape - like clusters ( < 10 cells ) .", "sentence_char_start_global": 547128, "sentence_char_end_global": 547443, "entities": [{"text": "deltaRaf", "type": "ENTITY", "char_start": 11, "char_end": 19, "token_start": 1, "token_end": 1}, {"text": "exogenous cytokines", "type": "ENTITY", "char_start": 69, "char_end": 88, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "deltaRaf", "type": "ENTITY", "char_start": 547139, "char_end": 547147, "token_start": 1, "token_end": 1, "note": null}, {"text": "exogenous cytokines", "type": "ENTITY", "char_start": 547197, "char_end": 547216, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 3287, "sentence_text": "FD / deltaRaf - 1 : ER cells growing in response to Raf activation displayed decreased levels of the Mac - 2 and Mac - 3 molecules on their cell surface .", "sentence_char_start_global": 547444, "sentence_char_end_global": 547598, "entities": [{"text": "Mac - 2 and Mac - 3 molecules", "type": "ENTITY", "char_start": 101, "char_end": 130, "token_start": 19, "token_end": 26}], "entities_global": [{"text": "Mac - 2 and Mac - 3 molecules", "type": "ENTITY", "char_start": 547545, "char_end": 547574, "token_start": 19, "token_end": 26, "note": null}]}
+{"sentence_id": 3288, "sentence_text": "In contrast , when these cells were cultured in IL - 3 , higher levels of these adhesion molecules were detected .", "sentence_char_start_global": 547599, "sentence_char_end_global": 547713, "entities": [{"text": "IL - 3", "type": "ENTITY", "char_start": 48, "char_end": 54, "token_start": 9, "token_end": 11}, {"text": "adhesion molecules", "type": "ENTITY", "char_start": 80, "char_end": 98, "token_start": 17, "token_end": 18}], "entities_global": [{"text": "IL - 3", "type": "ENTITY", "char_start": 547647, "char_end": 547653, "token_start": 9, "token_end": 11, "note": null}, {"text": "adhesion molecules", "type": "ENTITY", "char_start": 547679, "char_end": 547697, "token_start": 17, "token_end": 18, "note": null}]}
+{"sentence_id": 3289, "sentence_text": "Expression of activated Raf oncoproteins also abrogated cytokine dependency and prevented apoptosis of TF - 1 cells .", "sentence_char_start_global": 547714, "sentence_char_end_global": 547831, "entities": [{"text": "Raf oncoproteins", "type": "ENTITY", "char_start": 24, "char_end": 40, "token_start": 3, "token_end": 4}], "entities_global": [{"text": "Raf oncoproteins", "type": "ENTITY", "char_start": 547738, "char_end": 547754, "token_start": 3, "token_end": 4, "note": null}]}
+{"sentence_id": 3290, "sentence_text": "Moreover , the differentiation status of these Raf - responsive cells was more immature upon Raf activation as culture with the differentiation - inducing agent phorbol 12 myristate 13 - acetate ( PMA ) and beta - estradiol resulted in decreased levels of the CD11b and CD18 integrin molecules on the cell surface .", "sentence_char_start_global": 547832, "sentence_char_end_global": 548147, "entities": [{"text": "CD11b and CD18 integrin molecules", "type": "ENTITY", "char_start": 260, "char_end": 293, "token_start": 44, "token_end": 48}], "entities_global": [{"text": "CD11b and CD18 integrin molecules", "type": "ENTITY", "char_start": 548092, "char_end": 548125, "token_start": 44, "token_end": 48, "note": null}]}
+{"sentence_id": 3291, "sentence_text": "In contrast when the Raf - responsive cells were induced to differentiate with PMA and GM - CSF , in the absence of deltaRaf : ER activation , increased levels of the CD11b and CD18 molecules were detected .", "sentence_char_start_global": 548148, "sentence_char_end_global": 548355, "entities": [{"text": "GM - CSF", "type": "ENTITY", "char_start": 87, "char_end": 95, "token_start": 15, "token_end": 17}, {"text": "deltaRaf : ER", "type": "ENTITY", "char_start": 116, "char_end": 129, "token_start": 23, "token_end": 25}, {"text": "CD11b and CD18 molecules", "type": "ENTITY", "char_start": 167, "char_end": 191, "token_start": 32, "token_end": 35}], "entities_global": [{"text": "GM - CSF", "type": "ENTITY", "char_start": 548235, "char_end": 548243, "token_start": 15, "token_end": 17, "note": null}, {"text": "deltaRaf : ER", "type": "ENTITY", "char_start": 548264, "char_end": 548277, "token_start": 23, "token_end": 25, "note": null}, {"text": "CD11b and CD18 molecules", "type": "ENTITY", "char_start": 548315, "char_end": 548339, "token_start": 32, "token_end": 35, "note": null}]}
+{"sentence_id": 3292, "sentence_text": "Retinoic acid ( RA ) inhibited 3H - thymidine incorporation in response to GM - CSF .", "sentence_char_start_global": 548356, "sentence_char_end_global": 548441, "entities": [{"text": "GM - CSF", "type": "ENTITY", "char_start": 75, "char_end": 83, "token_start": 13, "token_end": 15}], "entities_global": [{"text": "GM - CSF", "type": "ENTITY", "char_start": 548431, "char_end": 548439, "token_start": 13, "token_end": 15, "note": null}]}
+{"sentence_id": 3293, "sentence_text": "Interestingly , Raf activation counterbalanced the inhibition of DNA synthesis caused by RA but not PMA .", "sentence_char_start_global": 548442, "sentence_char_end_global": 548547, "entities": [], "entities_global": []}
+{"sentence_id": 3294, "sentence_text": "Thus deregulated Raf expression can alter cytokine dependency , integrin expression and the stage of differentiation .", "sentence_char_start_global": 548548, "sentence_char_end_global": 548666, "entities": [], "entities_global": []}
+{"sentence_id": 3295, "sentence_text": "These Raf - responsive cell lines will be useful in elucidating the roles of the MAP kinase cascade on hematopoietic cell differentiation and malignant transformation", "sentence_char_start_global": 548667, "sentence_char_end_global": 548833, "entities": [], "entities_global": []}
+{"sentence_id": 3296, "sentence_text": "Cyclic AMP activates p38 mitogen - activated protein kinase in Th2 cells : phosphorylation of GATA - 3 and stimulation of Th2 cytokine gene expression .", "sentence_char_start_global": 548834, "sentence_char_end_global": 548986, "entities": [{"text": "p38 mitogen - activated protein kinase", "type": "ENTITY", "char_start": 21, "char_end": 59, "token_start": 3, "token_end": 8}, {"text": "GATA - 3", "type": "ENTITY", "char_start": 94, "char_end": 102, "token_start": 15, "token_end": 17}], "entities_global": [{"text": "p38 mitogen - activated protein kinase", "type": "ENTITY", "char_start": 548855, "char_end": 548893, "token_start": 3, "token_end": 8, "note": null}, {"text": "GATA - 3", "type": "ENTITY", "char_start": 548928, "char_end": 548936, "token_start": 15, "token_end": 17, "note": null}]}
+{"sentence_id": 3297, "sentence_text": "cAMP is an important second messenger with immunomodulatory properties .", "sentence_char_start_global": 548987, "sentence_char_end_global": 549059, "entities": [], "entities_global": []}
+{"sentence_id": 3298, "sentence_text": "Elevation of intracellular cAMP in T cells , induced by agents such as IL - 1alpha or PGs , inhibits T cell activation .", "sentence_char_start_global": 549060, "sentence_char_end_global": 549180, "entities": [{"text": "IL - 1alpha", "type": "ENTITY", "char_start": 71, "char_end": 82, "token_start": 13, "token_end": 15}, {"text": "PGs", "type": "ENTITY", "char_start": 86, "char_end": 89, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "IL - 1alpha", "type": "ENTITY", "char_start": 549131, "char_end": 549142, "token_start": 13, "token_end": 15, "note": null}, {"text": "PGs", "type": "ENTITY", "char_start": 549146, "char_end": 549149, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 3299, "sentence_text": "In effector T cells , an increase in the level of intracellular cAMP inhibits cytokine production in Th1 cells but stimulates cytokine production in Th2 cells .", "sentence_char_start_global": 549181, "sentence_char_end_global": 549341, "entities": [{"text": "cytokine", "type": "ENTITY", "char_start": 78, "char_end": 86, "token_start": 14, "token_end": 14}, {"text": "cytokine", "type": "ENTITY", "char_start": 126, "char_end": 134, "token_start": 21, "token_end": 21}], "entities_global": [{"text": "cytokine", "type": "ENTITY", "char_start": 549259, "char_end": 549267, "token_start": 14, "token_end": 14, "note": null}, {"text": "cytokine", "type": "ENTITY", "char_start": 549307, "char_end": 549315, "token_start": 21, "token_end": 21, "note": null}]}
+{"sentence_id": 3300, "sentence_text": "Here we report that cAMP - induced effects in Th2 cells occur independently of the protein kinase A pathway , which is the major mediator of cAMP - induced signaling events in most cell types .", "sentence_char_start_global": 549342, "sentence_char_end_global": 549535, "entities": [{"text": "protein kinase A", "type": "ENTITY", "char_start": 83, "char_end": 99, "token_start": 15, "token_end": 17}], "entities_global": [{"text": "protein kinase A", "type": "ENTITY", "char_start": 549425, "char_end": 549441, "token_start": 15, "token_end": 17, "note": null}]}
+{"sentence_id": 3301, "sentence_text": "Instead , cAMP stimulates activation of p38 mitogen - activated protein kinase in Th2 cells .", "sentence_char_start_global": 549536, "sentence_char_end_global": 549629, "entities": [{"text": "p38 mitogen - activated protein kinase", "type": "ENTITY", "char_start": 40, "char_end": 78, "token_start": 6, "token_end": 11}], "entities_global": [{"text": "p38 mitogen - activated protein kinase", "type": "ENTITY", "char_start": 549576, "char_end": 549614, "token_start": 6, "token_end": 11, "note": null}]}
+{"sentence_id": 3302, "sentence_text": "This appears to be a Th2 - selective event because cAMP barely increased p38 phosphorylation in Th1 cells .", "sentence_char_start_global": 549630, "sentence_char_end_global": 549737, "entities": [{"text": "p38", "type": "ENTITY", "char_start": 73, "char_end": 76, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "p38", "type": "ENTITY", "char_start": 549703, "char_end": 549706, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 3303, "sentence_text": "We show that in Th2 cells , cAMP promotes the production of both IL - 5 and IL - 13 , which play distinct but critical roles in asthma pathogenesis .", "sentence_char_start_global": 549738, "sentence_char_end_global": 549887, "entities": [{"text": "IL - 5", "type": "ENTITY", "char_start": 65, "char_end": 71, "token_start": 13, "token_end": 15}, {"text": "IL - 13", "type": "ENTITY", "char_start": 76, "char_end": 83, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "IL - 5", "type": "ENTITY", "char_start": 549803, "char_end": 549809, "token_start": 13, "token_end": 15, "note": null}, {"text": "IL - 13", "type": "ENTITY", "char_start": 549814, "char_end": 549821, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 3304, "sentence_text": "Our data also show that cAMP causes increased phosphorylation of the transcription factor GATA - 3 , which we have shown is a critical regulator of Th2 cytokine gene expression and , in turn , of airway inflammation in mice .", "sentence_char_start_global": 549888, "sentence_char_end_global": 550113, "entities": [{"text": "transcription factor GATA - 3", "type": "ENTITY", "char_start": 69, "char_end": 98, "token_start": 11, "token_end": 15}], "entities_global": [{"text": "transcription factor GATA - 3", "type": "ENTITY", "char_start": 549957, "char_end": 549986, "token_start": 11, "token_end": 15, "note": null}]}
+{"sentence_id": 3305, "sentence_text": "Thus , Th2 - specific GATA - 3 expression and p38 mitogen - activated protein kinase activation together provide a molecular basis for the differential effects of cAMP in the two T helper cell subsets .", "sentence_char_start_global": 550114, "sentence_char_end_global": 550316, "entities": [{"text": "GATA - 3", "type": "ENTITY", "char_start": 22, "char_end": 30, "token_start": 5, "token_end": 7}, {"text": "p38 mitogen - activated protein kinase", "type": "ENTITY", "char_start": 46, "char_end": 84, "token_start": 10, "token_end": 15}], "entities_global": [{"text": "GATA - 3", "type": "ENTITY", "char_start": 550136, "char_end": 550144, "token_start": 5, "token_end": 7, "note": null}, {"text": "p38 mitogen - activated protein kinase", "type": "ENTITY", "char_start": 550160, "char_end": 550198, "token_start": 10, "token_end": 15, "note": null}]}
+{"sentence_id": 3306, "sentence_text": "Characterization of IL - 4 and IL - 13 signals dependent on the human IL - 13 receptor alpha chain 1 : redundancy of requirement of tyrosine residue for STAT3 activation .", "sentence_char_start_global": 550317, "sentence_char_end_global": 550488, "entities": [{"text": "IL - 4", "type": "ENTITY", "char_start": 20, "char_end": 26, "token_start": 2, "token_end": 4}, {"text": "IL - 13", "type": "ENTITY", "char_start": 31, "char_end": 38, "token_start": 6, "token_end": 8}, {"text": "human IL - 13 receptor alpha chain 1", "type": "ENTITY", "char_start": 64, "char_end": 100, "token_start": 13, "token_end": 20}], "entities_global": [{"text": "IL - 4", "type": "ENTITY", "char_start": 550337, "char_end": 550343, "token_start": 2, "token_end": 4, "note": null}, {"text": "IL - 13", "type": "ENTITY", "char_start": 550348, "char_end": 550355, "token_start": 6, "token_end": 8, "note": null}, {"text": "human IL - 13 receptor alpha chain 1", "type": "ENTITY", "char_start": 550381, "char_end": 550417, "token_start": 13, "token_end": 20, "note": null}]}
+{"sentence_id": 3307, "sentence_text": "IL - 4 and IL - 13 are pleiotropic cytokines whose biological activities overlap with each other .", "sentence_char_start_global": 550489, "sentence_char_end_global": 550587, "entities": [{"text": "IL - 4", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 2}, {"text": "IL - 13", "type": "ENTITY", "char_start": 11, "char_end": 18, "token_start": 4, "token_end": 6}, {"text": "pleiotropic cytokines", "type": "ENTITY", "char_start": 23, "char_end": 44, "token_start": 8, "token_end": 9}], "entities_global": [{"text": "IL - 4", "type": "ENTITY", "char_start": 550489, "char_end": 550495, "token_start": 0, "token_end": 2, "note": null}, {"text": "IL - 13", "type": "ENTITY", "char_start": 550500, "char_end": 550507, "token_start": 4, "token_end": 6, "note": null}, {"text": "pleiotropic cytokines", "type": "ENTITY", "char_start": 550512, "char_end": 550533, "token_start": 8, "token_end": 9, "note": null}]}
+{"sentence_id": 3308, "sentence_text": "IL - 13 receptor alpha chain 1 ( IL - 13R alpha 1 ) is necessary for binding to IL - 13 , and the heterodimer composed of IL - 13R alpha 1 and IL - 4R alpha chain transduces IL - 13 and IL - 4 signals ; however , the functional mapping of the intracellular domain of IL - 13R alpha 1 is not fully understood .", "sentence_char_start_global": 550588, "sentence_char_end_global": 550897, "entities": [{"text": "IL - 13 receptor alpha chain 1", "type": "ENTITY", "char_start": 0, "char_end": 30, "token_start": 0, "token_end": 6}, {"text": "IL - 13R alpha 1", "type": "ENTITY", "char_start": 33, "char_end": 49, "token_start": 8, "token_end": 12}, {"text": "IL - 13", "type": "ENTITY", "char_start": 80, "char_end": 87, "token_start": 19, "token_end": 21}, {"text": "IL - 13R alpha 1", "type": "ENTITY", "char_start": 122, "char_end": 138, "token_start": 28, "token_end": 32}, {"text": "IL - 4R alpha chain", "type": "ENTITY", "char_start": 143, "char_end": 162, "token_start": 34, "token_end": 38}, {"text": "IL - 13", "type": "ENTITY", "char_start": 174, "char_end": 181, "token_start": 40, "token_end": 42}, {"text": "IL - 4", "type": "ENTITY", "char_start": 186, "char_end": 192, "token_start": 44, "token_end": 46}, {"text": "intracellular domain", "type": "ENTITY", "char_start": 243, "char_end": 263, "token_start": 56, "token_end": 57}, {"text": "IL - 13R alpha 1", "type": "ENTITY", "char_start": 267, "char_end": 283, "token_start": 59, "token_end": 63}], "entities_global": [{"text": "IL - 13 receptor alpha chain 1", "type": "ENTITY", "char_start": 550588, "char_end": 550618, "token_start": 0, "token_end": 6, "note": null}, {"text": "IL - 13R alpha 1", "type": "ENTITY", "char_start": 550621, "char_end": 550637, "token_start": 8, "token_end": 12, "note": null}, {"text": "IL - 13", "type": "ENTITY", "char_start": 550668, "char_end": 550675, "token_start": 19, "token_end": 21, "note": null}, {"text": "IL - 13R alpha 1", "type": "ENTITY", "char_start": 550710, "char_end": 550726, "token_start": 28, "token_end": 32, "note": null}, {"text": "IL - 4R alpha chain", "type": "ENTITY", "char_start": 550731, "char_end": 550750, "token_start": 34, "token_end": 38, "note": null}, {"text": "IL - 13", "type": "ENTITY", "char_start": 550762, "char_end": 550769, "token_start": 40, "token_end": 42, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 550774, "char_end": 550780, "token_start": 44, "token_end": 46, "note": null}, {"text": "intracellular domain", "type": "ENTITY", "char_start": 550831, "char_end": 550851, "token_start": 56, "token_end": 57, "note": null}, {"text": "IL - 13R alpha 1", "type": "ENTITY", "char_start": 550855, "char_end": 550871, "token_start": 59, "token_end": 63, "note": null}]}
+{"sentence_id": 3309, "sentence_text": "In this study , we constructed wild and mutated types of human IL - 13R alpha 1 , and analyzed IL - 4 and IL - 13 signals using an IL - 13R alpha 1 - transfected human B cell line .", "sentence_char_start_global": 550898, "sentence_char_end_global": 551079, "entities": [{"text": "human IL - 13R alpha 1", "type": "ENTITY", "char_start": 57, "char_end": 79, "token_start": 11, "token_end": 16}, {"text": "IL - 4", "type": "ENTITY", "char_start": 95, "char_end": 101, "token_start": 20, "token_end": 22}, {"text": "IL - 13", "type": "ENTITY", "char_start": 106, "char_end": 113, "token_start": 24, "token_end": 26}, {"text": "IL - 13R alpha 1", "type": "ENTITY", "char_start": 131, "char_end": 147, "token_start": 30, "token_end": 34}], "entities_global": [{"text": "human IL - 13R alpha 1", "type": "ENTITY", "char_start": 550955, "char_end": 550977, "token_start": 11, "token_end": 16, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 550993, "char_end": 550999, "token_start": 20, "token_end": 22, "note": null}, {"text": "IL - 13", "type": "ENTITY", "char_start": 551004, "char_end": 551011, "token_start": 24, "token_end": 26, "note": null}, {"text": "IL - 13R alpha 1", "type": "ENTITY", "char_start": 551029, "char_end": 551045, "token_start": 30, "token_end": 34, "note": null}]}
+{"sentence_id": 3310, "sentence_text": "Expression of IL - 13R alpha 1 evoked STAT3 activation by IL - 4 and IL - 13 , and in stimulated human B cells , on which IL - 13R alpha 1 was highly expressed , IL - 4 and IL - 13 induced STAT3 activation .", "sentence_char_start_global": 551080, "sentence_char_end_global": 551287, "entities": [{"text": "IL - 13R alpha 1", "type": "ENTITY", "char_start": 14, "char_end": 30, "token_start": 2, "token_end": 6}, {"text": "STAT3", "type": "ENTITY", "char_start": 38, "char_end": 43, "token_start": 8, "token_end": 8}, {"text": "IL - 4", "type": "ENTITY", "char_start": 58, "char_end": 64, "token_start": 11, "token_end": 13}, {"text": "IL - 13", "type": "ENTITY", "char_start": 69, "char_end": 76, "token_start": 15, "token_end": 17}, {"text": "IL - 13R alpha 1", "type": "ENTITY", "char_start": 122, "char_end": 138, "token_start": 28, "token_end": 32}, {"text": "IL - 4", "type": "ENTITY", "char_start": 162, "char_end": 168, "token_start": 37, "token_end": 39}, {"text": "IL - 13", "type": "ENTITY", "char_start": 173, "char_end": 180, "token_start": 41, "token_end": 43}, {"text": "STAT3", "type": "ENTITY", "char_start": 189, "char_end": 194, "token_start": 45, "token_end": 45}], "entities_global": [{"text": "IL - 13R alpha 1", "type": "ENTITY", "char_start": 551094, "char_end": 551110, "token_start": 2, "token_end": 6, "note": null}, {"text": "STAT3", "type": "ENTITY", "char_start": 551118, "char_end": 551123, "token_start": 8, "token_end": 8, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 551138, "char_end": 551144, "token_start": 11, "token_end": 13, "note": null}, {"text": "IL - 13", "type": "ENTITY", "char_start": 551149, "char_end": 551156, "token_start": 15, "token_end": 17, "note": null}, {"text": "IL - 13R alpha 1", "type": "ENTITY", "char_start": 551202, "char_end": 551218, "token_start": 28, "token_end": 32, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 551242, "char_end": 551248, "token_start": 37, "token_end": 39, "note": null}, {"text": "IL - 13", "type": "ENTITY", "char_start": 551253, "char_end": 551260, "token_start": 41, "token_end": 43, "note": null}, {"text": "STAT3", "type": "ENTITY", "char_start": 551269, "char_end": 551274, "token_start": 45, "token_end": 45, "note": null}]}
+{"sentence_id": 3311, "sentence_text": "Replacement of the two tyrosine residues completely abolished STAT3 activation , although replacing either tyrosine residue alone retained it .", "sentence_char_start_global": 551288, "sentence_char_end_global": 551431, "entities": [{"text": "STAT3", "type": "ENTITY", "char_start": 62, "char_end": 67, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "STAT3", "type": "ENTITY", "char_start": 551350, "char_end": 551355, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 3312, "sentence_text": "Furthermore , we found that the Box1 region and the C - terminal tail of IL - 13R alpha 1 were critical for binding to Tyk2 , and activation of Jak1 , Tyk2 , the insulin receptor substrate - 1 and STAT6 respectively .", "sentence_char_start_global": 551432, "sentence_char_end_global": 551649, "entities": [{"text": "Box1 region", "type": "ENTITY", "char_start": 32, "char_end": 43, "token_start": 6, "token_end": 7}, {"text": "C - terminal tail", "type": "ENTITY", "char_start": 52, "char_end": 69, "token_start": 10, "token_end": 13}, {"text": "IL - 13R alpha 1", "type": "ENTITY", "char_start": 73, "char_end": 89, "token_start": 15, "token_end": 19}, {"text": "Tyk2", "type": "ENTITY", "char_start": 119, "char_end": 123, "token_start": 25, "token_end": 25}, {"text": "Jak1", "type": "ENTITY", "char_start": 144, "char_end": 148, "token_start": 30, "token_end": 30}, {"text": "Tyk2", "type": "ENTITY", "char_start": 151, "char_end": 155, "token_start": 32, "token_end": 32}, {"text": "insulin receptor substrate - 1", "type": "ENTITY", "char_start": 162, "char_end": 192, "token_start": 35, "token_end": 39}, {"text": "STAT6", "type": "ENTITY", "char_start": 197, "char_end": 202, "token_start": 41, "token_end": 41}], "entities_global": [{"text": "Box1 region", "type": "ENTITY", "char_start": 551464, "char_end": 551475, "token_start": 6, "token_end": 7, "note": null}, {"text": "C - terminal tail", "type": "ENTITY", "char_start": 551484, "char_end": 551501, "token_start": 10, "token_end": 13, "note": null}, {"text": "IL - 13R alpha 1", "type": "ENTITY", "char_start": 551505, "char_end": 551521, "token_start": 15, "token_end": 19, "note": null}, {"text": "Tyk2", "type": "ENTITY", "char_start": 551551, "char_end": 551555, "token_start": 25, "token_end": 25, "note": null}, {"text": "Jak1", "type": "ENTITY", "char_start": 551576, "char_end": 551580, "token_start": 30, "token_end": 30, "note": null}, {"text": "Tyk2", "type": "ENTITY", "char_start": 551583, "char_end": 551587, "token_start": 32, "token_end": 32, "note": null}, {"text": "insulin receptor substrate - 1", "type": "ENTITY", "char_start": 551594, "char_end": 551624, "token_start": 35, "token_end": 39, "note": null}, {"text": "STAT6", "type": "ENTITY", "char_start": 551629, "char_end": 551634, "token_start": 41, "token_end": 41, "note": null}]}
+{"sentence_id": 3313, "sentence_text": "These results suggest that STAT3 activation is involved with IL - 4 and IL - 13 signals in human B cells along with the activation of STAT6 , and that there is a unique sequence in IL - 13R alpha 1 to activate STAT3 .", "sentence_char_start_global": 551650, "sentence_char_end_global": 551867, "entities": [{"text": "STAT3", "type": "ENTITY", "char_start": 27, "char_end": 32, "token_start": 4, "token_end": 4}, {"text": "IL - 4", "type": "ENTITY", "char_start": 61, "char_end": 67, "token_start": 9, "token_end": 11}, {"text": "IL - 13", "type": "ENTITY", "char_start": 72, "char_end": 79, "token_start": 13, "token_end": 15}, {"text": "STAT6", "type": "ENTITY", "char_start": 134, "char_end": 139, "token_start": 26, "token_end": 26}, {"text": "IL - 13R alpha 1", "type": "ENTITY", "char_start": 181, "char_end": 197, "token_start": 36, "token_end": 40}, {"text": "STAT3", "type": "ENTITY", "char_start": 210, "char_end": 215, "token_start": 43, "token_end": 43}], "entities_global": [{"text": "STAT3", "type": "ENTITY", "char_start": 551677, "char_end": 551682, "token_start": 4, "token_end": 4, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 551711, "char_end": 551717, "token_start": 9, "token_end": 11, "note": null}, {"text": "IL - 13", "type": "ENTITY", "char_start": 551722, "char_end": 551729, "token_start": 13, "token_end": 15, "note": null}, {"text": "STAT6", "type": "ENTITY", "char_start": 551784, "char_end": 551789, "token_start": 26, "token_end": 26, "note": null}, {"text": "IL - 13R alpha 1", "type": "ENTITY", "char_start": 551831, "char_end": 551847, "token_start": 36, "token_end": 40, "note": null}, {"text": "STAT3", "type": "ENTITY", "char_start": 551860, "char_end": 551865, "token_start": 43, "token_end": 43, "note": null}]}
+{"sentence_id": 3314, "sentence_text": "Functional uncoupling of the Janus kinase 3 - Stat5 pathway in malignant growth of human T cell leukemia virus type 1 - transformed human T cells .", "sentence_char_start_global": 551868, "sentence_char_end_global": 552015, "entities": [], "entities_global": []}
+{"sentence_id": 3315, "sentence_text": "Human T cell leukemia virus type 1 ( HTLV - 1 ) transforms cytokine - dependent T lymphocytes and causes adult T cell leukemia .", "sentence_char_start_global": 552016, "sentence_char_end_global": 552144, "entities": [{"text": "cytokine", "type": "ENTITY", "char_start": 59, "char_end": 67, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "cytokine", "type": "ENTITY", "char_start": 552075, "char_end": 552083, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 3316, "sentence_text": "Janus tyrosine kinase ( Jak ) 3 and transcription factors Stat5a and Stat5b are essential for the proliferation of normal T cells and are constitutively hyperactivated in both HTLV - 1 - transformed human T cell lines and lymphocytes isolated from HTLV - 1 - infected patients ; therefore , a critical role for the Jak3 - Stat5 pathway in the progression of this disease has been postulated .", "sentence_char_start_global": 552145, "sentence_char_end_global": 552537, "entities": [{"text": "Janus tyrosine kinase ( Jak ) 3", "type": "ENTITY", "char_start": 0, "char_end": 31, "token_start": 0, "token_end": 6}, {"text": "transcription factors", "type": "ENTITY", "char_start": 36, "char_end": 57, "token_start": 8, "token_end": 9}, {"text": "Stat5a", "type": "ENTITY", "char_start": 58, "char_end": 64, "token_start": 10, "token_end": 10}, {"text": "Stat5b", "type": "ENTITY", "char_start": 69, "char_end": 75, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "Janus tyrosine kinase ( Jak ) 3", "type": "ENTITY", "char_start": 552145, "char_end": 552176, "token_start": 0, "token_end": 6, "note": null}, {"text": "transcription factors", "type": "ENTITY", "char_start": 552181, "char_end": 552202, "token_start": 8, "token_end": 9, "note": null}, {"text": "Stat5a", "type": "ENTITY", "char_start": 552203, "char_end": 552209, "token_start": 10, "token_end": 10, "note": null}, {"text": "Stat5b", "type": "ENTITY", "char_start": 552214, "char_end": 552220, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 3317, "sentence_text": "We recently reported that tyrphostin AG - 490 selectively blocked IL - 2 activation of Jak3 / Stat5 and growth of murine T cell lines .", "sentence_char_start_global": 552538, "sentence_char_end_global": 552673, "entities": [{"text": "Jak3 / Stat5", "type": "ENTITY", "char_start": 87, "char_end": 99, "token_start": 15, "token_end": 17}], "entities_global": [{"text": "Jak3 / Stat5", "type": "ENTITY", "char_start": 552625, "char_end": 552637, "token_start": 15, "token_end": 17, "note": null}]}
+{"sentence_id": 3318, "sentence_text": "Here we demonstrate that disruption of Jak3 / Stat5a / b signaling with AG - 490 ( 50 & mgr ; M ) blocked the proliferation of primary human T lymphocytes , but paradoxically failed to inhibit the proliferation of HTLV - 1 - transformed human T cell lines , HuT - 102 and MT - 2 .", "sentence_char_start_global": 552674, "sentence_char_end_global": 552954, "entities": [], "entities_global": []}
+{"sentence_id": 3319, "sentence_text": "Structural homologues of AG - 490 also inhibited the proliferation of primary human T cells , but not HTLV - 1 - infected cells .", "sentence_char_start_global": 552955, "sentence_char_end_global": 553084, "entities": [], "entities_global": []}
+{"sentence_id": 3320, "sentence_text": "Disruption of constitutive Jak3 / Stat5 activation by AG - 490 was demonstrated by inhibition of 1 ) tyrosine phosphorylation of Jak3 , Stat5a ( Tyr ( 694 ) ) , and Stat5b ( Tyr ( 699 ) ) ; 2 ) serine phosphorylation of Stat5a ( Ser ( 726 ) ) as determined by a novel phosphospecific Ab ; and 3 ) Stat5a / b DNA binding to the Stat5 - responsive beta - casein promoter .", "sentence_char_start_global": 553085, "sentence_char_end_global": 553455, "entities": [{"text": "Jak3", "type": "ENTITY", "char_start": 129, "char_end": 133, "token_start": 21, "token_end": 21}, {"text": "Stat5a", "type": "ENTITY", "char_start": 136, "char_end": 142, "token_start": 23, "token_end": 23}, {"text": "Stat5b", "type": "ENTITY", "char_start": 165, "char_end": 171, "token_start": 32, "token_end": 32}, {"text": "Stat5a", "type": "ENTITY", "char_start": 220, "char_end": 226, "token_start": 45, "token_end": 45}, {"text": "phosphospecific Ab", "type": "ENTITY", "char_start": 268, "char_end": 286, "token_start": 57, "token_end": 58}, {"text": "Stat5 - responsive beta - casein promoter", "type": "ENTITY", "char_start": 327, "char_end": 368, "token_start": 70, "token_end": 76}], "entities_global": [{"text": "Jak3", "type": "ENTITY", "char_start": 553214, "char_end": 553218, "token_start": 21, "token_end": 21, "note": null}, {"text": "Stat5a", "type": "ENTITY", "char_start": 553221, "char_end": 553227, "token_start": 23, "token_end": 23, "note": null}, {"text": "Stat5b", "type": "ENTITY", "char_start": 553250, "char_end": 553256, "token_start": 32, "token_end": 32, "note": null}, {"text": "Stat5a", "type": "ENTITY", "char_start": 553305, "char_end": 553311, "token_start": 45, "token_end": 45, "note": null}, {"text": "phosphospecific Ab", "type": "ENTITY", "char_start": 553353, "char_end": 553371, "token_start": 57, "token_end": 58, "note": null}, {"text": "Stat5 - responsive beta - casein promoter", "type": "ENTITY", "char_start": 553412, "char_end": 553453, "token_start": 70, "token_end": 76, "note": null}]}
+{"sentence_id": 3321, "sentence_text": "In contrast , AG - 490 had no effect on DNA binding by p50 / p65 components of NF - kappaB , a transcription factor activated by the HTLV - 1 - encoded phosphoprotein , Tax .", "sentence_char_start_global": 553456, "sentence_char_end_global": 553630, "entities": [{"text": "p50 / p65 components", "type": "ENTITY", "char_start": 55, "char_end": 75, "token_start": 13, "token_end": 16}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 79, "char_end": 90, "token_start": 18, "token_end": 20}, {"text": "transcription factor", "type": "ENTITY", "char_start": 95, "char_end": 115, "token_start": 23, "token_end": 24}, {"text": "HTLV - 1 - encoded phosphoprotein , Tax", "type": "ENTITY", "char_start": 133, "char_end": 172, "token_start": 28, "token_end": 35}], "entities_global": [{"text": "p50 / p65 components", "type": "ENTITY", "char_start": 553511, "char_end": 553531, "token_start": 13, "token_end": 16, "note": null}, {"text": "NF - kappaB", "type": "ENTITY", "char_start": 553535, "char_end": 553546, "token_start": 18, "token_end": 20, "note": null}, {"text": "transcription factor", "type": "ENTITY", "char_start": 553551, "char_end": 553571, "token_start": 23, "token_end": 24, "note": null}, {"text": "HTLV - 1 - encoded phosphoprotein , Tax", "type": "ENTITY", "char_start": 553589, "char_end": 553628, "token_start": 28, "token_end": 35, "note": null}]}
+{"sentence_id": 3322, "sentence_text": "Collectively , these data suggest that the Jak3 - Stat5 pathway in HTLV - 1 - transformed T cells has become functionally redundant for proliferation .", "sentence_char_start_global": 553631, "sentence_char_end_global": 553782, "entities": [], "entities_global": []}
+{"sentence_id": 3323, "sentence_text": "Reversal of this functional uncoupling may be required before Jak3 / Stat5 inhibitors will be useful in the treatment of this malignancy .", "sentence_char_start_global": 553783, "sentence_char_end_global": 553921, "entities": [], "entities_global": []}
+{"sentence_id": 3324, "sentence_text": "The Epstein - Barr virus promoter initiating B - cell transformation is activated by RFX proteins and the B - cell - specific activator protein BSAP / Pax5 .", "sentence_char_start_global": 553922, "sentence_char_end_global": 554079, "entities": [{"text": "Epstein - Barr virus promoter", "type": "ENTITY", "char_start": 4, "char_end": 33, "token_start": 1, "token_end": 5}, {"text": "RFX proteins", "type": "ENTITY", "char_start": 85, "char_end": 97, "token_start": 14, "token_end": 15}, {"text": "B - cell - specific activator protein BSAP / Pax5", "type": "ENTITY", "char_start": 106, "char_end": 155, "token_start": 18, "token_end": 27}], "entities_global": [{"text": "Epstein - Barr virus promoter", "type": "ENTITY", "char_start": 553926, "char_end": 553955, "token_start": 1, "token_end": 5, "note": null}, {"text": "RFX proteins", "type": "ENTITY", "char_start": 554007, "char_end": 554019, "token_start": 14, "token_end": 15, "note": null}, {"text": "B - cell - specific activator protein BSAP / Pax5", "type": "ENTITY", "char_start": 554028, "char_end": 554077, "token_start": 18, "token_end": 27, "note": null}]}
+{"sentence_id": 3325, "sentence_text": "Epstein - Barr virus ( EBV ) - induced B - cell growth transformation , a central feature of the virus ' strategy for colonizing the human B - cell system , requires full virus latent gene expression and is initiated by transcription from the viral promoter Wp .", "sentence_char_start_global": 554080, "sentence_char_end_global": 554342, "entities": [{"text": "viral promoter Wp", "type": "ENTITY", "char_start": 243, "char_end": 260, "token_start": 45, "token_end": 47}], "entities_global": [{"text": "viral promoter Wp", "type": "ENTITY", "char_start": 554323, "char_end": 554340, "token_start": 45, "token_end": 47, "note": null}]}
+{"sentence_id": 3326, "sentence_text": "Interestingly , when EBV accesses other cell types , this growth - transforming program is not activated .", "sentence_char_start_global": 554343, "sentence_char_end_global": 554449, "entities": [], "entities_global": []}
+{"sentence_id": 3327, "sentence_text": "The present work focuses on a region of Wp which in reporter assays confers B - cell - specific activity .", "sentence_char_start_global": 554450, "sentence_char_end_global": 554556, "entities": [{"text": "Wp", "type": "ENTITY", "char_start": 40, "char_end": 42, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "Wp", "type": "ENTITY", "char_start": 554490, "char_end": 554492, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 3328, "sentence_text": "Bandshift studies indicate that this region contains three factor binding sites , termed sites B , C , and D , in addition to a previously characterized CREB site .", "sentence_char_start_global": 554557, "sentence_char_end_global": 554721, "entities": [{"text": "sites B , C , and D", "type": "ENTITY", "char_start": 89, "char_end": 108, "token_start": 13, "token_end": 19}, {"text": "CREB site", "type": "ENTITY", "char_start": 153, "char_end": 162, "token_start": 27, "token_end": 28}], "entities_global": [{"text": "sites B , C , and D", "type": "ENTITY", "char_start": 554646, "char_end": 554665, "token_start": 13, "token_end": 19, "note": null}, {"text": "CREB site", "type": "ENTITY", "char_start": 554710, "char_end": 554719, "token_start": 27, "token_end": 28, "note": null}]}
+{"sentence_id": 3329, "sentence_text": "Here we show that site C binds members of the ubiquitously expressed RFX family of proteins , notably RFX1 , RFX3 , and the associated factor MIBP1 , whereas sites B and D both bind the B - cell - specific activator protein BSAP / Pax5 .", "sentence_char_start_global": 554722, "sentence_char_end_global": 554959, "entities": [{"text": "site C", "type": "ENTITY", "char_start": 18, "char_end": 24, "token_start": 4, "token_end": 5}, {"text": "RFX family of proteins", "type": "ENTITY", "char_start": 69, "char_end": 91, "token_start": 12, "token_end": 15}, {"text": "RFX1", "type": "ENTITY", "char_start": 102, "char_end": 106, "token_start": 18, "token_end": 18}, {"text": "RFX3", "type": "ENTITY", "char_start": 109, "char_end": 113, "token_start": 20, "token_end": 20}, {"text": "MIBP1", "type": "ENTITY", "char_start": 142, "char_end": 147, "token_start": 26, "token_end": 26}, {"text": "sites B and D", "type": "ENTITY", "char_start": 158, "char_end": 171, "token_start": 29, "token_end": 32}, {"text": "B - cell - specific activator protein BSAP / Pax5", "type": "ENTITY", "char_start": 186, "char_end": 235, "token_start": 36, "token_end": 45}], "entities_global": [{"text": "site C", "type": "ENTITY", "char_start": 554740, "char_end": 554746, "token_start": 4, "token_end": 5, "note": null}, {"text": "RFX family of proteins", "type": "ENTITY", "char_start": 554791, "char_end": 554813, "token_start": 12, "token_end": 15, "note": null}, {"text": "RFX1", "type": "ENTITY", "char_start": 554824, "char_end": 554828, "token_start": 18, "token_end": 18, "note": null}, {"text": "RFX3", "type": "ENTITY", "char_start": 554831, "char_end": 554835, "token_start": 20, "token_end": 20, "note": null}, {"text": "MIBP1", "type": "ENTITY", "char_start": 554864, "char_end": 554869, "token_start": 26, "token_end": 26, "note": null}, {"text": "sites B and D", "type": "ENTITY", "char_start": 554880, "char_end": 554893, "token_start": 29, "token_end": 32, "note": null}, {"text": "B - cell - specific activator protein BSAP / Pax5", "type": "ENTITY", "char_start": 554908, "char_end": 554957, "token_start": 36, "token_end": 45, "note": null}]}
+{"sentence_id": 3330, "sentence_text": "In reporter assays with mutant Wp constructs , the loss of factor binding to any one of these sites severely impaired promoter activity in B cells , while the wild - type promoter could be activated in non - B cells by ectopic BSAP expression .", "sentence_char_start_global": 554960, "sentence_char_end_global": 555204, "entities": [{"text": "mutant Wp constructs", "type": "ENTITY", "char_start": 24, "char_end": 44, "token_start": 4, "token_end": 6}, {"text": "wild - type promoter", "type": "ENTITY", "char_start": 159, "char_end": 179, "token_start": 29, "token_end": 32}], "entities_global": [{"text": "mutant Wp constructs", "type": "ENTITY", "char_start": 554984, "char_end": 555004, "token_start": 4, "token_end": 6, "note": null}, {"text": "wild - type promoter", "type": "ENTITY", "char_start": 555119, "char_end": 555139, "token_start": 29, "token_end": 32, "note": null}]}
+{"sentence_id": 3331, "sentence_text": "We suggest that Wp regulation by BSAP helps to ensure the B - cell specificity of EBV ' s growth - transforming function .", "sentence_char_start_global": 555205, "sentence_char_end_global": 555327, "entities": [{"text": "Wp", "type": "ENTITY", "char_start": 16, "char_end": 18, "token_start": 3, "token_end": 3}, {"text": "BSAP", "type": "ENTITY", "char_start": 33, "char_end": 37, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "Wp", "type": "ENTITY", "char_start": 555221, "char_end": 555223, "token_start": 3, "token_end": 3, "note": null}, {"text": "BSAP", "type": "ENTITY", "char_start": 555238, "char_end": 555242, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 3332, "sentence_text": "Activation of the Lck tyrosine protein kinase by the Herpesvirus saimiri tip protein involves two binding interactions .", "sentence_char_start_global": 555328, "sentence_char_end_global": 555448, "entities": [{"text": "Lck tyrosine protein kinase", "type": "ENTITY", "char_start": 18, "char_end": 45, "token_start": 3, "token_end": 6}, {"text": "tip protein", "type": "ENTITY", "char_start": 73, "char_end": 84, "token_start": 11, "token_end": 12}], "entities_global": [{"text": "Lck tyrosine protein kinase", "type": "ENTITY", "char_start": 555346, "char_end": 555373, "token_start": 3, "token_end": 6, "note": null}, {"text": "tip protein", "type": "ENTITY", "char_start": 555401, "char_end": 555412, "token_start": 11, "token_end": 12, "note": null}]}
+{"sentence_id": 3333, "sentence_text": "The Tip protein of Herpesvirus saimiri strain 484C binds to and activates the Lck tyrosine protein kinase .", "sentence_char_start_global": 555449, "sentence_char_end_global": 555556, "entities": [{"text": "Tip protein", "type": "ENTITY", "char_start": 4, "char_end": 15, "token_start": 1, "token_end": 2}, {"text": "Lck tyrosine protein kinase", "type": "ENTITY", "char_start": 78, "char_end": 105, "token_start": 13, "token_end": 16}], "entities_global": [{"text": "Tip protein", "type": "ENTITY", "char_start": 555453, "char_end": 555464, "token_start": 1, "token_end": 2, "note": null}, {"text": "Lck tyrosine protein kinase", "type": "ENTITY", "char_start": 555527, "char_end": 555554, "token_start": 13, "token_end": 16, "note": null}]}
+{"sentence_id": 3334, "sentence_text": "Two sequences in the Tip protein were previously shown to be involved in binding to Lck .", "sentence_char_start_global": 555557, "sentence_char_end_global": 555646, "entities": [{"text": "Tip protein", "type": "ENTITY", "char_start": 21, "char_end": 32, "token_start": 4, "token_end": 5}, {"text": "Lck", "type": "ENTITY", "char_start": 84, "char_end": 87, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "Tip protein", "type": "ENTITY", "char_start": 555578, "char_end": 555589, "token_start": 4, "token_end": 5, "note": null}, {"text": "Lck", "type": "ENTITY", "char_start": 555641, "char_end": 555644, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 3335, "sentence_text": "A proline - rich region , residues 132 - 141 , binds to the SH3 domain of the Lck protein .", "sentence_char_start_global": 555647, "sentence_char_end_global": 555738, "entities": [{"text": "proline - rich region", "type": "ENTITY", "char_start": 2, "char_end": 23, "token_start": 1, "token_end": 4}, {"text": "SH3 domain", "type": "ENTITY", "char_start": 60, "char_end": 70, "token_start": 14, "token_end": 15}, {"text": "Lck protein", "type": "ENTITY", "char_start": 78, "char_end": 89, "token_start": 18, "token_end": 19}], "entities_global": [{"text": "proline - rich region", "type": "ENTITY", "char_start": 555649, "char_end": 555670, "token_start": 1, "token_end": 4, "note": null}, {"text": "SH3 domain", "type": "ENTITY", "char_start": 555707, "char_end": 555717, "token_start": 14, "token_end": 15, "note": null}, {"text": "Lck protein", "type": "ENTITY", "char_start": 555725, "char_end": 555736, "token_start": 18, "token_end": 19, "note": null}]}
+{"sentence_id": 3336, "sentence_text": "We show here that the other Lck - binding domain , residues 104 - 113 , binds to the carboxyl - terminal half of Lck and that this binding does not require the Lck SH3 domain .", "sentence_char_start_global": 555739, "sentence_char_end_global": 555915, "entities": [{"text": "Lck - binding domain", "type": "ENTITY", "char_start": 28, "char_end": 48, "token_start": 6, "token_end": 9}, {"text": "carboxyl - terminal half", "type": "ENTITY", "char_start": 85, "char_end": 109, "token_start": 19, "token_end": 22}, {"text": "Lck", "type": "ENTITY", "char_start": 113, "char_end": 116, "token_start": 24, "token_end": 24}, {"text": "Lck SH3 domain", "type": "ENTITY", "char_start": 160, "char_end": 174, "token_start": 33, "token_end": 35}], "entities_global": [{"text": "Lck - binding domain", "type": "ENTITY", "char_start": 555767, "char_end": 555787, "token_start": 6, "token_end": 9, "note": null}, {"text": "carboxyl - terminal half", "type": "ENTITY", "char_start": 555824, "char_end": 555848, "token_start": 19, "token_end": 22, "note": null}, {"text": "Lck", "type": "ENTITY", "char_start": 555852, "char_end": 555855, "token_start": 24, "token_end": 24, "note": null}, {"text": "Lck SH3 domain", "type": "ENTITY", "char_start": 555899, "char_end": 555913, "token_start": 33, "token_end": 35, "note": null}]}
+{"sentence_id": 3337, "sentence_text": "Mutated Tip containing only one functional Lck - binding domain can bind stably to Lck , although not as strongly as wild - type Tip .", "sentence_char_start_global": 555916, "sentence_char_end_global": 556050, "entities": [{"text": "Tip", "type": "ENTITY", "char_start": 8, "char_end": 11, "token_start": 1, "token_end": 1}, {"text": "Lck - binding domain", "type": "ENTITY", "char_start": 43, "char_end": 63, "token_start": 6, "token_end": 9}, {"text": "Lck", "type": "ENTITY", "char_start": 83, "char_end": 86, "token_start": 14, "token_end": 14}, {"text": "wild - type Tip", "type": "ENTITY", "char_start": 117, "char_end": 132, "token_start": 21, "token_end": 24}], "entities_global": [{"text": "Tip", "type": "ENTITY", "char_start": 555924, "char_end": 555927, "token_start": 1, "token_end": 1, "note": null}, {"text": "Lck - binding domain", "type": "ENTITY", "char_start": 555959, "char_end": 555979, "token_start": 6, "token_end": 9, "note": null}, {"text": "Lck", "type": "ENTITY", "char_start": 555999, "char_end": 556002, "token_start": 14, "token_end": 14, "note": null}, {"text": "wild - type Tip", "type": "ENTITY", "char_start": 556033, "char_end": 556048, "token_start": 21, "token_end": 24, "note": null}]}
+{"sentence_id": 3338, "sentence_text": "Interaction of Tip with Lck through either Lck - binding domain increases the activity of Lck in vivo .", "sentence_char_start_global": 556051, "sentence_char_end_global": 556154, "entities": [{"text": "Tip", "type": "ENTITY", "char_start": 15, "char_end": 18, "token_start": 2, "token_end": 2}, {"text": "Lck", "type": "ENTITY", "char_start": 24, "char_end": 27, "token_start": 4, "token_end": 4}, {"text": "Lck - binding domain", "type": "ENTITY", "char_start": 43, "char_end": 63, "token_start": 7, "token_end": 10}, {"text": "Lck", "type": "ENTITY", "char_start": 90, "char_end": 93, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "Tip", "type": "ENTITY", "char_start": 556066, "char_end": 556069, "token_start": 2, "token_end": 2, "note": null}, {"text": "Lck", "type": "ENTITY", "char_start": 556075, "char_end": 556078, "token_start": 4, "token_end": 4, "note": null}, {"text": "Lck - binding domain", "type": "ENTITY", "char_start": 556094, "char_end": 556114, "token_start": 7, "token_end": 10, "note": null}, {"text": "Lck", "type": "ENTITY", "char_start": 556141, "char_end": 556144, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 3339, "sentence_text": "Simultaneous binding of both domains is required for maximal activation of Lck .", "sentence_char_start_global": 556155, "sentence_char_end_global": 556235, "entities": [{"text": "Lck", "type": "ENTITY", "char_start": 75, "char_end": 78, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "Lck", "type": "ENTITY", "char_start": 556230, "char_end": 556233, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 3340, "sentence_text": "The transient expression of Tip in T cells was found to stimulate both Stat3 - dependent and NF - AT - dependent transcription .", "sentence_char_start_global": 556236, "sentence_char_end_global": 556364, "entities": [{"text": "Tip", "type": "ENTITY", "char_start": 28, "char_end": 31, "token_start": 4, "token_end": 4}, {"text": "Stat3", "type": "ENTITY", "char_start": 71, "char_end": 76, "token_start": 13, "token_end": 13}, {"text": "NF - AT", "type": "ENTITY", "char_start": 93, "char_end": 100, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "Tip", "type": "ENTITY", "char_start": 556264, "char_end": 556267, "token_start": 4, "token_end": 4, "note": null}, {"text": "Stat3", "type": "ENTITY", "char_start": 556307, "char_end": 556312, "token_start": 13, "token_end": 13, "note": null}, {"text": "NF - AT", "type": "ENTITY", "char_start": 556329, "char_end": 556336, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 3341, "sentence_text": "Mutant forms of Tip lacking one or the other of the two Lck - binding domains retained the ability to stimulate Stat3 - dependent transcription .", "sentence_char_start_global": 556365, "sentence_char_end_global": 556510, "entities": [{"text": "Tip", "type": "ENTITY", "char_start": 16, "char_end": 19, "token_start": 3, "token_end": 3}, {"text": "Lck - binding domains", "type": "ENTITY", "char_start": 56, "char_end": 77, "token_start": 12, "token_end": 15}, {"text": "Stat3", "type": "ENTITY", "char_start": 112, "char_end": 117, "token_start": 21, "token_end": 21}], "entities_global": [{"text": "Tip", "type": "ENTITY", "char_start": 556381, "char_end": 556384, "token_start": 3, "token_end": 3, "note": null}, {"text": "Lck - binding domains", "type": "ENTITY", "char_start": 556421, "char_end": 556442, "token_start": 12, "token_end": 15, "note": null}, {"text": "Stat3", "type": "ENTITY", "char_start": 556477, "char_end": 556482, "token_start": 21, "token_end": 21, "note": null}]}
+{"sentence_id": 3342, "sentence_text": "Tip lacking the proline - rich Lck - binding domain exhibited almost wild - type activity in this assay .", "sentence_char_start_global": 556511, "sentence_char_end_global": 556616, "entities": [{"text": "Tip", "type": "ENTITY", "char_start": 0, "char_end": 3, "token_start": 0, "token_end": 0}, {"text": "Lck - binding domain", "type": "ENTITY", "char_start": 31, "char_end": 51, "token_start": 6, "token_end": 9}], "entities_global": [{"text": "Tip", "type": "ENTITY", "char_start": 556511, "char_end": 556514, "token_start": 0, "token_end": 0, "note": null}, {"text": "Lck - binding domain", "type": "ENTITY", "char_start": 556542, "char_end": 556562, "token_start": 6, "token_end": 9, "note": null}]}
+{"sentence_id": 3343, "sentence_text": "In contrast , ablation of either Lck - binding domain abolished the ability of Tip to stimulate NF - AT - dependent transcription .", "sentence_char_start_global": 556617, "sentence_char_end_global": 556748, "entities": [{"text": "Lck - binding domain", "type": "ENTITY", "char_start": 33, "char_end": 53, "token_start": 6, "token_end": 9}, {"text": "Tip", "type": "ENTITY", "char_start": 79, "char_end": 82, "token_start": 14, "token_end": 14}, {"text": "NF - AT", "type": "ENTITY", "char_start": 96, "char_end": 103, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "Lck - binding domain", "type": "ENTITY", "char_start": 556650, "char_end": 556670, "token_start": 6, "token_end": 9, "note": null}, {"text": "Tip", "type": "ENTITY", "char_start": 556696, "char_end": 556699, "token_start": 14, "token_end": 14, "note": null}, {"text": "NF - AT", "type": "ENTITY", "char_start": 556713, "char_end": 556720, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 3344, "sentence_text": "Full biological activity of Tip , therefore , appears to require both Lck - binding domains .", "sentence_char_start_global": 556749, "sentence_char_end_global": 556842, "entities": [{"text": "Tip", "type": "ENTITY", "char_start": 28, "char_end": 31, "token_start": 4, "token_end": 4}, {"text": "Lck - binding domains", "type": "ENTITY", "char_start": 70, "char_end": 91, "token_start": 12, "token_end": 15}], "entities_global": [{"text": "Tip", "type": "ENTITY", "char_start": 556777, "char_end": 556780, "token_start": 4, "token_end": 4, "note": null}, {"text": "Lck - binding domains", "type": "ENTITY", "char_start": 556819, "char_end": 556840, "token_start": 12, "token_end": 15, "note": null}]}
+{"sentence_id": 3345, "sentence_text": "Accumulation of RXR alpha during activation of cycling human T lymphocytes : modulation of RXRE transactivation function by mitogen - activated protein kinase pathways .", "sentence_char_start_global": 556843, "sentence_char_end_global": 557012, "entities": [{"text": "RXR alpha", "type": "ENTITY", "char_start": 16, "char_end": 25, "token_start": 2, "token_end": 3}], "entities_global": [{"text": "RXR alpha", "type": "ENTITY", "char_start": 556859, "char_end": 556868, "token_start": 2, "token_end": 3, "note": null}]}
+{"sentence_id": 3346, "sentence_text": "We have previously reported that the activation of resting human immature peripheral blood T ( PBT ) lymphocytes is associated with the loss of retinoid X receptor alpha ( RXRalpha ) expression .", "sentence_char_start_global": 557013, "sentence_char_end_global": 557208, "entities": [{"text": "retinoid X receptor alpha", "type": "ENTITY", "char_start": 144, "char_end": 169, "token_start": 24, "token_end": 27}, {"text": "RXRalpha", "type": "ENTITY", "char_start": 172, "char_end": 180, "token_start": 29, "token_end": 29}], "entities_global": [{"text": "retinoid X receptor alpha", "type": "ENTITY", "char_start": 557157, "char_end": 557182, "token_start": 24, "token_end": 27, "note": null}, {"text": "RXRalpha", "type": "ENTITY", "char_start": 557185, "char_end": 557193, "token_start": 29, "token_end": 29, "note": null}]}
+{"sentence_id": 3347, "sentence_text": "In the present study , we have demonstrated that , unlike resting cells , activation of cycling human mature PBT lymphocytes , and T lymphocyte leukemia cell lines is accompanied by the accumulation of RXRalpha mRNA and protein .", "sentence_char_start_global": 557209, "sentence_char_end_global": 557438, "entities": [{"text": "RXRalpha", "type": "ENTITY", "char_start": 202, "char_end": 210, "token_start": 34, "token_end": 34}], "entities_global": [{"text": "RXRalpha", "type": "ENTITY", "char_start": 557411, "char_end": 557419, "token_start": 34, "token_end": 34, "note": null}]}
+{"sentence_id": 3348, "sentence_text": "Interestingly , cyclosporin A further augmented RXRalpha expression , indicating the involvement of calcineurin pathways in the process .", "sentence_char_start_global": 557439, "sentence_char_end_global": 557576, "entities": [{"text": "RXRalpha", "type": "ENTITY", "char_start": 48, "char_end": 56, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "RXRalpha", "type": "ENTITY", "char_start": 557487, "char_end": 557495, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 3349, "sentence_text": "9 - cis retinoic acid inhibited the accumulation , suggesting that retinoids can regulate the synthesis of their own receptors during T cell activation .", "sentence_char_start_global": 557577, "sentence_char_end_global": 557730, "entities": [], "entities_global": []}
+{"sentence_id": 3350, "sentence_text": "Transfection analysis in Jurkat cells , using RXRE - dependent reporter assays , showed that RXRalpha accumulated during T cell activation was transcriptionally inactive .", "sentence_char_start_global": 557731, "sentence_char_end_global": 557902, "entities": [{"text": "RXRalpha", "type": "ENTITY", "char_start": 93, "char_end": 101, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "RXRalpha", "type": "ENTITY", "char_start": 557824, "char_end": 557832, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 3351, "sentence_text": "To investigate the mechanism of such inhibition , the role of two mitogen - activated protein kinase pathways , c - Jun N - terminal kinase ( JNK ) and extracellular signal - regulated kinase ( ERK ) , in modulating RXRE - dependent transcription , was explored .", "sentence_char_start_global": 557903, "sentence_char_end_global": 558166, "entities": [{"text": "c - Jun N - terminal kinase", "type": "ENTITY", "char_start": 112, "char_end": 139, "token_start": 19, "token_end": 25}, {"text": "JNK", "type": "ENTITY", "char_start": 142, "char_end": 145, "token_start": 27, "token_end": 27}, {"text": "extracellular signal - regulated kinase", "type": "ENTITY", "char_start": 152, "char_end": 191, "token_start": 30, "token_end": 34}, {"text": "ERK", "type": "ENTITY", "char_start": 194, "char_end": 197, "token_start": 36, "token_end": 36}], "entities_global": [{"text": "c - Jun N - terminal kinase", "type": "ENTITY", "char_start": 558015, "char_end": 558042, "token_start": 19, "token_end": 25, "note": null}, {"text": "JNK", "type": "ENTITY", "char_start": 558045, "char_end": 558048, "token_start": 27, "token_end": 27, "note": null}, {"text": "extracellular signal - regulated kinase", "type": "ENTITY", "char_start": 558055, "char_end": 558094, "token_start": 30, "token_end": 34, "note": null}, {"text": "ERK", "type": "ENTITY", "char_start": 558097, "char_end": 558100, "token_start": 36, "token_end": 36, "note": null}]}
+{"sentence_id": 3352, "sentence_text": "The expression of constitutively active MAP / ERK kinase kinase 1 ( MEKK1 ) inhibited RXRE - dependent transcription , whereas dominant negative MEKK1 increased the transcription , indicating the involvement of JNK signaling pathways in the process .", "sentence_char_start_global": 558167, "sentence_char_end_global": 558417, "entities": [{"text": "MAP / ERK kinase kinase 1", "type": "ENTITY", "char_start": 40, "char_end": 65, "token_start": 5, "token_end": 10}, {"text": "MEKK1", "type": "ENTITY", "char_start": 68, "char_end": 73, "token_start": 12, "token_end": 12}, {"text": "dominant negative MEKK1", "type": "ENTITY", "char_start": 127, "char_end": 150, "token_start": 21, "token_end": 23}, {"text": "JNK", "type": "ENTITY", "char_start": 211, "char_end": 214, "token_start": 32, "token_end": 32}], "entities_global": [{"text": "MAP / ERK kinase kinase 1", "type": "ENTITY", "char_start": 558207, "char_end": 558232, "token_start": 5, "token_end": 10, "note": null}, {"text": "MEKK1", "type": "ENTITY", "char_start": 558235, "char_end": 558240, "token_start": 12, "token_end": 12, "note": null}, {"text": "dominant negative MEKK1", "type": "ENTITY", "char_start": 558294, "char_end": 558317, "token_start": 21, "token_end": 23, "note": null}, {"text": "JNK", "type": "ENTITY", "char_start": 558378, "char_end": 558381, "token_start": 32, "token_end": 32, "note": null}]}
+{"sentence_id": 3353, "sentence_text": "In contrast , expression of constitutively active MEK1 , which activates ERK pathway , enhanced RXRE - dependent activation .", "sentence_char_start_global": 558418, "sentence_char_end_global": 558543, "entities": [{"text": "constitutively active MEK1", "type": "ENTITY", "char_start": 28, "char_end": 54, "token_start": 5, "token_end": 7}, {"text": "ERK", "type": "ENTITY", "char_start": 73, "char_end": 76, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "constitutively active MEK1", "type": "ENTITY", "char_start": 558446, "char_end": 558472, "token_start": 5, "token_end": 7, "note": null}, {"text": "ERK", "type": "ENTITY", "char_start": 558491, "char_end": 558494, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 3354, "sentence_text": "When both were activated simultaneously , JNK pathway was dominant over ERK pathway and resulted in inhibition of RXRE - mediated transcription .", "sentence_char_start_global": 558544, "sentence_char_end_global": 558689, "entities": [{"text": "JNK", "type": "ENTITY", "char_start": 42, "char_end": 45, "token_start": 6, "token_end": 6}, {"text": "ERK", "type": "ENTITY", "char_start": 72, "char_end": 75, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "JNK", "type": "ENTITY", "char_start": 558586, "char_end": 558589, "token_start": 6, "token_end": 6, "note": null}, {"text": "ERK", "type": "ENTITY", "char_start": 558616, "char_end": 558619, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 3355, "sentence_text": "These data demonstrate a dual regulatory control of RXRalpha expression during the activation of resting and cycling T lymphocytes and indicate a dynamic balance between JNK and ERK pathways in modulating RXRE - mediated transactivation .", "sentence_char_start_global": 558690, "sentence_char_end_global": 558928, "entities": [{"text": "RXRalpha", "type": "ENTITY", "char_start": 52, "char_end": 60, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "RXRalpha", "type": "ENTITY", "char_start": 558742, "char_end": 558750, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 3356, "sentence_text": "The proteasome regulates receptor - mediated endocytosis of interleukin - 2 .", "sentence_char_start_global": 558929, "sentence_char_end_global": 559006, "entities": [{"text": "proteasome", "type": "ENTITY", "char_start": 4, "char_end": 14, "token_start": 1, "token_end": 1}, {"text": "interleukin - 2", "type": "ENTITY", "char_start": 60, "char_end": 75, "token_start": 8, "token_end": 10}], "entities_global": [{"text": "proteasome", "type": "ENTITY", "char_start": 558933, "char_end": 558943, "token_start": 1, "token_end": 1, "note": null}, {"text": "interleukin - 2", "type": "ENTITY", "char_start": 558989, "char_end": 559004, "token_start": 8, "token_end": 10, "note": null}]}
+{"sentence_id": 3357, "sentence_text": "Recent studies have increasingly implicated the proteasome in the regulation of cell surface receptors .", "sentence_char_start_global": 559007, "sentence_char_end_global": 559111, "entities": [{"text": "proteasome", "type": "ENTITY", "char_start": 48, "char_end": 58, "token_start": 6, "token_end": 6}, {"text": "cell surface receptors", "type": "ENTITY", "char_start": 80, "char_end": 102, "token_start": 11, "token_end": 13}], "entities_global": [{"text": "proteasome", "type": "ENTITY", "char_start": 559055, "char_end": 559065, "token_start": 6, "token_end": 6, "note": null}, {"text": "cell surface receptors", "type": "ENTITY", "char_start": 559087, "char_end": 559109, "token_start": 11, "token_end": 13, "note": null}]}
+{"sentence_id": 3358, "sentence_text": "In the present study , we investigated the role of the proteasome for ligand - dependent endocytosis and degradation of the interleukin - 2 ( IL - 2 ) - interleukin - 2 receptor ( IL - 2R ) complex .", "sentence_char_start_global": 559112, "sentence_char_end_global": 559311, "entities": [{"text": "proteasome", "type": "ENTITY", "char_start": 55, "char_end": 65, "token_start": 11, "token_end": 11}, {"text": "interleukin - 2 ( IL - 2 ) - interleukin - 2 receptor ( IL - 2R ) complex", "type": "ENTITY", "char_start": 124, "char_end": 197, "token_start": 21, "token_end": 39}], "entities_global": [{"text": "proteasome", "type": "ENTITY", "char_start": 559167, "char_end": 559177, "token_start": 11, "token_end": 11, "note": null}, {"text": "interleukin - 2 ( IL - 2 ) - interleukin - 2 receptor ( IL - 2R ) complex", "type": "ENTITY", "char_start": 559236, "char_end": 559309, "token_start": 21, "token_end": 39, "note": null}]}
+{"sentence_id": 3359, "sentence_text": "Proteasome inhibitors impaired internalization of IL - 2 . IL - 2R and prevented the lysosomal degradation of this cytokine .", "sentence_char_start_global": 559312, "sentence_char_end_global": 559437, "entities": [{"text": "IL - 2 . IL - 2R", "type": "ENTITY", "char_start": 50, "char_end": 66, "token_start": 5, "token_end": 11}, {"text": "cytokine", "type": "ENTITY", "char_start": 115, "char_end": 123, "token_start": 19, "token_end": 19}], "entities_global": [{"text": "IL - 2 . IL - 2R", "type": "ENTITY", "char_start": 559362, "char_end": 559378, "token_start": 5, "token_end": 11, "note": null}, {"text": "cytokine", "type": "ENTITY", "char_start": 559427, "char_end": 559435, "token_start": 19, "token_end": 19, "note": null}]}
+{"sentence_id": 3360, "sentence_text": "Based on time - course studies , proteasome activity is primarily required after initial endocytosis of the IL - 2 . IL - 2R .", "sentence_char_start_global": 559438, "sentence_char_end_global": 559564, "entities": [{"text": "proteasome", "type": "ENTITY", "char_start": 33, "char_end": 43, "token_start": 7, "token_end": 7}, {"text": "IL - 2 . IL - 2R", "type": "ENTITY", "char_start": 108, "char_end": 124, "token_start": 17, "token_end": 23}], "entities_global": [{"text": "proteasome", "type": "ENTITY", "char_start": 559471, "char_end": 559481, "token_start": 7, "token_end": 7, "note": null}, {"text": "IL - 2 . IL - 2R", "type": "ENTITY", "char_start": 559546, "char_end": 559562, "token_start": 17, "token_end": 23, "note": null}]}
+{"sentence_id": 3361, "sentence_text": "Proteasome function was also necessary for the lysosomal degradation of IL - 2 internalized by IL - 2R that were comprised of cytoplasmic tailless beta - or gamma c - subunits , suggesting that the target protein for the proteasome is independent of either the cytoplasmic tail of the IL - 2R beta - or gamma c - subunits and their associated signaling components .", "sentence_char_start_global": 559565, "sentence_char_end_global": 559930, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 72, "char_end": 78, "token_start": 10, "token_end": 12}, {"text": "IL - 2R", "type": "ENTITY", "char_start": 95, "char_end": 102, "token_start": 15, "token_end": 17}, {"text": "cytoplasmic tailless", "type": "ENTITY", "char_start": 126, "char_end": 146, "token_start": 22, "token_end": 23}, {"text": "beta - or gamma c - subunits", "type": "ENTITY", "char_start": 147, "char_end": 175, "token_start": 24, "token_end": 30}, {"text": "proteasome", "type": "ENTITY", "char_start": 221, "char_end": 231, "token_start": 39, "token_end": 39}, {"text": "cytoplasmic tail", "type": "ENTITY", "char_start": 261, "char_end": 277, "token_start": 45, "token_end": 46}, {"text": "IL - 2R", "type": "ENTITY", "char_start": 285, "char_end": 292, "token_start": 49, "token_end": 51}, {"text": "beta - or gamma c - subunits", "type": "ENTITY", "char_start": 293, "char_end": 321, "token_start": 52, "token_end": 58}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 559637, "char_end": 559643, "token_start": 10, "token_end": 12, "note": null}, {"text": "IL - 2R", "type": "ENTITY", "char_start": 559660, "char_end": 559667, "token_start": 15, "token_end": 17, "note": null}, {"text": "cytoplasmic tailless", "type": "ENTITY", "char_start": 559691, "char_end": 559711, "token_start": 22, "token_end": 23, "note": null}, {"text": "beta - or gamma c - subunits", "type": "ENTITY", "char_start": 559712, "char_end": 559740, "token_start": 24, "token_end": 30, "note": null}, {"text": "proteasome", "type": "ENTITY", "char_start": 559786, "char_end": 559796, "token_start": 39, "token_end": 39, "note": null}, {"text": "cytoplasmic tail", "type": "ENTITY", "char_start": 559826, "char_end": 559842, "token_start": 45, "token_end": 46, "note": null}, {"text": "IL - 2R", "type": "ENTITY", "char_start": 559850, "char_end": 559857, "token_start": 49, "token_end": 51, "note": null}, {"text": "beta - or gamma c - subunits", "type": "ENTITY", "char_start": 559858, "char_end": 559886, "token_start": 52, "token_end": 58, "note": null}]}
+{"sentence_id": 3362, "sentence_text": "Therefore , a functional proteasome is required for optimal endocytosis of the IL - 2R / ligand complex and is essential for the subsequent lysosomal degradation of IL - 2 , possibly by regulating trafficking to the lysosome .", "sentence_char_start_global": 559931, "sentence_char_end_global": 560157, "entities": [{"text": "proteasome", "type": "ENTITY", "char_start": 25, "char_end": 35, "token_start": 4, "token_end": 4}, {"text": "IL - 2R / ligand complex", "type": "ENTITY", "char_start": 79, "char_end": 103, "token_start": 12, "token_end": 17}, {"text": "IL - 2", "type": "ENTITY", "char_start": 165, "char_end": 171, "token_start": 27, "token_end": 29}], "entities_global": [{"text": "proteasome", "type": "ENTITY", "char_start": 559956, "char_end": 559966, "token_start": 4, "token_end": 4, "note": null}, {"text": "IL - 2R / ligand complex", "type": "ENTITY", "char_start": 560010, "char_end": 560034, "token_start": 12, "token_end": 17, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 560096, "char_end": 560102, "token_start": 27, "token_end": 29, "note": null}]}
+{"sentence_id": 3363, "sentence_text": "Functional characterization of the two alternative promoters of human p45 NF - E2 gene .", "sentence_char_start_global": 560158, "sentence_char_end_global": 560246, "entities": [{"text": "human p45 NF - E2 gene", "type": "ENTITY", "char_start": 64, "char_end": 86, "token_start": 8, "token_end": 13}], "entities_global": [{"text": "human p45 NF - E2 gene", "type": "ENTITY", "char_start": 560222, "char_end": 560244, "token_start": 8, "token_end": 13, "note": null}]}
+{"sentence_id": 3364, "sentence_text": "OBJECTIVE : The transcription factor NF - E2 , a heterodimeric protein complex composed of p45 and small Maf family proteins , is considered crucial for the proper differentiation of erythrocytes and megakaryocytes in vivo .", "sentence_char_start_global": 560247, "sentence_char_end_global": 560471, "entities": [{"text": "transcription factor NF - E2", "type": "ENTITY", "char_start": 16, "char_end": 44, "token_start": 3, "token_end": 7}, {"text": "heterodimeric protein complex", "type": "ENTITY", "char_start": 49, "char_end": 78, "token_start": 10, "token_end": 12}, {"text": "p45", "type": "ENTITY", "char_start": 91, "char_end": 94, "token_start": 15, "token_end": 15}, {"text": "Maf family proteins", "type": "ENTITY", "char_start": 105, "char_end": 124, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "transcription factor NF - E2", "type": "ENTITY", "char_start": 560263, "char_end": 560291, "token_start": 3, "token_end": 7, "note": null}, {"text": "heterodimeric protein complex", "type": "ENTITY", "char_start": 560296, "char_end": 560325, "token_start": 10, "token_end": 12, "note": null}, {"text": "p45", "type": "ENTITY", "char_start": 560338, "char_end": 560341, "token_start": 15, "token_end": 15, "note": null}, {"text": "Maf family proteins", "type": "ENTITY", "char_start": 560352, "char_end": 560371, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 3365, "sentence_text": "We report the results of studies aimed at understanding the regulatory mechanisms controlling p45 gene expression in erythroid cells .", "sentence_char_start_global": 560472, "sentence_char_end_global": 560606, "entities": [{"text": "p45 gene", "type": "ENTITY", "char_start": 94, "char_end": 102, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "p45 gene", "type": "ENTITY", "char_start": 560566, "char_end": 560574, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 3366, "sentence_text": "MATERIALS AND METHODS : Human p45 mRNAs have two alternative isoforms , aNF - E2 and fNF - E2 , and these isoforms are transcribed from the alternative promoters .", "sentence_char_start_global": 560607, "sentence_char_end_global": 560770, "entities": [{"text": "Human p45 mRNAs", "type": "ENTITY", "char_start": 24, "char_end": 39, "token_start": 4, "token_end": 6}, {"text": "aNF - E2", "type": "ENTITY", "char_start": 72, "char_end": 80, "token_start": 12, "token_end": 14}, {"text": "fNF - E2", "type": "ENTITY", "char_start": 85, "char_end": 93, "token_start": 16, "token_end": 18}, {"text": "alternative promoters", "type": "ENTITY", "char_start": 140, "char_end": 161, "token_start": 27, "token_end": 28}], "entities_global": [{"text": "Human p45 mRNAs", "type": "ENTITY", "char_start": 560631, "char_end": 560646, "token_start": 4, "token_end": 6, "note": null}, {"text": "aNF - E2", "type": "ENTITY", "char_start": 560679, "char_end": 560687, "token_start": 12, "token_end": 14, "note": null}, {"text": "fNF - E2", "type": "ENTITY", "char_start": 560692, "char_end": 560700, "token_start": 16, "token_end": 18, "note": null}, {"text": "alternative promoters", "type": "ENTITY", "char_start": 560747, "char_end": 560768, "token_start": 27, "token_end": 28, "note": null}]}
+{"sentence_id": 3367, "sentence_text": "We investigated lineage - specific expression of both isomers in human erythroid and megakaryocytic cells by reverse transcriptase polymerase chain reaction or Northern blot analysis .", "sentence_char_start_global": 560771, "sentence_char_end_global": 560955, "entities": [], "entities_global": []}
+{"sentence_id": 3368, "sentence_text": "For functional characterization of both promoters , plasmids in which reporter genes were placed under the control of a series of truncated or mutated promoter fragments were transfected to human hematopoietic cell lines .", "sentence_char_start_global": 560956, "sentence_char_end_global": 561178, "entities": [{"text": "reporter genes", "type": "ENTITY", "char_start": 70, "char_end": 84, "token_start": 10, "token_end": 11}, {"text": "promoter fragments", "type": "ENTITY", "char_start": 151, "char_end": 169, "token_start": 24, "token_end": 25}], "entities_global": [{"text": "reporter genes", "type": "ENTITY", "char_start": 561026, "char_end": 561040, "token_start": 10, "token_end": 11, "note": null}, {"text": "promoter fragments", "type": "ENTITY", "char_start": 561107, "char_end": 561125, "token_start": 24, "token_end": 25, "note": null}]}
+{"sentence_id": 3369, "sentence_text": "RESULTS : When CD34 ( + ) cells isolated from human cord blood were induced to unilineage erythroid or megakaryocytic differentiation in liquid suspension culture , both transcripts , although barely detected at day 0 , were induced in both erythroid and megakaryocytic cultures .", "sentence_char_start_global": 561179, "sentence_char_end_global": 561459, "entities": [], "entities_global": []}
+{"sentence_id": 3370, "sentence_text": "fNF - E2 mRNA was found to be more abundant in erythroid cells than megakaryocytic cells at day 7 of culture .", "sentence_char_start_global": 561460, "sentence_char_end_global": 561570, "entities": [{"text": "fNF - E2 mRNA", "type": "ENTITY", "char_start": 0, "char_end": 13, "token_start": 0, "token_end": 3}], "entities_global": [{"text": "fNF - E2 mRNA", "type": "ENTITY", "char_start": 561460, "char_end": 561473, "token_start": 0, "token_end": 3, "note": null}]}
+{"sentence_id": 3371, "sentence_text": "Although both isomers were expressed in human erythroid - megakaryocytic cell lines , megakaryocytic maturation with loss of erythroid phenotype induced by phorbol 12 - myristate 13 - acetate ( PMA ) resulted in exclusive downregulation of fNF - E2 , suggesting that fNF - E2 promoter is more erythroid specific .", "sentence_char_start_global": 561571, "sentence_char_end_global": 561884, "entities": [{"text": "fNF - E2", "type": "ENTITY", "char_start": 240, "char_end": 248, "token_start": 37, "token_end": 39}, {"text": "fNF - E2 promoter", "type": "ENTITY", "char_start": 267, "char_end": 284, "token_start": 43, "token_end": 46}], "entities_global": [{"text": "fNF - E2", "type": "ENTITY", "char_start": 561811, "char_end": 561819, "token_start": 37, "token_end": 39, "note": null}, {"text": "fNF - E2 promoter", "type": "ENTITY", "char_start": 561838, "char_end": 561855, "token_start": 43, "token_end": 46, "note": null}]}
+{"sentence_id": 3372, "sentence_text": "Functional analysis of fNF - E2 promoter showed that the promoter is active only in erythroid - megakaryocytic cells and that the double GATA sit e in the proximal region is necessary for its efficient activity .", "sentence_char_start_global": 561885, "sentence_char_end_global": 562097, "entities": [{"text": "fNF - E2 promoter", "type": "ENTITY", "char_start": 23, "char_end": 40, "token_start": 3, "token_end": 6}, {"text": "double GATA sit", "type": "ENTITY", "char_start": 130, "char_end": 145, "token_start": 22, "token_end": 24}], "entities_global": [{"text": "fNF - E2 promoter", "type": "ENTITY", "char_start": 561908, "char_end": 561925, "token_start": 3, "token_end": 6, "note": null}, {"text": "double GATA sit", "type": "ENTITY", "char_start": 562015, "char_end": 562030, "token_start": 22, "token_end": 24, "note": null}]}
+{"sentence_id": 3373, "sentence_text": "CONCLUSION : These results suggest that GATA proteins , which govern the differentiation of erythroid lineage cells , are required for full promoter activity of the p45 gene .", "sentence_char_start_global": 562098, "sentence_char_end_global": 562273, "entities": [{"text": "GATA proteins", "type": "ENTITY", "char_start": 40, "char_end": 53, "token_start": 6, "token_end": 7}, {"text": "p45 gene", "type": "ENTITY", "char_start": 165, "char_end": 173, "token_start": 26, "token_end": 27}], "entities_global": [{"text": "GATA proteins", "type": "ENTITY", "char_start": 562138, "char_end": 562151, "token_start": 6, "token_end": 7, "note": null}, {"text": "p45 gene", "type": "ENTITY", "char_start": 562263, "char_end": 562271, "token_start": 26, "token_end": 27, "note": null}]}
+{"sentence_id": 3374, "sentence_text": "Transcriptional activation of heme oxygenase - 1 and its functional significance in acetaminophen - induced hepatitis and hepatocellular injury in the rat .", "sentence_char_start_global": 562274, "sentence_char_end_global": 562430, "entities": [{"text": "heme oxygenase - 1", "type": "ENTITY", "char_start": 30, "char_end": 48, "token_start": 3, "token_end": 6}], "entities_global": [{"text": "heme oxygenase - 1", "type": "ENTITY", "char_start": 562304, "char_end": 562322, "token_start": 3, "token_end": 6, "note": null}]}
+{"sentence_id": 3375, "sentence_text": "BACKGROUND / AIM : Glutathione depletion contributes to acetaminophen hepatotoxicity and is known to induce the oxidative stress reactant heme oxygenase - 1 .", "sentence_char_start_global": 562431, "sentence_char_end_global": 562589, "entities": [{"text": "heme oxygenase - 1", "type": "ENTITY", "char_start": 138, "char_end": 156, "token_start": 19, "token_end": 22}], "entities_global": [{"text": "heme oxygenase - 1", "type": "ENTITY", "char_start": 562569, "char_end": 562587, "token_start": 19, "token_end": 22, "note": null}]}
+{"sentence_id": 3376, "sentence_text": "The metabolites of the heme oxygenase pathway , biliverdin , carbon monoxide , and iron may modulate acetaminophen toxicity .", "sentence_char_start_global": 562590, "sentence_char_end_global": 562715, "entities": [], "entities_global": []}
+{"sentence_id": 3377, "sentence_text": "The aim of this study was to assess cell - type specific expression of heme oxygenase - 1 and its impact on liver injury and microcirculatory disturbances in a model of acetaminophen - induced hepatitis .", "sentence_char_start_global": 562716, "sentence_char_end_global": 562920, "entities": [{"text": "heme oxygenase - 1", "type": "ENTITY", "char_start": 71, "char_end": 89, "token_start": 14, "token_end": 17}], "entities_global": [{"text": "heme oxygenase - 1", "type": "ENTITY", "char_start": 562787, "char_end": 562805, "token_start": 14, "token_end": 17, "note": null}]}
+{"sentence_id": 3378, "sentence_text": "METHODS : Gene expression of heme oxygenase - 1 was studied by Northern - and Western analysis as well as immunohistochemistry .", "sentence_char_start_global": 562921, "sentence_char_end_global": 563049, "entities": [{"text": "heme oxygenase - 1", "type": "ENTITY", "char_start": 29, "char_end": 47, "token_start": 5, "token_end": 8}], "entities_global": [{"text": "heme oxygenase - 1", "type": "ENTITY", "char_start": 562950, "char_end": 562968, "token_start": 5, "token_end": 8, "note": null}]}
+{"sentence_id": 3379, "sentence_text": "The time course of heme oxygenase - 1 and - 2 , cytokine - induced neutrophil chemoattractant - 1 , and intercellular adhesion molecule - 1 was studied by Northern analysis .", "sentence_char_start_global": 563050, "sentence_char_end_global": 563224, "entities": [{"text": "heme oxygenase - 1 and - 2", "type": "ENTITY", "char_start": 19, "char_end": 45, "token_start": 4, "token_end": 10}, {"text": "cytokine - induced neutrophil chemoattractant - 1", "type": "ENTITY", "char_start": 48, "char_end": 97, "token_start": 12, "token_end": 18}, {"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 104, "char_end": 139, "token_start": 21, "token_end": 25}], "entities_global": [{"text": "heme oxygenase - 1 and - 2", "type": "ENTITY", "char_start": 563069, "char_end": 563095, "token_start": 4, "token_end": 10, "note": null}, {"text": "cytokine - induced neutrophil chemoattractant - 1", "type": "ENTITY", "char_start": 563098, "char_end": 563147, "token_start": 12, "token_end": 18, "note": null}, {"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 563154, "char_end": 563189, "token_start": 21, "token_end": 25, "note": null}]}
+{"sentence_id": 3380, "sentence_text": "DNA - binding activity of nuclear factor - kappaB was determined by electrophoretic mobility shift assay .", "sentence_char_start_global": 563225, "sentence_char_end_global": 563331, "entities": [{"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 26, "char_end": 49, "token_start": 5, "token_end": 8}], "entities_global": [{"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 563251, "char_end": 563274, "token_start": 5, "token_end": 8, "note": null}]}
+{"sentence_id": 3381, "sentence_text": "Sinusoidal perfusion and leukocyte - endothelial interactions were assessed by intravital microscopy .", "sentence_char_start_global": 563332, "sentence_char_end_global": 563434, "entities": [], "entities_global": []}
+{"sentence_id": 3382, "sentence_text": "RESULTS : Acetaminophen caused a moderate sinusoidal perfusion failure ( - 15 % ) and infiltration of neutrophils along with activation of nuclear factor - kappaB and intercellular adhesion molecule - 1 and cytokine - induced neutrophil chemoattractant - 1 mRNAs .", "sentence_char_start_global": 563435, "sentence_char_end_global": 563699, "entities": [{"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 139, "char_end": 162, "token_start": 22, "token_end": 25}, {"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 167, "char_end": 202, "token_start": 27, "token_end": 31}, {"text": "cytokine - induced neutrophil chemoattractant - 1", "type": "ENTITY", "char_start": 207, "char_end": 256, "token_start": 33, "token_end": 39}], "entities_global": [{"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 563574, "char_end": 563597, "token_start": 22, "token_end": 25, "note": null}, {"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 563602, "char_end": 563637, "token_start": 27, "token_end": 31, "note": null}, {"text": "cytokine - induced neutrophil chemoattractant - 1", "type": "ENTITY", "char_start": 563642, "char_end": 563691, "token_start": 33, "token_end": 39, "note": null}]}
+{"sentence_id": 3383, "sentence_text": "Induction of heme oxygenase - 1 mRNA and protein ( approximately 30 - fold ) in hepatocytes and non - parenchymal cells paralleled the inflammatory response .", "sentence_char_start_global": 563700, "sentence_char_end_global": 563858, "entities": [{"text": "heme oxygenase - 1", "type": "ENTITY", "char_start": 13, "char_end": 31, "token_start": 2, "token_end": 5}], "entities_global": [{"text": "heme oxygenase - 1", "type": "ENTITY", "char_start": 563713, "char_end": 563731, "token_start": 2, "token_end": 5, "note": null}]}
+{"sentence_id": 3384, "sentence_text": "Blockade of heme oxygenase activity with tin - protoporphyrin - IX abrogated acetaminophen - induced hepatic neutrophil accumulation and nuclear factor - kappaB activation , but failed to affect sinusoidal perfusion and liver injury .", "sentence_char_start_global": 563859, "sentence_char_end_global": 564093, "entities": [{"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 137, "char_end": 160, "token_start": 19, "token_end": 22}], "entities_global": [{"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 563996, "char_end": 564019, "token_start": 19, "token_end": 22, "note": null}]}
+{"sentence_id": 3385, "sentence_text": "CONCLUSIONS : The inflammatory response associated with acetaminophen hepatotoxicity is modulated by the parallel induction of the heme oxygenase - 1 gene .", "sentence_char_start_global": 564094, "sentence_char_end_global": 564250, "entities": [{"text": "heme oxygenase - 1 gene", "type": "ENTITY", "char_start": 131, "char_end": 154, "token_start": 17, "token_end": 21}], "entities_global": [{"text": "heme oxygenase - 1 gene", "type": "ENTITY", "char_start": 564225, "char_end": 564248, "token_start": 17, "token_end": 21, "note": null}]}
+{"sentence_id": 3386, "sentence_text": "However , heme oxygenase - 1 has no permissive effect on sinusoidal perfusion and does not affect liver injury in this model .", "sentence_char_start_global": 564251, "sentence_char_end_global": 564377, "entities": [{"text": "heme oxygenase - 1", "type": "ENTITY", "char_start": 10, "char_end": 28, "token_start": 2, "token_end": 5}], "entities_global": [{"text": "heme oxygenase - 1", "type": "ENTITY", "char_start": 564261, "char_end": 564279, "token_start": 2, "token_end": 5, "note": null}]}
+{"sentence_id": 3387, "sentence_text": "These data argue against a central role of nuclear factor - kappaB activation and neutrophil infiltration as perpetuating factors of liver injury in acetaminophen toxicity .", "sentence_char_start_global": 564378, "sentence_char_end_global": 564551, "entities": [{"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 43, "char_end": 66, "token_start": 8, "token_end": 11}], "entities_global": [{"text": "nuclear factor - kappaB", "type": "ENTITY", "char_start": 564421, "char_end": 564444, "token_start": 8, "token_end": 11, "note": null}]}
+{"sentence_id": 3388, "sentence_text": "Tumor necrosis factor - alpha - induced proliferation requires synthesis of granulocyte - macrophage colony - stimulating factor .", "sentence_char_start_global": 564552, "sentence_char_end_global": 564682, "entities": [{"text": "Tumor necrosis factor - alpha", "type": "ENTITY", "char_start": 0, "char_end": 29, "token_start": 0, "token_end": 4}, {"text": "granulocyte - macrophage colony - stimulating factor", "type": "ENTITY", "char_start": 76, "char_end": 128, "token_start": 11, "token_end": 17}], "entities_global": [{"text": "Tumor necrosis factor - alpha", "type": "ENTITY", "char_start": 564552, "char_end": 564581, "token_start": 0, "token_end": 4, "note": null}, {"text": "granulocyte - macrophage colony - stimulating factor", "type": "ENTITY", "char_start": 564628, "char_end": 564680, "token_start": 11, "token_end": 17, "note": null}]}
+{"sentence_id": 3389, "sentence_text": "OBJECTIVE : Tumor necrosis factor - alpha ( TNF - alpha ) induces a variety of cellular responses , some of them being at least seemingly contradictory .", "sentence_char_start_global": 564683, "sentence_char_end_global": 564836, "entities": [{"text": "Tumor necrosis factor - alpha", "type": "ENTITY", "char_start": 12, "char_end": 41, "token_start": 2, "token_end": 6}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 44, "char_end": 55, "token_start": 8, "token_end": 10}], "entities_global": [{"text": "Tumor necrosis factor - alpha", "type": "ENTITY", "char_start": 564695, "char_end": 564724, "token_start": 2, "token_end": 6, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 564727, "char_end": 564738, "token_start": 8, "token_end": 10, "note": null}]}
+{"sentence_id": 3390, "sentence_text": "Thus , we set out to find differences in the modes of proliferative and apoptotic responses to TNF - alpha .", "sentence_char_start_global": 564837, "sentence_char_end_global": 564945, "entities": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 95, "char_end": 106, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 564932, "char_end": 564943, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 3391, "sentence_text": "MATERIALS AND METHODS : We screened a panel of acute myeloid leukemia - derived cell lines for TNF - alpha - responsiveness .", "sentence_char_start_global": 564946, "sentence_char_end_global": 565071, "entities": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 95, "char_end": 106, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 565041, "char_end": 565052, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 3392, "sentence_text": "In two lines ( OCI - AML - 1 , OCI - AML - 11 ) , TNF - alpha acted as an apoptotic agent ; in others ( HU - 3 , M - 07e , TF - 1 ) , it had the opposite effect , preventing apoptosis and inducing proliferation .", "sentence_char_start_global": 565072, "sentence_char_end_global": 565284, "entities": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 50, "char_end": 61, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 565122, "char_end": 565133, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 3393, "sentence_text": "Direct and indirect signaling mechanisms , including NF - kappaB activation and cytokine synthesis , were analyzed .", "sentence_char_start_global": 565285, "sentence_char_end_global": 565401, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 53, "char_end": 64, "token_start": 7, "token_end": 9}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 565338, "char_end": 565349, "token_start": 7, "token_end": 9, "note": null}]}
+{"sentence_id": 3394, "sentence_text": "RESULTS : All cell lines tested expressed TNF - alpha receptors I and II and responded to TNF - alpha by upregulation of intercellular adhesion molecule - 1 .", "sentence_char_start_global": 565402, "sentence_char_end_global": 565560, "entities": [{"text": "TNF - alpha receptors I and II", "type": "ENTITY", "char_start": 42, "char_end": 72, "token_start": 7, "token_end": 13}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 90, "char_end": 101, "token_start": 17, "token_end": 19}, {"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 121, "char_end": 156, "token_start": 23, "token_end": 27}], "entities_global": [{"text": "TNF - alpha receptors I and II", "type": "ENTITY", "char_start": 565444, "char_end": 565474, "token_start": 7, "token_end": 13, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 565492, "char_end": 565503, "token_start": 17, "token_end": 19, "note": null}, {"text": "intercellular adhesion molecule - 1", "type": "ENTITY", "char_start": 565523, "char_end": 565558, "token_start": 23, "token_end": 27, "note": null}]}
+{"sentence_id": 3395, "sentence_text": "In contrast to granulocyte - macrophage colony - stimulating factor ( GM - CSF ) , TNF - alpha did not activate the MAP kinase and p70S6 kinase pathways .", "sentence_char_start_global": 565561, "sentence_char_end_global": 565715, "entities": [{"text": "granulocyte - macrophage colony - stimulating factor", "type": "ENTITY", "char_start": 15, "char_end": 67, "token_start": 3, "token_end": 9}, {"text": "GM - CSF", "type": "ENTITY", "char_start": 70, "char_end": 78, "token_start": 11, "token_end": 13}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 83, "char_end": 94, "token_start": 16, "token_end": 18}, {"text": "MAP kinase", "type": "ENTITY", "char_start": 116, "char_end": 126, "token_start": 23, "token_end": 24}], "entities_global": [{"text": "granulocyte - macrophage colony - stimulating factor", "type": "ENTITY", "char_start": 565576, "char_end": 565628, "token_start": 3, "token_end": 9, "note": null}, {"text": "GM - CSF", "type": "ENTITY", "char_start": 565631, "char_end": 565639, "token_start": 11, "token_end": 13, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 565644, "char_end": 565655, "token_start": 16, "token_end": 18, "note": null}, {"text": "MAP kinase", "type": "ENTITY", "char_start": 565677, "char_end": 565687, "token_start": 23, "token_end": 24, "note": null}]}
+{"sentence_id": 3396, "sentence_text": "Nevertheless , inhibitors of these pathways clearly reduced the TNF - alpha - induced cell growth , indicating that TNF - alpha - proliferative cells produced a growth factor that induced proliferation upon stimulation of the above pathways .", "sentence_char_start_global": 565716, "sentence_char_end_global": 565958, "entities": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 64, "char_end": 75, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 565780, "char_end": 565791, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 3397, "sentence_text": "Anti - GM - CSF antibodies inhibited the TNF - alpha - induced growth , suggesting the presence of an autocrine loop for cell proliferation mediated by GM - CSF .", "sentence_char_start_global": 565959, "sentence_char_end_global": 566121, "entities": [{"text": "Anti - GM - CSF antibodies", "type": "ENTITY", "char_start": 0, "char_end": 26, "token_start": 0, "token_end": 5}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 41, "char_end": 52, "token_start": 8, "token_end": 10}, {"text": "GM - CSF", "type": "ENTITY", "char_start": 152, "char_end": 160, "token_start": 27, "token_end": 29}], "entities_global": [{"text": "Anti - GM - CSF antibodies", "type": "ENTITY", "char_start": 565959, "char_end": 565985, "token_start": 0, "token_end": 5, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 566000, "char_end": 566011, "token_start": 8, "token_end": 10, "note": null}, {"text": "GM - CSF", "type": "ENTITY", "char_start": 566111, "char_end": 566119, "token_start": 27, "token_end": 29, "note": null}]}
+{"sentence_id": 3398, "sentence_text": "Supporting this notion , TNF - alpha - induced upregulation of GM - CSF mRNA levels and protein secretion in the TNF - alpha - proliferative , but not in the TNF - alpha - apoptotic cell lines .", "sentence_char_start_global": 566122, "sentence_char_end_global": 566316, "entities": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 25, "char_end": 36, "token_start": 4, "token_end": 6}, {"text": "GM - CSF mRNA", "type": "ENTITY", "char_start": 63, "char_end": 76, "token_start": 11, "token_end": 14}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 113, "char_end": 124, "token_start": 21, "token_end": 23}], "entities_global": [{"text": "TNF - alpha", "type": "ENTITY", "char_start": 566147, "char_end": 566158, "token_start": 4, "token_end": 6, "note": null}, {"text": "GM - CSF mRNA", "type": "ENTITY", "char_start": 566185, "char_end": 566198, "token_start": 11, "token_end": 14, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 566235, "char_end": 566246, "token_start": 21, "token_end": 23, "note": null}]}
+{"sentence_id": 3399, "sentence_text": "CONCLUSION : These data identify GM - CSF synthesis as an early and essential step in TNF - alpha - induced proliferation .", "sentence_char_start_global": 566317, "sentence_char_end_global": 566440, "entities": [{"text": "GM - CSF", "type": "ENTITY", "char_start": 33, "char_end": 41, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "GM - CSF", "type": "ENTITY", "char_start": 566350, "char_end": 566358, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 3400, "sentence_text": "We show for the first time that TNF - alpha - treated cell lines producing no or only minimal amounts of GM - CSF demonstrate an apoptotic phenotype , while cell lines with high GM - CSF expression rates can escape from growth arrest or even apoptosis .", "sentence_char_start_global": 566441, "sentence_char_end_global": 566694, "entities": [{"text": "GM - CSF", "type": "ENTITY", "char_start": 105, "char_end": 113, "token_start": 21, "token_end": 23}, {"text": "GM - CSF", "type": "ENTITY", "char_start": 178, "char_end": 186, "token_start": 34, "token_end": 36}], "entities_global": [{"text": "GM - CSF", "type": "ENTITY", "char_start": 566546, "char_end": 566554, "token_start": 21, "token_end": 23, "note": null}, {"text": "GM - CSF", "type": "ENTITY", "char_start": 566619, "char_end": 566627, "token_start": 34, "token_end": 36, "note": null}]}
+{"sentence_id": 3401, "sentence_text": "In this context , we discuss arguments pointing at NF - kappaB as regulator of GM - CSF synthesis and thus indirectly as regulator for the escape of TNF - alpha - induced apoptosis", "sentence_char_start_global": 566695, "sentence_char_end_global": 566875, "entities": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 51, "char_end": 62, "token_start": 9, "token_end": 11}, {"text": "GM - CSF", "type": "ENTITY", "char_start": 79, "char_end": 87, "token_start": 15, "token_end": 17}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 149, "char_end": 160, "token_start": 28, "token_end": 30}], "entities_global": [{"text": "NF - kappaB", "type": "ENTITY", "char_start": 566746, "char_end": 566757, "token_start": 9, "token_end": 11, "note": null}, {"text": "GM - CSF", "type": "ENTITY", "char_start": 566774, "char_end": 566782, "token_start": 15, "token_end": 17, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 566844, "char_end": 566855, "token_start": 28, "token_end": 30, "note": null}]}
+{"sentence_id": 3402, "sentence_text": "Glucocorticoid receptor content of T lymphocytes : evidence for heterogeneity .", "sentence_char_start_global": 566876, "sentence_char_end_global": 566955, "entities": [{"text": "Glucocorticoid receptor", "type": "ENTITY", "char_start": 0, "char_end": 23, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "Glucocorticoid receptor", "type": "ENTITY", "char_start": 566876, "char_end": 566899, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 3403, "sentence_text": "Glucocorticoid receptors were measured in T lymphocytes that were isolated from peripheral blood by either nylon wool filtration or E - rosette sedimentation .", "sentence_char_start_global": 566956, "sentence_char_end_global": 567115, "entities": [{"text": "Glucocorticoid receptors", "type": "ENTITY", "char_start": 0, "char_end": 24, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "Glucocorticoid receptors", "type": "ENTITY", "char_start": 566956, "char_end": 566980, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 3404, "sentence_text": "T cells isolated by nylon wool filtration specifically bind 6 . 7 + / - 0 . 2 fmol of dexamethasone per million cells ( equivalent to 4000 + / - 200 receptors per cell ) , whereas T cells isolated by E - rosette sedimentation bind 12 . 0 + / - 0 . 7 fmol of dexamethasone per million cells ( equivalent to 7200 + / - 400 receptors per cell ) .", "sentence_char_start_global": 567116, "sentence_char_end_global": 567459, "entities": [], "entities_global": []}
+{"sentence_id": 3405, "sentence_text": "This difference in the amount of dexamethasone bound by the two T cell preparations was significant ( p less than . 001 ) and was present immediately after cell isolation .", "sentence_char_start_global": 567460, "sentence_char_end_global": 567632, "entities": [], "entities_global": []}
+{"sentence_id": 3406, "sentence_text": "The binding affinities of the different T cell preparations for dexamethasone were similar .", "sentence_char_start_global": 567633, "sentence_char_end_global": 567725, "entities": [], "entities_global": []}
+{"sentence_id": 3407, "sentence_text": "T cells that are isolated by a combination of nylon wool filtration followed by E - rosette sedimentation bind the same amount of dexamethasone as T cells isolated by nylon wool filtration alone .", "sentence_char_start_global": 567726, "sentence_char_end_global": 567922, "entities": [], "entities_global": []}
+{"sentence_id": 3408, "sentence_text": "T cells isolated by a combination of E - rosette sedimentation following by nylon wool filtration bind less dexamethasone than do T cells isolated by E - rosette sedimentation alone .", "sentence_char_start_global": 567923, "sentence_char_end_global": 568106, "entities": [], "entities_global": []}
+{"sentence_id": 3409, "sentence_text": "These findings suggest that T cells are heterogeneous with respect to their quantity of glucocorticoid receptors .", "sentence_char_start_global": 568107, "sentence_char_end_global": 568221, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 88, "char_end": 112, "token_start": 14, "token_end": 15}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 568195, "char_end": 568219, "token_start": 14, "token_end": 15, "note": null}]}
+{"sentence_id": 3410, "sentence_text": "Isolation of T cells by E - rosette sedimentation enriches for T cells that have a greater number of glucocorticoid receptors , and isolation of T cells by nylon wool filtration enriches for T cells that have a lesser number of glucocorticoid receptors .", "sentence_char_start_global": 568222, "sentence_char_end_global": 568476, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 101, "char_end": 125, "token_start": 19, "token_end": 20}, {"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 228, "char_end": 252, "token_start": 41, "token_end": 42}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 568323, "char_end": 568347, "token_start": 19, "token_end": 20, "note": null}, {"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 568450, "char_end": 568474, "token_start": 41, "token_end": 42, "note": null}]}
+{"sentence_id": 3411, "sentence_text": "Glucocorticoid receptors and glucocorticoid sensitivity of human leukemic cells .", "sentence_char_start_global": 568477, "sentence_char_end_global": 568558, "entities": [{"text": "Glucocorticoid receptors", "type": "ENTITY", "char_start": 0, "char_end": 24, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "Glucocorticoid receptors", "type": "ENTITY", "char_start": 568477, "char_end": 568501, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 3412, "sentence_text": "We have established optimal conditions for the measurement of glucocorticoid receptors ( GR ) in human white cells using a whole - cell binding assay with [ 3H ] dexamethasone as the ligand , and the subsequent determination of the GR content in normal human lymphocytes and in leukemic cells of patients with various forms of acute and chronic leukemia .", "sentence_char_start_global": 568559, "sentence_char_end_global": 568914, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 62, "char_end": 86, "token_start": 9, "token_end": 10}, {"text": "GR", "type": "ENTITY", "char_start": 89, "char_end": 91, "token_start": 12, "token_end": 12}, {"text": "GR", "type": "ENTITY", "char_start": 232, "char_end": 234, "token_start": 40, "token_end": 40}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 568621, "char_end": 568645, "token_start": 9, "token_end": 10, "note": null}, {"text": "GR", "type": "ENTITY", "char_start": 568648, "char_end": 568650, "token_start": 12, "token_end": 12, "note": null}, {"text": "GR", "type": "ENTITY", "char_start": 568791, "char_end": 568793, "token_start": 40, "token_end": 40, "note": null}]}
+{"sentence_id": 3413, "sentence_text": "A number of leukemia cell lines in continuous culture were also subjected to the GR assay , and the results were correlated with the sensitivity of these cell lines to glucocorticoid steroids in vitro .", "sentence_char_start_global": 568915, "sentence_char_end_global": 569117, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 81, "char_end": 83, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 568996, "char_end": 568998, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 3414, "sentence_text": "The GR content of normal human lymphocytes amounted to 4 , 850 + / - 1 , 340 ( mean + / - SD ) receptors / cell .", "sentence_char_start_global": 569118, "sentence_char_end_global": 569231, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 4, "char_end": 6, "token_start": 1, "token_end": 1}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 569122, "char_end": 569124, "token_start": 1, "token_end": 1, "note": null}]}
+{"sentence_id": 3415, "sentence_text": "The mean equilibrium dissociation constant ( KD ) of the interaction of [ 3H ] dexamethasone with the GR was 1 . 2 x 10 ( - 8 ) M .", "sentence_char_start_global": 569232, "sentence_char_end_global": 569363, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 102, "char_end": 104, "token_start": 18, "token_end": 18}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 569334, "char_end": 569336, "token_start": 18, "token_end": 18, "note": null}]}
+{"sentence_id": 3416, "sentence_text": "Steroidal compounds with a known glucocorticoid potency effectively competed for the binding , whereas steroids devoid of glucocorticoid activity ( e . g . estradiol - 17 beta and testosterone ) were ineffective .", "sentence_char_start_global": 569364, "sentence_char_end_global": 569577, "entities": [], "entities_global": []}
+{"sentence_id": 3417, "sentence_text": "The GR content of the blast cells obtained from eight patients suffering from acute leukemia and four patients with a blast crisis of chronic myelocytic leukemia was found to be highly variable ( 3 , 230 - 29 , 900 receptors / cell ) , while the lymphocytes of six patients with chronic lymphatic leukemia contained a rather stable GR content ( 2 , 930 - 5 , 120 receptors / cell ) , which was comparable with that of normal lymphocytes .", "sentence_char_start_global": 569578, "sentence_char_end_global": 570016, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 4, "char_end": 6, "token_start": 1, "token_end": 1}, {"text": "GR", "type": "ENTITY", "char_start": 332, "char_end": 334, "token_start": 59, "token_end": 59}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 569582, "char_end": 569584, "token_start": 1, "token_end": 1, "note": null}, {"text": "GR", "type": "ENTITY", "char_start": 569910, "char_end": 569912, "token_start": 59, "token_end": 59, "note": null}]}
+{"sentence_id": 3418, "sentence_text": "GR was identified in all the 12 malignant continuous white cell lines studied .", "sentence_char_start_global": 570017, "sentence_char_end_global": 570096, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 0, "char_end": 2, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 570017, "char_end": 570019, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 3419, "sentence_text": "Large cells contained more GR than the smaller ones .", "sentence_char_start_global": 570097, "sentence_char_end_global": 570150, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 27, "char_end": 29, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 570124, "char_end": 570126, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 3420, "sentence_text": "There was no apparent correlation between the GR concentration and the sensitivity of the cells in vitro to glucocorticoids as judged by [ 3H ] thymidine incorporation studies .", "sentence_char_start_global": 570151, "sentence_char_end_global": 570328, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 46, "char_end": 48, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 570197, "char_end": 570199, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 3421, "sentence_text": "Distribution of the surface markers in the leukemic cell lines did not relate to the GR concentration .", "sentence_char_start_global": 570329, "sentence_char_end_global": 570432, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 85, "char_end": 87, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 570414, "char_end": 570416, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 3422, "sentence_text": "We conclude that the presence of GR is probably a universal feature of the leukemic cells , and , from a clinical standpoint , probably does not alone imply steroid responsiveness .", "sentence_char_start_global": 570433, "sentence_char_end_global": 570614, "entities": [{"text": "GR", "type": "ENTITY", "char_start": 33, "char_end": 35, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "GR", "type": "ENTITY", "char_start": 570466, "char_end": 570468, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 3423, "sentence_text": "Evidence for a steroid receptor in rheumatoid synovial tissue cells .", "sentence_char_start_global": 570615, "sentence_char_end_global": 570684, "entities": [{"text": "steroid receptor", "type": "ENTITY", "char_start": 15, "char_end": 31, "token_start": 3, "token_end": 4}], "entities_global": [{"text": "steroid receptor", "type": "ENTITY", "char_start": 570630, "char_end": 570646, "token_start": 3, "token_end": 4, "note": null}]}
+{"sentence_id": 3424, "sentence_text": "One mechanism by which glucocorticoids could exert their anti - inflammatory action is via rapidly saturable , stereo - specific cytoplasmic protein receptors .", "sentence_char_start_global": 570685, "sentence_char_end_global": 570845, "entities": [{"text": "stereo - specific cytoplasmic protein receptors", "type": "ENTITY", "char_start": 111, "char_end": 158, "token_start": 17, "token_end": 22}], "entities_global": [{"text": "stereo - specific cytoplasmic protein receptors", "type": "ENTITY", "char_start": 570796, "char_end": 570843, "token_start": 17, "token_end": 22, "note": null}]}
+{"sentence_id": 3425, "sentence_text": "This report is of an investigation into such a possibility in synovial cells .", "sentence_char_start_global": 570846, "sentence_char_end_global": 570924, "entities": [], "entities_global": []}
+{"sentence_id": 3426, "sentence_text": "Synovium , obtained from knee joints of rheumatoid patients undergoing surgery , was incubated with clostridiopeptidase A and trypsin - EDTA to obtain cell suspensions .", "sentence_char_start_global": 570925, "sentence_char_end_global": 571094, "entities": [{"text": "clostridiopeptidase A", "type": "ENTITY", "char_start": 100, "char_end": 121, "token_start": 15, "token_end": 16}, {"text": "trypsin - EDTA", "type": "ENTITY", "char_start": 126, "char_end": 140, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "clostridiopeptidase A", "type": "ENTITY", "char_start": 571025, "char_end": 571046, "token_start": 15, "token_end": 16, "note": null}, {"text": "trypsin - EDTA", "type": "ENTITY", "char_start": 571051, "char_end": 571065, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 3427, "sentence_text": "These , together with cells obtained from synovial fluid aspirated from patients with rheumatoid arthritis , were identified by electron microscopy .", "sentence_char_start_global": 571095, "sentence_char_end_global": 571244, "entities": [], "entities_global": []}
+{"sentence_id": 3428, "sentence_text": "Duplicate samples of these cell suspensions were incubated with increasing concentrations of H3Dexamethasone ( 1 x 10 ( - 10 ) M - 1 x 10 ( - 9 ) M ) for 30 minutes at 37 degrees C .", "sentence_char_start_global": 571245, "sentence_char_end_global": 571427, "entities": [], "entities_global": []}
+{"sentence_id": 3429, "sentence_text": "Analysis of the proportion of steroid bound to whole cells showed evidence for specific , rapidly saturable , receptors in the cells obtained from synovial tissue , but this was not found in synovial fluid cells .", "sentence_char_start_global": 571428, "sentence_char_end_global": 571641, "entities": [], "entities_global": []}
+{"sentence_id": 3430, "sentence_text": "Electron micrographs showed that cells obtained from synovial tissue consisted of synovial fibroblast - and macrophage - types , lymphocytes , monocytes and macrophages .", "sentence_char_start_global": 571642, "sentence_char_end_global": 571812, "entities": [], "entities_global": []}
+{"sentence_id": 3431, "sentence_text": "Polymorphonuclear leucocytes appeared to be absent .", "sentence_char_start_global": 571813, "sentence_char_end_global": 571865, "entities": [], "entities_global": []}
+{"sentence_id": 3432, "sentence_text": "However , in synovial fluid cell type polymorphonuclear leucocytes were the predominant cell type .", "sentence_char_start_global": 571866, "sentence_char_end_global": 571965, "entities": [], "entities_global": []}
+{"sentence_id": 3433, "sentence_text": "We concluded from this , that one or more of the cell types present in synovial tissue contain a specific steroid receptor , but that this is lacking in synovial fluid polymorphonuclear leucocytes .", "sentence_char_start_global": 571966, "sentence_char_end_global": 572164, "entities": [{"text": "specific steroid receptor", "type": "ENTITY", "char_start": 97, "char_end": 122, "token_start": 19, "token_end": 21}], "entities_global": [{"text": "specific steroid receptor", "type": "ENTITY", "char_start": 572063, "char_end": 572088, "token_start": 19, "token_end": 21, "note": null}]}
+{"sentence_id": 3434, "sentence_text": "Clinical implications of glucocorticoid receptors in human leukemia .", "sentence_char_start_global": 572165, "sentence_char_end_global": 572234, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 25, "char_end": 49, "token_start": 3, "token_end": 4}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 572190, "char_end": 572214, "token_start": 3, "token_end": 4, "note": null}]}
+{"sentence_id": 3435, "sentence_text": "Glucorticoid receptors were studied in various populations of normal human peripheral blood lymphocytes and leukemic lymphoblasts .", "sentence_char_start_global": 572235, "sentence_char_end_global": 572366, "entities": [{"text": "Glucorticoid receptors", "type": "ENTITY", "char_start": 0, "char_end": 22, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "Glucorticoid receptors", "type": "ENTITY", "char_start": 572235, "char_end": 572257, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 3436, "sentence_text": "Normal lymphocytes contain low levels of glucocorticoid receptor ( approximately 2 , 500 sites / cell ) which are identical in T - and non - T - fractions .", "sentence_char_start_global": 572367, "sentence_char_end_global": 572523, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 41, "char_end": 64, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 572408, "char_end": 572431, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 3437, "sentence_text": "Phytohemagglutinin treatment increases levels about 3 - fold .", "sentence_char_start_global": 572524, "sentence_char_end_global": 572586, "entities": [{"text": "Phytohemagglutinin", "type": "ENTITY", "char_start": 0, "char_end": 18, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "Phytohemagglutinin", "type": "ENTITY", "char_start": 572524, "char_end": 572542, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 3438, "sentence_text": "Leukemic lymphoblasts contain larger numbers of receptor sites .", "sentence_char_start_global": 572587, "sentence_char_end_global": 572651, "entities": [], "entities_global": []}
+{"sentence_id": 3439, "sentence_text": "Presence of receptor is correlated with in vitro sensitivitiy to glucocorticoids and in vivo response to therapy .", "sentence_char_start_global": 572652, "sentence_char_end_global": 572766, "entities": [], "entities_global": []}
+{"sentence_id": 3440, "sentence_text": "Quantity of receptor is also correlated with complete remission duration independently of leukemic cell type ( T or null ) , initial WBC , or age of patient .", "sentence_char_start_global": 572767, "sentence_char_end_global": 572925, "entities": [], "entities_global": []}
+{"sentence_id": 3441, "sentence_text": "Quantitative determination of glucocorticoid receptor levels in acute lymphoblastic leukemia may be of value both as an independent prognostic variable and in suggesting which patients should receive glucocorticoid therapy .", "sentence_char_start_global": 572926, "sentence_char_end_global": 573150, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 30, "char_end": 53, "token_start": 3, "token_end": 4}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 572956, "char_end": 572979, "token_start": 3, "token_end": 4, "note": null}]}
+{"sentence_id": 3442, "sentence_text": "Functional and physical interaction of protein - tyrosine kinases Fyn and Csk in the T - cell signaling system .", "sentence_char_start_global": 573151, "sentence_char_end_global": 573263, "entities": [{"text": "protein - tyrosine kinases Fyn and Csk", "type": "ENTITY", "char_start": 39, "char_end": 77, "token_start": 5, "token_end": 11}], "entities_global": [{"text": "protein - tyrosine kinases Fyn and Csk", "type": "ENTITY", "char_start": 573190, "char_end": 573228, "token_start": 5, "token_end": 11, "note": null}]}
+{"sentence_id": 3443, "sentence_text": "The Src - like protein - tyrosine kinase Fyn is associated with T - cell antigen receptor .", "sentence_char_start_global": 573264, "sentence_char_end_global": 573355, "entities": [{"text": "Src - like protein - tyrosine kinase", "type": "ENTITY", "char_start": 4, "char_end": 40, "token_start": 1, "token_end": 7}, {"text": "Fyn", "type": "ENTITY", "char_start": 41, "char_end": 44, "token_start": 8, "token_end": 8}, {"text": "T - cell antigen receptor", "type": "ENTITY", "char_start": 64, "char_end": 89, "token_start": 12, "token_end": 16}], "entities_global": [{"text": "Src - like protein - tyrosine kinase", "type": "ENTITY", "char_start": 573268, "char_end": 573304, "token_start": 1, "token_end": 7, "note": null}, {"text": "Fyn", "type": "ENTITY", "char_start": 573305, "char_end": 573308, "token_start": 8, "token_end": 8, "note": null}, {"text": "T - cell antigen receptor", "type": "ENTITY", "char_start": 573328, "char_end": 573353, "token_start": 12, "token_end": 16, "note": null}]}
+{"sentence_id": 3444, "sentence_text": "Transient expression of actively mutated Fyn , having Phe - 528 instead of Tyr - 528 or Thr - 338 instead of Ile - 338 , in Jurkat T - cells stimulated the serum response element ( SRE ) , 12 - O - tetradecanoyl - phorbol - 13 - acetate response element , cyclic AMP response element , and c - fos promoter .", "sentence_char_start_global": 573356, "sentence_char_end_global": 573664, "entities": [{"text": "Fyn", "type": "ENTITY", "char_start": 41, "char_end": 44, "token_start": 5, "token_end": 5}, {"text": "stimulated the serum response element", "type": "ENTITY", "char_start": 141, "char_end": 178, "token_start": 31, "token_end": 35}, {"text": "SRE", "type": "ENTITY", "char_start": 181, "char_end": 184, "token_start": 37, "token_end": 37}, {"text": "12 - O - tetradecanoyl - phorbol - 13 - acetate response element", "type": "ENTITY", "char_start": 189, "char_end": 253, "token_start": 40, "token_end": 52}, {"text": "cyclic AMP response element", "type": "ENTITY", "char_start": 256, "char_end": 283, "token_start": 54, "token_end": 57}, {"text": "c - fos promoter", "type": "ENTITY", "char_start": 290, "char_end": 306, "token_start": 60, "token_end": 63}], "entities_global": [{"text": "Fyn", "type": "ENTITY", "char_start": 573397, "char_end": 573400, "token_start": 5, "token_end": 5, "note": null}, {"text": "stimulated the serum response element", "type": "ENTITY", "char_start": 573497, "char_end": 573534, "token_start": 31, "token_end": 35, "note": null}, {"text": "SRE", "type": "ENTITY", "char_start": 573537, "char_end": 573540, "token_start": 37, "token_end": 37, "note": null}, {"text": "12 - O - tetradecanoyl - phorbol - 13 - acetate response element", "type": "ENTITY", "char_start": 573545, "char_end": 573609, "token_start": 40, "token_end": 52, "note": null}, {"text": "cyclic AMP response element", "type": "ENTITY", "char_start": 573612, "char_end": 573639, "token_start": 54, "token_end": 57, "note": null}, {"text": "c - fos promoter", "type": "ENTITY", "char_start": 573646, "char_end": 573662, "token_start": 60, "token_end": 63, "note": null}]}
+{"sentence_id": 3445, "sentence_text": "The stimulation of SRE was particularly prominent not only with active Fyn but also with normal ( wild - type ) Fyn .", "sentence_char_start_global": 573665, "sentence_char_end_global": 573782, "entities": [{"text": "SRE", "type": "ENTITY", "char_start": 19, "char_end": 22, "token_start": 3, "token_end": 3}, {"text": "Fyn", "type": "ENTITY", "char_start": 71, "char_end": 74, "token_start": 11, "token_end": 11}, {"text": "normal ( wild - type ) Fyn", "type": "ENTITY", "char_start": 89, "char_end": 115, "token_start": 15, "token_end": 21}], "entities_global": [{"text": "SRE", "type": "ENTITY", "char_start": 573684, "char_end": 573687, "token_start": 3, "token_end": 3, "note": null}, {"text": "Fyn", "type": "ENTITY", "char_start": 573736, "char_end": 573739, "token_start": 11, "token_end": 11, "note": null}, {"text": "normal ( wild - type ) Fyn", "type": "ENTITY", "char_start": 573754, "char_end": 573780, "token_start": 15, "token_end": 21, "note": null}]}
+{"sentence_id": 3446, "sentence_text": "SRE was also stimulated by both normal and active Lck .", "sentence_char_start_global": 573783, "sentence_char_end_global": 573838, "entities": [{"text": "SRE", "type": "ENTITY", "char_start": 0, "char_end": 3, "token_start": 0, "token_end": 0}, {"text": "normal and active Lck", "type": "ENTITY", "char_start": 32, "char_end": 53, "token_start": 6, "token_end": 9}], "entities_global": [{"text": "SRE", "type": "ENTITY", "char_start": 573783, "char_end": 573786, "token_start": 0, "token_end": 0, "note": null}, {"text": "normal and active Lck", "type": "ENTITY", "char_start": 573815, "char_end": 573836, "token_start": 6, "token_end": 9, "note": null}]}
+{"sentence_id": 3447, "sentence_text": "Furthermore , normal and active Fyn stimulated transcription from the IL - 2 gene promoter when transfected cells were stimulated by concanavalin A plus 12 - O - tetradecanoylphorbol - 13 - acetate .", "sentence_char_start_global": 573839, "sentence_char_end_global": 574038, "entities": [{"text": "normal and active Fyn", "type": "ENTITY", "char_start": 14, "char_end": 35, "token_start": 2, "token_end": 5}, {"text": "IL - 2 gene promoter", "type": "ENTITY", "char_start": 70, "char_end": 90, "token_start": 10, "token_end": 14}, {"text": "concanavalin A", "type": "ENTITY", "char_start": 133, "char_end": 147, "token_start": 21, "token_end": 22}], "entities_global": [{"text": "normal and active Fyn", "type": "ENTITY", "char_start": 573853, "char_end": 573874, "token_start": 2, "token_end": 5, "note": null}, {"text": "IL - 2 gene promoter", "type": "ENTITY", "char_start": 573909, "char_end": 573929, "token_start": 10, "token_end": 14, "note": null}, {"text": "concanavalin A", "type": "ENTITY", "char_start": 573972, "char_end": 573986, "token_start": 21, "token_end": 22, "note": null}]}
+{"sentence_id": 3448, "sentence_text": "Under the same conditions , Lck did not stimulate IL - 2 promoter unless it was activated by mutation .", "sentence_char_start_global": 574039, "sentence_char_end_global": 574142, "entities": [{"text": "Lck", "type": "ENTITY", "char_start": 28, "char_end": 31, "token_start": 5, "token_end": 5}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 50, "char_end": 65, "token_start": 9, "token_end": 12}], "entities_global": [{"text": "Lck", "type": "ENTITY", "char_start": 574067, "char_end": 574070, "token_start": 5, "token_end": 5, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 574089, "char_end": 574104, "token_start": 9, "token_end": 12, "note": null}]}
+{"sentence_id": 3449, "sentence_text": "Interestingly , a mutant Fyn , which has deletions within the SH2 region and so is able to transform chicken embryo fibroblasts , did not stimulate either the c - fos or IL - 2 promoter , suggesting the importance of this region in T - cell signaling .", "sentence_char_start_global": 574143, "sentence_char_end_global": 574395, "entities": [{"text": "mutant Fyn", "type": "ENTITY", "char_start": 18, "char_end": 28, "token_start": 3, "token_end": 4}, {"text": "SH2 region", "type": "ENTITY", "char_start": 62, "char_end": 72, "token_start": 11, "token_end": 12}, {"text": "c - fos or IL - 2 promoter", "type": "ENTITY", "char_start": 159, "char_end": 185, "token_start": 28, "token_end": 35}], "entities_global": [{"text": "mutant Fyn", "type": "ENTITY", "char_start": 574161, "char_end": 574171, "token_start": 3, "token_end": 4, "note": null}, {"text": "SH2 region", "type": "ENTITY", "char_start": 574205, "char_end": 574215, "token_start": 11, "token_end": 12, "note": null}, {"text": "c - fos or IL - 2 promoter", "type": "ENTITY", "char_start": 574302, "char_end": 574328, "token_start": 28, "token_end": 35, "note": null}]}
+{"sentence_id": 3450, "sentence_text": "Csk , which phosphorylates tyrosine residues in the negative regulatory sites of Src family kinases , down - regulated Fyn - and Lck - mediated stimulation of the serum response element and Fyn - mediated enhancement of IL - 2 promoter activity .", "sentence_char_start_global": 574396, "sentence_char_end_global": 574642, "entities": [{"text": "Csk", "type": "ENTITY", "char_start": 0, "char_end": 3, "token_start": 0, "token_end": 0}, {"text": "Src family kinases", "type": "ENTITY", "char_start": 81, "char_end": 99, "token_start": 12, "token_end": 14}, {"text": "serum response element", "type": "ENTITY", "char_start": 163, "char_end": 185, "token_start": 28, "token_end": 30}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 220, "char_end": 235, "token_start": 37, "token_end": 40}], "entities_global": [{"text": "Csk", "type": "ENTITY", "char_start": 574396, "char_end": 574399, "token_start": 0, "token_end": 0, "note": null}, {"text": "Src family kinases", "type": "ENTITY", "char_start": 574477, "char_end": 574495, "token_start": 12, "token_end": 14, "note": null}, {"text": "serum response element", "type": "ENTITY", "char_start": 574559, "char_end": 574581, "token_start": 28, "token_end": 30, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 574616, "char_end": 574631, "token_start": 37, "token_end": 40, "note": null}]}
+{"sentence_id": 3451, "sentence_text": "These data suggest that Fyn and Lck , whose activities are regulated by Csk , are involved in different phases of T - cell activation .", "sentence_char_start_global": 574643, "sentence_char_end_global": 574778, "entities": [{"text": "Fyn", "type": "ENTITY", "char_start": 24, "char_end": 27, "token_start": 4, "token_end": 4}, {"text": "Lck", "type": "ENTITY", "char_start": 32, "char_end": 35, "token_start": 6, "token_end": 6}, {"text": "Csk", "type": "ENTITY", "char_start": 72, "char_end": 75, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "Fyn", "type": "ENTITY", "char_start": 574667, "char_end": 574670, "token_start": 4, "token_end": 4, "note": null}, {"text": "Lck", "type": "ENTITY", "char_start": 574675, "char_end": 574678, "token_start": 6, "token_end": 6, "note": null}, {"text": "Csk", "type": "ENTITY", "char_start": 574715, "char_end": 574718, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 3452, "sentence_text": "A novel NF - kappa B complex containing p65 homodimers : implications for transcriptional control at the level of subunit dimerization .", "sentence_char_start_global": 574779, "sentence_char_end_global": 574915, "entities": [{"text": "NF - kappa B complex", "type": "ENTITY", "char_start": 8, "char_end": 28, "token_start": 2, "token_end": 6}, {"text": "p65 homodimers", "type": "ENTITY", "char_start": 40, "char_end": 54, "token_start": 8, "token_end": 9}], "entities_global": [{"text": "NF - kappa B complex", "type": "ENTITY", "char_start": 574787, "char_end": 574807, "token_start": 2, "token_end": 6, "note": null}, {"text": "p65 homodimers", "type": "ENTITY", "char_start": 574819, "char_end": 574833, "token_start": 8, "token_end": 9, "note": null}]}
+{"sentence_id": 3453, "sentence_text": "The predominant inducible form of the NF - kappa B transcription factor is a heteromeric complex containing two Rel - related DNA - binding subunits , termed p65 and p50 .", "sentence_char_start_global": 574916, "sentence_char_end_global": 575087, "entities": [{"text": "NF - kappa B transcription factor", "type": "ENTITY", "char_start": 38, "char_end": 71, "token_start": 6, "token_end": 11}, {"text": "heteromeric complex", "type": "ENTITY", "char_start": 77, "char_end": 96, "token_start": 14, "token_end": 15}, {"text": "Rel - related DNA - binding subunits", "type": "ENTITY", "char_start": 112, "char_end": 148, "token_start": 18, "token_end": 24}, {"text": "termed p65", "type": "ENTITY", "char_start": 151, "char_end": 161, "token_start": 26, "token_end": 27}, {"text": "p50", "type": "ENTITY", "char_start": 166, "char_end": 169, "token_start": 29, "token_end": 29}], "entities_global": [{"text": "NF - kappa B transcription factor", "type": "ENTITY", "char_start": 574954, "char_end": 574987, "token_start": 6, "token_end": 11, "note": null}, {"text": "heteromeric complex", "type": "ENTITY", "char_start": 574993, "char_end": 575012, "token_start": 14, "token_end": 15, "note": null}, {"text": "Rel - related DNA - binding subunits", "type": "ENTITY", "char_start": 575028, "char_end": 575064, "token_start": 18, "token_end": 24, "note": null}, {"text": "termed p65", "type": "ENTITY", "char_start": 575067, "char_end": 575077, "token_start": 26, "token_end": 27, "note": null}, {"text": "p50", "type": "ENTITY", "char_start": 575082, "char_end": 575085, "token_start": 29, "token_end": 29, "note": null}]}
+{"sentence_id": 3454, "sentence_text": "Prior transfection studies have shown that when these p65 and p50 subunits are expressed independently as stable homodimers , p65 stimulates kappa B - directed transcription , whereas p50 functions as a kappa B - specific repressor .", "sentence_char_start_global": 575088, "sentence_char_end_global": 575321, "entities": [{"text": "p65 and p50 subunits", "type": "ENTITY", "char_start": 54, "char_end": 74, "token_start": 8, "token_end": 11}, {"text": "stable homodimers", "type": "ENTITY", "char_start": 106, "char_end": 123, "token_start": 16, "token_end": 17}, {"text": "p65", "type": "ENTITY", "char_start": 126, "char_end": 129, "token_start": 19, "token_end": 19}, {"text": "p50", "type": "ENTITY", "char_start": 184, "char_end": 187, "token_start": 28, "token_end": 28}], "entities_global": [{"text": "p65 and p50 subunits", "type": "ENTITY", "char_start": 575142, "char_end": 575162, "token_start": 8, "token_end": 11, "note": null}, {"text": "stable homodimers", "type": "ENTITY", "char_start": 575194, "char_end": 575211, "token_start": 16, "token_end": 17, "note": null}, {"text": "p65", "type": "ENTITY", "char_start": 575214, "char_end": 575217, "token_start": 19, "token_end": 19, "note": null}, {"text": "p50", "type": "ENTITY", "char_start": 575272, "char_end": 575275, "token_start": 28, "token_end": 28, "note": null}]}
+{"sentence_id": 3455, "sentence_text": "While authentic p50 homodimers ( previously termed KBF1 ) have been detected in nuclear extracts from nontransfected cells , experimental evidence supporting the existence of p65 homodimers in vivo was lacking .", "sentence_char_start_global": 575322, "sentence_char_end_global": 575533, "entities": [{"text": "p50 homodimers", "type": "ENTITY", "char_start": 16, "char_end": 30, "token_start": 2, "token_end": 3}, {"text": "KBF1", "type": "ENTITY", "char_start": 51, "char_end": 55, "token_start": 7, "token_end": 7}, {"text": "p65 homodimers", "type": "ENTITY", "char_start": 175, "char_end": 189, "token_start": 25, "token_end": 26}], "entities_global": [{"text": "p50 homodimers", "type": "ENTITY", "char_start": 575338, "char_end": 575352, "token_start": 2, "token_end": 3, "note": null}, {"text": "KBF1", "type": "ENTITY", "char_start": 575373, "char_end": 575377, "token_start": 7, "token_end": 7, "note": null}, {"text": "p65 homodimers", "type": "ENTITY", "char_start": 575497, "char_end": 575511, "token_start": 25, "token_end": 26, "note": null}]}
+{"sentence_id": 3456, "sentence_text": "We now provide direct biochemical evidence for the presence of an endogenous pool of inducible p65 homodimers in intact human T cells .", "sentence_char_start_global": 575534, "sentence_char_end_global": 575669, "entities": [{"text": "p65 homodimers", "type": "ENTITY", "char_start": 95, "char_end": 109, "token_start": 15, "token_end": 16}], "entities_global": [{"text": "p65 homodimers", "type": "ENTITY", "char_start": 575629, "char_end": 575643, "token_start": 15, "token_end": 16, "note": null}]}
+{"sentence_id": 3457, "sentence_text": "As with the prototypical NF - kappa B p50 - p65 heterodimer , this novel p65 homodimeric form of NF - kappa B is functionally sequestered in the cytoplasm but rapidly appears in the nuclear compartment following cellular stimulation .", "sentence_char_start_global": 575670, "sentence_char_end_global": 575904, "entities": [{"text": "NF - kappa B p50 - p65 heterodimer", "type": "ENTITY", "char_start": 25, "char_end": 59, "token_start": 4, "token_end": 11}, {"text": "p65 homodimeric form", "type": "ENTITY", "char_start": 73, "char_end": 93, "token_start": 15, "token_end": 17}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 97, "char_end": 109, "token_start": 19, "token_end": 22}], "entities_global": [{"text": "NF - kappa B p50 - p65 heterodimer", "type": "ENTITY", "char_start": 575695, "char_end": 575729, "token_start": 4, "token_end": 11, "note": null}, {"text": "p65 homodimeric form", "type": "ENTITY", "char_start": 575743, "char_end": 575763, "token_start": 15, "token_end": 17, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 575767, "char_end": 575779, "token_start": 19, "token_end": 22, "note": null}]}
+{"sentence_id": 3458, "sentence_text": "Site - directed mutagenesis studies indicate that the homodimerization function of p65 is dependent upon the presence of cysteine 216 and a conserved recognition motif for protein kinase A ( RRPS ; amino acids 273 to 276 ) , both of which reside within a 91 - amino - acid segment of the Rel homology domain that mediates self - association .", "sentence_char_start_global": 575905, "sentence_char_end_global": 576247, "entities": [{"text": "p65", "type": "ENTITY", "char_start": 83, "char_end": 86, "token_start": 11, "token_end": 11}, {"text": "protein kinase A", "type": "ENTITY", "char_start": 172, "char_end": 188, "token_start": 26, "token_end": 28}, {"text": "RRPS", "type": "ENTITY", "char_start": 191, "char_end": 195, "token_start": 30, "token_end": 30}, {"text": "Rel homology domain", "type": "ENTITY", "char_start": 288, "char_end": 307, "token_start": 53, "token_end": 55}], "entities_global": [{"text": "p65", "type": "ENTITY", "char_start": 575988, "char_end": 575991, "token_start": 11, "token_end": 11, "note": null}, {"text": "protein kinase A", "type": "ENTITY", "char_start": 576077, "char_end": 576093, "token_start": 26, "token_end": 28, "note": null}, {"text": "RRPS", "type": "ENTITY", "char_start": 576096, "char_end": 576100, "token_start": 30, "token_end": 30, "note": null}, {"text": "Rel homology domain", "type": "ENTITY", "char_start": 576193, "char_end": 576212, "token_start": 53, "token_end": 55, "note": null}]}
+{"sentence_id": 3459, "sentence_text": "In contrast , mutations at these two sites do not affect heterodimerization of p65 with p50 or its functional interaction with I kappa B alpha .", "sentence_char_start_global": 576248, "sentence_char_end_global": 576392, "entities": [{"text": "p65", "type": "ENTITY", "char_start": 79, "char_end": 82, "token_start": 13, "token_end": 13}, {"text": "p50", "type": "ENTITY", "char_start": 88, "char_end": 91, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "p65", "type": "ENTITY", "char_start": 576327, "char_end": 576330, "token_start": 13, "token_end": 13, "note": null}, {"text": "p50", "type": "ENTITY", "char_start": 576336, "char_end": 576339, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 3460, "sentence_text": "These later findings indicate that neither homo - nor heterodimer formation is an absolute prerequisite for I kappa B alpha recognition of p65 .", "sentence_char_start_global": 576393, "sentence_char_end_global": 576537, "entities": [{"text": "I kappa B alpha", "type": "ENTITY", "char_start": 108, "char_end": 123, "token_start": 16, "token_end": 19}, {"text": "p65", "type": "ENTITY", "char_start": 139, "char_end": 142, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "I kappa B alpha", "type": "ENTITY", "char_start": 576501, "char_end": 576516, "token_start": 16, "token_end": 19, "note": null}, {"text": "p65", "type": "ENTITY", "char_start": 576532, "char_end": 576535, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 3461, "sentence_text": "Taken together with prior in vivo transcription studies , these results suggest that the biological activities of p65 and p50 homodimers are independently regulated , thereby providing an integrated and flexible control mechanism for the rapid activation and repression of NF - kappa B / Rel - directed gene expression .", "sentence_char_start_global": 576538, "sentence_char_end_global": 576858, "entities": [{"text": "p65 and p50 homodimers", "type": "ENTITY", "char_start": 114, "char_end": 136, "token_start": 17, "token_end": 20}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 273, "char_end": 285, "token_start": 40, "token_end": 43}, {"text": "Rel", "type": "ENTITY", "char_start": 288, "char_end": 291, "token_start": 45, "token_end": 45}], "entities_global": [{"text": "p65 and p50 homodimers", "type": "ENTITY", "char_start": 576652, "char_end": 576674, "token_start": 17, "token_end": 20, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 576811, "char_end": 576823, "token_start": 40, "token_end": 43, "note": null}, {"text": "Rel", "type": "ENTITY", "char_start": 576826, "char_end": 576829, "token_start": 45, "token_end": 45, "note": null}]}
+{"sentence_id": 3462, "sentence_text": "Carrier determination for X - linked agammaglobulinemia using X inactivation analysis of purified B cells .", "sentence_char_start_global": 576859, "sentence_char_end_global": 576966, "entities": [], "entities_global": []}
+{"sentence_id": 3463, "sentence_text": "We report the development of a relatively quick and simple method for the assessment of X inactivation status for carrier determination in families affected by X - linked agammaglobulinemia ( XLA ) .", "sentence_char_start_global": 576967, "sentence_char_end_global": 577166, "entities": [], "entities_global": []}
+{"sentence_id": 3464, "sentence_text": "This method utilises an immunomagnetic separation technique for B cell purification and a polymerase chain reaction ( PCR ) based assay for the determination of methylation status at the androgen receptor ( AR ) gene locus to assess whether X inactivation is random or non - random at this locus .", "sentence_char_start_global": 577167, "sentence_char_end_global": 577464, "entities": [{"text": "androgen receptor ( AR ) gene locus", "type": "ENTITY", "char_start": 187, "char_end": 222, "token_start": 29, "token_end": 35}], "entities_global": [{"text": "androgen receptor ( AR ) gene locus", "type": "ENTITY", "char_start": 577354, "char_end": 577389, "token_start": 29, "token_end": 35, "note": null}]}
+{"sentence_id": 3465, "sentence_text": "We report the results we have obtained using this assay to investigate females known to be carriers of various X - linked immunodeficiency disorders .", "sentence_char_start_global": 577465, "sentence_char_end_global": 577615, "entities": [], "entities_global": []}
+{"sentence_id": 3466, "sentence_text": "In addition , we investigated four females from different families affected by XLA , two of whom were of unknown carrier status , and we discuss the results obtained with this and other X - inactivation assays .", "sentence_char_start_global": 577616, "sentence_char_end_global": 577827, "entities": [], "entities_global": []}
+{"sentence_id": 3467, "sentence_text": "A similar assay has recently been described by Allen et al . ( 1992 ) and applied to members of one family affected by XLA .", "sentence_char_start_global": 577828, "sentence_char_end_global": 577952, "entities": [], "entities_global": []}
+{"sentence_id": 3468, "sentence_text": "Effects of IL - 4 and Fc gamma receptor II engagement on Egr - 1 expression during stimulation of B lymphocytes by membrane immunoglobulin crosslinking .", "sentence_char_start_global": 577953, "sentence_char_end_global": 578106, "entities": [{"text": "IL - 4", "type": "ENTITY", "char_start": 11, "char_end": 17, "token_start": 2, "token_end": 4}, {"text": "Fc gamma receptor II", "type": "ENTITY", "char_start": 22, "char_end": 42, "token_start": 6, "token_end": 9}, {"text": "Egr - 1", "type": "ENTITY", "char_start": 57, "char_end": 64, "token_start": 12, "token_end": 14}], "entities_global": [{"text": "IL - 4", "type": "ENTITY", "char_start": 577964, "char_end": 577970, "token_start": 2, "token_end": 4, "note": null}, {"text": "Fc gamma receptor II", "type": "ENTITY", "char_start": 577975, "char_end": 577995, "token_start": 6, "token_end": 9, "note": null}, {"text": "Egr - 1", "type": "ENTITY", "char_start": 578010, "char_end": 578017, "token_start": 12, "token_end": 14, "note": null}]}
+{"sentence_id": 3469, "sentence_text": "Egr - 1 is an immediate early gene that is rapidly upregulated in response to mitogenic signals induced by antigen receptor crosslinking on murine B lymphocytes .", "sentence_char_start_global": 578107, "sentence_char_end_global": 578269, "entities": [{"text": "Egr - 1", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 2}, {"text": "immediate early gene", "type": "ENTITY", "char_start": 14, "char_end": 34, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "Egr - 1", "type": "ENTITY", "char_start": 578107, "char_end": 578114, "token_start": 0, "token_end": 2, "note": null}, {"text": "immediate early gene", "type": "ENTITY", "char_start": 578121, "char_end": 578141, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 3470, "sentence_text": "It has been shown that levels of Egr - 1 expression are closely correlated with B cell proliferation in several models of B cell activation and tolerance .", "sentence_char_start_global": 578270, "sentence_char_end_global": 578425, "entities": [{"text": "Egr - 1", "type": "ENTITY", "char_start": 33, "char_end": 40, "token_start": 7, "token_end": 9}], "entities_global": [{"text": "Egr - 1", "type": "ENTITY", "char_start": 578303, "char_end": 578310, "token_start": 7, "token_end": 9, "note": null}]}
+{"sentence_id": 3471, "sentence_text": "We compared the expression of Egr - 1 during B cell stimulation with Fab ' 2 and IgG anti - immunoglobulin ( anti - Ig ) , since it is known that Fab ' 2 anti - Ig is mitogenic while IgG anti - Ig is not , owing to a dominant inhibitory effect of crosslinking the B cell Fc gamma RII to membrane Ig .", "sentence_char_start_global": 578426, "sentence_char_end_global": 578726, "entities": [{"text": "Egr - 1", "type": "ENTITY", "char_start": 30, "char_end": 37, "token_start": 5, "token_end": 7}, {"text": "Fab ' 2", "type": "ENTITY", "char_start": 69, "char_end": 76, "token_start": 13, "token_end": 15}, {"text": "IgG anti - immunoglobulin", "type": "ENTITY", "char_start": 81, "char_end": 106, "token_start": 17, "token_end": 20}, {"text": "anti - Ig", "type": "ENTITY", "char_start": 109, "char_end": 118, "token_start": 22, "token_end": 24}, {"text": "Fab ' 2 anti - Ig", "type": "ENTITY", "char_start": 146, "char_end": 163, "token_start": 32, "token_end": 37}, {"text": "IgG anti - Ig", "type": "ENTITY", "char_start": 183, "char_end": 196, "token_start": 41, "token_end": 44}, {"text": "B cell Fc gamma RII", "type": "ENTITY", "char_start": 264, "char_end": 283, "token_start": 57, "token_end": 61}, {"text": "membrane Ig", "type": "ENTITY", "char_start": 287, "char_end": 298, "token_start": 63, "token_end": 64}], "entities_global": [{"text": "Egr - 1", "type": "ENTITY", "char_start": 578456, "char_end": 578463, "token_start": 5, "token_end": 7, "note": null}, {"text": "Fab ' 2", "type": "ENTITY", "char_start": 578495, "char_end": 578502, "token_start": 13, "token_end": 15, "note": null}, {"text": "IgG anti - immunoglobulin", "type": "ENTITY", "char_start": 578507, "char_end": 578532, "token_start": 17, "token_end": 20, "note": null}, {"text": "anti - Ig", "type": "ENTITY", "char_start": 578535, "char_end": 578544, "token_start": 22, "token_end": 24, "note": null}, {"text": "Fab ' 2 anti - Ig", "type": "ENTITY", "char_start": 578572, "char_end": 578589, "token_start": 32, "token_end": 37, "note": null}, {"text": "IgG anti - Ig", "type": "ENTITY", "char_start": 578609, "char_end": 578622, "token_start": 41, "token_end": 44, "note": null}, {"text": "B cell Fc gamma RII", "type": "ENTITY", "char_start": 578690, "char_end": 578709, "token_start": 57, "token_end": 61, "note": null}, {"text": "membrane Ig", "type": "ENTITY", "char_start": 578713, "char_end": 578724, "token_start": 63, "token_end": 64, "note": null}]}
+{"sentence_id": 3472, "sentence_text": "While mitogenic doses of Fab ' 2 anti - Ig induce large and rapid increases in Egr - 1 expression , IgG anti - Ig results in smaller increases in Egr - 1 mRNA , comparable to that seen with submitogenic concentrations of Fab ' 2 anti - Ig .", "sentence_char_start_global": 578727, "sentence_char_end_global": 578967, "entities": [{"text": "Fab ' 2 anti - Ig", "type": "ENTITY", "char_start": 25, "char_end": 42, "token_start": 4, "token_end": 9}, {"text": "IgG anti - Ig", "type": "ENTITY", "char_start": 100, "char_end": 113, "token_start": 21, "token_end": 24}, {"text": "Egr - 1 mRNA", "type": "ENTITY", "char_start": 146, "char_end": 158, "token_start": 30, "token_end": 33}, {"text": "Fab ' 2 anti - Ig", "type": "ENTITY", "char_start": 221, "char_end": 238, "token_start": 43, "token_end": 48}], "entities_global": [{"text": "Fab ' 2 anti - Ig", "type": "ENTITY", "char_start": 578752, "char_end": 578769, "token_start": 4, "token_end": 9, "note": null}, {"text": "IgG anti - Ig", "type": "ENTITY", "char_start": 578827, "char_end": 578840, "token_start": 21, "token_end": 24, "note": null}, {"text": "Egr - 1 mRNA", "type": "ENTITY", "char_start": 578873, "char_end": 578885, "token_start": 30, "token_end": 33, "note": null}, {"text": "Fab ' 2 anti - Ig", "type": "ENTITY", "char_start": 578948, "char_end": 578965, "token_start": 43, "token_end": 48, "note": null}]}
+{"sentence_id": 3473, "sentence_text": "However , the correlation between Egr - 1 expression and B cell proliferation breaks down when IL - 4 is added as a co - mitogen to induce B cell proliferation with IgG anti - Ig or submitogenic concentrations of Fab ' 2 anti - Ig .", "sentence_char_start_global": 578968, "sentence_char_end_global": 579200, "entities": [{"text": "IL - 4", "type": "ENTITY", "char_start": 95, "char_end": 101, "token_start": 16, "token_end": 18}, {"text": "IgG anti - Ig", "type": "ENTITY", "char_start": 165, "char_end": 178, "token_start": 32, "token_end": 35}, {"text": "Fab ' 2 anti - Ig", "type": "ENTITY", "char_start": 213, "char_end": 230, "token_start": 40, "token_end": 45}], "entities_global": [{"text": "IL - 4", "type": "ENTITY", "char_start": 579063, "char_end": 579069, "token_start": 16, "token_end": 18, "note": null}, {"text": "IgG anti - Ig", "type": "ENTITY", "char_start": 579133, "char_end": 579146, "token_start": 32, "token_end": 35, "note": null}, {"text": "Fab ' 2 anti - Ig", "type": "ENTITY", "char_start": 579181, "char_end": 579198, "token_start": 40, "token_end": 45, "note": null}]}
+{"sentence_id": 3474, "sentence_text": "No corresponding increases in Egr - 1 mRNA levels are observed when IL - 4 is added .", "sentence_char_start_global": 579201, "sentence_char_end_global": 579286, "entities": [{"text": "Egr - 1 mRNA", "type": "ENTITY", "char_start": 30, "char_end": 42, "token_start": 4, "token_end": 7}, {"text": "IL - 4", "type": "ENTITY", "char_start": 68, "char_end": 74, "token_start": 12, "token_end": 14}], "entities_global": [{"text": "Egr - 1 mRNA", "type": "ENTITY", "char_start": 579231, "char_end": 579243, "token_start": 4, "token_end": 7, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 579269, "char_end": 579275, "token_start": 12, "token_end": 14, "note": null}]}
+{"sentence_id": 3475, "sentence_text": "Therefore , IL - 4 overcomes Fc receptor - mediated inhibition of B cell proliferation without affecting inhibition of Egr - 1 mRNA induction , as demonstrated earlier for c - myc mRNA in this system .", "sentence_char_start_global": 579287, "sentence_char_end_global": 579488, "entities": [{"text": "IL - 4", "type": "ENTITY", "char_start": 12, "char_end": 18, "token_start": 2, "token_end": 4}, {"text": "Egr - 1 mRNA", "type": "ENTITY", "char_start": 119, "char_end": 131, "token_start": 19, "token_end": 22}, {"text": "c - myc mRNA", "type": "ENTITY", "char_start": 172, "char_end": 184, "token_start": 29, "token_end": 32}], "entities_global": [{"text": "IL - 4", "type": "ENTITY", "char_start": 579299, "char_end": 579305, "token_start": 2, "token_end": 4, "note": null}, {"text": "Egr - 1 mRNA", "type": "ENTITY", "char_start": 579406, "char_end": 579418, "token_start": 19, "token_end": 22, "note": null}, {"text": "c - myc mRNA", "type": "ENTITY", "char_start": 579459, "char_end": 579471, "token_start": 29, "token_end": 32, "note": null}]}
+{"sentence_id": 3476, "sentence_text": "Identification of a novel cyclosporin - sensitive element in the human tumor necrosis factor alpha gene promoter .", "sentence_char_start_global": 579489, "sentence_char_end_global": 579603, "entities": [{"text": "cyclosporin - sensitive element", "type": "ENTITY", "char_start": 26, "char_end": 57, "token_start": 4, "token_end": 7}, {"text": "human tumor necrosis factor alpha gene promoter", "type": "ENTITY", "char_start": 65, "char_end": 112, "token_start": 10, "token_end": 16}], "entities_global": [{"text": "cyclosporin - sensitive element", "type": "ENTITY", "char_start": 579515, "char_end": 579546, "token_start": 4, "token_end": 7, "note": null}, {"text": "human tumor necrosis factor alpha gene promoter", "type": "ENTITY", "char_start": 579554, "char_end": 579601, "token_start": 10, "token_end": 16, "note": null}]}
+{"sentence_id": 3477, "sentence_text": "Tumor necrosis factor alpha ( TNF - alpha ) , a cytokine with pleiotropic biological effects , is produced by a variety of cell types in response to induction by diverse stimuli .", "sentence_char_start_global": 579604, "sentence_char_end_global": 579783, "entities": [{"text": "Tumor necrosis factor alpha", "type": "ENTITY", "char_start": 0, "char_end": 27, "token_start": 0, "token_end": 3}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 30, "char_end": 41, "token_start": 5, "token_end": 7}, {"text": "cytokine", "type": "ENTITY", "char_start": 48, "char_end": 56, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "Tumor necrosis factor alpha", "type": "ENTITY", "char_start": 579604, "char_end": 579631, "token_start": 0, "token_end": 3, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 579634, "char_end": 579645, "token_start": 5, "token_end": 7, "note": null}, {"text": "cytokine", "type": "ENTITY", "char_start": 579652, "char_end": 579660, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 3478, "sentence_text": "In this paper , TNF - alpha mRNA is shown to be highly induced in a murine T cell clone by stimulation with T cell receptor ( TCR ) ligands or by calcium ionophores alone .", "sentence_char_start_global": 579784, "sentence_char_end_global": 579956, "entities": [{"text": "TNF - alpha mRNA", "type": "ENTITY", "char_start": 16, "char_end": 32, "token_start": 4, "token_end": 7}, {"text": "T cell receptor", "type": "ENTITY", "char_start": 108, "char_end": 123, "token_start": 23, "token_end": 25}, {"text": "TCR", "type": "ENTITY", "char_start": 126, "char_end": 129, "token_start": 27, "token_end": 27}], "entities_global": [{"text": "TNF - alpha mRNA", "type": "ENTITY", "char_start": 579800, "char_end": 579816, "token_start": 4, "token_end": 7, "note": null}, {"text": "T cell receptor", "type": "ENTITY", "char_start": 579892, "char_end": 579907, "token_start": 23, "token_end": 25, "note": null}, {"text": "TCR", "type": "ENTITY", "char_start": 579910, "char_end": 579913, "token_start": 27, "token_end": 27, "note": null}]}
+{"sentence_id": 3479, "sentence_text": "Induction is rapid , does not require de novo protein synthesis , and is completely blocked by the immunosuppressant cyclosporin A ( CsA ) .", "sentence_char_start_global": 579957, "sentence_char_end_global": 580097, "entities": [], "entities_global": []}
+{"sentence_id": 3480, "sentence_text": "We have identified a human TNF - alpha promoter element , kappa 3 , which plays a key role in the calcium - mediated inducibility and CsA sensitivity of the gene .", "sentence_char_start_global": 580098, "sentence_char_end_global": 580261, "entities": [{"text": "human TNF - alpha promoter element", "type": "ENTITY", "char_start": 21, "char_end": 55, "token_start": 4, "token_end": 9}, {"text": "kappa 3", "type": "ENTITY", "char_start": 58, "char_end": 65, "token_start": 11, "token_end": 12}], "entities_global": [{"text": "human TNF - alpha promoter element", "type": "ENTITY", "char_start": 580119, "char_end": 580153, "token_start": 4, "token_end": 9, "note": null}, {"text": "kappa 3", "type": "ENTITY", "char_start": 580156, "char_end": 580163, "token_start": 11, "token_end": 12, "note": null}]}
+{"sentence_id": 3481, "sentence_text": "In electrophoretic mobility shift assays , an oligonucleotide containing kappa 3 forms two DNA protein complexes with proteins that are present in extracts from unstimulated T cells .", "sentence_char_start_global": 580262, "sentence_char_end_global": 580445, "entities": [{"text": "kappa 3", "type": "ENTITY", "char_start": 73, "char_end": 80, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "kappa 3", "type": "ENTITY", "char_start": 580335, "char_end": 580342, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 3482, "sentence_text": "These complexes appear in nuclear extracts only after T cell stimulation .", "sentence_char_start_global": 580446, "sentence_char_end_global": 580520, "entities": [], "entities_global": []}
+{"sentence_id": 3483, "sentence_text": "Induction of the inducible nuclear complexes is rapid , independent of protein synthesis , and blocked by CsA , and thus , exactly parallels the induction of TNF - alpha mRNA by TCR ligands or by calcium ionophore .", "sentence_char_start_global": 580521, "sentence_char_end_global": 580736, "entities": [{"text": "nuclear complexes", "type": "ENTITY", "char_start": 27, "char_end": 44, "token_start": 4, "token_end": 5}, {"text": "TNF - alpha mRNA", "type": "ENTITY", "char_start": 158, "char_end": 174, "token_start": 27, "token_end": 30}], "entities_global": [{"text": "nuclear complexes", "type": "ENTITY", "char_start": 580548, "char_end": 580565, "token_start": 4, "token_end": 5, "note": null}, {"text": "TNF - alpha mRNA", "type": "ENTITY", "char_start": 580679, "char_end": 580695, "token_start": 27, "token_end": 30, "note": null}]}
+{"sentence_id": 3484, "sentence_text": "Our studies indicate that the kappa 3 binding factor resembles the preexisting component of nuclear factor of activated T cells .", "sentence_char_start_global": 580737, "sentence_char_end_global": 580866, "entities": [{"text": "kappa 3 binding factor", "type": "ENTITY", "char_start": 30, "char_end": 52, "token_start": 5, "token_end": 8}, {"text": "nuclear factor", "type": "ENTITY", "char_start": 92, "char_end": 106, "token_start": 14, "token_end": 15}], "entities_global": [{"text": "kappa 3 binding factor", "type": "ENTITY", "char_start": 580767, "char_end": 580789, "token_start": 5, "token_end": 8, "note": null}, {"text": "nuclear factor", "type": "ENTITY", "char_start": 580829, "char_end": 580843, "token_start": 14, "token_end": 15, "note": null}]}
+{"sentence_id": 3485, "sentence_text": "Thus , the TNF - alpha gene is an immediate early gene in activated T cells and provides a new model system in which to study CsA - sensitive gene induction in activated T cells .", "sentence_char_start_global": 580867, "sentence_char_end_global": 581046, "entities": [{"text": "TNF - alpha gene", "type": "ENTITY", "char_start": 11, "char_end": 27, "token_start": 3, "token_end": 6}, {"text": "CsA - sensitive gene", "type": "ENTITY", "char_start": 126, "char_end": 146, "token_start": 26, "token_end": 29}], "entities_global": [{"text": "TNF - alpha gene", "type": "ENTITY", "char_start": 580878, "char_end": 580894, "token_start": 3, "token_end": 6, "note": null}, {"text": "CsA - sensitive gene", "type": "ENTITY", "char_start": 580993, "char_end": 581013, "token_start": 26, "token_end": 29, "note": null}]}
+{"sentence_id": 3486, "sentence_text": "Differences in expression of transcription factor AP - 1 in human promyelocytic HL - 60 cells during differentiation towards macrophages versus granulocytes .", "sentence_char_start_global": 581047, "sentence_char_end_global": 581205, "entities": [{"text": "transcription factor AP - 1", "type": "ENTITY", "char_start": 29, "char_end": 56, "token_start": 4, "token_end": 8}], "entities_global": [{"text": "transcription factor AP - 1", "type": "ENTITY", "char_start": 581076, "char_end": 581103, "token_start": 4, "token_end": 8, "note": null}]}
+{"sentence_id": 3487, "sentence_text": "Commitment of HL - 60 cells to macrophage or granulocytic differentiation was achieved by incubation with 4 beta - phorbol 12 - myristate 13 - acetate ( PMA ) for 30 - 60 min or with dimethyl sulphoxide ( DMSO ) for 24 h respectively .", "sentence_char_start_global": 581206, "sentence_char_end_global": 581441, "entities": [], "entities_global": []}
+{"sentence_id": 3488, "sentence_text": "The commitment stage towards PMA - induced macrophage differentiation was associated with increases in jun B and c - fos mRNA levels , as well as with an increase in the binding activity of transcription factor AP - 1 .", "sentence_char_start_global": 581442, "sentence_char_end_global": 581661, "entities": [{"text": "transcription factor AP - 1", "type": "ENTITY", "char_start": 190, "char_end": 217, "token_start": 34, "token_end": 38}], "entities_global": [{"text": "transcription factor AP - 1", "type": "ENTITY", "char_start": 581632, "char_end": 581659, "token_start": 34, "token_end": 38, "note": null}]}
+{"sentence_id": 3489, "sentence_text": "Nevertheless , gel retardation analysis indicated that the AP - 1 activity detected in untreated cells was drastically reduced during the commitment stage of DMSO - induced HL - 60 differentiation towards granulocytes .", "sentence_char_start_global": 581662, "sentence_char_end_global": 581881, "entities": [{"text": "AP - 1", "type": "ENTITY", "char_start": 59, "char_end": 65, "token_start": 8, "token_end": 10}], "entities_global": [{"text": "AP - 1", "type": "ENTITY", "char_start": 581721, "char_end": 581727, "token_start": 8, "token_end": 10, "note": null}]}
+{"sentence_id": 3490, "sentence_text": "When HL - 60 cells were treated with sodium butyrate , which induced monocytic differentiation , a remarkable increase in AP - 1 binding activity was detected .", "sentence_char_start_global": 581882, "sentence_char_end_global": 582042, "entities": [], "entities_global": []}
+{"sentence_id": 3491, "sentence_text": "Treatment of HL - 60 cells with 1 alpha , 25 - dihydroxyvitamin D3 , another monocytic differentiation agent , induced a weak , but appreciable , increase in AP - 1 activity .", "sentence_char_start_global": 582043, "sentence_char_end_global": 582218, "entities": [{"text": "AP - 1", "type": "ENTITY", "char_start": 158, "char_end": 164, "token_start": 29, "token_end": 31}], "entities_global": [{"text": "AP - 1", "type": "ENTITY", "char_start": 582201, "char_end": 582207, "token_start": 29, "token_end": 31, "note": null}]}
+{"sentence_id": 3492, "sentence_text": "Furthermore , addition of sodium butyrate or 1 alpha , 25 - dihydroxyvitamin D3 to HL - 60 cells induced the expression of c - fos , c - jun , jun B and jun D proto - oncogenes .", "sentence_char_start_global": 582219, "sentence_char_end_global": 582397, "entities": [{"text": "c - fos , c - jun , jun B and jun D proto - oncogenes", "type": "ENTITY", "char_start": 123, "char_end": 176, "token_start": 23, "token_end": 38}], "entities_global": [{"text": "c - fos , c - jun , jun B and jun D proto - oncogenes", "type": "ENTITY", "char_start": 582342, "char_end": 582395, "token_start": 23, "token_end": 38, "note": null}]}
+{"sentence_id": 3493, "sentence_text": "In contrast , when HL - 60 cells were treated with retinoic acid , a granulocytic differentiation inducer , no enhanced AP - 1 binding activity was observed , and only a weak increase in jun D mRNA level was detected .", "sentence_char_start_global": 582398, "sentence_char_end_global": 582616, "entities": [{"text": "jun D mRNA", "type": "ENTITY", "char_start": 187, "char_end": 197, "token_start": 35, "token_end": 37}], "entities_global": [{"text": "jun D mRNA", "type": "ENTITY", "char_start": 582585, "char_end": 582595, "token_start": 35, "token_end": 37, "note": null}]}
+{"sentence_id": 3494, "sentence_text": "These data indicate that formation of AP - 1 is not required for the induction of HL - 60 differentiation towards granulocytes , whereas induction of monocytic differentiation is correlated with an increase in AP - 1 activity .", "sentence_char_start_global": 582617, "sentence_char_end_global": 582844, "entities": [{"text": "AP - 1", "type": "ENTITY", "char_start": 38, "char_end": 44, "token_start": 6, "token_end": 8}, {"text": "AP - 1", "type": "ENTITY", "char_start": 210, "char_end": 216, "token_start": 34, "token_end": 36}], "entities_global": [{"text": "AP - 1", "type": "ENTITY", "char_start": 582655, "char_end": 582661, "token_start": 6, "token_end": 8, "note": null}, {"text": "AP - 1", "type": "ENTITY", "char_start": 582827, "char_end": 582833, "token_start": 34, "token_end": 36, "note": null}]}
+{"sentence_id": 3495, "sentence_text": "The differential expression of AP - 1 activity may be critical in the differentiation of HL - 60 cells towards monocytic or granulocytic lineages", "sentence_char_start_global": 582845, "sentence_char_end_global": 582990, "entities": [{"text": "AP - 1", "type": "ENTITY", "char_start": 31, "char_end": 37, "token_start": 4, "token_end": 6}], "entities_global": [{"text": "AP - 1", "type": "ENTITY", "char_start": 582876, "char_end": 582882, "token_start": 4, "token_end": 6, "note": null}]}
+{"sentence_id": 3496, "sentence_text": "Glucocorticoid receptors and sensitivity in leukemias .", "sentence_char_start_global": 582991, "sentence_char_end_global": 583046, "entities": [{"text": "Glucocorticoid receptors", "type": "ENTITY", "char_start": 0, "char_end": 24, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "Glucocorticoid receptors", "type": "ENTITY", "char_start": 582991, "char_end": 583015, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 3497, "sentence_text": "In an attempt to investigate the utility of glucocorticoid receptor determination to predict clinical responsiveness in human leukemias we have studied glucocorticoid receptors in the leukemic cells from 46 patients and in the lymphocytes from 18 normal donors .", "sentence_char_start_global": 583047, "sentence_char_end_global": 583309, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 44, "char_end": 67, "token_start": 8, "token_end": 9}, {"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 152, "char_end": 176, "token_start": 21, "token_end": 22}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 583091, "char_end": 583114, "token_start": 8, "token_end": 9, "note": null}, {"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 583199, "char_end": 583223, "token_start": 21, "token_end": 22, "note": null}]}
+{"sentence_id": 3498, "sentence_text": "In the normal lymphocytes there were 3 , 875 ( Median ) specific binding sites per cell .", "sentence_char_start_global": 583310, "sentence_char_end_global": 583399, "entities": [], "entities_global": []}
+{"sentence_id": 3499, "sentence_text": "The blasts from 17 patients with ANLL had on average higher levels of binding sites per cell ( Median = 7 , 250 , range : 0 to 15 , 295 ) than the other leukemias .", "sentence_char_start_global": 583400, "sentence_char_end_global": 583564, "entities": [{"text": "binding sites", "type": "ENTITY", "char_start": 70, "char_end": 83, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "binding sites", "type": "ENTITY", "char_start": 583470, "char_end": 583483, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 3500, "sentence_text": "Of the 15 patients with CLL , six had received glucocorticoid treatment for 3 to 5 years .", "sentence_char_start_global": 583565, "sentence_char_end_global": 583655, "entities": [], "entities_global": []}
+{"sentence_id": 3501, "sentence_text": "Their lymphocytes had lower number of receptors ( Median = 2 , 000 ) than the other cases which were newly diagnosed ( Median = 4 , 500 ) .", "sentence_char_start_global": 583656, "sentence_char_end_global": 583795, "entities": [], "entities_global": []}
+{"sentence_id": 3502, "sentence_text": "Four patients had ALL / AUL , three patients had blast crisis as terminal phase of CML , and seven had leukemic Non - Hodgkin lymphomas ( Median = 3 , 500 sites / cell ) .", "sentence_char_start_global": 583796, "sentence_char_end_global": 583967, "entities": [], "entities_global": []}
+{"sentence_id": 3503, "sentence_text": "In 24 patients we have also studied the in vitro sensitivity of the leukemic cells to dexamethasone .", "sentence_char_start_global": 583968, "sentence_char_end_global": 584069, "entities": [], "entities_global": []}
+{"sentence_id": 3504, "sentence_text": "There was no marked correlation between glucocorticoid receptor levels and in vitro sensitivity .", "sentence_char_start_global": 584070, "sentence_char_end_global": 584167, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 40, "char_end": 63, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 584110, "char_end": 584133, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 3505, "sentence_text": "An attempt to correlate receptor levels with clinical responsiveness demonstrated that glucocorticoid receptor determination might be of value in patients with lymphoid malignancies but probably not in patients with other leukemias .", "sentence_char_start_global": 584168, "sentence_char_end_global": 584401, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 87, "char_end": 110, "token_start": 11, "token_end": 12}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 584255, "char_end": 584278, "token_start": 11, "token_end": 12, "note": null}]}
+{"sentence_id": 3506, "sentence_text": "' Activation - labile ' glucocorticoid - receptor complexes of a steroid - resistant variant of CEM - C7 human lymphoid cells .", "sentence_char_start_global": 584402, "sentence_char_end_global": 584529, "entities": [{"text": "' Activation - labile ' glucocorticoid - receptor complexes", "type": "ENTITY", "char_start": 0, "char_end": 59, "token_start": 0, "token_end": 8}], "entities_global": [{"text": "' Activation - labile ' glucocorticoid - receptor complexes", "type": "ENTITY", "char_start": 584402, "char_end": 584461, "token_start": 0, "token_end": 8, "note": null}]}
+{"sentence_id": 3507, "sentence_text": "For cytoplasmic glucocorticoid - receptor complexes to enter and accumulate in the nucleus a temperature - dependent event , ' activation ' is required .", "sentence_char_start_global": 584530, "sentence_char_end_global": 584683, "entities": [{"text": "cytoplasmic glucocorticoid - receptor complexes", "type": "ENTITY", "char_start": 4, "char_end": 51, "token_start": 1, "token_end": 5}], "entities_global": [{"text": "cytoplasmic glucocorticoid - receptor complexes", "type": "ENTITY", "char_start": 584534, "char_end": 584581, "token_start": 1, "token_end": 5, "note": null}]}
+{"sentence_id": 3508, "sentence_text": "Activation can be achieved in vitro by increased ionic strength , dilution or gel filtration and is manifested by an increased affinity of steroid - receptor complex for DNA and an altered elution profile from ion - exchange resins .", "sentence_char_start_global": 584684, "sentence_char_end_global": 584917, "entities": [{"text": "steroid - receptor complex", "type": "ENTITY", "char_start": 139, "char_end": 165, "token_start": 23, "token_end": 26}, {"text": "DNA", "type": "ENTITY", "char_start": 170, "char_end": 173, "token_start": 28, "token_end": 28}], "entities_global": [{"text": "steroid - receptor complex", "type": "ENTITY", "char_start": 584823, "char_end": 584849, "token_start": 23, "token_end": 26, "note": null}, {"text": "DNA", "type": "ENTITY", "char_start": 584854, "char_end": 584857, "token_start": 28, "token_end": 28, "note": null}]}
+{"sentence_id": 3509, "sentence_text": "Munck and Foley have shown that activated complexes isolated from thymocytes elute from DEAE - cellulose in a manner identical to complexes activated in vitro .", "sentence_char_start_global": 584918, "sentence_char_end_global": 585078, "entities": [{"text": "activated complexes", "type": "ENTITY", "char_start": 32, "char_end": 51, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "activated complexes", "type": "ENTITY", "char_start": 584950, "char_end": 584969, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 3510, "sentence_text": "We report here that DEAE - cellulose chromatography of steroid - receptor complexes from CEM - C7 , a cloned human leukaemic T - cell line sensitive to the cytolytic action of glucocorticoids , and its steroid - resistant subclone 4R4 demonstrated that steroid receptors of clone 4R4 can not form stable activated complexes .", "sentence_char_start_global": 585079, "sentence_char_end_global": 585404, "entities": [{"text": "steroid - receptor complexes", "type": "ENTITY", "char_start": 55, "char_end": 83, "token_start": 9, "token_end": 12}, {"text": "steroid receptors", "type": "ENTITY", "char_start": 253, "char_end": 270, "token_start": 43, "token_end": 44}], "entities_global": [{"text": "steroid - receptor complexes", "type": "ENTITY", "char_start": 585134, "char_end": 585162, "token_start": 9, "token_end": 12, "note": null}, {"text": "steroid receptors", "type": "ENTITY", "char_start": 585332, "char_end": 585349, "token_start": 43, "token_end": 44, "note": null}]}
+{"sentence_id": 3511, "sentence_text": "This defines a new defect in receptor action , activation lability ( r + act1 ) , which is unlike either the r - , r + nt - , or r + nti phenotypes previously described for mouse lymphoid variants .", "sentence_char_start_global": 585405, "sentence_char_end_global": 585603, "entities": [], "entities_global": []}
+{"sentence_id": 3512, "sentence_text": "Granulocytes in the endometrium of post - partum women .", "sentence_char_start_global": 585604, "sentence_char_end_global": 585660, "entities": [], "entities_global": []}
+{"sentence_id": 3513, "sentence_text": "Endometrial samples of women at various stages of gonadal activity after parturition were examined for the presence and numbers of endometrial granulocytes .", "sentence_char_start_global": 585661, "sentence_char_end_global": 585818, "entities": [], "entities_global": []}
+{"sentence_id": 3514, "sentence_text": "Although samples at all the stages contained significant numbers of the granulocytes ( i . e . greater than 7 / high - power field ) , the 100 % values for late - proliferative and adaptation hyperplasia were significantly higher than the values for the resting ( 81 . 8 % ) , early ( 82 . 4 % ) and mid - ( 87 . 9 % ) proliferative and secretory ( 83 . 3 % ) phases .", "sentence_char_start_global": 585819, "sentence_char_end_global": 586187, "entities": [], "entities_global": []}
+{"sentence_id": 3515, "sentence_text": "We suggest that this correlates with the suggestion that the granulocytes constitute a receptor system for oestrogens .", "sentence_char_start_global": 586188, "sentence_char_end_global": 586307, "entities": [], "entities_global": []}
+{"sentence_id": 3516, "sentence_text": "Interaction of glucocorticoids with macrophages .", "sentence_char_start_global": 586308, "sentence_char_end_global": 586357, "entities": [], "entities_global": []}
+{"sentence_id": 3517, "sentence_text": "Identification of glucocorticoid receptors in monocytes and macrophages .", "sentence_char_start_global": 586358, "sentence_char_end_global": 586431, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 18, "char_end": 42, "token_start": 2, "token_end": 3}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 586376, "char_end": 586400, "token_start": 2, "token_end": 3, "note": null}]}
+{"sentence_id": 3518, "sentence_text": "Glucocorticoid binding was measured in resident and thioglycollate - elicited mouse peritoneal macrophages , rabbit alveolar macrophages , and human monocytes .", "sentence_char_start_global": 586432, "sentence_char_end_global": 586592, "entities": [], "entities_global": []}
+{"sentence_id": 3519, "sentence_text": "Two assays of binding were used - - an assay with intact cells in suspension or monolayers , and an assay of cytosol and nuclear forms of glucocorticoid receptors .", "sentence_char_start_global": 586593, "sentence_char_end_global": 586757, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 138, "char_end": 162, "token_start": 27, "token_end": 28}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 586731, "char_end": 586755, "token_start": 27, "token_end": 28, "note": null}]}
+{"sentence_id": 3520, "sentence_text": "The mononuclear phagocytes contained approximately equal to 4 - - 10 X 10 ( 3 ) high affinity receptor sites per cell , with dissociation constants of approximately equal to 2 - - 8 nM dexamethasone .", "sentence_char_start_global": 586758, "sentence_char_end_global": 586958, "entities": [{"text": "high affinity receptor sites", "type": "ENTITY", "char_start": 80, "char_end": 108, "token_start": 16, "token_end": 19}], "entities_global": [{"text": "high affinity receptor sites", "type": "ENTITY", "char_start": 586838, "char_end": 586866, "token_start": 16, "token_end": 19, "note": null}]}
+{"sentence_id": 3521, "sentence_text": "The binding to the saturable sites was specific for steroids with glucocorticoid or antiglucocorticoid activity .", "sentence_char_start_global": 586959, "sentence_char_end_global": 587072, "entities": [{"text": "saturable sites", "type": "ENTITY", "char_start": 19, "char_end": 34, "token_start": 4, "token_end": 5}], "entities_global": [{"text": "saturable sites", "type": "ENTITY", "char_start": 586978, "char_end": 586993, "token_start": 4, "token_end": 5, "note": null}]}
+{"sentence_id": 3522, "sentence_text": "Cortisol , corticosterone , and progesterone competed with dexamethasone for binding , whereas estradiol , dihydrotestosterone , and 11 - epicortisol competed very little .", "sentence_char_start_global": 587073, "sentence_char_end_global": 587245, "entities": [], "entities_global": []}
+{"sentence_id": 3523, "sentence_text": "Binding of dexamethasone to cytosol and nuclear forms of the receptor complex and temperature - sensitive translocation of cytosol forms to nuclear forms were shown .", "sentence_char_start_global": 587246, "sentence_char_end_global": 587412, "entities": [{"text": "receptor complex", "type": "ENTITY", "char_start": 61, "char_end": 77, "token_start": 10, "token_end": 11}], "entities_global": [{"text": "receptor complex", "type": "ENTITY", "char_start": 587307, "char_end": 587323, "token_start": 10, "token_end": 11, "note": null}]}
+{"sentence_id": 3524, "sentence_text": "At 37 degrees C the predominant form of the hormone - receptor complex was nuclear .", "sentence_char_start_global": 587413, "sentence_char_end_global": 587497, "entities": [{"text": "hormone - receptor complex", "type": "ENTITY", "char_start": 44, "char_end": 70, "token_start": 9, "token_end": 12}], "entities_global": [{"text": "hormone - receptor complex", "type": "ENTITY", "char_start": 587457, "char_end": 587483, "token_start": 9, "token_end": 12, "note": null}]}
+{"sentence_id": 3525, "sentence_text": "These results demonstrate that corticosteroids interact with macrophages at physiological concentrations .", "sentence_char_start_global": 587498, "sentence_char_end_global": 587604, "entities": [], "entities_global": []}
+{"sentence_id": 3526, "sentence_text": "Nitric oxide signaling : a possible role for G proteins .", "sentence_char_start_global": 587605, "sentence_char_end_global": 587662, "entities": [{"text": "G proteins", "type": "ENTITY", "char_start": 45, "char_end": 55, "token_start": 8, "token_end": 9}], "entities_global": [{"text": "G proteins", "type": "ENTITY", "char_start": 587650, "char_end": 587660, "token_start": 8, "token_end": 9, "note": null}]}
+{"sentence_id": 3527, "sentence_text": "We have previously reported various inductive effects of nitric oxide on human PBMC .", "sentence_char_start_global": 587663, "sentence_char_end_global": 587748, "entities": [], "entities_global": []}
+{"sentence_id": 3528, "sentence_text": "We describe a novel and potentially important mechanism of nitric oxide signaling - through direct activation of guanine nucleotide - binding proteins ( G proteins ) .", "sentence_char_start_global": 587749, "sentence_char_end_global": 587916, "entities": [{"text": "guanine nucleotide - binding proteins", "type": "ENTITY", "char_start": 113, "char_end": 150, "token_start": 17, "token_end": 21}, {"text": "G proteins", "type": "ENTITY", "char_start": 153, "char_end": 163, "token_start": 23, "token_end": 24}], "entities_global": [{"text": "guanine nucleotide - binding proteins", "type": "ENTITY", "char_start": 587862, "char_end": 587899, "token_start": 17, "token_end": 21, "note": null}, {"text": "G proteins", "type": "ENTITY", "char_start": 587902, "char_end": 587912, "token_start": 23, "token_end": 24, "note": null}]}
+{"sentence_id": 3529, "sentence_text": "We have found that nitric oxide treatment of membranes isolated from fresh human PBMC enhances the ability of these membranes to hydrolyze [ gamma - 32P ] GTP and bind [ gamma - 35S ] GTP .", "sentence_char_start_global": 587917, "sentence_char_end_global": 588106, "entities": [], "entities_global": []}
+{"sentence_id": 3530, "sentence_text": "In addition , treatment of whole cells with nitric oxide yielded membranes with enhanced GTPase activity .", "sentence_char_start_global": 588107, "sentence_char_end_global": 588213, "entities": [], "entities_global": []}
+{"sentence_id": 3531, "sentence_text": "Furthermore , the GTPase activity of pure , recombinant Gs alpha , Gi alpha 1 , and p21ras was greatly enhanced by nitric oxide .", "sentence_char_start_global": 588214, "sentence_char_end_global": 588343, "entities": [{"text": "Gs alpha", "type": "ENTITY", "char_start": 56, "char_end": 64, "token_start": 9, "token_end": 10}, {"text": "Gi alpha 1", "type": "ENTITY", "char_start": 67, "char_end": 77, "token_start": 12, "token_end": 14}, {"text": "p21ras", "type": "ENTITY", "char_start": 84, "char_end": 90, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "Gs alpha", "type": "ENTITY", "char_start": 588270, "char_end": 588278, "token_start": 9, "token_end": 10, "note": null}, {"text": "Gi alpha 1", "type": "ENTITY", "char_start": 588281, "char_end": 588291, "token_start": 12, "token_end": 14, "note": null}, {"text": "p21ras", "type": "ENTITY", "char_start": 588298, "char_end": 588304, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 3532, "sentence_text": "In support of the existence of this pathway in whole cells , we found that the G protein inhibitor , GDP - beta - S , blocked NF - kappa B translocation induced by nitric oxide or LPS in permeabilized cells .", "sentence_char_start_global": 588344, "sentence_char_end_global": 588552, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 126, "char_end": 138, "token_start": 27, "token_end": 30}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 588470, "char_end": 588482, "token_start": 27, "token_end": 30, "note": null}]}
+{"sentence_id": 3533, "sentence_text": "In addition , nitric oxide greatly reduced the pertussis toxin - mediated ADP - ribosylation of 45 - and 41 - kDa proteins in membranes of these cells .", "sentence_char_start_global": 588553, "sentence_char_end_global": 588705, "entities": [{"text": "45 - and 41 - kDa proteins", "type": "ENTITY", "char_start": 96, "char_end": 122, "token_start": 16, "token_end": 22}], "entities_global": [{"text": "45 - and 41 - kDa proteins", "type": "ENTITY", "char_start": 588649, "char_end": 588675, "token_start": 16, "token_end": 22, "note": null}]}
+{"sentence_id": 3534, "sentence_text": "Because G proteins play a central role in many diverse signaling systems , activation by an endogenous and inducible oxidant may represent a novel signaling pathway .", "sentence_char_start_global": 588706, "sentence_char_end_global": 588872, "entities": [{"text": "G proteins", "type": "ENTITY", "char_start": 8, "char_end": 18, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "G proteins", "type": "ENTITY", "char_start": 588714, "char_end": 588724, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 3535, "sentence_text": "The granulocyte - macrophage colony - stimulating factor promoter cis - acting element CLE0 mediates induction signals in T cells and is recognized by factors related to AP1 and NFAT .", "sentence_char_start_global": 588873, "sentence_char_end_global": 589057, "entities": [{"text": "granulocyte - macrophage colony - stimulating factor promoter cis - acting element", "type": "ENTITY", "char_start": 4, "char_end": 86, "token_start": 1, "token_end": 12}, {"text": "CLE0", "type": "ENTITY", "char_start": 87, "char_end": 91, "token_start": 13, "token_end": 13}, {"text": "AP1", "type": "ENTITY", "char_start": 170, "char_end": 173, "token_start": 27, "token_end": 27}, {"text": "NFAT", "type": "ENTITY", "char_start": 178, "char_end": 182, "token_start": 29, "token_end": 29}], "entities_global": [{"text": "granulocyte - macrophage colony - stimulating factor promoter cis - acting element", "type": "ENTITY", "char_start": 588877, "char_end": 588959, "token_start": 1, "token_end": 12, "note": null}, {"text": "CLE0", "type": "ENTITY", "char_start": 588960, "char_end": 588964, "token_start": 13, "token_end": 13, "note": null}, {"text": "AP1", "type": "ENTITY", "char_start": 589043, "char_end": 589046, "token_start": 27, "token_end": 27, "note": null}, {"text": "NFAT", "type": "ENTITY", "char_start": 589051, "char_end": 589055, "token_start": 29, "token_end": 29, "note": null}]}
+{"sentence_id": 3536, "sentence_text": "Expression of the granulocyte - macrophage colony - stimulating factor ( GM - CSF ) gene in T cells is activated by the combination of phorbol ester ( phorbol myristate acetate ) and calcium ionophore ( A23187 ) , which mimic antigen stimulation through the T - cell receptor .", "sentence_char_start_global": 589058, "sentence_char_end_global": 589335, "entities": [{"text": "granulocyte - macrophage colony - stimulating factor ( GM - CSF ) gene", "type": "ENTITY", "char_start": 18, "char_end": 88, "token_start": 3, "token_end": 15}, {"text": "T - cell receptor", "type": "ENTITY", "char_start": 258, "char_end": 275, "token_start": 45, "token_end": 48}], "entities_global": [{"text": "granulocyte - macrophage colony - stimulating factor ( GM - CSF ) gene", "type": "ENTITY", "char_start": 589076, "char_end": 589146, "token_start": 3, "token_end": 15, "note": null}, {"text": "T - cell receptor", "type": "ENTITY", "char_start": 589316, "char_end": 589333, "token_start": 45, "token_end": 48, "note": null}]}
+{"sentence_id": 3537, "sentence_text": "We have previously shown that a fragment containing bp - 95 to + 27 of the mouse GM - CSF promoter can confer inducibility to reporter genes in the human Jurkat T - cell line .", "sentence_char_start_global": 589336, "sentence_char_end_global": 589512, "entities": [{"text": "bp - 95 to + 27", "type": "ENTITY", "char_start": 52, "char_end": 67, "token_start": 8, "token_end": 13}, {"text": "mouse GM - CSF promoter", "type": "ENTITY", "char_start": 75, "char_end": 98, "token_start": 16, "token_end": 20}, {"text": "reporter genes", "type": "ENTITY", "char_start": 126, "char_end": 140, "token_start": 25, "token_end": 26}], "entities_global": [{"text": "bp - 95 to + 27", "type": "ENTITY", "char_start": 589388, "char_end": 589403, "token_start": 8, "token_end": 13, "note": null}, {"text": "mouse GM - CSF promoter", "type": "ENTITY", "char_start": 589411, "char_end": 589434, "token_start": 16, "token_end": 20, "note": null}, {"text": "reporter genes", "type": "ENTITY", "char_start": 589462, "char_end": 589476, "token_start": 25, "token_end": 26, "note": null}]}
+{"sentence_id": 3538, "sentence_text": "Here we use an in vitro transcription system to demonstrate that a cis - acting element ( positions - 54 to - 40 ) , referred to as CLE0 , is a target for the induction signals .", "sentence_char_start_global": 589513, "sentence_char_end_global": 589691, "entities": [{"text": "cis - acting element", "type": "ENTITY", "char_start": 67, "char_end": 87, "token_start": 12, "token_end": 15}, {"text": "positions - 54 to - 40", "type": "ENTITY", "char_start": 90, "char_end": 112, "token_start": 17, "token_end": 22}, {"text": "CLE0", "type": "ENTITY", "char_start": 132, "char_end": 136, "token_start": 28, "token_end": 28}], "entities_global": [{"text": "cis - acting element", "type": "ENTITY", "char_start": 589580, "char_end": 589600, "token_start": 12, "token_end": 15, "note": null}, {"text": "positions - 54 to - 40", "type": "ENTITY", "char_start": 589603, "char_end": 589625, "token_start": 17, "token_end": 22, "note": null}, {"text": "CLE0", "type": "ENTITY", "char_start": 589645, "char_end": 589649, "token_start": 28, "token_end": 28, "note": null}]}
+{"sentence_id": 3539, "sentence_text": "We observed induction with templates containing intact CLE0 but not with templates with deleted or mutated CLE0 .", "sentence_char_start_global": 589692, "sentence_char_end_global": 589805, "entities": [{"text": "CLE0", "type": "ENTITY", "char_start": 55, "char_end": 59, "token_start": 7, "token_end": 7}, {"text": "deleted or mutated CLE0", "type": "ENTITY", "char_start": 88, "char_end": 111, "token_start": 13, "token_end": 16}], "entities_global": [{"text": "CLE0", "type": "ENTITY", "char_start": 589747, "char_end": 589751, "token_start": 7, "token_end": 7, "note": null}, {"text": "deleted or mutated CLE0", "type": "ENTITY", "char_start": 589780, "char_end": 589803, "token_start": 13, "token_end": 16, "note": null}]}
+{"sentence_id": 3540, "sentence_text": "We also observed that two distinct signals were required for the stimulation through CLE0 , since only extracts from cells treated with both phorbol myristate acetate and A23187 supported optimal induction .", "sentence_char_start_global": 589806, "sentence_char_end_global": 590013, "entities": [{"text": "CLE0", "type": "ENTITY", "char_start": 85, "char_end": 89, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "CLE0", "type": "ENTITY", "char_start": 589891, "char_end": 589895, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 3541, "sentence_text": "Stimulation probably was mediated by CLE0 - binding proteins because depletion of these proteins specifically reduced GM - CSF transcription .", "sentence_char_start_global": 590014, "sentence_char_end_global": 590156, "entities": [{"text": "CLE0 - binding proteins", "type": "ENTITY", "char_start": 37, "char_end": 60, "token_start": 5, "token_end": 8}, {"text": "GM - CSF", "type": "ENTITY", "char_start": 118, "char_end": 126, "token_start": 16, "token_end": 18}], "entities_global": [{"text": "CLE0 - binding proteins", "type": "ENTITY", "char_start": 590051, "char_end": 590074, "token_start": 5, "token_end": 8, "note": null}, {"text": "GM - CSF", "type": "ENTITY", "char_start": 590132, "char_end": 590140, "token_start": 16, "token_end": 18, "note": null}]}
+{"sentence_id": 3542, "sentence_text": "One of the binding factors possessed biochemical and immunological features identical to those of the transcription factor AP1 .", "sentence_char_start_global": 590157, "sentence_char_end_global": 590285, "entities": [{"text": "binding factors", "type": "ENTITY", "char_start": 11, "char_end": 26, "token_start": 3, "token_end": 4}, {"text": "transcription factor AP1", "type": "ENTITY", "char_start": 102, "char_end": 126, "token_start": 15, "token_end": 17}], "entities_global": [{"text": "binding factors", "type": "ENTITY", "char_start": 590168, "char_end": 590183, "token_start": 3, "token_end": 4, "note": null}, {"text": "transcription factor AP1", "type": "ENTITY", "char_start": 590259, "char_end": 590283, "token_start": 15, "token_end": 17, "note": null}]}
+{"sentence_id": 3543, "sentence_text": "Another factor resembled the T - cell - specific factor NFAT .", "sentence_char_start_global": 590286, "sentence_char_end_global": 590348, "entities": [{"text": "T - cell - specific factor NFAT", "type": "ENTITY", "char_start": 29, "char_end": 60, "token_start": 4, "token_end": 10}], "entities_global": [{"text": "T - cell - specific factor NFAT", "type": "ENTITY", "char_start": 590315, "char_end": 590346, "token_start": 4, "token_end": 10, "note": null}]}
+{"sentence_id": 3544, "sentence_text": "The characteristics of these two factors are consistent with their involvement in GM - CSF induction .", "sentence_char_start_global": 590349, "sentence_char_end_global": 590451, "entities": [], "entities_global": []}
+{"sentence_id": 3545, "sentence_text": "The presence of CLE0 - like elements in the promoters of interleukin - 3 ( IL - 3 ) , IL - 4 , IL - 5 , GM - CSF , and NFAT sites in the IL - 2 promoter suggests that the factors we detected , or related factors that recognize these sites , may account for the coordinate induction of these genes during T - cell activation .", "sentence_char_start_global": 590452, "sentence_char_end_global": 590777, "entities": [{"text": "CLE0 - like elements", "type": "ENTITY", "char_start": 16, "char_end": 36, "token_start": 3, "token_end": 6}, {"text": "promoters", "type": "ENTITY", "char_start": 44, "char_end": 53, "token_start": 9, "token_end": 9}, {"text": "interleukin - 3 ( IL - 3 ) , IL - 4 , IL - 5 , GM - CSF , and NFAT sites", "type": "ENTITY", "char_start": 57, "char_end": 129, "token_start": 11, "token_end": 34}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 137, "char_end": 152, "token_start": 37, "token_end": 40}], "entities_global": [{"text": "CLE0 - like elements", "type": "ENTITY", "char_start": 590468, "char_end": 590488, "token_start": 3, "token_end": 6, "note": null}, {"text": "promoters", "type": "ENTITY", "char_start": 590496, "char_end": 590505, "token_start": 9, "token_end": 9, "note": null}, {"text": "interleukin - 3 ( IL - 3 ) , IL - 4 , IL - 5 , GM - CSF , and NFAT sites", "type": "ENTITY", "char_start": 590509, "char_end": 590581, "token_start": 11, "token_end": 34, "note": null}, {"text": "IL - 2 promoter", "type": "ENTITY", "char_start": 590589, "char_end": 590604, "token_start": 37, "token_end": 40, "note": null}]}
+{"sentence_id": 3546, "sentence_text": "Identification and characterization of an Alu - containing , T - cell - specific enhancer located in the last intron of the human CD8 alpha gene .", "sentence_char_start_global": 590778, "sentence_char_end_global": 590924, "entities": [{"text": "Alu - containing , T - cell - specific enhancer", "type": "ENTITY", "char_start": 42, "char_end": 89, "token_start": 5, "token_end": 14}, {"text": "intron", "type": "ENTITY", "char_start": 110, "char_end": 116, "token_start": 19, "token_end": 19}, {"text": "human CD8 alpha gene", "type": "ENTITY", "char_start": 124, "char_end": 144, "token_start": 22, "token_end": 25}], "entities_global": [{"text": "Alu - containing , T - cell - specific enhancer", "type": "ENTITY", "char_start": 590820, "char_end": 590867, "token_start": 5, "token_end": 14, "note": null}, {"text": "intron", "type": "ENTITY", "char_start": 590888, "char_end": 590894, "token_start": 19, "token_end": 19, "note": null}, {"text": "human CD8 alpha gene", "type": "ENTITY", "char_start": 590902, "char_end": 590922, "token_start": 22, "token_end": 25, "note": null}]}
+{"sentence_id": 3547, "sentence_text": "Expression of the human CD8 alpha gene is restricted to cells of the lymphoid lineage and developmentally regulated during thymopoiesis .", "sentence_char_start_global": 590925, "sentence_char_end_global": 591062, "entities": [{"text": "human CD8 alpha gene", "type": "ENTITY", "char_start": 18, "char_end": 38, "token_start": 3, "token_end": 6}], "entities_global": [{"text": "human CD8 alpha gene", "type": "ENTITY", "char_start": 590943, "char_end": 590963, "token_start": 3, "token_end": 6, "note": null}]}
+{"sentence_id": 3548, "sentence_text": "As an initial step towards understanding the molecular basis for tissue - specific expression of this gene , we surveyed the surrounding chromatin structure for potential cis - acting regulatory regions by DNase I hypersensitivity mapping and found four hypersensitive sites , three of which were T cell restricted .", "sentence_char_start_global": 591063, "sentence_char_end_global": 591379, "entities": [{"text": "cis - acting regulatory regions", "type": "ENTITY", "char_start": 171, "char_end": 202, "token_start": 26, "token_end": 30}, {"text": "DNase I", "type": "ENTITY", "char_start": 206, "char_end": 213, "token_start": 32, "token_end": 33}], "entities_global": [{"text": "cis - acting regulatory regions", "type": "ENTITY", "char_start": 591234, "char_end": 591265, "token_start": 26, "token_end": 30, "note": null}, {"text": "DNase I", "type": "ENTITY", "char_start": 591269, "char_end": 591276, "token_start": 32, "token_end": 33, "note": null}]}
+{"sentence_id": 3549, "sentence_text": "By using a reporter - based expression approach , a T - cell - specific enhancer was identified by its close association with a prominent T - cell - restricted hypersensitive sites in the last intron of the CD8 alpha gene .", "sentence_char_start_global": 591380, "sentence_char_end_global": 591603, "entities": [{"text": "T - cell - specific enhancer", "type": "ENTITY", "char_start": 52, "char_end": 80, "token_start": 10, "token_end": 15}, {"text": "T - cell - restricted hypersensitive sites", "type": "ENTITY", "char_start": 138, "char_end": 180, "token_start": 25, "token_end": 31}, {"text": "CD8 alpha gene", "type": "ENTITY", "char_start": 207, "char_end": 221, "token_start": 38, "token_end": 40}], "entities_global": [{"text": "T - cell - specific enhancer", "type": "ENTITY", "char_start": 591432, "char_end": 591460, "token_start": 10, "token_end": 15, "note": null}, {"text": "T - cell - restricted hypersensitive sites", "type": "ENTITY", "char_start": 591518, "char_end": 591560, "token_start": 25, "token_end": 31, "note": null}, {"text": "CD8 alpha gene", "type": "ENTITY", "char_start": 591587, "char_end": 591601, "token_start": 38, "token_end": 40, "note": null}]}
+{"sentence_id": 3550, "sentence_text": "Deletion studies demonstrated that the minimal enhancer is adjacent to a negative regulatory element .", "sentence_char_start_global": 591604, "sentence_char_end_global": 591706, "entities": [], "entities_global": []}
+{"sentence_id": 3551, "sentence_text": "DNA sequence analysis of the minimal enhancer revealed a striking cluster of consensus binding sites for Ets - 1 , TCF - 1 , CRE , GATA - 3 , LyF - 1 , and bHLH proteins which were verified by electrophoretic mobility shift assays .", "sentence_char_start_global": 591707, "sentence_char_end_global": 591939, "entities": [{"text": "minimal enhancer", "type": "ENTITY", "char_start": 29, "char_end": 45, "token_start": 5, "token_end": 6}, {"text": "consensus binding sites", "type": "ENTITY", "char_start": 77, "char_end": 100, "token_start": 12, "token_end": 14}, {"text": "Ets - 1 , TCF - 1 , CRE , GATA - 3 , LyF - 1 , and bHLH proteins", "type": "ENTITY", "char_start": 105, "char_end": 169, "token_start": 16, "token_end": 36}], "entities_global": [{"text": "minimal enhancer", "type": "ENTITY", "char_start": 591736, "char_end": 591752, "token_start": 5, "token_end": 6, "note": null}, {"text": "consensus binding sites", "type": "ENTITY", "char_start": 591784, "char_end": 591807, "token_start": 12, "token_end": 14, "note": null}, {"text": "Ets - 1 , TCF - 1 , CRE , GATA - 3 , LyF - 1 , and bHLH proteins", "type": "ENTITY", "char_start": 591812, "char_end": 591876, "token_start": 16, "token_end": 36, "note": null}]}
+{"sentence_id": 3552, "sentence_text": "In addition , the 5 ' end of the enhancer was composed of an Alu repeat which contained the GATA - 3 , bHLH , and LyF - 1 binding sites .", "sentence_char_start_global": 591940, "sentence_char_end_global": 592077, "entities": [{"text": "5 ' end", "type": "ENTITY", "char_start": 18, "char_end": 25, "token_start": 4, "token_end": 6}, {"text": "enhancer", "type": "ENTITY", "char_start": 33, "char_end": 41, "token_start": 9, "token_end": 9}, {"text": "GATA - 3 , bHLH , and LyF - 1 binding sites", "type": "ENTITY", "char_start": 92, "char_end": 135, "token_start": 19, "token_end": 30}], "entities_global": [{"text": "5 ' end", "type": "ENTITY", "char_start": 591958, "char_end": 591965, "token_start": 4, "token_end": 6, "note": null}, {"text": "enhancer", "type": "ENTITY", "char_start": 591973, "char_end": 591981, "token_start": 9, "token_end": 9, "note": null}, {"text": "GATA - 3 , bHLH , and LyF - 1 binding sites", "type": "ENTITY", "char_start": 592032, "char_end": 592075, "token_start": 19, "token_end": 30, "note": null}]}
+{"sentence_id": 3553, "sentence_text": "Site - directed mutation of the Ets - 1 and GATA - 3 sites dramatically reduced enhancer activity .", "sentence_char_start_global": 592078, "sentence_char_end_global": 592177, "entities": [{"text": "Ets - 1 and GATA - 3 sites", "type": "ENTITY", "char_start": 32, "char_end": 58, "token_start": 6, "token_end": 13}], "entities_global": [{"text": "Ets - 1 and GATA - 3 sites", "type": "ENTITY", "char_start": 592110, "char_end": 592136, "token_start": 6, "token_end": 13, "note": null}]}
+{"sentence_id": 3554, "sentence_text": "The functional importance of the other binding sites only became apparent when combinations of mutations were analyzed .", "sentence_char_start_global": 592178, "sentence_char_end_global": 592298, "entities": [], "entities_global": []}
+{"sentence_id": 3555, "sentence_text": "Taken together , these results suggest that the human CD8 alpha gene is regulated by the interaction of multiple T - cell nuclear proteins with a transcriptional enhancer located in the last intron of the gene .", "sentence_char_start_global": 592299, "sentence_char_end_global": 592510, "entities": [{"text": "human CD8 alpha gene", "type": "ENTITY", "char_start": 48, "char_end": 68, "token_start": 8, "token_end": 11}, {"text": "T - cell nuclear proteins", "type": "ENTITY", "char_start": 113, "char_end": 138, "token_start": 19, "token_end": 23}, {"text": "intron", "type": "ENTITY", "char_start": 191, "char_end": 197, "token_start": 32, "token_end": 32}], "entities_global": [{"text": "human CD8 alpha gene", "type": "ENTITY", "char_start": 592347, "char_end": 592367, "token_start": 8, "token_end": 11, "note": null}, {"text": "T - cell nuclear proteins", "type": "ENTITY", "char_start": 592412, "char_end": 592437, "token_start": 19, "token_end": 23, "note": null}, {"text": "intron", "type": "ENTITY", "char_start": 592490, "char_end": 592496, "token_start": 32, "token_end": 32, "note": null}]}
+{"sentence_id": 3556, "sentence_text": "Comparison of the CD8 alpha enhancer with other recently identified T - cell - specific regulatory elements suggests that a common set of transcription factors regulates several T - cell genes .", "sentence_char_start_global": 592511, "sentence_char_end_global": 592705, "entities": [{"text": "CD8 alpha enhancer", "type": "ENTITY", "char_start": 18, "char_end": 36, "token_start": 3, "token_end": 5}, {"text": "T - cell - specific regulatory elements", "type": "ENTITY", "char_start": 68, "char_end": 107, "token_start": 10, "token_end": 16}, {"text": "transcription factors", "type": "ENTITY", "char_start": 138, "char_end": 159, "token_start": 23, "token_end": 24}, {"text": "T - cell genes", "type": "ENTITY", "char_start": 178, "char_end": 192, "token_start": 27, "token_end": 30}], "entities_global": [{"text": "CD8 alpha enhancer", "type": "ENTITY", "char_start": 592529, "char_end": 592547, "token_start": 3, "token_end": 5, "note": null}, {"text": "T - cell - specific regulatory elements", "type": "ENTITY", "char_start": 592579, "char_end": 592618, "token_start": 10, "token_end": 16, "note": null}, {"text": "transcription factors", "type": "ENTITY", "char_start": 592649, "char_end": 592670, "token_start": 23, "token_end": 24, "note": null}, {"text": "T - cell genes", "type": "ENTITY", "char_start": 592689, "char_end": 592703, "token_start": 27, "token_end": 30, "note": null}]}
+{"sentence_id": 3557, "sentence_text": "Molecular regulation of the human IL - 3 gene : inducible T cell - restricted expression requires intact AP - 1 and Elf - 1 nuclear protein binding sites .", "sentence_char_start_global": 592706, "sentence_char_end_global": 592861, "entities": [{"text": "human IL - 3 gene", "type": "ENTITY", "char_start": 28, "char_end": 45, "token_start": 4, "token_end": 8}, {"text": "AP - 1 and Elf - 1 nuclear protein binding sites", "type": "ENTITY", "char_start": 105, "char_end": 153, "token_start": 18, "token_end": 28}], "entities_global": [{"text": "human IL - 3 gene", "type": "ENTITY", "char_start": 592734, "char_end": 592751, "token_start": 4, "token_end": 8, "note": null}, {"text": "AP - 1 and Elf - 1 nuclear protein binding sites", "type": "ENTITY", "char_start": 592811, "char_end": 592859, "token_start": 18, "token_end": 28, "note": null}]}
+{"sentence_id": 3558, "sentence_text": "Interleukin 3 ( IL - 3 ) is a hematopoietic stem - cell growth and differentiation factor that is expressed solely in activated T and NK cells .", "sentence_char_start_global": 592862, "sentence_char_end_global": 593006, "entities": [{"text": "Interleukin 3", "type": "ENTITY", "char_start": 0, "char_end": 13, "token_start": 0, "token_end": 1}, {"text": "IL - 3", "type": "ENTITY", "char_start": 16, "char_end": 22, "token_start": 3, "token_end": 5}, {"text": "hematopoietic stem - cell growth and differentiation factor", "type": "ENTITY", "char_start": 30, "char_end": 89, "token_start": 9, "token_end": 16}], "entities_global": [{"text": "Interleukin 3", "type": "ENTITY", "char_start": 592862, "char_end": 592875, "token_start": 0, "token_end": 1, "note": null}, {"text": "IL - 3", "type": "ENTITY", "char_start": 592878, "char_end": 592884, "token_start": 3, "token_end": 5, "note": null}, {"text": "hematopoietic stem - cell growth and differentiation factor", "type": "ENTITY", "char_start": 592892, "char_end": 592951, "token_start": 9, "token_end": 16, "note": null}]}
+{"sentence_id": 3559, "sentence_text": "Studies to date have identified elements 5 ' to the IL - 3 coding sequences that regulate its transcription , but the sequences that confer T cell - specific expression remain to be clearly defined .", "sentence_char_start_global": 593007, "sentence_char_end_global": 593206, "entities": [{"text": "IL - 3 coding sequences", "type": "ENTITY", "char_start": 52, "char_end": 75, "token_start": 10, "token_end": 14}], "entities_global": [{"text": "IL - 3 coding sequences", "type": "ENTITY", "char_start": 593059, "char_end": 593082, "token_start": 10, "token_end": 14, "note": null}]}
+{"sentence_id": 3560, "sentence_text": "We have now identified DNA sequences that are required for T cell - restricted IL - 3 gene transcription .", "sentence_char_start_global": 593207, "sentence_char_end_global": 593313, "entities": [{"text": "DNA sequences", "type": "ENTITY", "char_start": 23, "char_end": 36, "token_start": 4, "token_end": 5}, {"text": "IL - 3 gene", "type": "ENTITY", "char_start": 79, "char_end": 90, "token_start": 14, "token_end": 17}], "entities_global": [{"text": "DNA sequences", "type": "ENTITY", "char_start": 593230, "char_end": 593243, "token_start": 4, "token_end": 5, "note": null}, {"text": "IL - 3 gene", "type": "ENTITY", "char_start": 593286, "char_end": 593297, "token_start": 14, "token_end": 17, "note": null}]}
+{"sentence_id": 3561, "sentence_text": "A series of transient transfections performed with human IL - 3 - chloramphenicol acetyltransferase ( CAT ) reporter plasmids in T and non - T cells revealed that a plasmid containing 319 bp of 5 ' flanking sequences was active exclusively in T cells .", "sentence_char_start_global": 593314, "sentence_char_end_global": 593566, "entities": [{"text": "human IL - 3 - chloramphenicol acetyltransferase ( CAT ) reporter plasmids", "type": "ENTITY", "char_start": 51, "char_end": 125, "token_start": 7, "token_end": 18}, {"text": "plasmid", "type": "ENTITY", "char_start": 165, "char_end": 172, "token_start": 29, "token_end": 29}, {"text": "5 ' flanking sequences", "type": "ENTITY", "char_start": 194, "char_end": 216, "token_start": 34, "token_end": 37}], "entities_global": [{"text": "human IL - 3 - chloramphenicol acetyltransferase ( CAT ) reporter plasmids", "type": "ENTITY", "char_start": 593365, "char_end": 593439, "token_start": 7, "token_end": 18, "note": null}, {"text": "plasmid", "type": "ENTITY", "char_start": 593479, "char_end": 593486, "token_start": 29, "token_end": 29, "note": null}, {"text": "5 ' flanking sequences", "type": "ENTITY", "char_start": 593508, "char_end": 593530, "token_start": 34, "token_end": 37, "note": null}]}
+{"sentence_id": 3562, "sentence_text": "Deletion analysis revealed that T cell specificity was conferred by a 49 - bp fragment ( bp - 319 to - 270 ) that included a potential binding site for AP - 1 transcription factors 6 bp upstream of a binding site for Elf - 1 , a member of the Ets family of transcription factors .", "sentence_char_start_global": 593567, "sentence_char_end_global": 593847, "entities": [{"text": "49 - bp fragment", "type": "ENTITY", "char_start": 70, "char_end": 86, "token_start": 11, "token_end": 14}, {"text": "bp - 319 to - 270", "type": "ENTITY", "char_start": 89, "char_end": 106, "token_start": 16, "token_end": 21}, {"text": "potential binding site", "type": "ENTITY", "char_start": 125, "char_end": 147, "token_start": 26, "token_end": 28}, {"text": "AP - 1 transcription factors", "type": "ENTITY", "char_start": 152, "char_end": 180, "token_start": 30, "token_end": 34}, {"text": "binding site for Elf - 1", "type": "ENTITY", "char_start": 200, "char_end": 224, "token_start": 40, "token_end": 45}, {"text": "Ets family", "type": "ENTITY", "char_start": 243, "char_end": 253, "token_start": 51, "token_end": 52}, {"text": "transcription factors", "type": "ENTITY", "char_start": 257, "char_end": 278, "token_start": 54, "token_end": 55}], "entities_global": [{"text": "49 - bp fragment", "type": "ENTITY", "char_start": 593637, "char_end": 593653, "token_start": 11, "token_end": 14, "note": null}, {"text": "bp - 319 to - 270", "type": "ENTITY", "char_start": 593656, "char_end": 593673, "token_start": 16, "token_end": 21, "note": null}, {"text": "potential binding site", "type": "ENTITY", "char_start": 593692, "char_end": 593714, "token_start": 26, "token_end": 28, "note": null}, {"text": "AP - 1 transcription factors", "type": "ENTITY", "char_start": 593719, "char_end": 593747, "token_start": 30, "token_end": 34, "note": null}, {"text": "binding site for Elf - 1", "type": "ENTITY", "char_start": 593767, "char_end": 593791, "token_start": 40, "token_end": 45, "note": null}, {"text": "Ets family", "type": "ENTITY", "char_start": 593810, "char_end": 593820, "token_start": 51, "token_end": 52, "note": null}, {"text": "transcription factors", "type": "ENTITY", "char_start": 593824, "char_end": 593845, "token_start": 54, "token_end": 55, "note": null}]}
+{"sentence_id": 3563, "sentence_text": "DNaseI footprint and electrophoretic mobility shift assay analyses performed with MLA - 144 T cell nuclear extracts demonstrated that this 49 - bp region contains a nuclear protein binding region that includes consensus AP - 1 and Elf - 1 binding sites .", "sentence_char_start_global": 593848, "sentence_char_end_global": 594102, "entities": [{"text": "DNaseI", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 0}, {"text": "49 - bp region", "type": "ENTITY", "char_start": 139, "char_end": 153, "token_start": 20, "token_end": 23}, {"text": "nuclear protein binding region", "type": "ENTITY", "char_start": 165, "char_end": 195, "token_start": 26, "token_end": 29}, {"text": "consensus AP - 1 and Elf - 1 binding sites", "type": "ENTITY", "char_start": 210, "char_end": 252, "token_start": 32, "token_end": 41}], "entities_global": [{"text": "DNaseI", "type": "ENTITY", "char_start": 593848, "char_end": 593854, "token_start": 0, "token_end": 0, "note": null}, {"text": "49 - bp region", "type": "ENTITY", "char_start": 593987, "char_end": 594001, "token_start": 20, "token_end": 23, "note": null}, {"text": "nuclear protein binding region", "type": "ENTITY", "char_start": 594013, "char_end": 594043, "token_start": 26, "token_end": 29, "note": null}, {"text": "consensus AP - 1 and Elf - 1 binding sites", "type": "ENTITY", "char_start": 594058, "char_end": 594100, "token_start": 32, "token_end": 41, "note": null}]}
+{"sentence_id": 3564, "sentence_text": "In addition , extracts prepared from purified human T cells contained proteins that bound to synthetic oligonucleotides corresponding to the AP - 1 and Elf - 1 binding sites .", "sentence_char_start_global": 594103, "sentence_char_end_global": 594278, "entities": [{"text": "AP - 1 and Elf - 1 binding sites", "type": "ENTITY", "char_start": 141, "char_end": 173, "token_start": 20, "token_end": 28}], "entities_global": [{"text": "AP - 1 and Elf - 1 binding sites", "type": "ENTITY", "char_start": 594244, "char_end": 594276, "token_start": 20, "token_end": 28, "note": null}]}
+{"sentence_id": 3565, "sentence_text": "In vitro - transcribed and - translated Elf - 1 protein bound specifically to the Elf - 1 site , and Elf - 1 antisera competed and super shifted nuclear protein complexes present in MLA - 144 nuclear extracts .", "sentence_char_start_global": 594279, "sentence_char_end_global": 594489, "entities": [{"text": "Elf - 1 protein", "type": "ENTITY", "char_start": 40, "char_end": 55, "token_start": 7, "token_end": 10}, {"text": "Elf - 1 site", "type": "ENTITY", "char_start": 82, "char_end": 94, "token_start": 15, "token_end": 18}], "entities_global": [{"text": "Elf - 1 protein", "type": "ENTITY", "char_start": 594319, "char_end": 594334, "token_start": 7, "token_end": 10, "note": null}, {"text": "Elf - 1 site", "type": "ENTITY", "char_start": 594361, "char_end": 594373, "token_start": 15, "token_end": 18, "note": null}]}
+{"sentence_id": 3566, "sentence_text": "Moreover , addition of anti - Jun family antiserum in electrophoretic mobility shift assay reactions completely blocked formation of the AP - 1 - related complexes .", "sentence_char_start_global": 594490, "sentence_char_end_global": 594655, "entities": [{"text": "AP - 1 - related complexes", "type": "ENTITY", "char_start": 137, "char_end": 163, "token_start": 20, "token_end": 25}], "entities_global": [{"text": "AP - 1 - related complexes", "type": "ENTITY", "char_start": 594627, "char_end": 594653, "token_start": 20, "token_end": 25, "note": null}]}
+{"sentence_id": 3567, "sentence_text": "Transient transfection studies in MLA - 144 T cells revealed that constructs containing mutations in the AP - 1 site almost completely abolished CAT activity while mutation of the Elf - 1 site or the NF - IL - 3 site , a previously described nuclear protein binding site ( bp . - 155 to - 148 ) in the IL - 3 promoter , reduced CAT activity to < 25 % of the activity given by wild - type constructs .", "sentence_char_start_global": 594656, "sentence_char_end_global": 595056, "entities": [{"text": "AP - 1 site", "type": "ENTITY", "char_start": 105, "char_end": 116, "token_start": 16, "token_end": 19}, {"text": "Elf - 1 site", "type": "ENTITY", "char_start": 180, "char_end": 192, "token_start": 29, "token_end": 32}, {"text": "NF - IL - 3 site", "type": "ENTITY", "char_start": 200, "char_end": 216, "token_start": 35, "token_end": 40}, {"text": "nuclear protein binding site", "type": "ENTITY", "char_start": 242, "char_end": 270, "token_start": 45, "token_end": 48}, {"text": "bp . - 155 to - 148", "type": "ENTITY", "char_start": 273, "char_end": 292, "token_start": 50, "token_end": 56}, {"text": "IL - 3 promoter", "type": "ENTITY", "char_start": 302, "char_end": 317, "token_start": 60, "token_end": 63}], "entities_global": [{"text": "AP - 1 site", "type": "ENTITY", "char_start": 594761, "char_end": 594772, "token_start": 16, "token_end": 19, "note": null}, {"text": "Elf - 1 site", "type": "ENTITY", "char_start": 594836, "char_end": 594848, "token_start": 29, "token_end": 32, "note": null}, {"text": "NF - IL - 3 site", "type": "ENTITY", "char_start": 594856, "char_end": 594872, "token_start": 35, "token_end": 40, "note": null}, {"text": "nuclear protein binding site", "type": "ENTITY", "char_start": 594898, "char_end": 594926, "token_start": 45, "token_end": 48, "note": null}, {"text": "bp . - 155 to - 148", "type": "ENTITY", "char_start": 594929, "char_end": 594948, "token_start": 50, "token_end": 56, "note": null}, {"text": "IL - 3 promoter", "type": "ENTITY", "char_start": 594958, "char_end": 594973, "token_start": 60, "token_end": 63, "note": null}]}
+{"sentence_id": 3568, "sentence_text": "We conclude that expression of the human IL - 3 gene requires the AP - 1 and Elf - 1 binding sites ; however , unlike other previously characterized cytokine genes such as IL - 2 , the AP - 1 and Elf - 1 factors can bind independently in the IL - 3 gene .", "sentence_char_start_global": 595057, "sentence_char_end_global": 595312, "entities": [{"text": "human IL - 3 gene", "type": "ENTITY", "char_start": 35, "char_end": 52, "token_start": 6, "token_end": 10}, {"text": "AP - 1 and Elf - 1 binding sites", "type": "ENTITY", "char_start": 66, "char_end": 98, "token_start": 13, "token_end": 21}, {"text": "cytokine genes", "type": "ENTITY", "char_start": 149, "char_end": 163, "token_start": 29, "token_end": 30}, {"text": "IL - 2", "type": "ENTITY", "char_start": 172, "char_end": 178, "token_start": 33, "token_end": 35}, {"text": "AP - 1 and Elf - 1 factors", "type": "ENTITY", "char_start": 185, "char_end": 211, "token_start": 38, "token_end": 45}, {"text": "IL - 3 gene", "type": "ENTITY", "char_start": 242, "char_end": 253, "token_start": 51, "token_end": 54}], "entities_global": [{"text": "human IL - 3 gene", "type": "ENTITY", "char_start": 595092, "char_end": 595109, "token_start": 6, "token_end": 10, "note": null}, {"text": "AP - 1 and Elf - 1 binding sites", "type": "ENTITY", "char_start": 595123, "char_end": 595155, "token_start": 13, "token_end": 21, "note": null}, {"text": "cytokine genes", "type": "ENTITY", "char_start": 595206, "char_end": 595220, "token_start": 29, "token_end": 30, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 595229, "char_end": 595235, "token_start": 33, "token_end": 35, "note": null}, {"text": "AP - 1 and Elf - 1 factors", "type": "ENTITY", "char_start": 595242, "char_end": 595268, "token_start": 38, "token_end": 45, "note": null}, {"text": "IL - 3 gene", "type": "ENTITY", "char_start": 595299, "char_end": 595310, "token_start": 51, "token_end": 54, "note": null}]}
+{"sentence_id": 3569, "sentence_text": "( ABSTRACT TRUNCATED AT 400 WORDS )", "sentence_char_start_global": 595313, "sentence_char_end_global": 595348, "entities": [], "entities_global": []}
+{"sentence_id": 3570, "sentence_text": "Combination IL - 2 and IL - 4 reduces glucocorticoid receptor - binding affinity and T cell response to glucocorticoids .", "sentence_char_start_global": 595349, "sentence_char_end_global": 595470, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 12, "char_end": 18, "token_start": 1, "token_end": 3}, {"text": "IL - 4", "type": "ENTITY", "char_start": 23, "char_end": 29, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 595361, "char_end": 595367, "token_start": 1, "token_end": 3, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 595372, "char_end": 595378, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 3571, "sentence_text": "The mechanisms contributing to persistent T cell activation and poor response to glucocorticoids in chronic inflammatory illnesses such as steroid resistant ( SR ) asthma are poorly defined .", "sentence_char_start_global": 595471, "sentence_char_end_global": 595662, "entities": [], "entities_global": []}
+{"sentence_id": 3572, "sentence_text": "We examined the possibility that certain cytokines , specifically IL - 2 and IL - 4 , could affect T cell response to glucocorticoids .", "sentence_char_start_global": 595663, "sentence_char_end_global": 595798, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 66, "char_end": 72, "token_start": 9, "token_end": 11}, {"text": "IL - 4", "type": "ENTITY", "char_start": 77, "char_end": 83, "token_start": 13, "token_end": 15}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 595729, "char_end": 595735, "token_start": 9, "token_end": 11, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 595740, "char_end": 595746, "token_start": 13, "token_end": 15, "note": null}]}
+{"sentence_id": 3573, "sentence_text": "A [ 3H ] dexamethasone radioligand - binding assay was used to measure the number of glucocorticoid receptors ( GR ) and dissociation constant ( Kd ) in PBMC from normal donors and patients with SR asthma , cultured in the absence and presence of these cytokines .", "sentence_char_start_global": 595799, "sentence_char_end_global": 596063, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 85, "char_end": 109, "token_start": 16, "token_end": 17}, {"text": "GR", "type": "ENTITY", "char_start": 112, "char_end": 114, "token_start": 19, "token_end": 19}, {"text": "cytokines", "type": "ENTITY", "char_start": 253, "char_end": 262, "token_start": 46, "token_end": 46}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 595884, "char_end": 595908, "token_start": 16, "token_end": 17, "note": null}, {"text": "GR", "type": "ENTITY", "char_start": 595911, "char_end": 595913, "token_start": 19, "token_end": 19, "note": null}, {"text": "cytokines", "type": "ENTITY", "char_start": 596052, "char_end": 596061, "token_start": 46, "token_end": 46, "note": null}]}
+{"sentence_id": 3574, "sentence_text": "PBMC from normal donors incubated for 48 h in the presence of combination IL - 2 + IL - 4 had nuclear GR with significantly reduced binding affinity ( GR Kd = 36 . 1 + / - 1 . 63 nM , mean + / - SEM ; p = 0 . 0001 ) as compared with PBMC incubated with medium alone ( GR Kd = 6 . 74 + / - 0 . 46 nM ) .", "sentence_char_start_global": 596064, "sentence_char_end_global": 596366, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 74, "char_end": 80, "token_start": 13, "token_end": 15}, {"text": "IL - 4", "type": "ENTITY", "char_start": 83, "char_end": 89, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 596138, "char_end": 596144, "token_start": 13, "token_end": 15, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 596147, "char_end": 596153, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 3575, "sentence_text": "The cytosolic GR Kd remained unchanged .", "sentence_char_start_global": 596367, "sentence_char_end_global": 596407, "entities": [], "entities_global": []}
+{"sentence_id": 3576, "sentence_text": "However , when PBMC were incubated with IL - 2 alone or IL - 4 alone , no change in GR - binding affinity was observed .", "sentence_char_start_global": 596408, "sentence_char_end_global": 596528, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 40, "char_end": 46, "token_start": 7, "token_end": 9}, {"text": "IL - 4", "type": "ENTITY", "char_start": 56, "char_end": 62, "token_start": 12, "token_end": 14}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 596448, "char_end": 596454, "token_start": 7, "token_end": 9, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 596464, "char_end": 596470, "token_start": 12, "token_end": 14, "note": null}]}
+{"sentence_id": 3577, "sentence_text": "Furthermore , when T cells and non - T cells were individually stimulated with combination IL - 2 + IL - 4 , a significant reduction in GR - binding affinity was observed only in the T cell population ( p = 0 . 0001 ) .", "sentence_char_start_global": 596529, "sentence_char_end_global": 596748, "entities": [], "entities_global": []}
+{"sentence_id": 3578, "sentence_text": "The IL - 2 + IL - 4 - induced alteration in PBMC GR Kd was associated with an increase in GR number ( 8348 + / - 964 vs 1710 + / - 228 sites / cell ; p = 0 . 0003 ) .", "sentence_char_start_global": 596749, "sentence_char_end_global": 596915, "entities": [], "entities_global": []}
+{"sentence_id": 3579, "sentence_text": "More importantly , the alteration in PBMC GR - binding affinity with IL - 2 + IL - 4 was associated with a functional change in T cell response to methylprednisolone MPN , i . e . , a reduced inhibitory effect of MPN on PMA / ionomycin - induced T cell proliferation .", "sentence_char_start_global": 596916, "sentence_char_end_global": 597184, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 69, "char_end": 75, "token_start": 12, "token_end": 14}, {"text": "IL - 4", "type": "ENTITY", "char_start": 78, "char_end": 84, "token_start": 16, "token_end": 18}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 596985, "char_end": 596991, "token_start": 12, "token_end": 14, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 596994, "char_end": 597000, "token_start": 16, "token_end": 18, "note": null}]}
+{"sentence_id": 3580, "sentence_text": "These effects of IL - 2 + IL - 4 on PBMC GR affinity and response to MPN were blocked by co - incubation with IFN - gamma .", "sentence_char_start_global": 597185, "sentence_char_end_global": 597308, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 17, "char_end": 23, "token_start": 3, "token_end": 5}, {"text": "IL - 4", "type": "ENTITY", "char_start": 26, "char_end": 32, "token_start": 7, "token_end": 9}, {"text": "GR", "type": "ENTITY", "char_start": 41, "char_end": 43, "token_start": 12, "token_end": 12}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 110, "char_end": 121, "token_start": 25, "token_end": 27}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 597202, "char_end": 597208, "token_start": 3, "token_end": 5, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 597211, "char_end": 597217, "token_start": 7, "token_end": 9, "note": null}, {"text": "GR", "type": "ENTITY", "char_start": 597226, "char_end": 597228, "token_start": 12, "token_end": 12, "note": null}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 597295, "char_end": 597306, "token_start": 25, "token_end": 27, "note": null}]}
+{"sentence_id": 3581, "sentence_text": "Freshly isolated PBMC from four patients with SR asthma had a significantly reduced GR - binding affinity ( Kd = 40 . 0 + / - 2 . 68 nM ; p = 0 . 0001 ) when compared with seven normal subjects ( 7 . 15 + / - 0 . 41 nM ) .", "sentence_char_start_global": 597309, "sentence_char_end_global": 597531, "entities": [], "entities_global": []}
+{"sentence_id": 3582, "sentence_text": "The altered PBMC GR binding from patients with SR asthma reversed to normal when incubated with medium alone , but was sustained with IL - 2 + IL - 4 .", "sentence_char_start_global": 597532, "sentence_char_end_global": 597683, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 134, "char_end": 140, "token_start": 23, "token_end": 25}, {"text": "IL - 4", "type": "ENTITY", "char_start": 143, "char_end": 149, "token_start": 27, "token_end": 29}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 597666, "char_end": 597672, "token_start": 23, "token_end": 25, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 597675, "char_end": 597681, "token_start": 27, "token_end": 29, "note": null}]}
+{"sentence_id": 3583, "sentence_text": "These observations suggest that with persistent inflammation certain cytokines may contribute to an impaired response to glucocorticoids .", "sentence_char_start_global": 597684, "sentence_char_end_global": 597822, "entities": [{"text": "cytokines", "type": "ENTITY", "char_start": 69, "char_end": 78, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "cytokines", "type": "ENTITY", "char_start": 597753, "char_end": 597762, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 3584, "sentence_text": "Furthermore , the effects of IL - 2 and IL - 4 were blocked by IFN - gamma .", "sentence_char_start_global": 597823, "sentence_char_end_global": 597899, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 29, "char_end": 35, "token_start": 5, "token_end": 7}, {"text": "IL - 4", "type": "ENTITY", "char_start": 40, "char_end": 46, "token_start": 9, "token_end": 11}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 63, "char_end": 74, "token_start": 15, "token_end": 17}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 597852, "char_end": 597858, "token_start": 5, "token_end": 7, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 597863, "char_end": 597869, "token_start": 9, "token_end": 11, "note": null}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 597886, "char_end": 597897, "token_start": 15, "token_end": 17, "note": null}]}
+{"sentence_id": 3585, "sentence_text": "Characterization of the human CD4 gene promoter : transcription from the CD4 gene core promoter is tissue - specific and is activated by Ets proteins .", "sentence_char_start_global": 597900, "sentence_char_end_global": 598051, "entities": [{"text": "human CD4 gene promoter", "type": "ENTITY", "char_start": 24, "char_end": 47, "token_start": 3, "token_end": 6}, {"text": "CD4 gene core promoter", "type": "ENTITY", "char_start": 73, "char_end": 95, "token_start": 11, "token_end": 14}, {"text": "Ets proteins", "type": "ENTITY", "char_start": 137, "char_end": 149, "token_start": 23, "token_end": 24}], "entities_global": [{"text": "human CD4 gene promoter", "type": "ENTITY", "char_start": 597924, "char_end": 597947, "token_start": 3, "token_end": 6, "note": null}, {"text": "CD4 gene core promoter", "type": "ENTITY", "char_start": 597973, "char_end": 597995, "token_start": 11, "token_end": 14, "note": null}, {"text": "Ets proteins", "type": "ENTITY", "char_start": 598037, "char_end": 598049, "token_start": 23, "token_end": 24, "note": null}]}
+{"sentence_id": 3586, "sentence_text": "We analyzed the 5 ' transcription control sequences of the human CD4 gene .", "sentence_char_start_global": 598052, "sentence_char_end_global": 598127, "entities": [{"text": "5 ' transcription control sequences", "type": "ENTITY", "char_start": 16, "char_end": 51, "token_start": 3, "token_end": 7}, {"text": "human CD4 gene", "type": "ENTITY", "char_start": 59, "char_end": 73, "token_start": 10, "token_end": 12}], "entities_global": [{"text": "5 ' transcription control sequences", "type": "ENTITY", "char_start": 598068, "char_end": 598103, "token_start": 3, "token_end": 7, "note": null}, {"text": "human CD4 gene", "type": "ENTITY", "char_start": 598111, "char_end": 598125, "token_start": 10, "token_end": 12, "note": null}]}
+{"sentence_id": 3587, "sentence_text": "We located the transcription initiation site and showed that the CD4 core promoter ( positions - 40 to + 16 ) lacks a classical ` ` TATA ' ' or initiator positioning consensus sequence but directs precise and efficient transcription when coupled to the ubiquitously active simian virus 40 enhancer .", "sentence_char_start_global": 598128, "sentence_char_end_global": 598427, "entities": [{"text": "transcription initiation site", "type": "ENTITY", "char_start": 15, "char_end": 44, "token_start": 3, "token_end": 5}, {"text": "CD4 core promoter", "type": "ENTITY", "char_start": 65, "char_end": 82, "token_start": 10, "token_end": 12}, {"text": "positions - 40 to + 16", "type": "ENTITY", "char_start": 85, "char_end": 107, "token_start": 14, "token_end": 19}, {"text": "initiator positioning consensus sequence", "type": "ENTITY", "char_start": 144, "char_end": 184, "token_start": 30, "token_end": 33}, {"text": "simian virus 40 enhancer", "type": "ENTITY", "char_start": 273, "char_end": 297, "token_start": 46, "token_end": 49}], "entities_global": [{"text": "transcription initiation site", "type": "ENTITY", "char_start": 598143, "char_end": 598172, "token_start": 3, "token_end": 5, "note": null}, {"text": "CD4 core promoter", "type": "ENTITY", "char_start": 598193, "char_end": 598210, "token_start": 10, "token_end": 12, "note": null}, {"text": "positions - 40 to + 16", "type": "ENTITY", "char_start": 598213, "char_end": 598235, "token_start": 14, "token_end": 19, "note": null}, {"text": "initiator positioning consensus sequence", "type": "ENTITY", "char_start": 598272, "char_end": 598312, "token_start": 30, "token_end": 33, "note": null}, {"text": "simian virus 40 enhancer", "type": "ENTITY", "char_start": 598401, "char_end": 598425, "token_start": 46, "token_end": 49, "note": null}]}
+{"sentence_id": 3588, "sentence_text": "The transcriptional activity of the CD4 gene promoter correlated with CD4 expression in various cell types .", "sentence_char_start_global": 598428, "sentence_char_end_global": 598536, "entities": [{"text": "CD4 gene promoter", "type": "ENTITY", "char_start": 36, "char_end": 53, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "CD4 gene promoter", "type": "ENTITY", "char_start": 598464, "char_end": 598481, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 3589, "sentence_text": "Interestingly , the CD4 core promoter also displayed a tissue - specific transcriptional activity .", "sentence_char_start_global": 598537, "sentence_char_end_global": 598636, "entities": [{"text": "CD4 core promoter", "type": "ENTITY", "char_start": 20, "char_end": 37, "token_start": 3, "token_end": 5}], "entities_global": [{"text": "CD4 core promoter", "type": "ENTITY", "char_start": 598557, "char_end": 598574, "token_start": 3, "token_end": 5, "note": null}]}
+{"sentence_id": 3590, "sentence_text": "Within this fragment , three nucleic acid sequences are completely conserved in the murine CD4 gene .", "sentence_char_start_global": 598637, "sentence_char_end_global": 598738, "entities": [{"text": "murine CD4 gene", "type": "ENTITY", "char_start": 84, "char_end": 99, "token_start": 13, "token_end": 15}], "entities_global": [{"text": "murine CD4 gene", "type": "ENTITY", "char_start": 598721, "char_end": 598736, "token_start": 13, "token_end": 15, "note": null}]}
+{"sentence_id": 3591, "sentence_text": "One of these sequences contains a perfect ETS consensus sequence .", "sentence_char_start_global": 598739, "sentence_char_end_global": 598805, "entities": [{"text": "perfect ETS consensus sequence", "type": "ENTITY", "char_start": 34, "char_end": 64, "token_start": 6, "token_end": 9}], "entities_global": [{"text": "perfect ETS consensus sequence", "type": "ENTITY", "char_start": 598773, "char_end": 598803, "token_start": 6, "token_end": 9, "note": null}]}
+{"sentence_id": 3592, "sentence_text": "Another ETS consensus sequence is located 1060 nt upstream .", "sentence_char_start_global": 598806, "sentence_char_end_global": 598866, "entities": [{"text": "ETS consensus sequence", "type": "ENTITY", "char_start": 8, "char_end": 30, "token_start": 1, "token_end": 3}], "entities_global": [{"text": "ETS consensus sequence", "type": "ENTITY", "char_start": 598814, "char_end": 598836, "token_start": 1, "token_end": 3, "note": null}]}
+{"sentence_id": 3593, "sentence_text": "Electrophoretic - mobility - shift assays showed that the core promoter ETS motif binds an Ets - related protein specifically expressed at high levels in CD4 + cells .", "sentence_char_start_global": 598867, "sentence_char_end_global": 599034, "entities": [{"text": "Ets - related protein", "type": "ENTITY", "char_start": 91, "char_end": 112, "token_start": 15, "token_end": 18}], "entities_global": [{"text": "Ets - related protein", "type": "ENTITY", "char_start": 598958, "char_end": 598979, "token_start": 15, "token_end": 18, "note": null}]}
+{"sentence_id": 3594, "sentence_text": "Moreover , in CD4 - cells , overexpression of Ets - 1 or Ets - 2 efficiently and specifically activated transcription from the CD4 promoter and core promoter .", "sentence_char_start_global": 599035, "sentence_char_end_global": 599194, "entities": [{"text": "Ets - 1", "type": "ENTITY", "char_start": 46, "char_end": 53, "token_start": 9, "token_end": 11}, {"text": "Ets - 2", "type": "ENTITY", "char_start": 57, "char_end": 64, "token_start": 13, "token_end": 15}, {"text": "CD4 promoter", "type": "ENTITY", "char_start": 127, "char_end": 139, "token_start": 23, "token_end": 24}, {"text": "core promoter", "type": "ENTITY", "char_start": 144, "char_end": 157, "token_start": 26, "token_end": 27}], "entities_global": [{"text": "Ets - 1", "type": "ENTITY", "char_start": 599081, "char_end": 599088, "token_start": 9, "token_end": 11, "note": null}, {"text": "Ets - 2", "type": "ENTITY", "char_start": 599092, "char_end": 599099, "token_start": 13, "token_end": 15, "note": null}, {"text": "CD4 promoter", "type": "ENTITY", "char_start": 599162, "char_end": 599174, "token_start": 23, "token_end": 24, "note": null}, {"text": "core promoter", "type": "ENTITY", "char_start": 599179, "char_end": 599192, "token_start": 26, "token_end": 27, "note": null}]}
+{"sentence_id": 3595, "sentence_text": "These data indicate that Ets transcription factors play a central role in controlling CD4 gene expression , by binding to both a classical remote site and an unusual proximal activator sequence", "sentence_char_start_global": 599195, "sentence_char_end_global": 599388, "entities": [{"text": "Ets transcription factors", "type": "ENTITY", "char_start": 25, "char_end": 50, "token_start": 4, "token_end": 6}, {"text": "classical remote site", "type": "ENTITY", "char_start": 129, "char_end": 150, "token_start": 22, "token_end": 24}, {"text": "proximal activator sequence", "type": "ENTITY", "char_start": 166, "char_end": 193, "token_start": 28, "token_end": 30}], "entities_global": [{"text": "Ets transcription factors", "type": "ENTITY", "char_start": 599220, "char_end": 599245, "token_start": 4, "token_end": 6, "note": null}, {"text": "classical remote site", "type": "ENTITY", "char_start": 599324, "char_end": 599345, "token_start": 22, "token_end": 24, "note": null}, {"text": "proximal activator sequence", "type": "ENTITY", "char_start": 599361, "char_end": 599388, "token_start": 28, "token_end": 30, "note": null}]}
+{"sentence_id": 3596, "sentence_text": "Glucocorticoid receptor activation and inactivation in c ultured human lymphocytes .", "sentence_char_start_global": 599389, "sentence_char_end_global": 599473, "entities": [], "entities_global": []}
+{"sentence_id": 3597, "sentence_text": "Although glucocorticoids are not cytolytic for and do not inhibit the growth of the IM - 9 line of cultured human lymphoblasts , these cells have a high steroid - binding capacity .", "sentence_char_start_global": 599474, "sentence_char_end_global": 599655, "entities": [], "entities_global": []}
+{"sentence_id": 3598, "sentence_text": "We have used IM - 9 cells in order to examine whether unoccupied glucocorticoid receptors are inactivated and activated in intact cells .", "sentence_char_start_global": 599656, "sentence_char_end_global": 599793, "entities": [{"text": "unoccupied glucocorticoid receptors", "type": "ENTITY", "char_start": 54, "char_end": 89, "token_start": 12, "token_end": 14}], "entities_global": [{"text": "unoccupied glucocorticoid receptors", "type": "ENTITY", "char_start": 599710, "char_end": 599745, "token_start": 12, "token_end": 14, "note": null}]}
+{"sentence_id": 3599, "sentence_text": "when IM - 9 cells are incubated in glucose - free medium in a nitrogen atmosphere , both their ability to bind triamcinolone acetonide and their ATP levels decline and , when glucose and oxygen are reintroduced , ATP levels and receptor activity return .", "sentence_char_start_global": 599794, "sentence_char_end_global": 600048, "entities": [], "entities_global": []}
+{"sentence_id": 3600, "sentence_text": "The specific glucocorticoid - binding activity of cytosol prepared from cells exposed to various degrees of energy limitation is directly correlated with the ATP content .", "sentence_char_start_global": 600049, "sentence_char_end_global": 600220, "entities": [], "entities_global": []}
+{"sentence_id": 3601, "sentence_text": "Receptor activation in intact cells is rapid and independent of protein synthesis .", "sentence_char_start_global": 600221, "sentence_char_end_global": 600304, "entities": [], "entities_global": []}
+{"sentence_id": 3602, "sentence_text": "Cytosol prepared from inactivated cells can not be activated by addition of ATP .", "sentence_char_start_global": 600305, "sentence_char_end_global": 600386, "entities": [], "entities_global": []}
+{"sentence_id": 3603, "sentence_text": "The inactivation of glucocorticoid receptors that occurs when cytosol from normal IM - 9 cells is incubated at 25 degrees C is inhibited by molybdate , vanadate , fluoride , ATP , and several other nucleotides .", "sentence_char_start_global": 600387, "sentence_char_end_global": 600598, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 20, "char_end": 44, "token_start": 3, "token_end": 4}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 600407, "char_end": 600431, "token_start": 3, "token_end": 4, "note": null}]}
+{"sentence_id": 3604, "sentence_text": "The experiments with intact human lymphoblasts suggest that assays of specific glucocorticoid - binding capacity do not necessarily reflect the cellular content of receptor protein .", "sentence_char_start_global": 600599, "sentence_char_end_global": 600781, "entities": [{"text": "receptor protein", "type": "ENTITY", "char_start": 164, "char_end": 180, "token_start": 23, "token_end": 24}], "entities_global": [{"text": "receptor protein", "type": "ENTITY", "char_start": 600763, "char_end": 600779, "token_start": 23, "token_end": 24, "note": null}]}
+{"sentence_id": 3605, "sentence_text": "Glucocorticoids and lymphocytes .", "sentence_char_start_global": 600782, "sentence_char_end_global": 600815, "entities": [], "entities_global": []}
+{"sentence_id": 3606, "sentence_text": "II .", "sentence_char_start_global": 600816, "sentence_char_end_global": 600820, "entities": [], "entities_global": []}
+{"sentence_id": 3607, "sentence_text": "Cell cycle - dependent changes in glucocorticoid receptor content .", "sentence_char_start_global": 600821, "sentence_char_end_global": 600888, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 34, "char_end": 57, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 600855, "char_end": 600878, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 3608, "sentence_text": "To study variations in glucocorticoid receptor levels during the cell cycle , we have separated mitogen - stimulated human peripheral lymphocytes and rat lymph node cells by unit gravity sedimentation and measured glucocorticoid binding in the resultant fractions .", "sentence_char_start_global": 600889, "sentence_char_end_global": 601154, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 23, "char_end": 46, "token_start": 4, "token_end": 5}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 600912, "char_end": 600935, "token_start": 4, "token_end": 5, "note": null}]}
+{"sentence_id": 3609, "sentence_text": "By morphologic criteria and thymidine incorporation , the fractions were separated into populations of G0 and G1 phase and S and post - S phase cells .", "sentence_char_start_global": 601155, "sentence_char_end_global": 601306, "entities": [], "entities_global": []}
+{"sentence_id": 3610, "sentence_text": "A 2 - to 3 - fold increase in glucocorticoid receptor sites per cell , for cells in the S and post - S phase over those in G0 and G1 , was observed with both nonstimulated rat lymph node cell suspensions and concanavalin A - stimulated human peripheral lymphocytes .", "sentence_char_start_global": 601307, "sentence_char_end_global": 601573, "entities": [], "entities_global": []}
+{"sentence_id": 3611, "sentence_text": "These observations together with those from other studies indicate that formation of new glucocorticoid receptors near the S phase may be a general phenomenon in proliferating cells .", "sentence_char_start_global": 601574, "sentence_char_end_global": 601757, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 89, "char_end": 113, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 601663, "char_end": 601687, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 3612, "sentence_text": "We propose that this increase in glucocorticoid receptors during the cell cycle may explain the increase in glucocorticoid receptors in mitogen - stimulated lymphocytes .", "sentence_char_start_global": 601758, "sentence_char_end_global": 601928, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 33, "char_end": 57, "token_start": 6, "token_end": 7}, {"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 108, "char_end": 132, "token_start": 17, "token_end": 18}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 601791, "char_end": 601815, "token_start": 6, "token_end": 7, "note": null}, {"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 601866, "char_end": 601890, "token_start": 17, "token_end": 18, "note": null}]}
+{"sentence_id": 3613, "sentence_text": "The leukocyte migration inhibition response to certain breast cancer - related antigens ( MCF - 7 and MuMTV ) : their potential as discriminants .", "sentence_char_start_global": 601929, "sentence_char_end_global": 602075, "entities": [{"text": "breast cancer - related antigens", "type": "ENTITY", "char_start": 55, "char_end": 87, "token_start": 7, "token_end": 11}, {"text": "MCF - 7", "type": "ENTITY", "char_start": 90, "char_end": 97, "token_start": 13, "token_end": 15}, {"text": "MuMTV", "type": "ENTITY", "char_start": 102, "char_end": 107, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "breast cancer - related antigens", "type": "ENTITY", "char_start": 601984, "char_end": 602016, "token_start": 7, "token_end": 11, "note": null}, {"text": "MCF - 7", "type": "ENTITY", "char_start": 602019, "char_end": 602026, "token_start": 13, "token_end": 15, "note": null}, {"text": "MuMTV", "type": "ENTITY", "char_start": 602031, "char_end": 602036, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 3614, "sentence_text": "Certain oncogenic viruses have been implicated in human breast cancer , including the murine mammary tumor virus ( MuMTV ) and the Mason - Pfizer monkey virus ( MPMV ) .", "sentence_char_start_global": 602076, "sentence_char_end_global": 602245, "entities": [], "entities_global": []}
+{"sentence_id": 3615, "sentence_text": "We have used the leukocyte migration inhibition ( LMI ) response to assay the response to several potential breast cancer - related antigens , including MuMTV , MPMV , and a breast cancer cultured cell line , MCF - 7 , in 96 breast cancer patients , in 32 women with benign breast disease , and in 67 normal women .", "sentence_char_start_global": 602246, "sentence_char_end_global": 602561, "entities": [{"text": "MuMTV", "type": "ENTITY", "char_start": 153, "char_end": 158, "token_start": 25, "token_end": 25}, {"text": "MPMV", "type": "ENTITY", "char_start": 161, "char_end": 165, "token_start": 27, "token_end": 27}], "entities_global": [{"text": "MuMTV", "type": "ENTITY", "char_start": 602399, "char_end": 602404, "token_start": 25, "token_end": 25, "note": null}, {"text": "MPMV", "type": "ENTITY", "char_start": 602407, "char_end": 602411, "token_start": 27, "token_end": 27, "note": null}]}
+{"sentence_id": 3616, "sentence_text": "The lowest tenth percentile of control ( LMI ) responses was used as the cutoff point to designate responders .", "sentence_char_start_global": 602562, "sentence_char_end_global": 602673, "entities": [], "entities_global": []}
+{"sentence_id": 3617, "sentence_text": "Breast cancer patients showed significant responses to MuMTV ( 49 % and to MCF - 7 ( 50 % ) , but not to MPMV ( 29 % ) .", "sentence_char_start_global": 602674, "sentence_char_end_global": 602794, "entities": [{"text": "MuMTV", "type": "ENTITY", "char_start": 55, "char_end": 60, "token_start": 7, "token_end": 7}, {"text": "MPMV", "type": "ENTITY", "char_start": 105, "char_end": 109, "token_start": 24, "token_end": 24}], "entities_global": [{"text": "MuMTV", "type": "ENTITY", "char_start": 602729, "char_end": 602734, "token_start": 7, "token_end": 7, "note": null}, {"text": "MPMV", "type": "ENTITY", "char_start": 602779, "char_end": 602783, "token_start": 24, "token_end": 24, "note": null}]}
+{"sentence_id": 3618, "sentence_text": "In a paired - antigen study using MuMTV and MCF - 7 , 75 % of the breast cancer patients responded , versus 18 % of the normal women ( P less than 0 . 0050 ) .", "sentence_char_start_global": 602795, "sentence_char_end_global": 602954, "entities": [{"text": "MuMTV", "type": "ENTITY", "char_start": 34, "char_end": 39, "token_start": 7, "token_end": 7}, {"text": "MCF - 7", "type": "ENTITY", "char_start": 44, "char_end": 51, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "MuMTV", "type": "ENTITY", "char_start": 602829, "char_end": 602834, "token_start": 7, "token_end": 7, "note": null}, {"text": "MCF - 7", "type": "ENTITY", "char_start": 602839, "char_end": 602846, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 3619, "sentence_text": "The potential for this assay to distinguish ` ` normal ' ' from ` ` breast cancer ' ' was analyzed using a migration index derived from discriminant analysis .", "sentence_char_start_global": 602955, "sentence_char_end_global": 603114, "entities": [], "entities_global": []}
+{"sentence_id": 3620, "sentence_text": "The ability of the assay to discriminate ` ` normal ' ' from ` ` cancer ' ' was significant ( P less than 0 . 001 ) and showed a sensitivity of detecting ` ` cancer ' ' of 75 % .", "sentence_char_start_global": 603115, "sentence_char_end_global": 603293, "entities": [], "entities_global": []}
+{"sentence_id": 3621, "sentence_text": "The overall responses to MuMTV and MCF - 7 were analyzed with reference to certain prognostic factors , but showed no relation to age , menstrual status , estrogen receptor status , or stage of disease .", "sentence_char_start_global": 603294, "sentence_char_end_global": 603497, "entities": [{"text": "MuMTV", "type": "ENTITY", "char_start": 25, "char_end": 30, "token_start": 4, "token_end": 4}, {"text": "MCF - 7", "type": "ENTITY", "char_start": 35, "char_end": 42, "token_start": 6, "token_end": 8}], "entities_global": [{"text": "MuMTV", "type": "ENTITY", "char_start": 603319, "char_end": 603324, "token_start": 4, "token_end": 4, "note": null}, {"text": "MCF - 7", "type": "ENTITY", "char_start": 603329, "char_end": 603336, "token_start": 6, "token_end": 8, "note": null}]}
+{"sentence_id": 3622, "sentence_text": "The above reactions suggest that a large proportion of breast cancer patients exhibit presensitization to antigenfs found in MuMTV and MCF - 7 , which may be cross - reactive with antigens in the primary cancer .", "sentence_char_start_global": 603498, "sentence_char_end_global": 603710, "entities": [{"text": "MuMTV", "type": "ENTITY", "char_start": 125, "char_end": 130, "token_start": 18, "token_end": 18}, {"text": "MCF - 7", "type": "ENTITY", "char_start": 135, "char_end": 142, "token_start": 20, "token_end": 22}], "entities_global": [{"text": "MuMTV", "type": "ENTITY", "char_start": 603623, "char_end": 603628, "token_start": 18, "token_end": 18, "note": null}, {"text": "MCF - 7", "type": "ENTITY", "char_start": 603633, "char_end": 603640, "token_start": 20, "token_end": 22, "note": null}]}
+{"sentence_id": 3623, "sentence_text": "These responses appear to be independent of major prognostic variables .", "sentence_char_start_global": 603711, "sentence_char_end_global": 603783, "entities": [], "entities_global": []}
+{"sentence_id": 3624, "sentence_text": "Further refinement of this assay may yield one which is more highly discriminating for breast cancer .", "sentence_char_start_global": 603784, "sentence_char_end_global": 603886, "entities": [], "entities_global": []}
+{"sentence_id": 3625, "sentence_text": "Chronic lymphatic leukaemia : cellular effects of glucocorticoids in vitro .", "sentence_char_start_global": 603887, "sentence_char_end_global": 603963, "entities": [], "entities_global": []}
+{"sentence_id": 3626, "sentence_text": "Glucocorticoid receptor levels and steroid induced inhibition of nucleic acid precursors have been examined in lymphocytes from 27 patients at different stages of chronic lymphatic leukaemia .", "sentence_char_start_global": 603964, "sentence_char_end_global": 604156, "entities": [{"text": "Glucocorticoid receptor", "type": "ENTITY", "char_start": 0, "char_end": 23, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "Glucocorticoid receptor", "type": "ENTITY", "char_start": 603964, "char_end": 603987, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 3627, "sentence_text": "No correlation can be found between the level of glucocorticoid receptors and the stage of the disease .", "sentence_char_start_global": 604157, "sentence_char_end_global": 604261, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 49, "char_end": 73, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 604206, "char_end": 604230, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 3628, "sentence_text": "On the other hand , a significant difference ( P less than 0 . 02 ) was found between stage O and stage III / IV patients , in terms of the in vitro effect of dexamethasone on [ 3H ] uridine incorporation .", "sentence_char_start_global": 604262, "sentence_char_end_global": 604468, "entities": [], "entities_global": []}
+{"sentence_id": 3629, "sentence_text": "Pyrrolidine dithiocarbamate inhibits NF - kappa B mobilization and TNF production in human monocytes .", "sentence_char_start_global": 604469, "sentence_char_end_global": 604571, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 37, "char_end": 49, "token_start": 3, "token_end": 6}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 604506, "char_end": 604518, "token_start": 3, "token_end": 6, "note": null}]}
+{"sentence_id": 3630, "sentence_text": "The human TNF promoter contains four potential nuclear factor - kappa B ( NF - kappa B ) - binding sites , with the strongest binding seen for the - 605 motif .", "sentence_char_start_global": 604572, "sentence_char_end_global": 604732, "entities": [{"text": "human TNF promoter", "type": "ENTITY", "char_start": 4, "char_end": 22, "token_start": 1, "token_end": 3}, {"text": "nuclear factor - kappa B ( NF - kappa B ) - binding sites", "type": "ENTITY", "char_start": 47, "char_end": 104, "token_start": 7, "token_end": 20}], "entities_global": [{"text": "human TNF promoter", "type": "ENTITY", "char_start": 604576, "char_end": 604594, "token_start": 1, "token_end": 3, "note": null}, {"text": "nuclear factor - kappa B ( NF - kappa B ) - binding sites", "type": "ENTITY", "char_start": 604619, "char_end": 604676, "token_start": 7, "token_end": 20, "note": null}]}
+{"sentence_id": 3631, "sentence_text": "Nuclear extracts from unstimulated cells of the human monocytic cell line , Mono Mac 6 , contain one specific binding protein ( complex II ) , consistent with a constitutive p50 homodimer .", "sentence_char_start_global": 604733, "sentence_char_end_global": 604922, "entities": [{"text": "specific binding protein", "type": "ENTITY", "char_start": 101, "char_end": 125, "token_start": 18, "token_end": 20}, {"text": "complex II", "type": "ENTITY", "char_start": 128, "char_end": 138, "token_start": 22, "token_end": 23}, {"text": "constitutive p50 homodimer", "type": "ENTITY", "char_start": 161, "char_end": 187, "token_start": 29, "token_end": 31}], "entities_global": [{"text": "specific binding protein", "type": "ENTITY", "char_start": 604834, "char_end": 604858, "token_start": 18, "token_end": 20, "note": null}, {"text": "complex II", "type": "ENTITY", "char_start": 604861, "char_end": 604871, "token_start": 22, "token_end": 23, "note": null}, {"text": "constitutive p50 homodimer", "type": "ENTITY", "char_start": 604894, "char_end": 604920, "token_start": 29, "token_end": 31, "note": null}]}
+{"sentence_id": 3632, "sentence_text": "Stimulation of Mono Mac 6 cells with LPS will increase complex II and will strongly induce a second specific complex ( complex I ) , which represents the p50 / 65 heterodimer .", "sentence_char_start_global": 604923, "sentence_char_end_global": 605099, "entities": [{"text": "complex II", "type": "ENTITY", "char_start": 55, "char_end": 65, "token_start": 10, "token_end": 11}, {"text": "complex I", "type": "ENTITY", "char_start": 119, "char_end": 128, "token_start": 21, "token_end": 22}, {"text": "p50 / 65 heterodimer", "type": "ENTITY", "char_start": 154, "char_end": 174, "token_start": 28, "token_end": 31}], "entities_global": [{"text": "complex II", "type": "ENTITY", "char_start": 604978, "char_end": 604988, "token_start": 10, "token_end": 11, "note": null}, {"text": "complex I", "type": "ENTITY", "char_start": 605042, "char_end": 605051, "token_start": 21, "token_end": 22, "note": null}, {"text": "p50 / 65 heterodimer", "type": "ENTITY", "char_start": 605077, "char_end": 605097, "token_start": 28, "token_end": 31, "note": null}]}
+{"sentence_id": 3633, "sentence_text": "Treatment of Mono Mac 6 cells with pyrrolidine - dithiocarbamate ( PDTC ) at 300 microM will block the LPS - induced complex I almost completely and will reduce complex II to the constitutive level .", "sentence_char_start_global": 605100, "sentence_char_end_global": 605299, "entities": [{"text": "LPS - induced complex I", "type": "ENTITY", "char_start": 103, "char_end": 126, "token_start": 19, "token_end": 23}, {"text": "complex II", "type": "ENTITY", "char_start": 161, "char_end": 171, "token_start": 29, "token_end": 30}], "entities_global": [{"text": "LPS - induced complex I", "type": "ENTITY", "char_start": 605203, "char_end": 605226, "token_start": 19, "token_end": 23, "note": null}, {"text": "complex II", "type": "ENTITY", "char_start": 605261, "char_end": 605271, "token_start": 29, "token_end": 30, "note": null}]}
+{"sentence_id": 3634, "sentence_text": "Binding activity of other nuclear factors that recognize the SP - 1 and c / EBP motifs of the human TNF promoter is not affected by such treatment .", "sentence_char_start_global": 605300, "sentence_char_end_global": 605448, "entities": [{"text": "nuclear factors", "type": "ENTITY", "char_start": 26, "char_end": 41, "token_start": 4, "token_end": 5}, {"text": "human TNF promoter", "type": "ENTITY", "char_start": 94, "char_end": 112, "token_start": 19, "token_end": 21}], "entities_global": [{"text": "nuclear factors", "type": "ENTITY", "char_start": 605326, "char_end": 605341, "token_start": 4, "token_end": 5, "note": null}, {"text": "human TNF promoter", "type": "ENTITY", "char_start": 605394, "char_end": 605412, "token_start": 19, "token_end": 21, "note": null}]}
+{"sentence_id": 3635, "sentence_text": "Northern blot analysis demonstrates that PDTC treatment will strongly reduce LPS - induced TNF transcripts .", "sentence_char_start_global": 605449, "sentence_char_end_global": 605557, "entities": [{"text": "LPS - induced TNF transcripts", "type": "ENTITY", "char_start": 77, "char_end": 106, "token_start": 10, "token_end": 14}], "entities_global": [{"text": "LPS - induced TNF transcripts", "type": "ENTITY", "char_start": 605526, "char_end": 605555, "token_start": 10, "token_end": 14, "note": null}]}
+{"sentence_id": 3636, "sentence_text": "Secreted TNF protein as detected in the Wehi 164S / ActD bioassay and in a sandwich immunoassay was similarly reduced by PDTC .", "sentence_char_start_global": 605558, "sentence_char_end_global": 605685, "entities": [{"text": "TNF protein", "type": "ENTITY", "char_start": 9, "char_end": 20, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "TNF protein", "type": "ENTITY", "char_start": 605567, "char_end": 605578, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 3637, "sentence_text": "Kinetic analyses show that after LPS stimulation , NF - kappa B will peak at 1 h , TNF transcript prevalence at 2 h , and TNF protein at 4 h .", "sentence_char_start_global": 605686, "sentence_char_end_global": 605828, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 51, "char_end": 63, "token_start": 8, "token_end": 11}, {"text": "TNF protein", "type": "ENTITY", "char_start": 122, "char_end": 133, "token_start": 26, "token_end": 27}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 605737, "char_end": 605749, "token_start": 8, "token_end": 11, "note": null}, {"text": "TNF protein", "type": "ENTITY", "char_start": 605808, "char_end": 605819, "token_start": 26, "token_end": 27, "note": null}]}
+{"sentence_id": 3638, "sentence_text": "PDTC did not shift this response to LPS to a later time , but suppressed NF - kappa B mobilization , TNF transcripts , and TNF protein over the entire 8 - h observation period .", "sentence_char_start_global": 605829, "sentence_char_end_global": 606006, "entities": [{"text": "TNF transcripts", "type": "ENTITY", "char_start": 101, "char_end": 116, "token_start": 21, "token_end": 22}, {"text": "TNF protein", "type": "ENTITY", "char_start": 123, "char_end": 134, "token_start": 25, "token_end": 26}], "entities_global": [{"text": "TNF transcripts", "type": "ENTITY", "char_start": 605930, "char_end": 605945, "token_start": 21, "token_end": 22, "note": null}, {"text": "TNF protein", "type": "ENTITY", "char_start": 605952, "char_end": 605963, "token_start": 25, "token_end": 26, "note": null}]}
+{"sentence_id": 3639, "sentence_text": "Analysis of freshly isolated , LPS - stimulated blood monocytes showed a similar blockade of NF - kappa B .", "sentence_char_start_global": 606007, "sentence_char_end_global": 606114, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 93, "char_end": 105, "token_start": 15, "token_end": 18}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 606100, "char_end": 606112, "token_start": 15, "token_end": 18, "note": null}]}
+{"sentence_id": 3640, "sentence_text": "Furthermore , in these primary cells , induction of TNF transcripts , as determined by Northern blot analysis and by quantitative polymerase chain reaction , was prevented by PDTC as was TNF protein production .", "sentence_char_start_global": 606115, "sentence_char_end_global": 606326, "entities": [{"text": "TNF transcripts", "type": "ENTITY", "char_start": 52, "char_end": 67, "token_start": 9, "token_end": 10}, {"text": "TNF protein", "type": "ENTITY", "char_start": 187, "char_end": 198, "token_start": 31, "token_end": 32}], "entities_global": [{"text": "TNF transcripts", "type": "ENTITY", "char_start": 606167, "char_end": 606182, "token_start": 9, "token_end": 10, "note": null}, {"text": "TNF protein", "type": "ENTITY", "char_start": 606302, "char_end": 606313, "token_start": 31, "token_end": 32, "note": null}]}
+{"sentence_id": 3641, "sentence_text": "These data show that dithiocarbamates can profoundly affect cytokine expression and suggest that NF - kappa B is involved in LPS - induced TNF gene expression in human monocytes .", "sentence_char_start_global": 606327, "sentence_char_end_global": 606506, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 97, "char_end": 109, "token_start": 13, "token_end": 16}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 606424, "char_end": 606436, "token_start": 13, "token_end": 16, "note": null}]}
+{"sentence_id": 3642, "sentence_text": "Comparing regions of the Epstein - Barr virus ZEBRA protein which function as transcriptional activating sequences in Saccharomyces cerevisiae and in B cells .", "sentence_char_start_global": 606507, "sentence_char_end_global": 606666, "entities": [{"text": "Epstein - Barr virus ZEBRA protein", "type": "ENTITY", "char_start": 25, "char_end": 59, "token_start": 4, "token_end": 9}, {"text": "transcriptional activating sequences", "type": "ENTITY", "char_start": 78, "char_end": 114, "token_start": 13, "token_end": 15}], "entities_global": [{"text": "Epstein - Barr virus ZEBRA protein", "type": "ENTITY", "char_start": 606532, "char_end": 606566, "token_start": 4, "token_end": 9, "note": null}, {"text": "transcriptional activating sequences", "type": "ENTITY", "char_start": 606585, "char_end": 606621, "token_start": 13, "token_end": 15, "note": null}]}
+{"sentence_id": 3643, "sentence_text": "The ZEBRA protein activates expression of Epstein - Barr virus early - lytic - cycle genes in human B lymphocytes .", "sentence_char_start_global": 606667, "sentence_char_end_global": 606782, "entities": [{"text": "ZEBRA protein", "type": "ENTITY", "char_start": 4, "char_end": 17, "token_start": 1, "token_end": 2}, {"text": "early - lytic - cycle genes", "type": "ENTITY", "char_start": 63, "char_end": 90, "token_start": 10, "token_end": 15}], "entities_global": [{"text": "ZEBRA protein", "type": "ENTITY", "char_start": 606671, "char_end": 606684, "token_start": 1, "token_end": 2, "note": null}, {"text": "early - lytic - cycle genes", "type": "ENTITY", "char_start": 606730, "char_end": 606757, "token_start": 10, "token_end": 15, "note": null}]}
+{"sentence_id": 3644, "sentence_text": "Here it is shown that ZEBRA also behaves as a sequence - specific transcriptional activator in Saccharomyces cerevisiae .", "sentence_char_start_global": 606783, "sentence_char_end_global": 606904, "entities": [{"text": "ZEBRA", "type": "ENTITY", "char_start": 22, "char_end": 27, "token_start": 5, "token_end": 5}, {"text": "sequence - specific transcriptional activator", "type": "ENTITY", "char_start": 46, "char_end": 91, "token_start": 10, "token_end": 14}], "entities_global": [{"text": "ZEBRA", "type": "ENTITY", "char_start": 606805, "char_end": 606810, "token_start": 5, "token_end": 5, "note": null}, {"text": "sequence - specific transcriptional activator", "type": "ENTITY", "char_start": 606829, "char_end": 606874, "token_start": 10, "token_end": 14, "note": null}]}
+{"sentence_id": 3645, "sentence_text": "Deletional mutagenesis defined three regions of ZEBRA that participate in activation in S . cerevisiae .", "sentence_char_start_global": 606905, "sentence_char_end_global": 607009, "entities": [{"text": "ZEBRA", "type": "ENTITY", "char_start": 48, "char_end": 53, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "ZEBRA", "type": "ENTITY", "char_start": 606953, "char_end": 606958, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 3646, "sentence_text": "These regions are designated YI ( amino acids [ aa ] 1 to 25 ) , YII ( aa 51 to 102 ) , and YIII ( aa 228 to 245 ) .", "sentence_char_start_global": 607010, "sentence_char_end_global": 607126, "entities": [{"text": "YI", "type": "ENTITY", "char_start": 29, "char_end": 31, "token_start": 4, "token_end": 4}, {"text": "amino acids [ aa ] 1 to 25", "type": "ENTITY", "char_start": 34, "char_end": 60, "token_start": 6, "token_end": 13}, {"text": "YII", "type": "ENTITY", "char_start": 65, "char_end": 68, "token_start": 16, "token_end": 16}, {"text": "aa 51 to 102", "type": "ENTITY", "char_start": 71, "char_end": 83, "token_start": 18, "token_end": 21}, {"text": "YIII", "type": "ENTITY", "char_start": 92, "char_end": 96, "token_start": 25, "token_end": 25}, {"text": "aa 228 to 245", "type": "ENTITY", "char_start": 99, "char_end": 112, "token_start": 27, "token_end": 30}], "entities_global": [{"text": "YI", "type": "ENTITY", "char_start": 607039, "char_end": 607041, "token_start": 4, "token_end": 4, "note": null}, {"text": "amino acids [ aa ] 1 to 25", "type": "ENTITY", "char_start": 607044, "char_end": 607070, "token_start": 6, "token_end": 13, "note": null}, {"text": "YII", "type": "ENTITY", "char_start": 607075, "char_end": 607078, "token_start": 16, "token_end": 16, "note": null}, {"text": "aa 51 to 102", "type": "ENTITY", "char_start": 607081, "char_end": 607093, "token_start": 18, "token_end": 21, "note": null}, {"text": "YIII", "type": "ENTITY", "char_start": 607102, "char_end": 607106, "token_start": 25, "token_end": 25, "note": null}, {"text": "aa 228 to 245", "type": "ENTITY", "char_start": 607109, "char_end": 607122, "token_start": 27, "token_end": 30, "note": null}]}
+{"sentence_id": 3647, "sentence_text": "Two of the three regions of the native ZEBRA protein act together to mediate activation when assayed on ZEBRA binding sites .", "sentence_char_start_global": 607127, "sentence_char_end_global": 607252, "entities": [{"text": "ZEBRA protein", "type": "ENTITY", "char_start": 39, "char_end": 52, "token_start": 8, "token_end": 9}, {"text": "ZEBRA binding sites", "type": "ENTITY", "char_start": 104, "char_end": 123, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "ZEBRA protein", "type": "ENTITY", "char_start": 607166, "char_end": 607179, "token_start": 8, "token_end": 9, "note": null}, {"text": "ZEBRA binding sites", "type": "ENTITY", "char_start": 607231, "char_end": 607250, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 3648, "sentence_text": "However , when fused to the DNA binding domain of GAL 4 and assayed on GAL4 binding sites , regions YII and YIII were each sufficient to confer activation in S . cerevisiae .", "sentence_char_start_global": 607253, "sentence_char_end_global": 607427, "entities": [{"text": "DNA binding domain", "type": "ENTITY", "char_start": 28, "char_end": 46, "token_start": 6, "token_end": 8}, {"text": "GAL", "type": "ENTITY", "char_start": 50, "char_end": 53, "token_start": 10, "token_end": 10}, {"text": "GAL4 binding sites", "type": "ENTITY", "char_start": 71, "char_end": 89, "token_start": 15, "token_end": 17}, {"text": "regions YII and YIII", "type": "ENTITY", "char_start": 92, "char_end": 112, "token_start": 19, "token_end": 22}], "entities_global": [{"text": "DNA binding domain", "type": "ENTITY", "char_start": 607281, "char_end": 607299, "token_start": 6, "token_end": 8, "note": null}, {"text": "GAL", "type": "ENTITY", "char_start": 607303, "char_end": 607306, "token_start": 10, "token_end": 10, "note": null}, {"text": "GAL4 binding sites", "type": "ENTITY", "char_start": 607324, "char_end": 607342, "token_start": 15, "token_end": 17, "note": null}, {"text": "regions YII and YIII", "type": "ENTITY", "char_start": 607345, "char_end": 607365, "token_start": 19, "token_end": 22, "note": null}]}
+{"sentence_id": 3649, "sentence_text": "Regions of ZEBRA which affected activation in S . cerevisiae were also required in human B lymphocytes .", "sentence_char_start_global": 607428, "sentence_char_end_global": 607532, "entities": [{"text": "ZEBRA", "type": "ENTITY", "char_start": 11, "char_end": 16, "token_start": 2, "token_end": 2}], "entities_global": [{"text": "ZEBRA", "type": "ENTITY", "char_start": 607439, "char_end": 607444, "token_start": 2, "token_end": 2, "note": null}]}
+{"sentence_id": 3650, "sentence_text": "The amino - terminal region of ZEBRA ( aa 1 to 98 ) was required for activation both in S . cerevisiae and in human B cells ; deletion of the carboxy - terminal 18 aa also significantly reduced activation in both cell types .", "sentence_char_start_global": 607533, "sentence_char_end_global": 607758, "entities": [{"text": "amino - terminal region", "type": "ENTITY", "char_start": 4, "char_end": 27, "token_start": 1, "token_end": 4}, {"text": "ZEBRA", "type": "ENTITY", "char_start": 31, "char_end": 36, "token_start": 6, "token_end": 6}, {"text": "aa 1 to 98", "type": "ENTITY", "char_start": 39, "char_end": 49, "token_start": 8, "token_end": 11}, {"text": "carboxy - terminal 18 aa", "type": "ENTITY", "char_start": 142, "char_end": 166, "token_start": 31, "token_end": 35}], "entities_global": [{"text": "amino - terminal region", "type": "ENTITY", "char_start": 607537, "char_end": 607560, "token_start": 1, "token_end": 4, "note": null}, {"text": "ZEBRA", "type": "ENTITY", "char_start": 607564, "char_end": 607569, "token_start": 6, "token_end": 6, "note": null}, {"text": "aa 1 to 98", "type": "ENTITY", "char_start": 607572, "char_end": 607582, "token_start": 8, "token_end": 11, "note": null}, {"text": "carboxy - terminal 18 aa", "type": "ENTITY", "char_start": 607675, "char_end": 607699, "token_start": 31, "token_end": 35, "note": null}]}
+{"sentence_id": 3651, "sentence_text": "Thus , the behavior of ZEBRA in human B cells and S . cerevisiae suggests that the protein contains universal activation motifs that interact with conserved components of the transcription machinery .", "sentence_char_start_global": 607759, "sentence_char_end_global": 607959, "entities": [{"text": "ZEBRA", "type": "ENTITY", "char_start": 23, "char_end": 28, "token_start": 5, "token_end": 5}, {"text": "universal activation motifs", "type": "ENTITY", "char_start": 100, "char_end": 127, "token_start": 19, "token_end": 21}], "entities_global": [{"text": "ZEBRA", "type": "ENTITY", "char_start": 607782, "char_end": 607787, "token_start": 5, "token_end": 5, "note": null}, {"text": "universal activation motifs", "type": "ENTITY", "char_start": 607859, "char_end": 607886, "token_start": 19, "token_end": 21, "note": null}]}
+{"sentence_id": 3652, "sentence_text": "However , certain deletion mutants of ZEBRA containing mutations in the N - terminal region exhibited discordant behaviors in S . cerevisiae and in B cells .", "sentence_char_start_global": 607960, "sentence_char_end_global": 608117, "entities": [{"text": "deletion mutants", "type": "ENTITY", "char_start": 18, "char_end": 34, "token_start": 3, "token_end": 4}, {"text": "ZEBRA", "type": "ENTITY", "char_start": 38, "char_end": 43, "token_start": 6, "token_end": 6}, {"text": "N - terminal region", "type": "ENTITY", "char_start": 72, "char_end": 91, "token_start": 11, "token_end": 14}], "entities_global": [{"text": "deletion mutants", "type": "ENTITY", "char_start": 607978, "char_end": 607994, "token_start": 3, "token_end": 4, "note": null}, {"text": "ZEBRA", "type": "ENTITY", "char_start": 607998, "char_end": 608003, "token_start": 6, "token_end": 6, "note": null}, {"text": "N - terminal region", "type": "ENTITY", "char_start": 608032, "char_end": 608051, "token_start": 11, "token_end": 14, "note": null}]}
+{"sentence_id": 3653, "sentence_text": "For example , deletion of ZEBRA aa 26 to 51 impaired activation to a great extent in B cells but had little or no effect in S . cerevisiae .", "sentence_char_start_global": 608118, "sentence_char_end_global": 608258, "entities": [{"text": "ZEBRA aa 26 to 51", "type": "ENTITY", "char_start": 26, "char_end": 43, "token_start": 5, "token_end": 9}], "entities_global": [{"text": "ZEBRA aa 26 to 51", "type": "ENTITY", "char_start": 608144, "char_end": 608161, "token_start": 5, "token_end": 9, "note": null}]}
+{"sentence_id": 3654, "sentence_text": "The discordant mutants may reflect interactions with a variable domain of a conserved component or unique interactions with specialized components of the basal transcription apparatus in different cells .", "sentence_char_start_global": 608259, "sentence_char_end_global": 608463, "entities": [{"text": "variable domain", "type": "ENTITY", "char_start": 55, "char_end": 70, "token_start": 8, "token_end": 9}], "entities_global": [{"text": "variable domain", "type": "ENTITY", "char_start": 608314, "char_end": 608329, "token_start": 8, "token_end": 9, "note": null}]}
+{"sentence_id": 3655, "sentence_text": "Functional interaction of the v - Rel and c - Rel oncoproteins with the TATA - binding protein and association with transcription factor IIB .", "sentence_char_start_global": 608464, "sentence_char_end_global": 608606, "entities": [{"text": "v - Rel and c - Rel oncoproteins", "type": "ENTITY", "char_start": 30, "char_end": 62, "token_start": 4, "token_end": 11}, {"text": "TATA - binding protein", "type": "ENTITY", "char_start": 72, "char_end": 94, "token_start": 14, "token_end": 17}, {"text": "transcription factor IIB", "type": "ENTITY", "char_start": 116, "char_end": 140, "token_start": 21, "token_end": 23}], "entities_global": [{"text": "v - Rel and c - Rel oncoproteins", "type": "ENTITY", "char_start": 608494, "char_end": 608526, "token_start": 4, "token_end": 11, "note": null}, {"text": "TATA - binding protein", "type": "ENTITY", "char_start": 608536, "char_end": 608558, "token_start": 14, "token_end": 17, "note": null}, {"text": "transcription factor IIB", "type": "ENTITY", "char_start": 608580, "char_end": 608604, "token_start": 21, "token_end": 23, "note": null}]}
+{"sentence_id": 3656, "sentence_text": "Rel family proteins regulate the expression of genes linked to kappa B - binding motifs .", "sentence_char_start_global": 608607, "sentence_char_end_global": 608696, "entities": [{"text": "Rel family proteins", "type": "ENTITY", "char_start": 0, "char_end": 19, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "Rel family proteins", "type": "ENTITY", "char_start": 608607, "char_end": 608626, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 3657, "sentence_text": "Little is known , however , of the mechanism by which they enhance transcription .", "sentence_char_start_global": 608697, "sentence_char_end_global": 608779, "entities": [], "entities_global": []}
+{"sentence_id": 3658, "sentence_text": "We have investigated the ability of the v - Rel and c - Rel oncoproteins to interact with components of the basal transcription machinery .", "sentence_char_start_global": 608780, "sentence_char_end_global": 608919, "entities": [{"text": "v - Rel and c - Rel oncoproteins", "type": "ENTITY", "char_start": 40, "char_end": 72, "token_start": 7, "token_end": 14}], "entities_global": [{"text": "v - Rel and c - Rel oncoproteins", "type": "ENTITY", "char_start": 608820, "char_end": 608852, "token_start": 7, "token_end": 14, "note": null}]}
+{"sentence_id": 3659, "sentence_text": "Here we report that both the acidic transcription activation domain mapping to the unique C terminus of chicken c - Rel and the F9 cell - specific activation region common to both v - Rel and c - Rel interact with the TATA - binding protein ( TBP ) and transcription factor IIB ( TFIIB ) in vitro and in vivo .", "sentence_char_start_global": 608920, "sentence_char_end_global": 609230, "entities": [{"text": "C terminus", "type": "ENTITY", "char_start": 90, "char_end": 100, "token_start": 14, "token_end": 15}, {"text": "chicken c - Rel", "type": "ENTITY", "char_start": 104, "char_end": 119, "token_start": 17, "token_end": 20}, {"text": "F9 cell - specific activation region", "type": "ENTITY", "char_start": 128, "char_end": 164, "token_start": 23, "token_end": 28}, {"text": "v - Rel", "type": "ENTITY", "char_start": 180, "char_end": 187, "token_start": 32, "token_end": 34}, {"text": "c - Rel", "type": "ENTITY", "char_start": 192, "char_end": 199, "token_start": 36, "token_end": 38}, {"text": "TATA - binding protein", "type": "ENTITY", "char_start": 218, "char_end": 240, "token_start": 42, "token_end": 45}, {"text": "TBP", "type": "ENTITY", "char_start": 243, "char_end": 246, "token_start": 47, "token_end": 47}, {"text": "transcription factor IIB", "type": "ENTITY", "char_start": 253, "char_end": 277, "token_start": 50, "token_end": 52}, {"text": "TFIIB", "type": "ENTITY", "char_start": 280, "char_end": 285, "token_start": 54, "token_end": 54}], "entities_global": [{"text": "C terminus", "type": "ENTITY", "char_start": 609010, "char_end": 609020, "token_start": 14, "token_end": 15, "note": null}, {"text": "chicken c - Rel", "type": "ENTITY", "char_start": 609024, "char_end": 609039, "token_start": 17, "token_end": 20, "note": null}, {"text": "F9 cell - specific activation region", "type": "ENTITY", "char_start": 609048, "char_end": 609084, "token_start": 23, "token_end": 28, "note": null}, {"text": "v - Rel", "type": "ENTITY", "char_start": 609100, "char_end": 609107, "token_start": 32, "token_end": 34, "note": null}, {"text": "c - Rel", "type": "ENTITY", "char_start": 609112, "char_end": 609119, "token_start": 36, "token_end": 38, "note": null}, {"text": "TATA - binding protein", "type": "ENTITY", "char_start": 609138, "char_end": 609160, "token_start": 42, "token_end": 45, "note": null}, {"text": "TBP", "type": "ENTITY", "char_start": 609163, "char_end": 609166, "token_start": 47, "token_end": 47, "note": null}, {"text": "transcription factor IIB", "type": "ENTITY", "char_start": 609173, "char_end": 609197, "token_start": 50, "token_end": 52, "note": null}, {"text": "TFIIB", "type": "ENTITY", "char_start": 609200, "char_end": 609205, "token_start": 54, "token_end": 54, "note": null}]}
+{"sentence_id": 3660, "sentence_text": "We also demonstrate that TPB interaction with Rel activation regions leads to synergistic activation of transcription of a kappa B - linked reporter gene .", "sentence_char_start_global": 609231, "sentence_char_end_global": 609386, "entities": [{"text": "TPB", "type": "ENTITY", "char_start": 25, "char_end": 28, "token_start": 4, "token_end": 4}, {"text": "Rel activation regions", "type": "ENTITY", "char_start": 46, "char_end": 68, "token_start": 7, "token_end": 9}, {"text": "kappa B - linked reporter gene", "type": "ENTITY", "char_start": 123, "char_end": 153, "token_start": 18, "token_end": 23}], "entities_global": [{"text": "TPB", "type": "ENTITY", "char_start": 609256, "char_end": 609259, "token_start": 4, "token_end": 4, "note": null}, {"text": "Rel activation regions", "type": "ENTITY", "char_start": 609277, "char_end": 609299, "token_start": 7, "token_end": 9, "note": null}, {"text": "kappa B - linked reporter gene", "type": "ENTITY", "char_start": 609354, "char_end": 609384, "token_start": 18, "token_end": 23, "note": null}]}
+{"sentence_id": 3661, "sentence_text": "Combined with the observation that the mouse c - Rel and human RelA proteins also interact with TBP and TFIIB in vitro , these results suggest that association with basal transcription factors is important for the transcriptional activities of Rel family proteins .", "sentence_char_start_global": 609387, "sentence_char_end_global": 609652, "entities": [{"text": "mouse c - Rel and human RelA proteins", "type": "ENTITY", "char_start": 39, "char_end": 76, "token_start": 6, "token_end": 13}, {"text": "TBP", "type": "ENTITY", "char_start": 96, "char_end": 99, "token_start": 17, "token_end": 17}, {"text": "TFIIB", "type": "ENTITY", "char_start": 104, "char_end": 109, "token_start": 19, "token_end": 19}, {"text": "basal transcription factors", "type": "ENTITY", "char_start": 165, "char_end": 192, "token_start": 29, "token_end": 31}, {"text": "Rel family proteins", "type": "ENTITY", "char_start": 244, "char_end": 263, "token_start": 39, "token_end": 41}], "entities_global": [{"text": "mouse c - Rel and human RelA proteins", "type": "ENTITY", "char_start": 609426, "char_end": 609463, "token_start": 6, "token_end": 13, "note": null}, {"text": "TBP", "type": "ENTITY", "char_start": 609483, "char_end": 609486, "token_start": 17, "token_end": 17, "note": null}, {"text": "TFIIB", "type": "ENTITY", "char_start": 609491, "char_end": 609496, "token_start": 19, "token_end": 19, "note": null}, {"text": "basal transcription factors", "type": "ENTITY", "char_start": 609552, "char_end": 609579, "token_start": 29, "token_end": 31, "note": null}, {"text": "Rel family proteins", "type": "ENTITY", "char_start": 609631, "char_end": 609650, "token_start": 39, "token_end": 41, "note": null}]}
+{"sentence_id": 3662, "sentence_text": "p21ras and calcineurin synergize to regulate the nuclear factor of activated T cells .", "sentence_char_start_global": 609653, "sentence_char_end_global": 609739, "entities": [{"text": "p21ras", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 0}, {"text": "nuclear factor", "type": "ENTITY", "char_start": 49, "char_end": 63, "token_start": 7, "token_end": 8}], "entities_global": [{"text": "p21ras", "type": "ENTITY", "char_start": 609653, "char_end": 609659, "token_start": 0, "token_end": 0, "note": null}, {"text": "nuclear factor", "type": "ENTITY", "char_start": 609702, "char_end": 609716, "token_start": 7, "token_end": 8, "note": null}]}
+{"sentence_id": 3663, "sentence_text": "In T lymphocytes , triggering of the T cell receptor ( TCR ) induces several signaling cascades which ultimately synergize to induce the activity of the nuclear factor of activated T cells ( NFAT ) , a DNA binding complex critical to the inducibility and T cell specificity of the T cell growth factor interleukin 2 .", "sentence_char_start_global": 609740, "sentence_char_end_global": 610057, "entities": [{"text": "T cell receptor", "type": "ENTITY", "char_start": 37, "char_end": 52, "token_start": 7, "token_end": 9}, {"text": "TCR", "type": "ENTITY", "char_start": 55, "char_end": 58, "token_start": 11, "token_end": 11}, {"text": "nuclear factor", "type": "ENTITY", "char_start": 153, "char_end": 167, "token_start": 26, "token_end": 27}, {"text": "DNA binding complex", "type": "ENTITY", "char_start": 202, "char_end": 221, "token_start": 37, "token_end": 39}, {"text": "T cell growth factor", "type": "ENTITY", "char_start": 281, "char_end": 301, "token_start": 50, "token_end": 53}, {"text": "interleukin 2", "type": "ENTITY", "char_start": 302, "char_end": 315, "token_start": 54, "token_end": 55}], "entities_global": [{"text": "T cell receptor", "type": "ENTITY", "char_start": 609777, "char_end": 609792, "token_start": 7, "token_end": 9, "note": null}, {"text": "TCR", "type": "ENTITY", "char_start": 609795, "char_end": 609798, "token_start": 11, "token_end": 11, "note": null}, {"text": "nuclear factor", "type": "ENTITY", "char_start": 609893, "char_end": 609907, "token_start": 26, "token_end": 27, "note": null}, {"text": "DNA binding complex", "type": "ENTITY", "char_start": 609942, "char_end": 609961, "token_start": 37, "token_end": 39, "note": null}, {"text": "T cell growth factor", "type": "ENTITY", "char_start": 610021, "char_end": 610041, "token_start": 50, "token_end": 53, "note": null}, {"text": "interleukin 2", "type": "ENTITY", "char_start": 610042, "char_end": 610055, "token_start": 54, "token_end": 55, "note": null}]}
+{"sentence_id": 3664, "sentence_text": "One immediate consequence of T cell activation via the TCR is an increase in cytosolic calcium .", "sentence_char_start_global": 610058, "sentence_char_end_global": 610154, "entities": [{"text": "TCR", "type": "ENTITY", "char_start": 55, "char_end": 58, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "TCR", "type": "ENTITY", "char_start": 610113, "char_end": 610116, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 3665, "sentence_text": "Calcium signals are important for NFAT induction , and recent studies have identified calcineurin , a calcium - calmodulin dependent serine - threonine phosphatase , as a prominent component of the calcium signaling pathway in T cells .", "sentence_char_start_global": 610155, "sentence_char_end_global": 610391, "entities": [{"text": "calcineurin", "type": "ENTITY", "char_start": 86, "char_end": 97, "token_start": 13, "token_end": 13}, {"text": "calcium - calmodulin dependent serine - threonine phosphatase", "type": "ENTITY", "char_start": 102, "char_end": 163, "token_start": 16, "token_end": 23}], "entities_global": [{"text": "calcineurin", "type": "ENTITY", "char_start": 610241, "char_end": 610252, "token_start": 13, "token_end": 13, "note": null}, {"text": "calcium - calmodulin dependent serine - threonine phosphatase", "type": "ENTITY", "char_start": 610257, "char_end": 610318, "token_start": 16, "token_end": 23, "note": null}]}
+{"sentence_id": 3666, "sentence_text": "A second important molecule in TCR signal transduction is the guanine nucleotide binding protein , p21ras , which is coupled to the TCR by a protein tyrosine kinase dependent mechanism .", "sentence_char_start_global": 610392, "sentence_char_end_global": 610578, "entities": [{"text": "guanine nucleotide binding protein", "type": "ENTITY", "char_start": 62, "char_end": 96, "token_start": 10, "token_end": 13}, {"text": "p21ras", "type": "ENTITY", "char_start": 99, "char_end": 105, "token_start": 15, "token_end": 15}, {"text": "TCR", "type": "ENTITY", "char_start": 132, "char_end": 135, "token_start": 22, "token_end": 22}, {"text": "protein tyrosine kinase", "type": "ENTITY", "char_start": 141, "char_end": 164, "token_start": 25, "token_end": 27}], "entities_global": [{"text": "guanine nucleotide binding protein", "type": "ENTITY", "char_start": 610454, "char_end": 610488, "token_start": 10, "token_end": 13, "note": null}, {"text": "p21ras", "type": "ENTITY", "char_start": 610491, "char_end": 610497, "token_start": 15, "token_end": 15, "note": null}, {"text": "TCR", "type": "ENTITY", "char_start": 610524, "char_end": 610527, "token_start": 22, "token_end": 22, "note": null}, {"text": "protein tyrosine kinase", "type": "ENTITY", "char_start": 610533, "char_end": 610556, "token_start": 25, "token_end": 27, "note": null}]}
+{"sentence_id": 3667, "sentence_text": "The experiments presented here show that expression by transfection of mutationally activated calcineurin or activated p21ras alone is insufficient for NFAT transactivation .", "sentence_char_start_global": 610579, "sentence_char_end_global": 610753, "entities": [{"text": "calcineurin", "type": "ENTITY", "char_start": 94, "char_end": 105, "token_start": 12, "token_end": 12}, {"text": "p21ras", "type": "ENTITY", "char_start": 119, "char_end": 125, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "calcineurin", "type": "ENTITY", "char_start": 610673, "char_end": 610684, "token_start": 12, "token_end": 12, "note": null}, {"text": "p21ras", "type": "ENTITY", "char_start": 610698, "char_end": 610704, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 3668, "sentence_text": "However , coexpression of the activated calcineurin with activated p21ras could mimic TCR signals in NFAT induction .", "sentence_char_start_global": 610754, "sentence_char_end_global": 610871, "entities": [], "entities_global": []}
+{"sentence_id": 3669, "sentence_text": "These data identify calcineurin and p21ras as cooperative partners in T cell activation .", "sentence_char_start_global": 610872, "sentence_char_end_global": 610961, "entities": [{"text": "calcineurin", "type": "ENTITY", "char_start": 20, "char_end": 31, "token_start": 3, "token_end": 3}, {"text": "p21ras", "type": "ENTITY", "char_start": 36, "char_end": 42, "token_start": 5, "token_end": 5}], "entities_global": [{"text": "calcineurin", "type": "ENTITY", "char_start": 610892, "char_end": 610903, "token_start": 3, "token_end": 3, "note": null}, {"text": "p21ras", "type": "ENTITY", "char_start": 610908, "char_end": 610914, "token_start": 5, "token_end": 5, "note": null}]}
+{"sentence_id": 3670, "sentence_text": "Expression of the chicken GATA factor family during early erythroid development and differentiation .", "sentence_char_start_global": 610962, "sentence_char_end_global": 611063, "entities": [{"text": "chicken GATA factor family", "type": "ENTITY", "char_start": 18, "char_end": 44, "token_start": 3, "token_end": 6}], "entities_global": [{"text": "chicken GATA factor family", "type": "ENTITY", "char_start": 610980, "char_end": 611006, "token_start": 3, "token_end": 6, "note": null}]}
+{"sentence_id": 3671, "sentence_text": "The DNA motif WGATAR has been identified within transcriptional regulatory domains of globin and other erythroid - specific genes and the activator proteins that bind to this regulatory element , the GATA factors , belong to a multi - gene family that is expressed in chicken erythroid cells .", "sentence_char_start_global": 611064, "sentence_char_end_global": 611357, "entities": [{"text": "transcriptional regulatory domains", "type": "ENTITY", "char_start": 48, "char_end": 82, "token_start": 8, "token_end": 10}, {"text": "globin", "type": "ENTITY", "char_start": 86, "char_end": 92, "token_start": 12, "token_end": 12}, {"text": "erythroid - specific genes", "type": "ENTITY", "char_start": 103, "char_end": 129, "token_start": 15, "token_end": 18}, {"text": "activator proteins", "type": "ENTITY", "char_start": 138, "char_end": 156, "token_start": 21, "token_end": 22}, {"text": "regulatory element", "type": "ENTITY", "char_start": 175, "char_end": 193, "token_start": 27, "token_end": 28}, {"text": "GATA factors", "type": "ENTITY", "char_start": 200, "char_end": 212, "token_start": 31, "token_end": 32}, {"text": "multi - gene family", "type": "ENTITY", "char_start": 227, "char_end": 246, "token_start": 37, "token_end": 40}], "entities_global": [{"text": "transcriptional regulatory domains", "type": "ENTITY", "char_start": 611112, "char_end": 611146, "token_start": 8, "token_end": 10, "note": null}, {"text": "globin", "type": "ENTITY", "char_start": 611150, "char_end": 611156, "token_start": 12, "token_end": 12, "note": null}, {"text": "erythroid - specific genes", "type": "ENTITY", "char_start": 611167, "char_end": 611193, "token_start": 15, "token_end": 18, "note": null}, {"text": "activator proteins", "type": "ENTITY", "char_start": 611202, "char_end": 611220, "token_start": 21, "token_end": 22, "note": null}, {"text": "regulatory element", "type": "ENTITY", "char_start": 611239, "char_end": 611257, "token_start": 27, "token_end": 28, "note": null}, {"text": "GATA factors", "type": "ENTITY", "char_start": 611264, "char_end": 611276, "token_start": 31, "token_end": 32, "note": null}, {"text": "multi - gene family", "type": "ENTITY", "char_start": 611291, "char_end": 611310, "token_start": 37, "token_end": 40, "note": null}]}
+{"sentence_id": 3672, "sentence_text": "Here we show that , as in chickens , multiple members of the GATA factor family are expressed in human and murine erythroid cells .", "sentence_char_start_global": 611358, "sentence_char_end_global": 611489, "entities": [{"text": "GATA factor family", "type": "ENTITY", "char_start": 61, "char_end": 79, "token_start": 13, "token_end": 15}], "entities_global": [{"text": "GATA factor family", "type": "ENTITY", "char_start": 611419, "char_end": 611437, "token_start": 13, "token_end": 15, "note": null}]}
+{"sentence_id": 3673, "sentence_text": "During the early stages of chicken embryogenesis ( well before blood island formation ) , each of the GATA family members is transcribed with a unique temporal and spatial pattern .", "sentence_char_start_global": 611490, "sentence_char_end_global": 611671, "entities": [{"text": "GATA family members", "type": "ENTITY", "char_start": 102, "char_end": 121, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "GATA family members", "type": "ENTITY", "char_start": 611592, "char_end": 611611, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 3674, "sentence_text": "In the primitive erythroid lineage , transcription of the embryonic epsilon - globin gene parallels GATA - 1 expression while the switch to beta - globin transcription in definitive erythroid cells is directly preceded by a pronounced increase in GATA - 3 accumulation .", "sentence_char_start_global": 611672, "sentence_char_end_global": 611942, "entities": [{"text": "embryonic epsilon - globin gene", "type": "ENTITY", "char_start": 58, "char_end": 89, "token_start": 9, "token_end": 13}, {"text": "GATA - 3", "type": "ENTITY", "char_start": 247, "char_end": 255, "token_start": 39, "token_end": 41}], "entities_global": [{"text": "embryonic epsilon - globin gene", "type": "ENTITY", "char_start": 611730, "char_end": 611761, "token_start": 9, "token_end": 13, "note": null}, {"text": "GATA - 3", "type": "ENTITY", "char_start": 611919, "char_end": 611927, "token_start": 39, "token_end": 41, "note": null}]}
+{"sentence_id": 3675, "sentence_text": "The timing and pattern of expression of these different mRNAs during avian erythroid development and differentiation suggests that temporally regulated changes in GATA factor expression are required for vertebrate hematopoiesis .", "sentence_char_start_global": 611943, "sentence_char_end_global": 612172, "entities": [{"text": "mRNAs", "type": "ENTITY", "char_start": 56, "char_end": 61, "token_start": 9, "token_end": 9}, {"text": "GATA factor", "type": "ENTITY", "char_start": 163, "char_end": 174, "token_start": 22, "token_end": 23}], "entities_global": [{"text": "mRNAs", "type": "ENTITY", "char_start": 611999, "char_end": 612004, "token_start": 9, "token_end": 9, "note": null}, {"text": "GATA factor", "type": "ENTITY", "char_start": 612106, "char_end": 612117, "token_start": 22, "token_end": 23, "note": null}]}
+{"sentence_id": 3676, "sentence_text": "Molecular regulation of human interleukin 2 and T - cell function by interleukin 4 .", "sentence_char_start_global": 612173, "sentence_char_end_global": 612257, "entities": [{"text": "human interleukin 2", "type": "ENTITY", "char_start": 24, "char_end": 43, "token_start": 3, "token_end": 5}, {"text": "interleukin 4", "type": "ENTITY", "char_start": 69, "char_end": 82, "token_start": 12, "token_end": 13}], "entities_global": [{"text": "human interleukin 2", "type": "ENTITY", "char_start": 612197, "char_end": 612216, "token_start": 3, "token_end": 5, "note": null}, {"text": "interleukin 4", "type": "ENTITY", "char_start": 612242, "char_end": 612255, "token_start": 12, "token_end": 13, "note": null}]}
+{"sentence_id": 3677, "sentence_text": "Distinct functional T - cell subsets , differing in the patterns of lymphokines produced , regulate cell - mediated and humoral immune responses .", "sentence_char_start_global": 612258, "sentence_char_end_global": 612404, "entities": [{"text": "lymphokines", "type": "ENTITY", "char_start": 68, "char_end": 79, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "lymphokines", "type": "ENTITY", "char_start": 612326, "char_end": 612337, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 3678, "sentence_text": "The two major types and their principal products , interleukin 4 and interferon gamma ( IL - 4 and IFN - gamma ) , are reciprocally negatively interactive .", "sentence_char_start_global": 612405, "sentence_char_end_global": 612561, "entities": [{"text": "interleukin 4", "type": "ENTITY", "char_start": 51, "char_end": 64, "token_start": 9, "token_end": 10}, {"text": "interferon gamma", "type": "ENTITY", "char_start": 69, "char_end": 85, "token_start": 12, "token_end": 13}, {"text": "IL - 4", "type": "ENTITY", "char_start": 88, "char_end": 94, "token_start": 15, "token_end": 17}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 99, "char_end": 110, "token_start": 19, "token_end": 21}], "entities_global": [{"text": "interleukin 4", "type": "ENTITY", "char_start": 612456, "char_end": 612469, "token_start": 9, "token_end": 10, "note": null}, {"text": "interferon gamma", "type": "ENTITY", "char_start": 612474, "char_end": 612490, "token_start": 12, "token_end": 13, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 612493, "char_end": 612499, "token_start": 15, "token_end": 17, "note": null}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 612504, "char_end": 612515, "token_start": 19, "token_end": 21, "note": null}]}
+{"sentence_id": 3679, "sentence_text": "To analyze the molecular mechanism of IL - 4 - mediated suppression of cell - mediated immunity we studied its effects on expression of interleukin 2 ( IL - 2 ) and IFN - gamma .", "sentence_char_start_global": 612562, "sentence_char_end_global": 612740, "entities": [{"text": "interleukin 2", "type": "ENTITY", "char_start": 136, "char_end": 149, "token_start": 24, "token_end": 25}, {"text": "IL - 2", "type": "ENTITY", "char_start": 152, "char_end": 158, "token_start": 27, "token_end": 29}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 165, "char_end": 176, "token_start": 32, "token_end": 34}], "entities_global": [{"text": "interleukin 2", "type": "ENTITY", "char_start": 612698, "char_end": 612711, "token_start": 24, "token_end": 25, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 612714, "char_end": 612720, "token_start": 27, "token_end": 29, "note": null}, {"text": "IFN - gamma", "type": "ENTITY", "char_start": 612727, "char_end": 612738, "token_start": 32, "token_end": 34, "note": null}]}
+{"sentence_id": 3680, "sentence_text": "IL - 4 pretreatment of Jurkat cells prior to stimulation resulted in a decrease in transcription of the IL2 gene .", "sentence_char_start_global": 612741, "sentence_char_end_global": 612855, "entities": [{"text": "IL - 4", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 2}, {"text": "IL2 gene", "type": "ENTITY", "char_start": 104, "char_end": 112, "token_start": 18, "token_end": 19}], "entities_global": [{"text": "IL - 4", "type": "ENTITY", "char_start": 612741, "char_end": 612747, "token_start": 0, "token_end": 2, "note": null}, {"text": "IL2 gene", "type": "ENTITY", "char_start": 612845, "char_end": 612853, "token_start": 18, "token_end": 19, "note": null}]}
+{"sentence_id": 3681, "sentence_text": "IL - 4 suppressed IL - 2 and IFN - gamma mRNA levels in primary human T cells , and addition of anti - CD28 antibodies relieved this suppression .", "sentence_char_start_global": 612856, "sentence_char_end_global": 613002, "entities": [{"text": "IL - 4", "type": "ENTITY", "char_start": 0, "char_end": 6, "token_start": 0, "token_end": 2}, {"text": "anti - CD28 antibodies", "type": "ENTITY", "char_start": 96, "char_end": 118, "token_start": 22, "token_end": 25}], "entities_global": [{"text": "IL - 4", "type": "ENTITY", "char_start": 612856, "char_end": 612862, "token_start": 0, "token_end": 2, "note": null}, {"text": "anti - CD28 antibodies", "type": "ENTITY", "char_start": 612952, "char_end": 612974, "token_start": 22, "token_end": 25, "note": null}]}
+{"sentence_id": 3682, "sentence_text": "Using enhancer - reporter constructs , IL - 4 specifically down - regulated the NFIL - 2B element .", "sentence_char_start_global": 613003, "sentence_char_end_global": 613102, "entities": [{"text": "enhancer - reporter constructs", "type": "ENTITY", "char_start": 6, "char_end": 36, "token_start": 1, "token_end": 4}, {"text": "IL - 4", "type": "ENTITY", "char_start": 39, "char_end": 45, "token_start": 6, "token_end": 8}, {"text": "NFIL - 2B element", "type": "ENTITY", "char_start": 80, "char_end": 97, "token_start": 14, "token_end": 17}], "entities_global": [{"text": "enhancer - reporter constructs", "type": "ENTITY", "char_start": 613009, "char_end": 613039, "token_start": 1, "token_end": 4, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 613042, "char_end": 613048, "token_start": 6, "token_end": 8, "note": null}, {"text": "NFIL - 2B element", "type": "ENTITY", "char_start": 613083, "char_end": 613100, "token_start": 14, "token_end": 17, "note": null}]}
+{"sentence_id": 3683, "sentence_text": "Electrophoretic mobility shift assays using a DNA oligomer containing the NFIL - 2B binding site indicated that IL - 4 inhibited the NFIL - 2B complex and that the NFIL - 2B DNA binding factor is distinct from AP - 1 .", "sentence_char_start_global": 613103, "sentence_char_end_global": 613321, "entities": [{"text": "NFIL - 2B binding site", "type": "ENTITY", "char_start": 74, "char_end": 96, "token_start": 10, "token_end": 14}, {"text": "IL - 4", "type": "ENTITY", "char_start": 112, "char_end": 118, "token_start": 17, "token_end": 19}, {"text": "NFIL - 2B complex", "type": "ENTITY", "char_start": 133, "char_end": 150, "token_start": 22, "token_end": 25}, {"text": "NFIL - 2B DNA binding factor", "type": "ENTITY", "char_start": 164, "char_end": 192, "token_start": 29, "token_end": 34}, {"text": "AP -", "type": "ENTITY", "char_start": 210, "char_end": 214, "token_start": 38, "token_end": 39}], "entities_global": [{"text": "NFIL - 2B binding site", "type": "ENTITY", "char_start": 613177, "char_end": 613199, "token_start": 10, "token_end": 14, "note": null}, {"text": "IL - 4", "type": "ENTITY", "char_start": 613215, "char_end": 613221, "token_start": 17, "token_end": 19, "note": null}, {"text": "NFIL - 2B complex", "type": "ENTITY", "char_start": 613236, "char_end": 613253, "token_start": 22, "token_end": 25, "note": null}, {"text": "NFIL - 2B DNA binding factor", "type": "ENTITY", "char_start": 613267, "char_end": 613295, "token_start": 29, "token_end": 34, "note": null}, {"text": "AP -", "type": "ENTITY", "char_start": 613313, "char_end": 613317, "token_start": 38, "token_end": 39, "note": null}]}
+{"sentence_id": 3684, "sentence_text": "These results suggest that IL - 4 may regulate development and function of T - cell subsets involved in cell - mediated immunity in part by inhibiting factors required for transcription of the IL2 gene", "sentence_char_start_global": 613322, "sentence_char_end_global": 613523, "entities": [{"text": "IL - 4", "type": "ENTITY", "char_start": 27, "char_end": 33, "token_start": 4, "token_end": 6}, {"text": "inhibiting factors", "type": "ENTITY", "char_start": 140, "char_end": 158, "token_start": 26, "token_end": 27}, {"text": "IL2 gene", "type": "ENTITY", "char_start": 193, "char_end": 201, "token_start": 33, "token_end": 34}], "entities_global": [{"text": "IL - 4", "type": "ENTITY", "char_start": 613349, "char_end": 613355, "token_start": 4, "token_end": 6, "note": null}, {"text": "inhibiting factors", "type": "ENTITY", "char_start": 613462, "char_end": 613480, "token_start": 26, "token_end": 27, "note": null}, {"text": "IL2 gene", "type": "ENTITY", "char_start": 613515, "char_end": 613523, "token_start": 33, "token_end": 34, "note": null}]}
+{"sentence_id": 3685, "sentence_text": "Immunochemical differences between glucocorticoid receptors from corticoid - sensitive and - resistant malignant lymphocytes .", "sentence_char_start_global": 613524, "sentence_char_end_global": 613650, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 35, "char_end": 59, "token_start": 3, "token_end": 4}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 613559, "char_end": 613583, "token_start": 3, "token_end": 4, "note": null}]}
+{"sentence_id": 3686, "sentence_text": "We have explored the possibility of using antibodies against purified rat liver glucocorticoid receptors to study the immunochemical properties of glucocorticoid receptors from murine and human malignant lymphocytes .", "sentence_char_start_global": 613651, "sentence_char_end_global": 613868, "entities": [{"text": "antibodies", "type": "ENTITY", "char_start": 42, "char_end": 52, "token_start": 7, "token_end": 7}, {"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 80, "char_end": 104, "token_start": 12, "token_end": 13}, {"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 147, "char_end": 171, "token_start": 20, "token_end": 21}], "entities_global": [{"text": "antibodies", "type": "ENTITY", "char_start": 613693, "char_end": 613703, "token_start": 7, "token_end": 7, "note": null}, {"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 613731, "char_end": 613755, "token_start": 12, "token_end": 13, "note": null}, {"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 613798, "char_end": 613822, "token_start": 20, "token_end": 21, "note": null}]}
+{"sentence_id": 3687, "sentence_text": "For this purpose , purified immune immunoglobulin G was covalently linked to Sepharose CL - 4B .", "sentence_char_start_global": 613869, "sentence_char_end_global": 613965, "entities": [{"text": "purified immune immunoglobulin G", "type": "ENTITY", "char_start": 19, "char_end": 51, "token_start": 4, "token_end": 7}, {"text": "Sepharose CL - 4B", "type": "ENTITY", "char_start": 77, "char_end": 94, "token_start": 12, "token_end": 15}], "entities_global": [{"text": "purified immune immunoglobulin G", "type": "ENTITY", "char_start": 613888, "char_end": 613920, "token_start": 4, "token_end": 7, "note": null}, {"text": "Sepharose CL - 4B", "type": "ENTITY", "char_start": 613946, "char_end": 613963, "token_start": 12, "token_end": 15, "note": null}]}
+{"sentence_id": 3688, "sentence_text": "We then examined the ability of the affinity gel to recognize cytosolic [ 3H ] triamcinolone acetonide - receptor complexes from the corticoid - sensitive ( CS ) and - resistant strains of mouse lymphoma P1798 , from CS lymphocytes of patients with chronic lymphatic leukemia , and from a CS clone of human leukemic lymphoblasts in tissue culture ( CH6 ) .", "sentence_char_start_global": 613966, "sentence_char_end_global": 614322, "entities": [{"text": "cytosolic [ 3H ] triamcinolone acetonide - receptor complexes", "type": "ENTITY", "char_start": 62, "char_end": 123, "token_start": 11, "token_end": 19}], "entities_global": [{"text": "cytosolic [ 3H ] triamcinolone acetonide - receptor complexes", "type": "ENTITY", "char_start": 614028, "char_end": 614089, "token_start": 11, "token_end": 19, "note": null}]}
+{"sentence_id": 3689, "sentence_text": "Mouse thymus was used as a source of glucocorticoid receptor from normal CS lymphocytes .", "sentence_char_start_global": 614323, "sentence_char_end_global": 614412, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 37, "char_end": 60, "token_start": 8, "token_end": 9}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 614360, "char_end": 614383, "token_start": 8, "token_end": 9, "note": null}]}
+{"sentence_id": 3690, "sentence_text": "Whereas the immunoaffinity column retained 70 to 84 % of the 58 - to 62 - A ( Stokes radius ) [ 3H ] triamcinolone acetonide - receptor complexes characteristic of the CS mouse and human lymphocytes , it failed to recognize the 27 - to 28 - A ( Stokes radius ) glucocorticoid receptor present in corticoid - resistant mouse lymphoma P1798 cells .", "sentence_char_start_global": 614413, "sentence_char_end_global": 614759, "entities": [{"text": "[ 3H ] triamcinolone acetonide - receptor complexes", "type": "ENTITY", "char_start": 94, "char_end": 145, "token_start": 21, "token_end": 28}, {"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 261, "char_end": 284, "token_start": 53, "token_end": 54}], "entities_global": [{"text": "[ 3H ] triamcinolone acetonide - receptor complexes", "type": "ENTITY", "char_start": 614507, "char_end": 614558, "token_start": 21, "token_end": 28, "note": null}, {"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 614674, "char_end": 614697, "token_start": 53, "token_end": 54, "note": null}]}
+{"sentence_id": 3691, "sentence_text": "Therefore , under appropriate experimental conditions , it was possible to demonstrate cross - reactivity between the antiserum against rat liver glucocorticoid receptor and the 58 - to 62 - A ( Stokes radius ) glucocorticoid receptor from species as diverse as mouse and humans .", "sentence_char_start_global": 614760, "sentence_char_end_global": 615040, "entities": [{"text": "rat liver glucocorticoid receptor", "type": "ENTITY", "char_start": 136, "char_end": 169, "token_start": 19, "token_end": 22}, {"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 211, "char_end": 234, "token_start": 35, "token_end": 36}], "entities_global": [{"text": "rat liver glucocorticoid receptor", "type": "ENTITY", "char_start": 614896, "char_end": 614929, "token_start": 19, "token_end": 22, "note": null}, {"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 614971, "char_end": 614994, "token_start": 35, "token_end": 36, "note": null}]}
+{"sentence_id": 3692, "sentence_text": "Heterogeneity of the in vitro responses to glucocorticoids in acute leukemia .", "sentence_char_start_global": 615041, "sentence_char_end_global": 615119, "entities": [], "entities_global": []}
+{"sentence_id": 3693, "sentence_text": "In leukocyte population freshly isolated from the blood of 26 patients with acute leukemia , we have measured several parameters including glucocorticoid receptors , nucleoside incorporation , percentage of cells in S phase , and steroid - induced cell lysis .", "sentence_char_start_global": 615120, "sentence_char_end_global": 615380, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 139, "char_end": 163, "token_start": 21, "token_end": 22}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 615259, "char_end": 615283, "token_start": 21, "token_end": 22, "note": null}]}
+{"sentence_id": 3694, "sentence_text": "In addition , in some cases , the short - term response to steroid therapy was determined .", "sentence_char_start_global": 615381, "sentence_char_end_global": 615472, "entities": [], "entities_global": []}
+{"sentence_id": 3695, "sentence_text": "Although , in all the patients studied , leukocytes were found to contain glucocorticoid receptors , we failed to demonstrate any correlation between the level of binding sites and the in vitro or in vivo response to glucocorticoids .", "sentence_char_start_global": 615473, "sentence_char_end_global": 615707, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 74, "char_end": 98, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 615547, "char_end": 615571, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 3696, "sentence_text": "This absence of correlation could be in part explained by the marked heterogeneity of the steroid response demonstrated in leukocyte subpopulations .", "sentence_char_start_global": 615708, "sentence_char_end_global": 615857, "entities": [], "entities_global": []}
+{"sentence_id": 3697, "sentence_text": "It appears , however , that the degree of steroid action in vitro as well as the extent of spontaneous and dexamethasone - induced cell death may be related to the number of cells in the S phase of the cell cycle .", "sentence_char_start_global": 615858, "sentence_char_end_global": 616072, "entities": [], "entities_global": []}
+{"sentence_id": 3698, "sentence_text": "Glucocorticoid receptors in cytosol and nuclear extract of human leukocytes .", "sentence_char_start_global": 616073, "sentence_char_end_global": 616150, "entities": [{"text": "Glucocorticoid receptors", "type": "ENTITY", "char_start": 0, "char_end": 24, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "Glucocorticoid receptors", "type": "ENTITY", "char_start": 616073, "char_end": 616097, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 3699, "sentence_text": "Cortisol binding by cytosol and 0 . 4 M KCl extract of the nuclear fraction of human leukocytes were studied by gel chromatography and ion exchange filtration on DEAE cellulose .", "sentence_char_start_global": 616151, "sentence_char_end_global": 616329, "entities": [], "entities_global": []}
+{"sentence_id": 3700, "sentence_text": "The cytoplasmic cortisol binding protein has a molecular weight 95 000 and the soluble nuclear binding protein 50 000 .", "sentence_char_start_global": 616330, "sentence_char_end_global": 616449, "entities": [{"text": "cytoplasmic cortisol binding protein", "type": "ENTITY", "char_start": 4, "char_end": 40, "token_start": 1, "token_end": 4}, {"text": "soluble nuclear binding protein", "type": "ENTITY", "char_start": 79, "char_end": 110, "token_start": 13, "token_end": 16}], "entities_global": [{"text": "cytoplasmic cortisol binding protein", "type": "ENTITY", "char_start": 616334, "char_end": 616370, "token_start": 1, "token_end": 4, "note": null}, {"text": "soluble nuclear binding protein", "type": "ENTITY", "char_start": 616409, "char_end": 616440, "token_start": 13, "token_end": 16, "note": null}]}
+{"sentence_id": 3701, "sentence_text": "The absence of the uptake of radioactive cortisol by isolated nuclei and the apparent requirement of the cytosol for glucocorticoid specific binding in nuclear receptor sites was observed .", "sentence_char_start_global": 616450, "sentence_char_end_global": 616639, "entities": [], "entities_global": []}
+{"sentence_id": 3702, "sentence_text": "The association constant characterising the binding of cortisol to cytosol was KA = 3 . 5 . 10 ( 9 ) l / mol .", "sentence_char_start_global": 616640, "sentence_char_end_global": 616750, "entities": [], "entities_global": []}
+{"sentence_id": 3703, "sentence_text": "Corticosteroid - induced lymphopenia , immunosuppression , and body defense .", "sentence_char_start_global": 616751, "sentence_char_end_global": 616828, "entities": [], "entities_global": []}
+{"sentence_id": 3704, "sentence_text": "The apparent paradox of heightened adrenal corticosteroid levels associated with reduction in the competence of the body ' s defensive apparatus to cope with exposure to new microbial antigens is considered .", "sentence_char_start_global": 616829, "sentence_char_end_global": 617037, "entities": [{"text": "microbial antigens", "type": "ENTITY", "char_start": 174, "char_end": 192, "token_start": 27, "token_end": 28}], "entities_global": [{"text": "microbial antigens", "type": "ENTITY", "char_start": 617003, "char_end": 617021, "token_start": 27, "token_end": 28, "note": null}]}
+{"sentence_id": 3705, "sentence_text": "The question is asked how this lowered defensive capability , which occurs in the face of a threat to body integrity , is consistent with Cannon ' s principals of the ` ` wisdom of the body . ' '", "sentence_char_start_global": 617038, "sentence_char_end_global": 617233, "entities": [], "entities_global": []}
+{"sentence_id": 3706, "sentence_text": "The suggestion is offered that the immunologic response to self - antigens exposed by disease or trauma may be suppressed by corticosteroid to offset the likelihood of autoimmune attack .", "sentence_char_start_global": 617234, "sentence_char_end_global": 617421, "entities": [{"text": "self - antigens", "type": "ENTITY", "char_start": 59, "char_end": 74, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "self - antigens", "type": "ENTITY", "char_start": 617293, "char_end": 617308, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 3707, "sentence_text": "Protein tyrosine kinase activation is required for lipopolysaccharide induction of cytokines in human blood monocytes .", "sentence_char_start_global": 617422, "sentence_char_end_global": 617541, "entities": [{"text": "Protein tyrosine kinase", "type": "ENTITY", "char_start": 0, "char_end": 23, "token_start": 0, "token_end": 2}, {"text": "cytokines", "type": "ENTITY", "char_start": 83, "char_end": 92, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "Protein tyrosine kinase", "type": "ENTITY", "char_start": 617422, "char_end": 617445, "token_start": 0, "token_end": 2, "note": null}, {"text": "cytokines", "type": "ENTITY", "char_start": 617505, "char_end": 617514, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 3708, "sentence_text": "Bacterial LPS induce production of cytokines such as IL - 1 , IL - 6 , and TNF in mononuclear phagocytes , and this represents a central component in the pathogenesis of septic shock syndrome .", "sentence_char_start_global": 617542, "sentence_char_end_global": 617735, "entities": [{"text": "cytokines", "type": "ENTITY", "char_start": 35, "char_end": 44, "token_start": 5, "token_end": 5}, {"text": "IL - 1", "type": "ENTITY", "char_start": 53, "char_end": 59, "token_start": 8, "token_end": 10}, {"text": "IL - 6", "type": "ENTITY", "char_start": 62, "char_end": 68, "token_start": 12, "token_end": 14}, {"text": "TNF", "type": "ENTITY", "char_start": 75, "char_end": 78, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "cytokines", "type": "ENTITY", "char_start": 617577, "char_end": 617586, "token_start": 5, "token_end": 5, "note": null}, {"text": "IL - 1", "type": "ENTITY", "char_start": 617595, "char_end": 617601, "token_start": 8, "token_end": 10, "note": null}, {"text": "IL - 6", "type": "ENTITY", "char_start": 617604, "char_end": 617610, "token_start": 12, "token_end": 14, "note": null}, {"text": "TNF", "type": "ENTITY", "char_start": 617617, "char_end": 617620, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 3709, "sentence_text": "However , the mechanisms by which LPS activates these cells to express cytokines are not completely characterized .", "sentence_char_start_global": 617736, "sentence_char_end_global": 617851, "entities": [{"text": "cytokines", "type": "ENTITY", "char_start": 71, "char_end": 80, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "cytokines", "type": "ENTITY", "char_start": 617807, "char_end": 617816, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 3710, "sentence_text": "The present study addressed the role of different protein kinases in the LPS induction of cytokines .", "sentence_char_start_global": 617852, "sentence_char_end_global": 617953, "entities": [{"text": "protein kinases", "type": "ENTITY", "char_start": 50, "char_end": 65, "token_start": 8, "token_end": 9}, {"text": "cytokines", "type": "ENTITY", "char_start": 90, "char_end": 99, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "protein kinases", "type": "ENTITY", "char_start": 617902, "char_end": 617917, "token_start": 8, "token_end": 9, "note": null}, {"text": "cytokines", "type": "ENTITY", "char_start": 617942, "char_end": 617951, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 3711, "sentence_text": "It is shown that LPS induced a 12 - to 16 - fold increase in IL - 1 beta , IL - 6 , and TNF - alpha mRNA levels , and this was completely or more than 80 % blocked by the protein tyrosine kinase specific inhibitors herbimycin A and genistein at the concentrations of 1 . 7 and 37 microM , respectively .", "sentence_char_start_global": 617954, "sentence_char_end_global": 618257, "entities": [], "entities_global": []}
+{"sentence_id": 3712, "sentence_text": "Protein kinase C inhibition by staurosporine reduced LPS induction of TNF - alpha , whereas it had no effects on IL - 6 and IL - 1 beta .", "sentence_char_start_global": 618258, "sentence_char_end_global": 618395, "entities": [{"text": "Protein kinase C", "type": "ENTITY", "char_start": 0, "char_end": 16, "token_start": 0, "token_end": 2}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 70, "char_end": 81, "token_start": 10, "token_end": 12}, {"text": "IL - 6", "type": "ENTITY", "char_start": 113, "char_end": 119, "token_start": 20, "token_end": 22}], "entities_global": [{"text": "Protein kinase C", "type": "ENTITY", "char_start": 618258, "char_end": 618274, "token_start": 0, "token_end": 2, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 618328, "char_end": 618339, "token_start": 10, "token_end": 12, "note": null}, {"text": "IL - 6", "type": "ENTITY", "char_start": 618371, "char_end": 618377, "token_start": 20, "token_end": 22, "note": null}]}
+{"sentence_id": 3713, "sentence_text": "Inhibition of protein kinase A by H89 reduced IL - 6 mRNA levels but did not detectably change IL - 1 beta or TNF - alpha mRNA levels .", "sentence_char_start_global": 618396, "sentence_char_end_global": 618531, "entities": [{"text": "protein kinase A", "type": "ENTITY", "char_start": 14, "char_end": 30, "token_start": 2, "token_end": 4}, {"text": "IL - 6 mRNA", "type": "ENTITY", "char_start": 46, "char_end": 57, "token_start": 8, "token_end": 11}], "entities_global": [{"text": "protein kinase A", "type": "ENTITY", "char_start": 618410, "char_end": 618426, "token_start": 2, "token_end": 4, "note": null}, {"text": "IL - 6 mRNA", "type": "ENTITY", "char_start": 618442, "char_end": 618453, "token_start": 8, "token_end": 11, "note": null}]}
+{"sentence_id": 3714, "sentence_text": "In contrast , LPS did not increase leukemia inhibitory factor mRNA , which was constitutively expressed and not significantly reduced by these inhibitors .", "sentence_char_start_global": 618532, "sentence_char_end_global": 618687, "entities": [{"text": "leukemia inhibitory factor mRNA", "type": "ENTITY", "char_start": 35, "char_end": 66, "token_start": 7, "token_end": 10}], "entities_global": [{"text": "leukemia inhibitory factor mRNA", "type": "ENTITY", "char_start": 618567, "char_end": 618598, "token_start": 7, "token_end": 10, "note": null}]}
+{"sentence_id": 3715, "sentence_text": "In addition to cytokine mRNA levels , LPS - induced IL - 6 protein synthesis and IL - 6 bioactivity were also reduced to baseline levels by the PTK inhibitors herbimycin A and genistein .", "sentence_char_start_global": 618688, "sentence_char_end_global": 618875, "entities": [{"text": "cytokine mRNA", "type": "ENTITY", "char_start": 15, "char_end": 28, "token_start": 3, "token_end": 4}], "entities_global": [{"text": "cytokine mRNA", "type": "ENTITY", "char_start": 618703, "char_end": 618716, "token_start": 3, "token_end": 4, "note": null}]}
+{"sentence_id": 3716, "sentence_text": "Both PTK inhibitors also reduced the LPS activation of nuclear factor - kappa B ( NF - kappa B ) , which is a transcription factor involved in the expression of cytokine genes such as IL - 6 and TNF - alpha .", "sentence_char_start_global": 618876, "sentence_char_end_global": 619084, "entities": [{"text": "nuclear factor - kappa B", "type": "ENTITY", "char_start": 55, "char_end": 79, "token_start": 9, "token_end": 13}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 82, "char_end": 94, "token_start": 15, "token_end": 18}, {"text": "transcription factor", "type": "ENTITY", "char_start": 110, "char_end": 130, "token_start": 24, "token_end": 25}, {"text": "cytokine genes", "type": "ENTITY", "char_start": 161, "char_end": 175, "token_start": 31, "token_end": 32}, {"text": "IL - 6", "type": "ENTITY", "char_start": 184, "char_end": 190, "token_start": 35, "token_end": 37}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 195, "char_end": 206, "token_start": 39, "token_end": 41}], "entities_global": [{"text": "nuclear factor - kappa B", "type": "ENTITY", "char_start": 618931, "char_end": 618955, "token_start": 9, "token_end": 13, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 618958, "char_end": 618970, "token_start": 15, "token_end": 18, "note": null}, {"text": "transcription factor", "type": "ENTITY", "char_start": 618986, "char_end": 619006, "token_start": 24, "token_end": 25, "note": null}, {"text": "cytokine genes", "type": "ENTITY", "char_start": 619037, "char_end": 619051, "token_start": 31, "token_end": 32, "note": null}, {"text": "IL - 6", "type": "ENTITY", "char_start": 619060, "char_end": 619066, "token_start": 35, "token_end": 37, "note": null}, {"text": "TNF - alpha", "type": "ENTITY", "char_start": 619071, "char_end": 619082, "token_start": 39, "token_end": 41, "note": null}]}
+{"sentence_id": 3717, "sentence_text": "The activation of NF - kappa B was also reduced by H89 , whereas staurosporine had no effect on this response .", "sentence_char_start_global": 619085, "sentence_char_end_global": 619196, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 18, "char_end": 30, "token_start": 3, "token_end": 6}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 619103, "char_end": 619115, "token_start": 3, "token_end": 6, "note": null}]}
+{"sentence_id": 3718, "sentence_text": "In summary , these findings suggest that protein kinase C and protein kinase A appear to have selective effects in the LPS induction of cytokines , whereas PTK is required for LPS induction of a broad spectrum of cytokines and NF - kappa B activation in monocytes .", "sentence_char_start_global": 619197, "sentence_char_end_global": 619462, "entities": [{"text": "protein kinase C", "type": "ENTITY", "char_start": 41, "char_end": 57, "token_start": 7, "token_end": 9}, {"text": "protein kinase A", "type": "ENTITY", "char_start": 62, "char_end": 78, "token_start": 11, "token_end": 13}, {"text": "cytokines", "type": "ENTITY", "char_start": 136, "char_end": 145, "token_start": 24, "token_end": 24}, {"text": "PTK", "type": "ENTITY", "char_start": 156, "char_end": 159, "token_start": 27, "token_end": 27}, {"text": "cytokines", "type": "ENTITY", "char_start": 213, "char_end": 222, "token_start": 38, "token_end": 38}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 227, "char_end": 239, "token_start": 40, "token_end": 43}], "entities_global": [{"text": "protein kinase C", "type": "ENTITY", "char_start": 619238, "char_end": 619254, "token_start": 7, "token_end": 9, "note": null}, {"text": "protein kinase A", "type": "ENTITY", "char_start": 619259, "char_end": 619275, "token_start": 11, "token_end": 13, "note": null}, {"text": "cytokines", "type": "ENTITY", "char_start": 619333, "char_end": 619342, "token_start": 24, "token_end": 24, "note": null}, {"text": "PTK", "type": "ENTITY", "char_start": 619353, "char_end": 619356, "token_start": 27, "token_end": 27, "note": null}, {"text": "cytokines", "type": "ENTITY", "char_start": 619410, "char_end": 619419, "token_start": 38, "token_end": 38, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 619424, "char_end": 619436, "token_start": 40, "token_end": 43, "note": null}]}
+{"sentence_id": 3719, "sentence_text": "In vivo control of NF - kappa B activation by I kappa B alpha .", "sentence_char_start_global": 619463, "sentence_char_end_global": 619526, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 19, "char_end": 31, "token_start": 4, "token_end": 7}, {"text": "I kappa B alpha", "type": "ENTITY", "char_start": 46, "char_end": 61, "token_start": 10, "token_end": 13}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 619482, "char_end": 619494, "token_start": 4, "token_end": 7, "note": null}, {"text": "I kappa B alpha", "type": "ENTITY", "char_start": 619509, "char_end": 619524, "token_start": 10, "token_end": 13, "note": null}]}
+{"sentence_id": 3720, "sentence_text": "The transcription factor NF - kappa B is stored in the cytoplasm in complexes with the inhibitor protein I kappa B alpha .", "sentence_char_start_global": 619527, "sentence_char_end_global": 619649, "entities": [{"text": "transcription factor", "type": "ENTITY", "char_start": 4, "char_end": 24, "token_start": 1, "token_end": 2}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 25, "char_end": 37, "token_start": 3, "token_end": 6}, {"text": "inhibitor protein I kappa B alpha", "type": "ENTITY", "char_start": 87, "char_end": 120, "token_start": 16, "token_end": 21}], "entities_global": [{"text": "transcription factor", "type": "ENTITY", "char_start": 619531, "char_end": 619551, "token_start": 1, "token_end": 2, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 619552, "char_end": 619564, "token_start": 3, "token_end": 6, "note": null}, {"text": "inhibitor protein I kappa B alpha", "type": "ENTITY", "char_start": 619614, "char_end": 619647, "token_start": 16, "token_end": 21, "note": null}]}
+{"sentence_id": 3721, "sentence_text": "It has been shown in vitro that dissociation of I kappa B alpha from these complexes results in active NF - kappa B .", "sentence_char_start_global": 619650, "sentence_char_end_global": 619767, "entities": [{"text": "I kappa B alpha", "type": "ENTITY", "char_start": 48, "char_end": 63, "token_start": 9, "token_end": 12}, {"text": "active NF - kappa B", "type": "ENTITY", "char_start": 96, "char_end": 115, "token_start": 18, "token_end": 22}], "entities_global": [{"text": "I kappa B alpha", "type": "ENTITY", "char_start": 619698, "char_end": 619713, "token_start": 9, "token_end": 12, "note": null}, {"text": "active NF - kappa B", "type": "ENTITY", "char_start": 619746, "char_end": 619765, "token_start": 18, "token_end": 22, "note": null}]}
+{"sentence_id": 3722, "sentence_text": "In this report we show that lipopolysaccharide ( LPS ) - induced activation of B or pre - B cells results in loss of I kappa B alpha from NF - kappa B complexes in vivo .", "sentence_char_start_global": 619768, "sentence_char_end_global": 619938, "entities": [{"text": "I kappa B alpha", "type": "ENTITY", "char_start": 117, "char_end": 132, "token_start": 24, "token_end": 27}, {"text": "NF - kappa B complexes", "type": "ENTITY", "char_start": 138, "char_end": 160, "token_start": 29, "token_end": 33}], "entities_global": [{"text": "I kappa B alpha", "type": "ENTITY", "char_start": 619885, "char_end": 619900, "token_start": 24, "token_end": 27, "note": null}, {"text": "NF - kappa B complexes", "type": "ENTITY", "char_start": 619906, "char_end": 619928, "token_start": 29, "token_end": 33, "note": null}]}
+{"sentence_id": 3723, "sentence_text": "Many liberated NF - kappa B dimers reached the nucleus , where increased c - rel , p65 and p50 were detected by immunoblotting and by DNA binding assays .", "sentence_char_start_global": 619939, "sentence_char_end_global": 620093, "entities": [{"text": "NF - kappa B dimers", "type": "ENTITY", "char_start": 15, "char_end": 34, "token_start": 2, "token_end": 6}, {"text": "c - rel", "type": "ENTITY", "char_start": 73, "char_end": 80, "token_start": 13, "token_end": 15}], "entities_global": [{"text": "NF - kappa B dimers", "type": "ENTITY", "char_start": 619954, "char_end": 619973, "token_start": 2, "token_end": 6, "note": null}, {"text": "c - rel", "type": "ENTITY", "char_start": 620012, "char_end": 620019, "token_start": 13, "token_end": 15, "note": null}]}
+{"sentence_id": 3724, "sentence_text": "Some liberated dimers were retained in the cytoplasm , however , through binding to newly synthesized I kappa B alpha , a finding which strongly suggests ( i ) that the LPS - induced signal causes dissociation of complexes rather than preventing their association and ( ii ) that dissociation results from modification of I kappa B alpha and not of c - rel or p65 .", "sentence_char_start_global": 620094, "sentence_char_end_global": 620459, "entities": [{"text": "liberated dimers", "type": "ENTITY", "char_start": 5, "char_end": 21, "token_start": 1, "token_end": 2}, {"text": "I kappa B alpha", "type": "ENTITY", "char_start": 102, "char_end": 117, "token_start": 16, "token_end": 19}, {"text": "I kappa B alpha", "type": "ENTITY", "char_start": 322, "char_end": 337, "token_start": 54, "token_end": 57}, {"text": "c - rel", "type": "ENTITY", "char_start": 349, "char_end": 356, "token_start": 61, "token_end": 63}, {"text": "p65", "type": "ENTITY", "char_start": 360, "char_end": 363, "token_start": 65, "token_end": 65}], "entities_global": [{"text": "liberated dimers", "type": "ENTITY", "char_start": 620099, "char_end": 620115, "token_start": 1, "token_end": 2, "note": null}, {"text": "I kappa B alpha", "type": "ENTITY", "char_start": 620196, "char_end": 620211, "token_start": 16, "token_end": 19, "note": null}, {"text": "I kappa B alpha", "type": "ENTITY", "char_start": 620416, "char_end": 620431, "token_start": 54, "token_end": 57, "note": null}, {"text": "c - rel", "type": "ENTITY", "char_start": 620443, "char_end": 620450, "token_start": 61, "token_end": 63, "note": null}, {"text": "p65", "type": "ENTITY", "char_start": 620454, "char_end": 620457, "token_start": 65, "token_end": 65, "note": null}]}
+{"sentence_id": 3725, "sentence_text": "No effect of LPS treatment was detected on p105 or p100 , which also retain rel family members in the cytoplasm .", "sentence_char_start_global": 620460, "sentence_char_end_global": 620573, "entities": [{"text": "p105", "type": "ENTITY", "char_start": 43, "char_end": 47, "token_start": 8, "token_end": 8}, {"text": "p100", "type": "ENTITY", "char_start": 51, "char_end": 55, "token_start": 10, "token_end": 10}, {"text": "rel family members", "type": "ENTITY", "char_start": 76, "char_end": 94, "token_start": 15, "token_end": 17}], "entities_global": [{"text": "p105", "type": "ENTITY", "char_start": 620503, "char_end": 620507, "token_start": 8, "token_end": 8, "note": null}, {"text": "p100", "type": "ENTITY", "char_start": 620511, "char_end": 620515, "token_start": 10, "token_end": 10, "note": null}, {"text": "rel family members", "type": "ENTITY", "char_start": 620536, "char_end": 620554, "token_start": 15, "token_end": 17, "note": null}]}
+{"sentence_id": 3726, "sentence_text": "Quite unexpectedly , we also found that in unstimulated cells there is a constant ongoing process of degradation and replacement of complexed I kappa B alpha .", "sentence_char_start_global": 620574, "sentence_char_end_global": 620733, "entities": [{"text": "complexed I kappa B alpha", "type": "ENTITY", "char_start": 132, "char_end": 157, "token_start": 21, "token_end": 25}], "entities_global": [{"text": "complexed I kappa B alpha", "type": "ENTITY", "char_start": 620706, "char_end": 620731, "token_start": 21, "token_end": 25, "note": null}]}
+{"sentence_id": 3727, "sentence_text": "We propose that this turnover results in the low level of active NF - kappa B presumably necessary even in the unstimulated cell , and that the high rate of synthesis of I kappa B alpha provides the ability to turn off NF - kappa B activity rapidly as soon as the activating signal ceases .", "sentence_char_start_global": 620734, "sentence_char_end_global": 621024, "entities": [{"text": "active NF - kappa B", "type": "ENTITY", "char_start": 58, "char_end": 77, "token_start": 11, "token_end": 15}, {"text": "I kappa B alpha", "type": "ENTITY", "char_start": 170, "char_end": 185, "token_start": 32, "token_end": 35}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 219, "char_end": 231, "token_start": 42, "token_end": 45}], "entities_global": [{"text": "active NF - kappa B", "type": "ENTITY", "char_start": 620792, "char_end": 620811, "token_start": 11, "token_end": 15, "note": null}, {"text": "I kappa B alpha", "type": "ENTITY", "char_start": 620904, "char_end": 620919, "token_start": 32, "token_end": 35, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 620953, "char_end": 620965, "token_start": 42, "token_end": 45, "note": null}]}
+{"sentence_id": 3728, "sentence_text": "Identification of a killer cell - specific regulatory element of the mouse perforin gene : an Ets - binding site - homologous motif that interacts with Ets - related proteins .", "sentence_char_start_global": 621025, "sentence_char_end_global": 621201, "entities": [{"text": "killer cell - specific regulatory element", "type": "ENTITY", "char_start": 20, "char_end": 61, "token_start": 3, "token_end": 8}, {"text": "mouse perforin gene", "type": "ENTITY", "char_start": 69, "char_end": 88, "token_start": 11, "token_end": 13}, {"text": "Ets - related proteins", "type": "ENTITY", "char_start": 152, "char_end": 174, "token_start": 26, "token_end": 29}], "entities_global": [{"text": "killer cell - specific regulatory element", "type": "ENTITY", "char_start": 621045, "char_end": 621086, "token_start": 3, "token_end": 8, "note": null}, {"text": "mouse perforin gene", "type": "ENTITY", "char_start": 621094, "char_end": 621113, "token_start": 11, "token_end": 13, "note": null}, {"text": "Ets - related proteins", "type": "ENTITY", "char_start": 621177, "char_end": 621199, "token_start": 26, "token_end": 29, "note": null}]}
+{"sentence_id": 3729, "sentence_text": "The gene encoding the cytolytic protein perforin is selectively expressed by activated killer lymphocytes .", "sentence_char_start_global": 621202, "sentence_char_end_global": 621309, "entities": [{"text": "cytolytic protein", "type": "ENTITY", "char_start": 22, "char_end": 39, "token_start": 4, "token_end": 5}, {"text": "perforin", "type": "ENTITY", "char_start": 40, "char_end": 48, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "cytolytic protein", "type": "ENTITY", "char_start": 621224, "char_end": 621241, "token_start": 4, "token_end": 5, "note": null}, {"text": "perforin", "type": "ENTITY", "char_start": 621242, "char_end": 621250, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 3730, "sentence_text": "To understand the mechanisms underlying the cell - type - specific expression of this gene , we have characterized the regulatory functions and the DNA - protein interactions of the 5 ' - flanking region of the mouse perforin gene ( Pfp ) .", "sentence_char_start_global": 621310, "sentence_char_end_global": 621550, "entities": [{"text": "5 ' - flanking region", "type": "ENTITY", "char_start": 182, "char_end": 203, "token_start": 30, "token_end": 34}, {"text": "mouse perforin gene", "type": "ENTITY", "char_start": 211, "char_end": 230, "token_start": 37, "token_end": 39}, {"text": "Pfp", "type": "ENTITY", "char_start": 233, "char_end": 236, "token_start": 41, "token_end": 41}], "entities_global": [{"text": "5 ' - flanking region", "type": "ENTITY", "char_start": 621492, "char_end": 621513, "token_start": 30, "token_end": 34, "note": null}, {"text": "mouse perforin gene", "type": "ENTITY", "char_start": 621521, "char_end": 621540, "token_start": 37, "token_end": 39, "note": null}, {"text": "Pfp", "type": "ENTITY", "char_start": 621543, "char_end": 621546, "token_start": 41, "token_end": 41, "note": null}]}
+{"sentence_id": 3731, "sentence_text": "A region extending from residues + 62 through - 141 , which possesses the essential promoter activity , and regions further upstream , which are able to either enhance or suppress gene expression , were identified .", "sentence_char_start_global": 621551, "sentence_char_end_global": 621766, "entities": [{"text": "residues + 62 through - 141", "type": "ENTITY", "char_start": 24, "char_end": 51, "token_start": 4, "token_end": 9}], "entities_global": [{"text": "residues + 62 through - 141", "type": "ENTITY", "char_start": 621575, "char_end": 621602, "token_start": 4, "token_end": 9, "note": null}]}
+{"sentence_id": 3732, "sentence_text": "The region between residues - 411 and - 566 was chosen for further characterization , since it contains an enhancer - like activity .", "sentence_char_start_global": 621767, "sentence_char_end_global": 621900, "entities": [{"text": "residues - 411 and - 566", "type": "ENTITY", "char_start": 19, "char_end": 43, "token_start": 3, "token_end": 8}], "entities_global": [{"text": "residues - 411 and - 566", "type": "ENTITY", "char_start": 621786, "char_end": 621810, "token_start": 3, "token_end": 8, "note": null}]}
+{"sentence_id": 3733, "sentence_text": "We have identified a 32 - mer sequence ( residues - 491 to - 522 ) which appeared to be capable of enhancing gene expression in a killer cell - specific manner .", "sentence_char_start_global": 621901, "sentence_char_end_global": 622062, "entities": [{"text": "residues - 491 to - 522", "type": "ENTITY", "char_start": 41, "char_end": 64, "token_start": 9, "token_end": 14}], "entities_global": [{"text": "residues - 491 to - 522", "type": "ENTITY", "char_start": 621942, "char_end": 621965, "token_start": 9, "token_end": 14, "note": null}]}
+{"sentence_id": 3734, "sentence_text": "Within this segment , a 9 - mer motif ( 5 ' - ACAGGAAGT - 3 ' , residues - 505 to - 497 ; designated NF - P motif ) , which is highly homologous to the Ets proto - oncoprotein - binding site , was found to interact with two proteins , NF - P1 and NF - P2 .", "sentence_char_start_global": 622063, "sentence_char_end_global": 622319, "entities": [{"text": "residues - 505 to - 497", "type": "ENTITY", "char_start": 64, "char_end": 87, "token_start": 18, "token_end": 23}, {"text": "Ets proto - oncoprotein - binding site", "type": "ENTITY", "char_start": 152, "char_end": 190, "token_start": 38, "token_end": 44}, {"text": "NF - P1", "type": "ENTITY", "char_start": 235, "char_end": 242, "token_start": 54, "token_end": 56}, {"text": "NF - P2", "type": "ENTITY", "char_start": 247, "char_end": 254, "token_start": 58, "token_end": 60}], "entities_global": [{"text": "residues - 505 to - 497", "type": "ENTITY", "char_start": 622127, "char_end": 622150, "token_start": 18, "token_end": 23, "note": null}, {"text": "Ets proto - oncoprotein - binding site", "type": "ENTITY", "char_start": 622215, "char_end": 622253, "token_start": 38, "token_end": 44, "note": null}, {"text": "NF - P1", "type": "ENTITY", "char_start": 622298, "char_end": 622305, "token_start": 54, "token_end": 56, "note": null}, {"text": "NF - P2", "type": "ENTITY", "char_start": 622310, "char_end": 622317, "token_start": 58, "token_end": 60, "note": null}]}
+{"sentence_id": 3735, "sentence_text": "NF - P2 appears to be induced by reagents known to up - regulate the perforin message level and is present exclusively in killer cells .", "sentence_char_start_global": 622320, "sentence_char_end_global": 622456, "entities": [{"text": "NF - P2", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "NF - P2", "type": "ENTITY", "char_start": 622320, "char_end": 622327, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 3736, "sentence_text": "Electrophoretic mobility shift assay and UV cross - linking experiments revealed that NF - P1 and NF - P2 may possess common DNA - binding subunits .", "sentence_char_start_global": 622457, "sentence_char_end_global": 622606, "entities": [{"text": "NF - P1", "type": "ENTITY", "char_start": 86, "char_end": 93, "token_start": 12, "token_end": 14}, {"text": "NF - P2", "type": "ENTITY", "char_start": 98, "char_end": 105, "token_start": 16, "token_end": 18}, {"text": "DNA - binding subunits", "type": "ENTITY", "char_start": 125, "char_end": 147, "token_start": 22, "token_end": 25}], "entities_global": [{"text": "NF - P1", "type": "ENTITY", "char_start": 622543, "char_end": 622550, "token_start": 12, "token_end": 14, "note": null}, {"text": "NF - P2", "type": "ENTITY", "char_start": 622555, "char_end": 622562, "token_start": 16, "token_end": 18, "note": null}, {"text": "DNA - binding subunits", "type": "ENTITY", "char_start": 622582, "char_end": 622604, "token_start": 22, "token_end": 25, "note": null}]}
+{"sentence_id": 3737, "sentence_text": "However , the larger native molecular mass of NF - P1 suggests that NF - P1 contains an additional non - DNA - binding subunit ( s ) .", "sentence_char_start_global": 622607, "sentence_char_end_global": 622741, "entities": [{"text": "NF - P1", "type": "ENTITY", "char_start": 46, "char_end": 53, "token_start": 8, "token_end": 10}, {"text": "NF - P1", "type": "ENTITY", "char_start": 68, "char_end": 75, "token_start": 13, "token_end": 15}, {"text": "non - DNA - binding subunit", "type": "ENTITY", "char_start": 99, "char_end": 126, "token_start": 19, "token_end": 24}], "entities_global": [{"text": "NF - P1", "type": "ENTITY", "char_start": 622653, "char_end": 622660, "token_start": 8, "token_end": 10, "note": null}, {"text": "NF - P1", "type": "ENTITY", "char_start": 622675, "char_end": 622682, "token_start": 13, "token_end": 15, "note": null}, {"text": "non - DNA - binding subunit", "type": "ENTITY", "char_start": 622706, "char_end": 622733, "token_start": 19, "token_end": 24, "note": null}]}
+{"sentence_id": 3738, "sentence_text": "In view of the homology between the NF - P motif and other Ets proto - oncoprotein - binding sites , it is postulated that NF - P1 and NF - P2 belong to the Ets protein family .", "sentence_char_start_global": 622742, "sentence_char_end_global": 622919, "entities": [{"text": "NF - P motif", "type": "ENTITY", "char_start": 36, "char_end": 48, "token_start": 7, "token_end": 10}, {"text": "Ets proto - oncoprotein - binding sites", "type": "ENTITY", "char_start": 59, "char_end": 98, "token_start": 13, "token_end": 19}, {"text": "NF - P1", "type": "ENTITY", "char_start": 123, "char_end": 130, "token_start": 25, "token_end": 27}, {"text": "NF - P2", "type": "ENTITY", "char_start": 135, "char_end": 142, "token_start": 29, "token_end": 31}, {"text": "Ets protein family", "type": "ENTITY", "char_start": 157, "char_end": 175, "token_start": 35, "token_end": 37}], "entities_global": [{"text": "NF - P motif", "type": "ENTITY", "char_start": 622778, "char_end": 622790, "token_start": 7, "token_end": 10, "note": null}, {"text": "Ets proto - oncoprotein - binding sites", "type": "ENTITY", "char_start": 622801, "char_end": 622840, "token_start": 13, "token_end": 19, "note": null}, {"text": "NF - P1", "type": "ENTITY", "char_start": 622865, "char_end": 622872, "token_start": 25, "token_end": 27, "note": null}, {"text": "NF - P2", "type": "ENTITY", "char_start": 622877, "char_end": 622884, "token_start": 29, "token_end": 31, "note": null}, {"text": "Ets protein family", "type": "ENTITY", "char_start": 622899, "char_end": 622917, "token_start": 35, "token_end": 37, "note": null}]}
+{"sentence_id": 3739, "sentence_text": "Results obtained from the binding competition assay , nevertheless , suggest that NF - P1 and NF - P2 are related to but distinct from Ets proteins , e . g . , Ets - 1 , Ets - 2 , and NF - AT / Elf - 1 , known to be expressed in T cells .", "sentence_char_start_global": 622920, "sentence_char_end_global": 623158, "entities": [{"text": "NF - P1", "type": "ENTITY", "char_start": 82, "char_end": 89, "token_start": 12, "token_end": 14}, {"text": "NF - P2", "type": "ENTITY", "char_start": 94, "char_end": 101, "token_start": 16, "token_end": 18}, {"text": "Ets proteins", "type": "ENTITY", "char_start": 135, "char_end": 147, "token_start": 25, "token_end": 26}, {"text": "Ets - 1", "type": "ENTITY", "char_start": 160, "char_end": 167, "token_start": 33, "token_end": 35}, {"text": "Ets - 2", "type": "ENTITY", "char_start": 170, "char_end": 177, "token_start": 37, "token_end": 39}, {"text": "NF - AT / Elf - 1", "type": "ENTITY", "char_start": 184, "char_end": 201, "token_start": 42, "token_end": 48}], "entities_global": [{"text": "NF - P1", "type": "ENTITY", "char_start": 623002, "char_end": 623009, "token_start": 12, "token_end": 14, "note": null}, {"text": "NF - P2", "type": "ENTITY", "char_start": 623014, "char_end": 623021, "token_start": 16, "token_end": 18, "note": null}, {"text": "Ets proteins", "type": "ENTITY", "char_start": 623055, "char_end": 623067, "token_start": 25, "token_end": 26, "note": null}, {"text": "Ets - 1", "type": "ENTITY", "char_start": 623080, "char_end": 623087, "token_start": 33, "token_end": 35, "note": null}, {"text": "Ets - 2", "type": "ENTITY", "char_start": 623090, "char_end": 623097, "token_start": 37, "token_end": 39, "note": null}, {"text": "NF - AT / Elf - 1", "type": "ENTITY", "char_start": 623104, "char_end": 623121, "token_start": 42, "token_end": 48, "note": null}]}
+{"sentence_id": 3740, "sentence_text": "The role of NF - kappa B1 ( p50 / p105 ) gene expression in activation of human blood T - lymphocytes via CD2 and CD28 adhesion molecules .", "sentence_char_start_global": 623159, "sentence_char_end_global": 623298, "entities": [{"text": "NF - kappa B1 ( p50 / p105 ) gene", "type": "ENTITY", "char_start": 12, "char_end": 45, "token_start": 3, "token_end": 12}, {"text": "CD2 and CD28 adhesion molecules", "type": "ENTITY", "char_start": 106, "char_end": 137, "token_start": 23, "token_end": 27}], "entities_global": [{"text": "NF - kappa B1 ( p50 / p105 ) gene", "type": "ENTITY", "char_start": 623171, "char_end": 623204, "token_start": 3, "token_end": 12, "note": null}, {"text": "CD2 and CD28 adhesion molecules", "type": "ENTITY", "char_start": 623265, "char_end": 623296, "token_start": 23, "token_end": 27, "note": null}]}
+{"sentence_id": 3741, "sentence_text": "Stimulation of primary human T - lymphocytes via CD2 and CD28 adhesion molecules induces a long - lasting proliferation ( > 3 weeks ) .", "sentence_char_start_global": 623299, "sentence_char_end_global": 623434, "entities": [{"text": "CD2 and CD28 adhesion molecules", "type": "ENTITY", "char_start": 49, "char_end": 80, "token_start": 8, "token_end": 12}], "entities_global": [{"text": "CD2 and CD28 adhesion molecules", "type": "ENTITY", "char_start": 623348, "char_end": 623379, "token_start": 8, "token_end": 12, "note": null}]}
+{"sentence_id": 3742, "sentence_text": "This potent activation does not require accessory cells , such as monocytes , but depends on persistent interleukin 2 ( IL - 2 ) secretion and receptivity , which is associated with high and prolonged expression of the inducible CD25 / IL - 2 receptor alpha ( IL - 2R alpha ) chain gene .", "sentence_char_start_global": 623435, "sentence_char_end_global": 623723, "entities": [{"text": "interleukin 2", "type": "ENTITY", "char_start": 104, "char_end": 117, "token_start": 17, "token_end": 18}, {"text": "IL - 2", "type": "ENTITY", "char_start": 120, "char_end": 126, "token_start": 20, "token_end": 22}, {"text": "CD25 / IL - 2 receptor alpha ( IL - 2R alpha ) chain gene", "type": "ENTITY", "char_start": 229, "char_end": 286, "token_start": 39, "token_end": 53}], "entities_global": [{"text": "interleukin 2", "type": "ENTITY", "char_start": 623539, "char_end": 623552, "token_start": 17, "token_end": 18, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 623555, "char_end": 623561, "token_start": 20, "token_end": 22, "note": null}, {"text": "CD25 / IL - 2 receptor alpha ( IL - 2R alpha ) chain gene", "type": "ENTITY", "char_start": 623664, "char_end": 623721, "token_start": 39, "token_end": 53, "note": null}]}
+{"sentence_id": 3743, "sentence_text": "The transcription factor NF - kappa B participates in the regulation of both IL - 2 and IL - 2R alpha genes , as well as multiple cellular genes involved in T - cell proliferation .", "sentence_char_start_global": 623724, "sentence_char_end_global": 623905, "entities": [{"text": "transcription factor NF - kappa B", "type": "ENTITY", "char_start": 4, "char_end": 37, "token_start": 1, "token_end": 6}, {"text": "IL - 2 and IL - 2R alpha genes", "type": "ENTITY", "char_start": 77, "char_end": 107, "token_start": 13, "token_end": 21}, {"text": "multiple cellular genes", "type": "ENTITY", "char_start": 121, "char_end": 144, "token_start": 26, "token_end": 28}], "entities_global": [{"text": "transcription factor NF - kappa B", "type": "ENTITY", "char_start": 623728, "char_end": 623761, "token_start": 1, "token_end": 6, "note": null}, {"text": "IL - 2 and IL - 2R alpha genes", "type": "ENTITY", "char_start": 623801, "char_end": 623831, "token_start": 13, "token_end": 21, "note": null}, {"text": "multiple cellular genes", "type": "ENTITY", "char_start": 623845, "char_end": 623868, "token_start": 26, "token_end": 28, "note": null}]}
+{"sentence_id": 3744, "sentence_text": "To evaluate the role of NF - kappa B in human peripheral blood T - lymphocytes , we previously analyzed the activation of NF - kappa B - related complexes in response to CD2 + CD28 costimulation .", "sentence_char_start_global": 623906, "sentence_char_end_global": 624102, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 24, "char_end": 36, "token_start": 5, "token_end": 8}, {"text": "NF - kappa B - related complexes", "type": "ENTITY", "char_start": 122, "char_end": 154, "token_start": 23, "token_end": 29}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 623930, "char_end": 623942, "token_start": 5, "token_end": 8, "note": null}, {"text": "NF - kappa B - related complexes", "type": "ENTITY", "char_start": 624028, "char_end": 624060, "token_start": 23, "token_end": 29, "note": null}]}
+{"sentence_id": 3745, "sentence_text": "We demonstrated a long - term induction of p50 / p65 heterodimer , a putative p65 / c - Rel heterodimer , and a constitutive nuclear expression of KBF1 / p50 homodimers .", "sentence_char_start_global": 624103, "sentence_char_end_global": 624273, "entities": [{"text": "p50 / p65 heterodimer", "type": "ENTITY", "char_start": 43, "char_end": 64, "token_start": 8, "token_end": 11}, {"text": "putative p65 / c - Rel heterodimer", "type": "ENTITY", "char_start": 69, "char_end": 103, "token_start": 14, "token_end": 20}, {"text": "KBF1 / p50 homodimers .", "type": "ENTITY", "char_start": 147, "char_end": 170, "token_start": 28, "token_end": 32}], "entities_global": [{"text": "p50 / p65 heterodimer", "type": "ENTITY", "char_start": 624146, "char_end": 624167, "token_start": 8, "token_end": 11, "note": null}, {"text": "putative p65 / c - Rel heterodimer", "type": "ENTITY", "char_start": 624172, "char_end": 624206, "token_start": 14, "token_end": 20, "note": null}, {"text": "KBF1 / p50 homodimers .", "type": "ENTITY", "char_start": 624250, "char_end": 624273, "token_start": 28, "token_end": 32, "note": null}]}
+{"sentence_id": 3746, "sentence_text": "As the role of p50 remains unclear , we focused our present study on NF - kappa B1 ( p50 / p105 ) gene regulation .", "sentence_char_start_global": 624274, "sentence_char_end_global": 624389, "entities": [{"text": "p50", "type": "ENTITY", "char_start": 15, "char_end": 18, "token_start": 4, "token_end": 4}, {"text": "NF - kappa B1", "type": "ENTITY", "char_start": 69, "char_end": 82, "token_start": 14, "token_end": 17}, {"text": "p50 / p105", "type": "ENTITY", "char_start": 85, "char_end": 95, "token_start": 19, "token_end": 21}], "entities_global": [{"text": "p50", "type": "ENTITY", "char_start": 624289, "char_end": 624292, "token_start": 4, "token_end": 4, "note": null}, {"text": "NF - kappa B1", "type": "ENTITY", "char_start": 624343, "char_end": 624356, "token_start": 14, "token_end": 17, "note": null}, {"text": "p50 / p105", "type": "ENTITY", "char_start": 624359, "char_end": 624369, "token_start": 19, "token_end": 21, "note": null}]}
+{"sentence_id": 3747, "sentence_text": "Using electrophoretic mobility shift assays and Western and Northern blot analyses , we studied NF - kappa B1 gene expression during T - cell stimulation via CD2 + CD28 .", "sentence_char_start_global": 624390, "sentence_char_end_global": 624560, "entities": [{"text": "NF - kappa B1 gene", "type": "ENTITY", "char_start": 96, "char_end": 114, "token_start": 14, "token_end": 18}, {"text": "CD2 + CD28", "type": "ENTITY", "char_start": 158, "char_end": 168, "token_start": 26, "token_end": 28}], "entities_global": [{"text": "NF - kappa B1 gene", "type": "ENTITY", "char_start": 624486, "char_end": 624504, "token_start": 14, "token_end": 18, "note": null}, {"text": "CD2 + CD28", "type": "ENTITY", "char_start": 624548, "char_end": 624558, "token_start": 26, "token_end": 28, "note": null}]}
+{"sentence_id": 3748, "sentence_text": "We observed a transient 4 - to 5 - fold increase of NF - kappa B1 gene expression at both the mRNA and protein levels , lasting for at least 24 h .", "sentence_char_start_global": 624561, "sentence_char_end_global": 624708, "entities": [], "entities_global": []}
+{"sentence_id": 3749, "sentence_text": "p50 DNA - binding activity apparently stays highly controlled when p105 expression is enhanced by a physiological stimulus of peripheral blood T - cells .", "sentence_char_start_global": 624709, "sentence_char_end_global": 624863, "entities": [], "entities_global": []}
+{"sentence_id": 3750, "sentence_text": "Partial inhibition of p50 and p105 expression by NF - kappa B1 antisense oligonucleotides significantly reduced T - cell proliferation and CD25 / IL - 2R alpha cell surface expression .", "sentence_char_start_global": 624864, "sentence_char_end_global": 625049, "entities": [{"text": "NF - kappa B1", "type": "ENTITY", "char_start": 49, "char_end": 62, "token_start": 8, "token_end": 11}, {"text": "CD25 / IL - 2R alpha", "type": "ENTITY", "char_start": 139, "char_end": 159, "token_start": 21, "token_end": 26}], "entities_global": [{"text": "NF - kappa B1", "type": "ENTITY", "char_start": 624913, "char_end": 624926, "token_start": 8, "token_end": 11, "note": null}, {"text": "CD25 / IL - 2R alpha", "type": "ENTITY", "char_start": 625003, "char_end": 625023, "token_start": 21, "token_end": 26, "note": null}]}
+{"sentence_id": 3751, "sentence_text": "( ABSTRACT TRUNCATED AT 250 WORDS )", "sentence_char_start_global": 625050, "sentence_char_end_global": 625085, "entities": [], "entities_global": []}
+{"sentence_id": 3752, "sentence_text": "Vitamin D receptor quantitation in human blood mononuclear cells in health and disease .", "sentence_char_start_global": 625086, "sentence_char_end_global": 625174, "entities": [{"text": "Vitamin D receptor", "type": "ENTITY", "char_start": 0, "char_end": 18, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "Vitamin D receptor", "type": "ENTITY", "char_start": 625086, "char_end": 625104, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 3753, "sentence_text": "Vitamin D receptor ( VDR ) concentration was quantitated in human peripheral blood mononuclear cells ( PBMC ) from patients with absorptive hypercalciuria ( AH ) and patients with high 1 , 25 ( OH ) 2D3 due to acquired or transient disease states and the results compared to those in normal subjects .", "sentence_char_start_global": 625175, "sentence_char_end_global": 625476, "entities": [{"text": "Vitamin D receptor", "type": "ENTITY", "char_start": 0, "char_end": 18, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "Vitamin D receptor", "type": "ENTITY", "char_start": 625175, "char_end": 625193, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 3754, "sentence_text": "VDR concentration in resting cells was not different between the three groups and represented constitutive receptor expression of monocytes .", "sentence_char_start_global": 625477, "sentence_char_end_global": 625618, "entities": [], "entities_global": []}
+{"sentence_id": 3755, "sentence_text": "Following activation with phytohemagglutinin , patients with hypercalcitriolemia demonstrated significantly greater VDR concentrations .", "sentence_char_start_global": 625619, "sentence_char_end_global": 625755, "entities": [{"text": "phytohemagglutinin", "type": "ENTITY", "char_start": 26, "char_end": 44, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "phytohemagglutinin", "type": "ENTITY", "char_start": 625645, "char_end": 625663, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 3756, "sentence_text": "Patients with AH demonstrated a normal value for the group , but 6 patients had significantly greater concentrations of VDR despite normal plasma 1 , 25 ( OH ) 2D3 in four of the patients .", "sentence_char_start_global": 625756, "sentence_char_end_global": 625945, "entities": [{"text": "VDR", "type": "ENTITY", "char_start": 120, "char_end": 123, "token_start": 19, "token_end": 19}], "entities_global": [{"text": "VDR", "type": "ENTITY", "char_start": 625876, "char_end": 625879, "token_start": 19, "token_end": 19, "note": null}]}
+{"sentence_id": 3757, "sentence_text": "Proliferation , as assessed from [ 3H ] thymidine incorporation was inversely correlated with serum 1 , 25 ( OH ) 2D3 and was significant ( R = - 0 . 299 , p = 0 . 048 ) .", "sentence_char_start_global": 625946, "sentence_char_end_global": 626117, "entities": [], "entities_global": []}
+{"sentence_id": 3758, "sentence_text": "Taken together , the results suggest that PBMC provide a useful system for studying VDR status in transient or acquired states of hypercalcitriolemia .", "sentence_char_start_global": 626118, "sentence_char_end_global": 626269, "entities": [{"text": "VDR", "type": "ENTITY", "char_start": 84, "char_end": 87, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "VDR", "type": "ENTITY", "char_start": 626202, "char_end": 626205, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 3759, "sentence_text": "Furthermore , the studies in patients with absorptive hypercalciuria disclosed it to be a heterogeneous disorder , characterized by both vitamin D - dependent and D - independent forms of receptor up - regulation .", "sentence_char_start_global": 626270, "sentence_char_end_global": 626484, "entities": [], "entities_global": []}
+{"sentence_id": 3760, "sentence_text": "Reactive oxygen intermediates activate NF - kappa B in a tyrosine kinase - dependent mechanism and in combination with vanadate activate the p56lck and p59fyn tyrosine kinases in human lymphocytes .", "sentence_char_start_global": 626485, "sentence_char_end_global": 626683, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 39, "char_end": 51, "token_start": 4, "token_end": 7}, {"text": "p56lck and p59fyn tyrosine kinases", "type": "ENTITY", "char_start": 141, "char_end": 175, "token_start": 22, "token_end": 26}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 626524, "char_end": 626536, "token_start": 4, "token_end": 7, "note": null}, {"text": "p56lck and p59fyn tyrosine kinases", "type": "ENTITY", "char_start": 626626, "char_end": 626660, "token_start": 22, "token_end": 26, "note": null}]}
+{"sentence_id": 3761, "sentence_text": "We have previously observed that ionizing radiation induces tyrosine phosphorylation in human B - lymphocyte precursors by stimulation of unidentified tyrosine kinases and this phosphorylation is substantially augmented by vanadate .", "sentence_char_start_global": 626684, "sentence_char_end_global": 626917, "entities": [{"text": "tyrosine kinases", "type": "ENTITY", "char_start": 151, "char_end": 167, "token_start": 20, "token_end": 21}], "entities_global": [{"text": "tyrosine kinases", "type": "ENTITY", "char_start": 626835, "char_end": 626851, "token_start": 20, "token_end": 21, "note": null}]}
+{"sentence_id": 3762, "sentence_text": "Ionizing radiation generates reactive oxygen intermediates ( ROI ) .", "sentence_char_start_global": 626918, "sentence_char_end_global": 626986, "entities": [], "entities_global": []}
+{"sentence_id": 3763, "sentence_text": "Because H2O2 is a potent ROI generator that readily crosses the plasma membrane , we used H2O2 to examine the effects of ROI on signal transduction .", "sentence_char_start_global": 626987, "sentence_char_end_global": 627136, "entities": [], "entities_global": []}
+{"sentence_id": 3764, "sentence_text": "We now provide evidence that the tyrosine kinase inhibitor herbimycin A and the free radical scavenger N - acetyl - cysteine inhibit both radiation - induced and H2O2 - induced activation of NF - kappa B , indicating that activation triggered by ROI is dependent on tyrosine kinase activity .", "sentence_char_start_global": 627137, "sentence_char_end_global": 627429, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 191, "char_end": 203, "token_start": 32, "token_end": 35}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 627328, "char_end": 627340, "token_start": 32, "token_end": 35, "note": null}]}
+{"sentence_id": 3765, "sentence_text": "H2O2 was found to stimulate Ins - 1 , 4 , 5 - P3 production in a tyrosine kinase - dependent manner and to induce calcium signals that were greatly augmented by vanadate .", "sentence_char_start_global": 627430, "sentence_char_end_global": 627601, "entities": [{"text": "Ins - 1 , 4 , 5 - P3", "type": "ENTITY", "char_start": 28, "char_end": 48, "token_start": 5, "token_end": 13}], "entities_global": [{"text": "Ins - 1 , 4 , 5 - P3", "type": "ENTITY", "char_start": 627458, "char_end": 627478, "token_start": 5, "token_end": 13, "note": null}]}
+{"sentence_id": 3766, "sentence_text": "The synergistic induction of tyrosine phosphorylation by H2O2 plus vanadate included physiologically relevant proteins such as PLC gamma 1 .", "sentence_char_start_global": 627602, "sentence_char_end_global": 627742, "entities": [{"text": "PLC gamma 1", "type": "ENTITY", "char_start": 127, "char_end": 138, "token_start": 16, "token_end": 18}], "entities_global": [{"text": "PLC gamma 1", "type": "ENTITY", "char_start": 627729, "char_end": 627740, "token_start": 16, "token_end": 18, "note": null}]}
+{"sentence_id": 3767, "sentence_text": "Although treatment of cells with H2O2 alone did not affect the activity of src family kinases , treatment with H2O2 plus vanadate led to activation of the p56lck and p59fyn tyrosine kinases .", "sentence_char_start_global": 627743, "sentence_char_end_global": 627934, "entities": [{"text": "src family kinases", "type": "ENTITY", "char_start": 75, "char_end": 93, "token_start": 13, "token_end": 15}, {"text": "p56lck and p59fyn tyrosine kinases", "type": "ENTITY", "char_start": 155, "char_end": 189, "token_start": 27, "token_end": 31}], "entities_global": [{"text": "src family kinases", "type": "ENTITY", "char_start": 627818, "char_end": 627836, "token_start": 13, "token_end": 15, "note": null}, {"text": "p56lck and p59fyn tyrosine kinases", "type": "ENTITY", "char_start": 627898, "char_end": 627932, "token_start": 27, "token_end": 31, "note": null}]}
+{"sentence_id": 3768, "sentence_text": "The combined inhibition of phosphatases and activation of kinases provides a potent mechanism for the synergistic effects of H2O2 plus vanadate .", "sentence_char_start_global": 627935, "sentence_char_end_global": 628080, "entities": [{"text": "phosphatases", "type": "ENTITY", "char_start": 27, "char_end": 39, "token_start": 4, "token_end": 4}, {"text": "kinases", "type": "ENTITY", "char_start": 58, "char_end": 65, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "phosphatases", "type": "ENTITY", "char_start": 627962, "char_end": 627974, "token_start": 4, "token_end": 4, "note": null}, {"text": "kinases", "type": "ENTITY", "char_start": 627993, "char_end": 628000, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 3769, "sentence_text": "Induction of tyrosine phosphorylation by ROI may thus lead to many of the pleiotropic effects of ROI in lymphoid cells , including downstream activation of PLC gamma 1 and NF - kappa B", "sentence_char_start_global": 628081, "sentence_char_end_global": 628265, "entities": [{"text": "PLC gamma 1", "type": "ENTITY", "char_start": 156, "char_end": 167, "token_start": 25, "token_end": 27}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 172, "char_end": 184, "token_start": 29, "token_end": 32}], "entities_global": [{"text": "PLC gamma 1", "type": "ENTITY", "char_start": 628237, "char_end": 628248, "token_start": 25, "token_end": 27, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 628253, "char_end": 628265, "token_start": 29, "token_end": 32, "note": null}]}
+{"sentence_id": 3770, "sentence_text": "Influence of sex hormone binding globulin and serum albumin on the conversion of androstenedione to testosterone by human erythrocytes .", "sentence_char_start_global": 628266, "sentence_char_end_global": 628402, "entities": [{"text": "sex hormone binding globulin", "type": "ENTITY", "char_start": 13, "char_end": 41, "token_start": 2, "token_end": 5}, {"text": "serum albumin", "type": "ENTITY", "char_start": 46, "char_end": 59, "token_start": 7, "token_end": 8}], "entities_global": [{"text": "sex hormone binding globulin", "type": "ENTITY", "char_start": 628279, "char_end": 628307, "token_start": 2, "token_end": 5, "note": null}, {"text": "serum albumin", "type": "ENTITY", "char_start": 628312, "char_end": 628325, "token_start": 7, "token_end": 8, "note": null}]}
+{"sentence_id": 3771, "sentence_text": "The influence of human serum albumin and sex hormone binding globulin ( SHBG ) on the enzymic conversion of androstenedione to testosterone in human erythrocytes was investigated in vitro .", "sentence_char_start_global": 628403, "sentence_char_end_global": 628592, "entities": [{"text": "human serum albumin", "type": "ENTITY", "char_start": 17, "char_end": 36, "token_start": 3, "token_end": 5}, {"text": "sex hormone binding globulin", "type": "ENTITY", "char_start": 41, "char_end": 69, "token_start": 7, "token_end": 10}, {"text": "SHBG", "type": "ENTITY", "char_start": 72, "char_end": 76, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "human serum albumin", "type": "ENTITY", "char_start": 628420, "char_end": 628439, "token_start": 3, "token_end": 5, "note": null}, {"text": "sex hormone binding globulin", "type": "ENTITY", "char_start": 628444, "char_end": 628472, "token_start": 7, "token_end": 10, "note": null}, {"text": "SHBG", "type": "ENTITY", "char_start": 628475, "char_end": 628479, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 3772, "sentence_text": "Total plasma and albumin delayed the conversion rate of androstenedione , while SHBG increased it markedly .", "sentence_char_start_global": 628593, "sentence_char_end_global": 628701, "entities": [{"text": "albumin", "type": "ENTITY", "char_start": 17, "char_end": 24, "token_start": 3, "token_end": 3}, {"text": "SHBG", "type": "ENTITY", "char_start": 80, "char_end": 84, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "albumin", "type": "ENTITY", "char_start": 628610, "char_end": 628617, "token_start": 3, "token_end": 3, "note": null}, {"text": "SHBG", "type": "ENTITY", "char_start": 628673, "char_end": 628677, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 3773, "sentence_text": "The effect of SHBG was largely abolished by heating to 60 degrees C for 1 h and by saturating its binding sites by DHT .", "sentence_char_start_global": 628702, "sentence_char_end_global": 628822, "entities": [{"text": "SHBG", "type": "ENTITY", "char_start": 14, "char_end": 18, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "SHBG", "type": "ENTITY", "char_start": 628716, "char_end": 628720, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 3774, "sentence_text": "The effect of both proteins was found to be related to their concentration .", "sentence_char_start_global": 628823, "sentence_char_end_global": 628899, "entities": [], "entities_global": []}
+{"sentence_id": 3775, "sentence_text": "It appears that the binding sites of albumin provide a mechanism for retarding androstenedione uptake by the erythrocytes and that the high binding affinity of SHBG for testosterone facilitates the diffusion of this steroid out of the cell and thus , displaces the chemical equilibrium within the cell .", "sentence_char_start_global": 628900, "sentence_char_end_global": 629203, "entities": [{"text": "albumin", "type": "ENTITY", "char_start": 37, "char_end": 44, "token_start": 7, "token_end": 7}, {"text": "SHBG", "type": "ENTITY", "char_start": 160, "char_end": 164, "token_start": 25, "token_end": 25}], "entities_global": [{"text": "albumin", "type": "ENTITY", "char_start": 628937, "char_end": 628944, "token_start": 7, "token_end": 7, "note": null}, {"text": "SHBG", "type": "ENTITY", "char_start": 629060, "char_end": 629064, "token_start": 25, "token_end": 25, "note": null}]}
+{"sentence_id": 3776, "sentence_text": "Glucocorticoids and lymphocytes .", "sentence_char_start_global": 629204, "sentence_char_end_global": 629237, "entities": [], "entities_global": []}
+{"sentence_id": 3777, "sentence_text": "I .", "sentence_char_start_global": 629238, "sentence_char_end_global": 629241, "entities": [], "entities_global": []}
+{"sentence_id": 3778, "sentence_text": "Increased glucocorticoid receptor levels in antigen - stimulated lymphocytes .", "sentence_char_start_global": 629242, "sentence_char_end_global": 629320, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 10, "char_end": 33, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 629252, "char_end": 629275, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 3779, "sentence_text": "Recently a 2 - to 3 - fold increase in the number of glucocorticoid receptors in human peripheral lymphocytes has been noted after in vitro mitogen stimulation .", "sentence_char_start_global": 629321, "sentence_char_end_global": 629482, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 53, "char_end": 77, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 629374, "char_end": 629398, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 3780, "sentence_text": "Here , we extend these observations to in vivo immunization .", "sentence_char_start_global": 629483, "sentence_char_end_global": 629544, "entities": [], "entities_global": []}
+{"sentence_id": 3781, "sentence_text": "After unilateral immunization of adrenalectomized male rats , a 50 % increase in glucocorticoid receptor sites per cell , determined by binding of dexamethasone , was observed in cell suspensions of homolateral lymph nodes over those from the contralateral nonimmunized side of the same animal .", "sentence_char_start_global": 629545, "sentence_char_end_global": 629840, "entities": [], "entities_global": []}
+{"sentence_id": 3782, "sentence_text": "The association constant for dexamethasone was similar in both groups , as was the stereospecificity for various steroids , the time course of cytoplasmic and nuclear association , and cytoplasmic - to - nuclear translocation .", "sentence_char_start_global": 629841, "sentence_char_end_global": 630068, "entities": [], "entities_global": []}
+{"sentence_id": 3783, "sentence_text": "Despite a 50 % increase in the number of glucocorticoid receptor sites per cell , the cells from the homolateral and controlateral lymph nodes were equally sensitive to the inhibitory effects of dexamethasone , as determined by measurements of the incorporation of radiolabeled precursors of protein , RNA , and DNA , or measurements of in vitro cell survival .", "sentence_char_start_global": 630069, "sentence_char_end_global": 630430, "entities": [], "entities_global": []}
+{"sentence_id": 3784, "sentence_text": "Glucocorticoid receptors and actions in rat thymocytes and immunologically stimulated human peripheral lymphocytes .", "sentence_char_start_global": 630431, "sentence_char_end_global": 630547, "entities": [], "entities_global": []}
+{"sentence_id": 3785, "sentence_text": "After reviewing briefly our earlier studies on glucocorticoid receptors and mechanisms in thymus cells , we have outlined results from the following two areas of current interest in our laboratories : the ` ` life - cycle ' ' of glucocorticoid receptors and complexes in thymus cells , and the levels of glucocorticoid receptors and sensitivity in immunologically stimulated human peripheral lymphocytes .", "sentence_char_start_global": 630548, "sentence_char_end_global": 630953, "entities": [], "entities_global": []}
+{"sentence_id": 3786, "sentence_text": "Several of our results on energetics and kinetics of hormone binding to glucocorticoid receptors in rat thymus cells seem to require extension of the simplest model of hormone - receptor transformations in intact cells .", "sentence_char_start_global": 630954, "sentence_char_end_global": 631174, "entities": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 72, "char_end": 96, "token_start": 12, "token_end": 13}], "entities_global": [{"text": "glucocorticoid receptors", "type": "ENTITY", "char_start": 631026, "char_end": 631050, "token_start": 12, "token_end": 13, "note": null}]}
+{"sentence_id": 3787, "sentence_text": "ATP - depletion experiments suggest the existence of a nonbinding form of the receptor ; ` ` chase ' ' experiments suggest reaction of hormone directly with nuclear - bound receptor ; experiments on depletion and replenishment of cytoplasmic receptor using cortisol and dexamethasone suggest the existence of at least two subpopulations of nuclear - bound hormone - receptor complex .", "sentence_char_start_global": 631175, "sentence_char_end_global": 631559, "entities": [{"text": "cytoplasmic receptor", "type": "ENTITY", "char_start": 230, "char_end": 250, "token_start": 38, "token_end": 39}, {"text": "nuclear - bound hormone - receptor complex", "type": "ENTITY", "char_start": 340, "char_end": 382, "token_start": 53, "token_end": 59}], "entities_global": [{"text": "cytoplasmic receptor", "type": "ENTITY", "char_start": 631405, "char_end": 631425, "token_start": 38, "token_end": 39, "note": null}, {"text": "nuclear - bound hormone - receptor complex", "type": "ENTITY", "char_start": 631515, "char_end": 631557, "token_start": 53, "token_end": 59, "note": null}]}
+{"sentence_id": 3788, "sentence_text": "We have found that mitogen or immunologic stimulation of human peripheral lymphocytes in culture leads within 24 h or so to a striking increase in the number of glucocorticoid receptor sites per cell .", "sentence_char_start_global": 631560, "sentence_char_end_global": 631761, "entities": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 161, "char_end": 184, "token_start": 28, "token_end": 29}], "entities_global": [{"text": "glucocorticoid receptor", "type": "ENTITY", "char_start": 631721, "char_end": 631744, "token_start": 28, "token_end": 29, "note": null}]}
+{"sentence_id": 3789, "sentence_text": "We believe this increase may be due to partial synchronization of the cell population in a phase of the cell cycle in which receptor content is high .", "sentence_char_start_global": 631762, "sentence_char_end_global": 631912, "entities": [], "entities_global": []}
+{"sentence_id": 3790, "sentence_text": "Contrary to the widely held view that mitogen - stimulated cells become insensitive to glucocorticoids , our experiments show that with respect to inhibition of thymidine and uridine incorporation and glucose uptake , the cells are highly sensitive to dexamethasone at 24 , 48 , and 72 h after stimulation with concanavalin A .", "sentence_char_start_global": 631913, "sentence_char_end_global": 632240, "entities": [{"text": "concanavalin A", "type": "ENTITY", "char_start": 311, "char_end": 325, "token_start": 51, "token_end": 52}], "entities_global": [{"text": "concanavalin A", "type": "ENTITY", "char_start": 632224, "char_end": 632238, "token_start": 51, "token_end": 52, "note": null}]}
+{"sentence_id": 3791, "sentence_text": "Nuclear glucocorticoid binding in chronic lymphatic leukemia lymphocytes .", "sentence_char_start_global": 632241, "sentence_char_end_global": 632315, "entities": [], "entities_global": []}
+{"sentence_id": 3792, "sentence_text": "A reliable procedure is described for isolating 3H - triamcinolone acetonide ( 3H - TA ) receptor complexes from purified chronic lymphatic leukemia ( CLL ) lymphocyte nuclei , based on the use of carbobenzoxy - L - phenylalanine ( CBZ - L - phe ) to prevent breakdown of hormone - receptor complexes during extraction of nuclei with 0 . 6M KCl .", "sentence_char_start_global": 632316, "sentence_char_end_global": 632662, "entities": [{"text": "3H - triamcinolone acetonide ( 3H - TA ) receptor complexes", "type": "ENTITY", "char_start": 48, "char_end": 107, "token_start": 7, "token_end": 17}, {"text": "hormone - receptor complexes", "type": "ENTITY", "char_start": 272, "char_end": 300, "token_start": 50, "token_end": 53}], "entities_global": [{"text": "3H - triamcinolone acetonide ( 3H - TA ) receptor complexes", "type": "ENTITY", "char_start": 632364, "char_end": 632423, "token_start": 7, "token_end": 17, "note": null}, {"text": "hormone - receptor complexes", "type": "ENTITY", "char_start": 632588, "char_end": 632616, "token_start": 50, "token_end": 53, "note": null}]}
+{"sentence_id": 3793, "sentence_text": "Using this method , specific nuclear glucocorticoid binding was demonstrated in 14 / 14 patients with untreated CLL .", "sentence_char_start_global": 632663, "sentence_char_end_global": 632780, "entities": [], "entities_global": []}
+{"sentence_id": 3794, "sentence_text": "No correlation was found between levels of nuclear - associated 3H - TA and peripheral white blood cell count or rosetting ability of circulating lymphocytes .", "sentence_char_start_global": 632781, "sentence_char_end_global": 632940, "entities": [], "entities_global": []}
+{"sentence_id": 3795, "sentence_text": "Multiple closely - linked NFAT / octamer and HMG I ( Y ) binding sites are part of the interleukin - 4 promoter .", "sentence_char_start_global": 632941, "sentence_char_end_global": 633054, "entities": [{"text": "NFAT / octamer", "type": "ENTITY", "char_start": 26, "char_end": 40, "token_start": 4, "token_end": 6}, {"text": "HMG I ( Y ) binding sites", "type": "ENTITY", "char_start": 45, "char_end": 70, "token_start": 8, "token_end": 14}], "entities_global": [{"text": "NFAT / octamer", "type": "ENTITY", "char_start": 632967, "char_end": 632981, "token_start": 4, "token_end": 6, "note": null}, {"text": "HMG I ( Y ) binding sites", "type": "ENTITY", "char_start": 632986, "char_end": 633011, "token_start": 8, "token_end": 14, "note": null}]}
+{"sentence_id": 3796, "sentence_text": "We show here that the immediate upstream region ( from position - 12 to - 270 ) of the murine interleukin 4 ( Il - 4 ) gene harbors a strong cell - type specific transcriptional enhancer .", "sentence_char_start_global": 633055, "sentence_char_end_global": 633243, "entities": [{"text": "immediate upstream region", "type": "ENTITY", "char_start": 22, "char_end": 47, "token_start": 5, "token_end": 7}, {"text": "murine interleukin 4 ( Il - 4 ) gene", "type": "ENTITY", "char_start": 87, "char_end": 123, "token_start": 19, "token_end": 27}, {"text": "transcriptional enhancer", "type": "ENTITY", "char_start": 162, "char_end": 186, "token_start": 35, "token_end": 36}], "entities_global": [{"text": "immediate upstream region", "type": "ENTITY", "char_start": 633077, "char_end": 633102, "token_start": 5, "token_end": 7, "note": null}, {"text": "murine interleukin 4 ( Il - 4 ) gene", "type": "ENTITY", "char_start": 633142, "char_end": 633178, "token_start": 19, "token_end": 27, "note": null}, {"text": "transcriptional enhancer", "type": "ENTITY", "char_start": 633217, "char_end": 633241, "token_start": 35, "token_end": 36, "note": null}]}
+{"sentence_id": 3797, "sentence_text": "In T lymphoma cells , the activity of the Il - 4 promoter / enhancer is stimulated by phorbol esters , Ca + + ionophores and agonists of protein kinase A and inhibited by low doses of the immunosuppressant cyclosporin A .", "sentence_char_start_global": 633244, "sentence_char_end_global": 633465, "entities": [{"text": "Il - 4 promoter / enhancer", "type": "ENTITY", "char_start": 42, "char_end": 68, "token_start": 9, "token_end": 14}, {"text": "protein kinase A", "type": "ENTITY", "char_start": 137, "char_end": 153, "token_start": 28, "token_end": 30}], "entities_global": [{"text": "Il - 4 promoter / enhancer", "type": "ENTITY", "char_start": 633286, "char_end": 633312, "token_start": 9, "token_end": 14, "note": null}, {"text": "protein kinase A", "type": "ENTITY", "char_start": 633381, "char_end": 633397, "token_start": 28, "token_end": 30, "note": null}]}
+{"sentence_id": 3798, "sentence_text": "The Il - 4 promoter / enhancer is transcriptionally inactive in B lymphoma cells and HeLa cells .", "sentence_char_start_global": 633466, "sentence_char_end_global": 633563, "entities": [{"text": "Il - 4 promoter / enhancer", "type": "ENTITY", "char_start": 4, "char_end": 30, "token_start": 1, "token_end": 6}], "entities_global": [{"text": "Il - 4 promoter / enhancer", "type": "ENTITY", "char_start": 633470, "char_end": 633496, "token_start": 1, "token_end": 6, "note": null}]}
+{"sentence_id": 3799, "sentence_text": "DNase I footprint protection experiments revealed six sites of the Il - 4 promoter / enhancer to be bound by nuclear proteins from lymphoid and myeloid cells .", "sentence_char_start_global": 633564, "sentence_char_end_global": 633723, "entities": [{"text": "Il - 4 promoter / enhancer", "type": "ENTITY", "char_start": 67, "char_end": 93, "token_start": 10, "token_end": 15}, {"text": "nuclear proteins", "type": "ENTITY", "char_start": 109, "char_end": 125, "token_start": 20, "token_end": 21}], "entities_global": [{"text": "Il - 4 promoter / enhancer", "type": "ENTITY", "char_start": 633631, "char_end": 633657, "token_start": 10, "token_end": 15, "note": null}, {"text": "nuclear proteins", "type": "ENTITY", "char_start": 633673, "char_end": 633689, "token_start": 20, "token_end": 21, "note": null}]}
+{"sentence_id": 3800, "sentence_text": "Among them are four purine boxes which have been described to be important sequence motifs of the Il - 2 promoter .", "sentence_char_start_global": 633724, "sentence_char_end_global": 633839, "entities": [{"text": "Il - 2 promoter", "type": "ENTITY", "char_start": 98, "char_end": 113, "token_start": 17, "token_end": 20}], "entities_global": [{"text": "Il - 2 promoter", "type": "ENTITY", "char_start": 633822, "char_end": 633837, "token_start": 17, "token_end": 20, "note": null}]}
+{"sentence_id": 3801, "sentence_text": "They contain the motif GGAAA and are recognized by the inducible and cyclosporin A - sensitive transcription factor NFAT - 1 .", "sentence_char_start_global": 633840, "sentence_char_end_global": 633966, "entities": [{"text": "inducible and cyclosporin A - sensitive transcription factor NFAT - 1", "type": "ENTITY", "char_start": 55, "char_end": 124, "token_start": 10, "token_end": 20}], "entities_global": [{"text": "inducible and cyclosporin A - sensitive transcription factor NFAT - 1", "type": "ENTITY", "char_start": 633895, "char_end": 633964, "token_start": 10, "token_end": 20, "note": null}]}
+{"sentence_id": 3802, "sentence_text": "Three of the Il - 4 NFAT - 1 sites are closely linked to weak binding sites of Octamer factors .", "sentence_char_start_global": 633967, "sentence_char_end_global": 634063, "entities": [{"text": "Il - 4 NFAT - 1 sites", "type": "ENTITY", "char_start": 13, "char_end": 34, "token_start": 3, "token_end": 9}, {"text": "Octamer factors", "type": "ENTITY", "char_start": 79, "char_end": 94, "token_start": 18, "token_end": 19}], "entities_global": [{"text": "Il - 4 NFAT - 1 sites", "type": "ENTITY", "char_start": 633980, "char_end": 634001, "token_start": 3, "token_end": 9, "note": null}, {"text": "Octamer factors", "type": "ENTITY", "char_start": 634046, "char_end": 634061, "token_start": 18, "token_end": 19, "note": null}]}
+{"sentence_id": 3803, "sentence_text": "Several purine boxes and an AT - rich protein - binding site of the Il - 4 promoter are also recognized by the high mobility group protein HMG I ( Y ) .", "sentence_char_start_global": 634064, "sentence_char_end_global": 634216, "entities": [{"text": "AT - rich protein - binding site", "type": "ENTITY", "char_start": 28, "char_end": 60, "token_start": 5, "token_end": 11}, {"text": "high mobility group protein", "type": "ENTITY", "char_start": 111, "char_end": 138, "token_start": 23, "token_end": 26}, {"text": "HMG I ( Y", "type": "ENTITY", "char_start": 139, "char_end": 148, "token_start": 27, "token_end": 30}], "entities_global": [{"text": "AT - rich protein - binding site", "type": "ENTITY", "char_start": 634092, "char_end": 634124, "token_start": 5, "token_end": 11, "note": null}, {"text": "high mobility group protein", "type": "ENTITY", "char_start": 634175, "char_end": 634202, "token_start": 23, "token_end": 26, "note": null}, {"text": "HMG I ( Y", "type": "ENTITY", "char_start": 634203, "char_end": 634212, "token_start": 27, "token_end": 30, "note": null}]}
+{"sentence_id": 3804, "sentence_text": "Whereas the binding of NFAT - 1 and Octamer factors enhance the activity of the Il - 4 promoter , the binding of HMG I ( Y ) suppresses its activity and , therefore , appears to be involved in the suppression of Il - 4 transcription in resting T lymphocytes .", "sentence_char_start_global": 634217, "sentence_char_end_global": 634476, "entities": [{"text": "NFAT - 1", "type": "ENTITY", "char_start": 23, "char_end": 31, "token_start": 4, "token_end": 6}, {"text": "Octamer factors", "type": "ENTITY", "char_start": 36, "char_end": 51, "token_start": 8, "token_end": 9}, {"text": "Il - 4 promoter", "type": "ENTITY", "char_start": 80, "char_end": 95, "token_start": 15, "token_end": 18}, {"text": "Il - 4", "type": "ENTITY", "char_start": 212, "char_end": 218, "token_start": 43, "token_end": 45}], "entities_global": [{"text": "NFAT - 1", "type": "ENTITY", "char_start": 634240, "char_end": 634248, "token_start": 4, "token_end": 6, "note": null}, {"text": "Octamer factors", "type": "ENTITY", "char_start": 634253, "char_end": 634268, "token_start": 8, "token_end": 9, "note": null}, {"text": "Il - 4 promoter", "type": "ENTITY", "char_start": 634297, "char_end": 634312, "token_start": 15, "token_end": 18, "note": null}, {"text": "Il - 4", "type": "ENTITY", "char_start": 634429, "char_end": 634435, "token_start": 43, "token_end": 45, "note": null}]}
+{"sentence_id": 3805, "sentence_text": "Reversibility of the differentiated state in somatic cells .", "sentence_char_start_global": 634477, "sentence_char_end_global": 634537, "entities": [], "entities_global": []}
+{"sentence_id": 3806, "sentence_text": "Analysis of de novo gene activation in multinucleated heterokaryons has shown that the differentiated state , although stable , is not irreversible , and can be reprogrammed in the presence of appropriate combinations of trans - acting regulatory molecules .", "sentence_char_start_global": 634538, "sentence_char_end_global": 634796, "entities": [{"text": "trans - acting regulatory molecules", "type": "ENTITY", "char_start": 221, "char_end": 256, "token_start": 34, "token_end": 38}], "entities_global": [{"text": "trans - acting regulatory molecules", "type": "ENTITY", "char_start": 634759, "char_end": 634794, "token_start": 34, "token_end": 38, "note": null}]}
+{"sentence_id": 3807, "sentence_text": "These properties have been exploited to design strategies for identifying novel regulators of cellular differentiation .", "sentence_char_start_global": 634797, "sentence_char_end_global": 634917, "entities": [], "entities_global": []}
+{"sentence_id": 3808, "sentence_text": "Phosphatidylcholine hydrolysis activates NF - kappa B and increases human immunodeficiency virus replication in human monocytes and T lymphocytes .", "sentence_char_start_global": 634918, "sentence_char_end_global": 635065, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 41, "char_end": 53, "token_start": 3, "token_end": 6}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 634959, "char_end": 634971, "token_start": 3, "token_end": 6, "note": null}]}
+{"sentence_id": 3809, "sentence_text": "We have tested whether breakdown of phosphatidylcholine ( PC ) initiated by exogenous addition of a PC - specific phospholipase C ( PC - PLC ) from Bacillus cereus or by endogenous overexpression of PC - PLC induces functional activation of NF - kappa B and increases human immunodeficiency virus ( HIV ) enhancer activity .", "sentence_char_start_global": 635066, "sentence_char_end_global": 635390, "entities": [{"text": "PC - specific phospholipase C", "type": "ENTITY", "char_start": 100, "char_end": 129, "token_start": 16, "token_end": 20}, {"text": "PC - PLC", "type": "ENTITY", "char_start": 132, "char_end": 140, "token_start": 22, "token_end": 24}, {"text": "PC - PLC", "type": "ENTITY", "char_start": 199, "char_end": 207, "token_start": 34, "token_end": 36}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 241, "char_end": 253, "token_start": 41, "token_end": 44}, {"text": "human immunodeficiency virus ( HIV ) enhancer", "type": "ENTITY", "char_start": 268, "char_end": 313, "token_start": 47, "token_end": 53}], "entities_global": [{"text": "PC - specific phospholipase C", "type": "ENTITY", "char_start": 635166, "char_end": 635195, "token_start": 16, "token_end": 20, "note": null}, {"text": "PC - PLC", "type": "ENTITY", "char_start": 635198, "char_end": 635206, "token_start": 22, "token_end": 24, "note": null}, {"text": "PC - PLC", "type": "ENTITY", "char_start": 635265, "char_end": 635273, "token_start": 34, "token_end": 36, "note": null}, {"text": "NF - kappa B", "type": "ENTITY", "char_start": 635307, "char_end": 635319, "token_start": 41, "token_end": 44, "note": null}, {"text": "human immunodeficiency virus ( HIV ) enhancer", "type": "ENTITY", "char_start": 635334, "char_end": 635379, "token_start": 47, "token_end": 53, "note": null}]}
+{"sentence_id": 3810, "sentence_text": "PC - PLC - activated hydrolysis of PC was found to induce bona fide p50 / p65 NF - kappa B binding activity in three different cell lines of human or murine origin .", "sentence_char_start_global": 635391, "sentence_char_end_global": 635556, "entities": [{"text": "p50 / p65 NF - kappa B", "type": "ENTITY", "char_start": 68, "char_end": 90, "token_start": 14, "token_end": 20}], "entities_global": [{"text": "p50 / p65 NF - kappa B", "type": "ENTITY", "char_start": 635459, "char_end": 635481, "token_start": 14, "token_end": 20, "note": null}]}
+{"sentence_id": 3811, "sentence_text": "No significant changes in the turnover of other cellular phospholipids were detected in PC - PLC - treated cells .", "sentence_char_start_global": 635557, "sentence_char_end_global": 635671, "entities": [], "entities_global": []}
+{"sentence_id": 3812, "sentence_text": "Induction of NF - kappa B by PC - PLC did not depend on de novo synthesis of proteins or autocrine secretion of either tumor necrosis factor or interleukin 1 .", "sentence_char_start_global": 635672, "sentence_char_end_global": 635831, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 13, "char_end": 25, "token_start": 2, "token_end": 5}, {"text": "PC - PLC", "type": "ENTITY", "char_start": 29, "char_end": 37, "token_start": 7, "token_end": 9}, {"text": "tumor necrosis factor", "type": "ENTITY", "char_start": 119, "char_end": 140, "token_start": 24, "token_end": 26}, {"text": "interleukin 1", "type": "ENTITY", "char_start": 144, "char_end": 157, "token_start": 28, "token_end": 29}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 635685, "char_end": 635697, "token_start": 2, "token_end": 5, "note": null}, {"text": "PC - PLC", "type": "ENTITY", "char_start": 635701, "char_end": 635709, "token_start": 7, "token_end": 9, "note": null}, {"text": "tumor necrosis factor", "type": "ENTITY", "char_start": 635791, "char_end": 635812, "token_start": 24, "token_end": 26, "note": null}, {"text": "interleukin 1", "type": "ENTITY", "char_start": 635816, "char_end": 635829, "token_start": 28, "token_end": 29, "note": null}]}
+{"sentence_id": 3813, "sentence_text": "In human monocytic and lymphoblastoid T - cell lines , induction of NF - kappa B by PC - PLC resulted in clear induction of luciferase expression vectors placed under the control of synthetic kappa B enhancers or wild type , but not kappa B - mutated , HIV long terminal repeat constructs .", "sentence_char_start_global": 635832, "sentence_char_end_global": 636122, "entities": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 68, "char_end": 80, "token_start": 12, "token_end": 15}, {"text": "PC - PLC", "type": "ENTITY", "char_start": 84, "char_end": 92, "token_start": 17, "token_end": 19}, {"text": "luciferase", "type": "ENTITY", "char_start": 124, "char_end": 134, "token_start": 25, "token_end": 25}, {"text": "synthetic kappa B enhancers", "type": "ENTITY", "char_start": 182, "char_end": 209, "token_start": 33, "token_end": 36}, {"text": "HIV long terminal repeat constructs", "type": "ENTITY", "char_start": 253, "char_end": 288, "token_start": 48, "token_end": 52}], "entities_global": [{"text": "NF - kappa B", "type": "ENTITY", "char_start": 635900, "char_end": 635912, "token_start": 12, "token_end": 15, "note": null}, {"text": "PC - PLC", "type": "ENTITY", "char_start": 635916, "char_end": 635924, "token_start": 17, "token_end": 19, "note": null}, {"text": "luciferase", "type": "ENTITY", "char_start": 635956, "char_end": 635966, "token_start": 25, "token_end": 25, "note": null}, {"text": "synthetic kappa B enhancers", "type": "ENTITY", "char_start": 636014, "char_end": 636041, "token_start": 33, "token_end": 36, "note": null}, {"text": "HIV long terminal repeat constructs", "type": "ENTITY", "char_start": 636085, "char_end": 636120, "token_start": 48, "token_end": 52, "note": null}]}
+{"sentence_id": 3814, "sentence_text": "HIV replication was increased by PC - PLC in chronically infected monocytes and T lymphocytes .", "sentence_char_start_global": 636123, "sentence_char_end_global": 636218, "entities": [{"text": "PC - PLC", "type": "ENTITY", "char_start": 33, "char_end": 41, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "PC - PLC", "type": "ENTITY", "char_start": 636156, "char_end": 636164, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 3815, "sentence_text": "NF - kappa B activation promoted by addition of exogenous PC - PLC correlated with an intense production of diacylglycerol .", "sentence_char_start_global": 636219, "sentence_char_end_global": 636343, "entities": [{"text": "exogenous PC - PLC", "type": "ENTITY", "char_start": 48, "char_end": 66, "token_start": 9, "token_end": 12}], "entities_global": [{"text": "exogenous PC - PLC", "type": "ENTITY", "char_start": 636267, "char_end": 636285, "token_start": 9, "token_end": 12, "note": null}]}
+{"sentence_id": 3816, "sentence_text": "However , addition of a phosphatidylinositol - specific PLC from B . cereus also induced diacylglycerol but did not activate kappa B enhancer - directed vectors .", "sentence_char_start_global": 636344, "sentence_char_end_global": 636506, "entities": [{"text": "phosphatidylinositol - specific PLC", "type": "ENTITY", "char_start": 24, "char_end": 59, "token_start": 5, "token_end": 8}, {"text": "kappa B enhancer - directed vectors", "type": "ENTITY", "char_start": 125, "char_end": 160, "token_start": 20, "token_end": 25}], "entities_global": [{"text": "phosphatidylinositol - specific PLC", "type": "ENTITY", "char_start": 636368, "char_end": 636403, "token_start": 5, "token_end": 8, "note": null}, {"text": "kappa B enhancer - directed vectors", "type": "ENTITY", "char_start": 636469, "char_end": 636504, "token_start": 20, "token_end": 25, "note": null}]}
+{"sentence_id": 3817, "sentence_text": "PC - PLC - induced NF - kappa B activation could not be blocked by a specific inhibitor of phorbol ester - inducible protein kinases C .", "sentence_char_start_global": 636507, "sentence_char_end_global": 636643, "entities": [{"text": "phorbol ester - inducible protein kinases C", "type": "ENTITY", "char_start": 91, "char_end": 134, "token_start": 19, "token_end": 25}], "entities_global": [{"text": "phorbol ester - inducible protein kinases C", "type": "ENTITY", "char_start": 636598, "char_end": 636641, "token_start": 19, "token_end": 25, "note": null}]}
+{"sentence_id": 3818, "sentence_text": "These results indicate that a cellular transduction pathway , dependent on specific PC breakdown , is functional in T lymphocytes and monocytes and may be used by various transmembrane receptors to activate HIV transcription through NF - kappa B - dependent induction of the HIV enhancer .", "sentence_char_start_global": 636644, "sentence_char_end_global": 636933, "entities": [{"text": "HIV enhancer", "type": "ENTITY", "char_start": 275, "char_end": 287, "token_start": 44, "token_end": 45}], "entities_global": [{"text": "HIV enhancer", "type": "ENTITY", "char_start": 636919, "char_end": 636931, "token_start": 44, "token_end": 45, "note": null}]}
+{"sentence_id": 3819, "sentence_text": "Novel mechanism for inhibition of human T cells by glucocorticoids .", "sentence_char_start_global": 636934, "sentence_char_end_global": 637002, "entities": [], "entities_global": []}
+{"sentence_id": 3820, "sentence_text": "Glucocorticoids inhibit signal transduction through IL - 2 receptor .", "sentence_char_start_global": 637003, "sentence_char_end_global": 637072, "entities": [{"text": "IL - 2 receptor", "type": "ENTITY", "char_start": 52, "char_end": 67, "token_start": 5, "token_end": 8}], "entities_global": [{"text": "IL - 2 receptor", "type": "ENTITY", "char_start": 637055, "char_end": 637070, "token_start": 5, "token_end": 8, "note": null}]}
+{"sentence_id": 3821, "sentence_text": "Interaction of IL - 2 with its high affinity membrane receptor complex ( IL - 2R ) present on activated T lymphocytes induces cell proliferation and mediates effector functions .", "sentence_char_start_global": 637073, "sentence_char_end_global": 637251, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 15, "char_end": 21, "token_start": 2, "token_end": 4}, {"text": "high affinity membrane receptor complex", "type": "ENTITY", "char_start": 31, "char_end": 70, "token_start": 7, "token_end": 11}, {"text": "IL - 2R", "type": "ENTITY", "char_start": 73, "char_end": 80, "token_start": 13, "token_end": 15}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 637088, "char_end": 637094, "token_start": 2, "token_end": 4, "note": null}, {"text": "high affinity membrane receptor complex", "type": "ENTITY", "char_start": 637104, "char_end": 637143, "token_start": 7, "token_end": 11, "note": null}, {"text": "IL - 2R", "type": "ENTITY", "char_start": 637146, "char_end": 637153, "token_start": 13, "token_end": 15, "note": null}]}
+{"sentence_id": 3822, "sentence_text": "Glucocorticoids inhibit IL - 2 production by inhibiting TCR - mediated signal transduction .", "sentence_char_start_global": 637252, "sentence_char_end_global": 637344, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 24, "char_end": 30, "token_start": 2, "token_end": 4}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 637276, "char_end": 637282, "token_start": 2, "token_end": 4, "note": null}]}
+{"sentence_id": 3823, "sentence_text": "We asked whether they also inhibit the action of IL - 2 by inhibiting signal transduction through IL - 2R .", "sentence_char_start_global": 637345, "sentence_char_end_global": 637452, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 49, "char_end": 55, "token_start": 9, "token_end": 11}, {"text": "IL - 2R", "type": "ENTITY", "char_start": 98, "char_end": 105, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 637394, "char_end": 637400, "token_start": 9, "token_end": 11, "note": null}, {"text": "IL - 2R", "type": "ENTITY", "char_start": 637443, "char_end": 637450, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 3824, "sentence_text": "Human peripheral blood T cells , stimulated with PMA for 48 h ( PMA blasts ) , were incubated with IL - 2 in the presence of incremental dosages of dexamethasone ( Dex ; 10 ( - 5 ) - 10 ( - 9 ) M ) .", "sentence_char_start_global": 637453, "sentence_char_end_global": 637652, "entities": [{"text": "IL - 2", "type": "ENTITY", "char_start": 99, "char_end": 105, "token_start": 20, "token_end": 22}], "entities_global": [{"text": "IL - 2", "type": "ENTITY", "char_start": 637552, "char_end": 637558, "token_start": 20, "token_end": 22, "note": null}]}
+{"sentence_id": 3825, "sentence_text": "Dex inhibited the IL - 2 - dependent proliferation of PMA blasts in a dose - dependent fashion ( IC50 , 5 x 10 ( - 8 ) M ) .", "sentence_char_start_global": 637653, "sentence_char_end_global": 637777, "entities": [], "entities_global": []}
+{"sentence_id": 3826, "sentence_text": "Cell surface expression of IL - 2R alpha - and beta - chains as determined by immunofluorescence analysis was not affected by Dex .", "sentence_char_start_global": 637778, "sentence_char_end_global": 637909, "entities": [{"text": "IL - 2R alpha - and beta - chains", "type": "ENTITY", "char_start": 27, "char_end": 60, "token_start": 4, "token_end": 12}], "entities_global": [{"text": "IL - 2R alpha - and beta - chains", "type": "ENTITY", "char_start": 637805, "char_end": 637838, "token_start": 4, "token_end": 12, "note": null}]}
+{"sentence_id": 3827, "sentence_text": "In addition , Scatchard plot analysis of 125I - labeled IL - 2 showed that Dex did not affect the binding of IL - 2 , thus suggesting that inhibition is due to a postreceptor effect .", "sentence_char_start_global": 637910, "sentence_char_end_global": 638093, "entities": [{"text": "125I - labeled IL - 2", "type": "ENTITY", "char_start": 41, "char_end": 62, "token_start": 7, "token_end": 12}, {"text": "IL - 2", "type": "ENTITY", "char_start": 109, "char_end": 115, "token_start": 22, "token_end": 24}], "entities_global": [{"text": "125I - labeled IL - 2", "type": "ENTITY", "char_start": 637951, "char_end": 637972, "token_start": 7, "token_end": 12, "note": null}, {"text": "IL - 2", "type": "ENTITY", "char_start": 638019, "char_end": 638025, "token_start": 22, "token_end": 24, "note": null}]}
+{"sentence_id": 3828, "sentence_text": "Inhibition of T cell proliferation by Dex was associated with decreased IL - 2 - dependent tyrosine phosphorylation of several intracellular proteins and decreased phosphorylation of the retinoblastoma gene product Rb , a protein essential for controlling the progression of cells through the cell cycle .", "sentence_char_start_global": 638094, "sentence_char_end_global": 638399, "entities": [{"text": "intracellular proteins", "type": "ENTITY", "char_start": 127, "char_end": 149, "token_start": 20, "token_end": 21}, {"text": "retinoblastoma gene product Rb", "type": "ENTITY", "char_start": 187, "char_end": 217, "token_start": 27, "token_end": 30}], "entities_global": [{"text": "intracellular proteins", "type": "ENTITY", "char_start": 638221, "char_end": 638243, "token_start": 20, "token_end": 21, "note": null}, {"text": "retinoblastoma gene product Rb", "type": "ENTITY", "char_start": 638281, "char_end": 638311, "token_start": 27, "token_end": 30, "note": null}]}
+{"sentence_id": 3829, "sentence_text": "IL - 2 - dependent IL - 2R alpha expression in PMA blasts and NF - kB induction in resting human T cells were also inhibited by Dex .", "sentence_char_start_global": 638400, "sentence_char_end_global": 638533, "entities": [{"text": "NF - kB", "type": "ENTITY", "char_start": 62, "char_end": 69, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "NF - kB", "type": "ENTITY", "char_start": 638462, "char_end": 638469, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 3830, "sentence_text": "These results demonstrate that glucocorticoids inhibit preactivated T cells by down - regulating signal transduction through IL - 2R .", "sentence_char_start_global": 638534, "sentence_char_end_global": 638668, "entities": [{"text": "IL - 2R", "type": "ENTITY", "char_start": 125, "char_end": 132, "token_start": 16, "token_end": 18}], "entities_global": [{"text": "IL - 2R", "type": "ENTITY", "char_start": 638659, "char_end": 638666, "token_start": 16, "token_end": 18, "note": null}]}
+{"sentence_id": 3831, "sentence_text": "Chronic human immunodeficiency virus type 1 infection stimulates distinct NF - kappa B / rel DNA binding activities in myelomonoblastic cells .", "sentence_char_start_global": 638669, "sentence_char_end_global": 638812, "entities": [], "entities_global": []}
+{"sentence_id": 3832, "sentence_text": "The relationship between human immunodeficiency virus type 1 ( HIV - 1 ) infection and the induction of NF - kappa B binding activity was examined in a myeloid cell model of HIV - 1 infection derived from the PLB - 985 cell line .", "sentence_char_start_global": 638813, "sentence_char_end_global": 639043, "entities": [], "entities_global": []}
+{"sentence_id": 3833, "sentence_text": "Chronic infection of PLB - 985 cells led to increased monocyte - specific surface marker expression , increased c - fms gene transcription , and morphological alterations consistent with differentiation along the monocytic pathway .", "sentence_char_start_global": 639044, "sentence_char_end_global": 639276, "entities": [], "entities_global": []}
+{"sentence_id": 3834, "sentence_text": "PLB - IIIB cells displayed a constitutive NF - kappa B - like binding activity that was distinct from that induced by tumor necrosis factor alpha or phorbol 12 - myristate 13 - acetate treatment of the parental PLB - 985 cell line .", "sentence_char_start_global": 639277, "sentence_char_end_global": 639509, "entities": [{"text": "tumor necrosis factor alpha", "type": "ENTITY", "char_start": 118, "char_end": 145, "token_start": 22, "token_end": 25}], "entities_global": [{"text": "tumor necrosis factor alpha", "type": "ENTITY", "char_start": 639395, "char_end": 639422, "token_start": 22, "token_end": 25, "note": null}]}
+{"sentence_id": 3835, "sentence_text": "This unique DNA binding activity consisted of proteins of 70 , 90 , and 100 kDa with a high degree of binding specificity for the NF - kappa B site within the PRDII domain of beta interferon .", "sentence_char_start_global": 639510, "sentence_char_end_global": 639702, "entities": [{"text": "70 , 90 , and 100 kDa", "type": "ENTITY", "char_start": 58, "char_end": 79, "token_start": 9, "token_end": 15}, {"text": "NF - kappa B site", "type": "ENTITY", "char_start": 130, "char_end": 147, "token_start": 25, "token_end": 29}, {"text": "PRDII domain", "type": "ENTITY", "char_start": 159, "char_end": 171, "token_start": 32, "token_end": 33}, {"text": "beta interferon", "type": "ENTITY", "char_start": 175, "char_end": 190, "token_start": 35, "token_end": 36}], "entities_global": [{"text": "70 , 90 , and 100 kDa", "type": "ENTITY", "char_start": 639568, "char_end": 639589, "token_start": 9, "token_end": 15, "note": null}, {"text": "NF - kappa B site", "type": "ENTITY", "char_start": 639640, "char_end": 639657, "token_start": 25, "token_end": 29, "note": null}, {"text": "PRDII domain", "type": "ENTITY", "char_start": 639669, "char_end": 639681, "token_start": 32, "token_end": 33, "note": null}, {"text": "beta interferon", "type": "ENTITY", "char_start": 639685, "char_end": 639700, "token_start": 35, "token_end": 36, "note": null}]}
+{"sentence_id": 3836, "sentence_text": "In this report , we characterize the nature of these proteins and demonstrate that binding of these proteins is also induced following Sendai paramyxovirus infection .", "sentence_char_start_global": 639703, "sentence_char_end_global": 639870, "entities": [], "entities_global": []}
+{"sentence_id": 3837, "sentence_text": "The 70 - kDa protein corresponds to the NF - kappa B RelA ( p65 ) subunit , which is activated in response to an acute paramyxovirus infection or a chronic HIV - 1 infection .", "sentence_char_start_global": 639871, "sentence_char_end_global": 640046, "entities": [{"text": "70 - kDa protein", "type": "ENTITY", "char_start": 4, "char_end": 20, "token_start": 1, "token_end": 4}, {"text": "NF - kappa B RelA ( p65 ) subunit", "type": "ENTITY", "char_start": 40, "char_end": 73, "token_start": 8, "token_end": 16}], "entities_global": [{"text": "70 - kDa protein", "type": "ENTITY", "char_start": 639875, "char_end": 639891, "token_start": 1, "token_end": 4, "note": null}, {"text": "NF - kappa B RelA ( p65 ) subunit", "type": "ENTITY", "char_start": 639911, "char_end": 639944, "token_start": 8, "token_end": 16, "note": null}]}
+{"sentence_id": 3838, "sentence_text": "Virus infection does not appear to alter the amount of RelA ( p65 ) or NFKB1 ( p50 ) but rather affects the capacity of I kappa B alpha to sequester RelA ( p65 ) , therefore leading to constitutive levels of RelA DNA binding activity and to increased levels of NF - kappa B - dependent gene activity .", "sentence_char_start_global": 640047, "sentence_char_end_global": 640348, "entities": [{"text": "RelA", "type": "ENTITY", "char_start": 55, "char_end": 59, "token_start": 10, "token_end": 10}, {"text": "p65", "type": "ENTITY", "char_start": 62, "char_end": 65, "token_start": 12, "token_end": 12}, {"text": "NFKB1", "type": "ENTITY", "char_start": 71, "char_end": 76, "token_start": 15, "token_end": 15}, {"text": "p50", "type": "ENTITY", "char_start": 79, "char_end": 82, "token_start": 17, "token_end": 17}, {"text": "I kappa B alpha", "type": "ENTITY", "char_start": 120, "char_end": 135, "token_start": 25, "token_end": 28}, {"text": "RelA ( p65 )", "type": "ENTITY", "char_start": 149, "char_end": 161, "token_start": 31, "token_end": 34}], "entities_global": [{"text": "RelA", "type": "ENTITY", "char_start": 640102, "char_end": 640106, "token_start": 10, "token_end": 10, "note": null}, {"text": "p65", "type": "ENTITY", "char_start": 640109, "char_end": 640112, "token_start": 12, "token_end": 12, "note": null}, {"text": "NFKB1", "type": "ENTITY", "char_start": 640118, "char_end": 640123, "token_start": 15, "token_end": 15, "note": null}, {"text": "p50", "type": "ENTITY", "char_start": 640126, "char_end": 640129, "token_start": 17, "token_end": 17, "note": null}, {"text": "I kappa B alpha", "type": "ENTITY", "char_start": 640167, "char_end": 640182, "token_start": 25, "token_end": 28, "note": null}, {"text": "RelA ( p65 )", "type": "ENTITY", "char_start": 640196, "char_end": 640208, "token_start": 31, "token_end": 34, "note": null}]}
+{"sentence_id": 3839, "sentence_text": "The virally induced 90 - to 100 - kDa proteins have a distinct binding specificity for the PRDII domain and an AT - rich sequence but do not cross - react with NF - kappa B subunit - specific antisera directed against NFKB1 ( p105 or p50 ) , NFKB2 ( p100 or p52 ) , RelA ( p65 ) , or c - rel .", "sentence_char_start_global": 640349, "sentence_char_end_global": 640642, "entities": [{"text": "90 - to 100 - kDa proteins", "type": "ENTITY", "char_start": 20, "char_end": 46, "token_start": 3, "token_end": 9}, {"text": "PRDII domain", "type": "ENTITY", "char_start": 91, "char_end": 103, "token_start": 17, "token_end": 18}, {"text": "AT - rich sequence", "type": "ENTITY", "char_start": 111, "char_end": 129, "token_start": 21, "token_end": 24}, {"text": "NFKB1", "type": "ENTITY", "char_start": 218, "char_end": 223, "token_start": 42, "token_end": 42}, {"text": "p105", "type": "ENTITY", "char_start": 226, "char_end": 230, "token_start": 44, "token_end": 44}, {"text": "p50", "type": "ENTITY", "char_start": 234, "char_end": 237, "token_start": 46, "token_end": 46}, {"text": "NFKB2", "type": "ENTITY", "char_start": 242, "char_end": 247, "token_start": 49, "token_end": 49}, {"text": "p100", "type": "ENTITY", "char_start": 250, "char_end": 254, "token_start": 51, "token_end": 51}, {"text": "p52", "type": "ENTITY", "char_start": 258, "char_end": 261, "token_start": 53, "token_end": 53}, {"text": "RelA", "type": "ENTITY", "char_start": 266, "char_end": 270, "token_start": 56, "token_end": 56}, {"text": "p65", "type": "ENTITY", "char_start": 273, "char_end": 276, "token_start": 58, "token_end": 58}, {"text": "c - rel", "type": "ENTITY", "char_start": 284, "char_end": 291, "token_start": 62, "token_end": 64}], "entities_global": [{"text": "90 - to 100 - kDa proteins", "type": "ENTITY", "char_start": 640369, "char_end": 640395, "token_start": 3, "token_end": 9, "note": null}, {"text": "PRDII domain", "type": "ENTITY", "char_start": 640440, "char_end": 640452, "token_start": 17, "token_end": 18, "note": null}, {"text": "AT - rich sequence", "type": "ENTITY", "char_start": 640460, "char_end": 640478, "token_start": 21, "token_end": 24, "note": null}, {"text": "NFKB1", "type": "ENTITY", "char_start": 640567, "char_end": 640572, "token_start": 42, "token_end": 42, "note": null}, {"text": "p105", "type": "ENTITY", "char_start": 640575, "char_end": 640579, "token_start": 44, "token_end": 44, "note": null}, {"text": "p50", "type": "ENTITY", "char_start": 640583, "char_end": 640586, "token_start": 46, "token_end": 46, "note": null}, {"text": "NFKB2", "type": "ENTITY", "char_start": 640591, "char_end": 640596, "token_start": 49, "token_end": 49, "note": null}, {"text": "p100", "type": "ENTITY", "char_start": 640599, "char_end": 640603, "token_start": 51, "token_end": 51, "note": null}, {"text": "p52", "type": "ENTITY", "char_start": 640607, "char_end": 640610, "token_start": 53, "token_end": 53, "note": null}, {"text": "RelA", "type": "ENTITY", "char_start": 640615, "char_end": 640619, "token_start": 56, "token_end": 56, "note": null}, {"text": "p65", "type": "ENTITY", "char_start": 640622, "char_end": 640625, "token_start": 58, "token_end": 58, "note": null}, {"text": "c - rel", "type": "ENTITY", "char_start": 640633, "char_end": 640640, "token_start": 62, "token_end": 64, "note": null}]}
+{"sentence_id": 3840, "sentence_text": "DNA binding of the 90 - to 100 - kDa proteins was not inhibited by recombinant I kappa B alpha / MAD - 3 and was resistant to tryptic digestion , suggesting that these proteins may not be NF - kappa B related .", "sentence_char_start_global": 640643, "sentence_char_end_global": 640853, "entities": [{"text": "90 - to 100 - kDa proteins", "type": "ENTITY", "char_start": 19, "char_end": 45, "token_start": 4, "token_end": 10}, {"text": "recombinant I kappa B alpha / MAD - 3", "type": "ENTITY", "char_start": 67, "char_end": 104, "token_start": 15, "token_end": 23}, {"text": "NF - kappa B related", "type": "ENTITY", "char_start": 188, "char_end": 208, "token_start": 38, "token_end": 42}], "entities_global": [{"text": "90 - to 100 - kDa proteins", "type": "ENTITY", "char_start": 640662, "char_end": 640688, "token_start": 4, "token_end": 10, "note": null}, {"text": "recombinant I kappa B alpha / MAD - 3", "type": "ENTITY", "char_start": 640710, "char_end": 640747, "token_start": 15, "token_end": 23, "note": null}, {"text": "NF - kappa B related", "type": "ENTITY", "char_start": 640831, "char_end": 640851, "token_start": 38, "token_end": 42, "note": null}]}
+{"sentence_id": 3841, "sentence_text": "Transient cotransfection experiments demonstrated that RelA and NFKB1 expression maximally stimulated HIV - 1 LTR - and NF - kappa B - dependent reporter genes ; differences in NF - kappa B - like binding activity were also reflected in higher constitutive levels of NF - kappa B - regulated gene expression in HIV - 1 - infected myeloid cells .", "sentence_char_start_global": 640854, "sentence_char_end_global": 641199, "entities": [{"text": "HIV - 1 LTR - and NF - kappa B - dependent reporter genes", "type": "ENTITY", "char_start": 102, "char_end": 159, "token_start": 11, "token_end": 24}], "entities_global": [{"text": "HIV - 1 LTR - and NF - kappa B - dependent reporter genes", "type": "ENTITY", "char_start": 640956, "char_end": 641013, "token_start": 11, "token_end": 24, "note": null}]}
+{"sentence_id": 3842, "sentence_text": "Presence of estrogen - binding sites on macrophage - like synoviocytes and CD8 + , CD29 + , CD45RO + T lymphocytes in normal and rheumatoid synovium .", "sentence_char_start_global": 641200, "sentence_char_end_global": 641350, "entities": [], "entities_global": []}
+{"sentence_id": 3843, "sentence_text": "OBJECTIVE .", "sentence_char_start_global": 641351, "sentence_char_end_global": 641362, "entities": [], "entities_global": []}
+{"sentence_id": 3844, "sentence_text": "To study the presence of estrogen - binding sites ( EBS ) in the synovial tissues of male and female patients with rheumatoid arthritis ( RA ) and in age - and sex - matched healthy controls .", "sentence_char_start_global": 641363, "sentence_char_end_global": 641555, "entities": [], "entities_global": []}
+{"sentence_id": 3845, "sentence_text": "METHODS .", "sentence_char_start_global": 641556, "sentence_char_end_global": 641565, "entities": [], "entities_global": []}
+{"sentence_id": 3846, "sentence_text": "Both type 1 ( high affinity , low binding capacity ) and type 2 ( reduced affinity , higher binding capacity ) EBS were investigated in both soluble and nuclear fractions of homogenized synovial tissue samples by a dextran - coated charcoal method .", "sentence_char_start_global": 641566, "sentence_char_end_global": 641815, "entities": [], "entities_global": []}
+{"sentence_id": 3847, "sentence_text": "To determine what type of synovial cell was positive for EBS , cryosections of synovial tissues were immunostained with a specific monoclonal anti - estrogen receptor antibody ( anti - ER MAb ) using both immunofluorescence and immunoperoxidase techniques .", "sentence_char_start_global": 641816, "sentence_char_end_global": 642073, "entities": [{"text": "monoclonal anti - estrogen receptor antibody", "type": "ENTITY", "char_start": 131, "char_end": 175, "token_start": 21, "token_end": 26}, {"text": "anti - ER MAb", "type": "ENTITY", "char_start": 178, "char_end": 191, "token_start": 28, "token_end": 31}], "entities_global": [{"text": "monoclonal anti - estrogen receptor antibody", "type": "ENTITY", "char_start": 641947, "char_end": 641991, "token_start": 21, "token_end": 26, "note": null}, {"text": "anti - ER MAb", "type": "ENTITY", "char_start": 641994, "char_end": 642007, "token_start": 28, "token_end": 31, "note": null}]}
+{"sentence_id": 3848, "sentence_text": "Double immunostaining with the anti - ER MAb and with specific MAb to detect different macrophage antigens ( Ber - MAC3 , MAC387 , CD68 ) and CD8 + T cell subsets ( CD29 + , CD45RO + and CD29 - , CD45RO - ) was performed .", "sentence_char_start_global": 642074, "sentence_char_end_global": 642296, "entities": [{"text": "anti - ER MAb", "type": "ENTITY", "char_start": 31, "char_end": 44, "token_start": 4, "token_end": 7}, {"text": "specific MAb", "type": "ENTITY", "char_start": 54, "char_end": 66, "token_start": 10, "token_end": 11}, {"text": "macrophage antigens", "type": "ENTITY", "char_start": 87, "char_end": 106, "token_start": 15, "token_end": 16}, {"text": "Ber - MAC3", "type": "ENTITY", "char_start": 109, "char_end": 119, "token_start": 18, "token_end": 20}, {"text": "MAC387", "type": "ENTITY", "char_start": 122, "char_end": 128, "token_start": 22, "token_end": 22}, {"text": "CD68", "type": "ENTITY", "char_start": 131, "char_end": 135, "token_start": 24, "token_end": 24}], "entities_global": [{"text": "anti - ER MAb", "type": "ENTITY", "char_start": 642105, "char_end": 642118, "token_start": 4, "token_end": 7, "note": null}, {"text": "specific MAb", "type": "ENTITY", "char_start": 642128, "char_end": 642140, "token_start": 10, "token_end": 11, "note": null}, {"text": "macrophage antigens", "type": "ENTITY", "char_start": 642161, "char_end": 642180, "token_start": 15, "token_end": 16, "note": null}, {"text": "Ber - MAC3", "type": "ENTITY", "char_start": 642183, "char_end": 642193, "token_start": 18, "token_end": 20, "note": null}, {"text": "MAC387", "type": "ENTITY", "char_start": 642196, "char_end": 642202, "token_start": 22, "token_end": 22, "note": null}, {"text": "CD68", "type": "ENTITY", "char_start": 642205, "char_end": 642209, "token_start": 24, "token_end": 24, "note": null}]}
+{"sentence_id": 3849, "sentence_text": "RESULTS .", "sentence_char_start_global": 642297, "sentence_char_end_global": 642306, "entities": [], "entities_global": []}
+{"sentence_id": 3850, "sentence_text": "Higher affinity EBS were found mostly in nuclear cell fractions of either RA or control synovial tissues ( 28 of the 33 ) .", "sentence_char_start_global": 642307, "sentence_char_end_global": 642430, "entities": [], "entities_global": []}
+{"sentence_id": 3851, "sentence_text": "These EBS were present to a lesser extent in soluble cell fractions ( 11 of the 33 ) .", "sentence_char_start_global": 642431, "sentence_char_end_global": 642517, "entities": [], "entities_global": []}
+{"sentence_id": 3852, "sentence_text": "Immunostaining showed the estrogen receptor - positive cells to be the macrophage - like synoviocytes and the CD8 + , CD29 + T cells both in RA and in control synovial tissues .", "sentence_char_start_global": 642518, "sentence_char_end_global": 642695, "entities": [], "entities_global": []}
+{"sentence_id": 3853, "sentence_text": "Higher nuclear content of EBS was consistent with more intense nuclear staining of synoviocytes and T cells .", "sentence_char_start_global": 642696, "sentence_char_end_global": 642805, "entities": [], "entities_global": []}
+{"sentence_id": 3854, "sentence_text": "CONCLUSION .", "sentence_char_start_global": 642806, "sentence_char_end_global": 642818, "entities": [], "entities_global": []}
+{"sentence_id": 3855, "sentence_text": "It is conceivable that the immunomodulatory activity exerted by estrogens is at least partly mediated through their interaction with EBS that are present on macrophage - like synoviocytes , functioning as antigen - processing and antigen - presenting cells , and on antigen - experienced ( memory ) CD8 + T lymphocytes ( CD29 + , CD45RO +", "sentence_char_start_global": 642819, "sentence_char_end_global": 643157, "entities": [], "entities_global": []}
diff --git a/evaluation/benchmark/JNLPBA_gene_protein_test_text.txt b/evaluation/benchmark/JNLPBA_gene_protein_test_text.txt
new file mode 100644
index 0000000..404d366
--- /dev/null
+++ b/evaluation/benchmark/JNLPBA_gene_protein_test_text.txt
@@ -0,0 +1 @@
+Number of glucocorticoid receptors in lymphocytes and their sensitivity to hormone action . The study demonstrated a decreased level of glucocorticoid receptors ( GR ) in peripheral blood lymphocytes from hypercholesterolemic subjects , and an elevated level in patients with acute myocardial infarction . In the lymphocytes with a high GR number , dexamethasone inhibited [ 3H ] - thymidine and [ 3H ] - acetate incorporation into DNA and cholesterol , respectively , in the same manner as in the control cells . On the other hand , a decreased GR number resulted in a less efficient dexamethasone inhibition of the incorporation of labeled compounds . These data showed that the sensitivity of lymphocytes to glucocorticoids changed only with a decrease of GR level . [ 1 , 25 - Dihydroxyvitamin D3 receptors in lymphocytes and T - and B - lymphocyte count in patients with glomerulonephritis ] Content of receptors to hormonal form of vitamin D3 , 1 . 25 ( OH ) 2D3 , constituted 27 . 3 fmole / mg of protein in lymphocytes of peripheric blood of children with glomerulonephritis . In the patients concentration of total and ionized form of Ca2 + was decreased down to 2 . 04 mmole / L and 1 . 09 mmole / L , respectively , while an increase in parathormone ( PTH ) by 36 % and a distinct decrease in 25 ( OH ) D concentration ( lower than 1 . 25 ng / ml ) was found in blood ; content of cAMP was also decreased in lymphocytes by 33 % . At the same time , total content of T lymphocytes was decreased 1 . 5 - fold in peripheric blood . Treatment with I - hydroxyvitamin D3 ( 1 - 1 . 5 mg daily , within 4 weeks ) led to normalization of total and ionized form of Ca2 + and of 25 ( OH ) D , but did not affect the PTH content in blood . Concentration of the receptors to 1 . 25 ( OH ) 2D3 was elevated up to 39 . 7 fmole / mg after I week of the treatment , whereas it was decreased to the initial level 24 . 8 fmole / mg within 4 weeks ; simultaneous alteration in the cAMP content was observed in lymphocytes . Treatment with 1 - ( OH ) D3 normalized also the T lymphocytes content in peripheric blood . The data obtained suggest that under conditions of glomerulonephritis only high content of receptors to 1 . 25 ( OH ) 2D3 in lymphocytes enabled to perform the cell response to the hormone effect . Tumor and serum beta - 2 - microglobulin expression in women with breast cancer . To investigate whether the tumor expression of beta - 2 - microglobulin ( beta 2 - M ) could serve as a marker of tumor biologic behavior , the authors studied specimens of breast carcinomas from 60 consecutive female patients . Presence of beta 2 - M was analyzed by immunohistochemistry . No significant correlations were found between tumor beta 2 - M expression and several histologic attributes such as type , histologic and nuclear grades , mitotic index , necrosis , vascular invasion , and lymphocytic infiltration . Likewise , beta 2 - M was not associated with markers of disease extension such as TNM , ( UICC , classification of malignant tumors ) staging and axillary lymph node involvement or with estrogen , progesterone , and glucocorticoid receptor levels . However , there was a significantly positive association between tumor beta 2 - M expression and the degree of lymphocytic infiltration in the tumor tissue . Beta 2 - M serum levels were determined by an enzyme - linked immunosorbent assay in samples from 22 of the above women . Although some of the highest values had been obtained in women with larger ( T4 ) primary tumors , the authors failed to detect any statistical relationship between beta 2 - M expression in the tumor with serum levels or between serum beta 2 - M and the above histologic , laboratory , and clinical factors . [ Preliminary observation of level free - form E receptor levels in serum of normal childbearing - aged and pregnant women ] In 137 cases of childbearing - aged and pregnant women , free form E receptor levels ( sE ) in serum were measured by ELISA . The level of sE was significantly decreased during the first trimester , slightly higher in the second trimester , and recovered to normal in the third trimester . The level remained lower in 29 PIH women but appeared higher in overdue pregnancies as compared with the normal 3rd trimester range . The results indicate that there is a relationship between a change in T cell function and pregnancy . Kappa B - specific DNA binding proteins : role in the regulation of human interleukin - 2 gene expression . Transcriptional activation of the human interleukin - 2 ( IL - 2 ) gene , like induction of the IL - 2 receptor alpha ( IL - 2R alpha ) gene and the type 1 human immunodeficiency virus ( HIV - 1 ) , is shown to be modulated by a kappa B - like enhancer element . Mutation of a kappa B core sequence identified in the IL - 2 promoter ( - 206 to - 195 ) partially inhibits both mitogen - and HTLV - I Tax - mediated activation of this transcription unit and blocks the specific binding of two inducible cellular factors . These kappa B - specific proteins ( 80 to 90 and 50 to 55 kilodaltons ) similarly interact with the functional kappa B enhancer present in the IL - 2R alpha promoter . These data suggest that these kappa B - specific proteins have a role in the coordinate regulation of this growth factor - growth factor receptor gene system that controls T cell proliferation . Novel region within the V kappa gene promoter is responsible for tissue and stage - specific expression of immunoglobulin genes in human lymphoid neoplasms . Immunoglobulin gene - specific transacting factors have been shown to play a role in lymphoid tissue - specific expression of immunoglobulin genes . The role of these factors in B - cell differentiation and stage - specific expression of these genes is , however , not fully understood . We have used a model of human lymphoid neoplasia to address this question . Different fragments of unrearranged human variable region of immunoglobulin kappa gene ( V kappa ) were used for cell - free in vitro transcription and DNA mobility shift assays . Previously described enhancement of in vitro transcription that was only seen with nuclear extracts derived from B - cell neoplasms corresponding to the late stages of B - cell differentiation was shown to be dependent on the actions of these factor ( s ) on the DNA region within the V kappa gene promoter . This region is located within the 920 bp fragment located 210 bp upstream from the coding region and this fragment represents a possible novel DNA region , which plays a role in the stage - and tissue - specific expression of immunoglobulin genes . [ Determination of the sensitivity to glucocorticoids in vitro ] A modified method for the determination of glucocorticoid receptors in human lymphocytes is suggested . The principal distinction of the method is standardization by the lymphocyte count in a sample ( 1 mln ) and the labeled hormone concentration . The modification saves time and money , limits the range of the data variations , and makes use of a lesser volume of blood . Examinations of 70 children aged 4 to 15 suffering from the nephrotic form of glomerulonephritis have made it possible to distinguish two groups of patients : with relatively high values of specific binding X = 6820 . 1 + / - 530 . 0 ( n = 30 , p = 0 . 95 , t = 2 . 04 ) , this corresponding to a clinical form of hormone - sensitive glomerulonephritis , and with relatively low values of specific binding X = 1815 . 2 + / - 302 . 8 ( n = 40 , p = 0 . 95 , t = 1 . 96 ) , that corresponds to hormone - resistant glomerulonephritis . Dynamic studies have not shown any statistically significant changes in the specific binding values . These results permit regarding the specific binding value as a prognostic criterion in the assessment of corticosteroid therapy ; this allows a wide employment of the described method in practical nephrology . Octamer - binding proteins from B or HeLa cells stimulate transcription of the immunoglobulin heavy - chain promoter in vitro . The B - cell - type specificity of the immunoglobulin ( Ig ) heavy - chain and light - chain promoters is mediated by an octanucleotide ( OCTA ) element , ATGCAAAT , that is also a functional component of other RNA polymerase II promoters , such as snRNA and histone H2B promoters . Two nuclear proteins that bind specifically and with high affinity to the OCTA element have been identified . NF - A1 is present in a variety of cell types , whereas the presence of NF - A2 is essentially confined to B cells , leading to the hypothesis that NF - A2 activates cell - type - specific transcription of the Ig promoter and NF - A1 mediates the other responses of the OCTA element . Extracts of the B - cell line , BJA - B , contain high levels of NF - A2 and specifically transcribe Ig promoters . In contrast , extracts from HeLa cells transcribed the Ig promoter poorly . Surprisingly , addition of either affinity - enriched NF - A2 or NF - A1 to either a HeLa extract or a partially purified reaction system specifically stimulates the Ig promoter . This suggests that the constitutive OCTA - binding factor NF - A1 can activate transcription of the Ig promoter and that B - cell - specific transcription of this promoter , at least in vitro , is partially due to a quantitative difference in the amount of OCTA - binding protein . Because NF - A1 can stimulate Ig transcription , the inability of this factor to activate in vivo the Ig promoter to the same degree as the snRNA promoters probably reflects a difference in the context of the OCTA element in these two types of promoters . Identification of a putative regulator of early T cell activation genes . Molecules involved in the antigen receptor - dependent regulation of early T cell activation genes were investigated with the use of functional sequences of the T cell activation - specific enhancer of interleukin - 2 ( IL - 2 ) . One of these sequences forms a protein complex , NFAT - 1 , specifically with nuclear extracts of activated T cells . This complex appeared 10 to 25 minutes before the activation of the IL - 2 gene . Studies with inhibitors of protein synthesis indicated that the time of synthesis of the activator of the IL - 2 gene in Jurkat T cells corresponds to the time of appearance of NFAT - 1 . NFAT - 1 , or a very similar protein , bound functional sequences of the long terminal repeat ( LTR ) of the human immunodeficiency virus type 1 ; the LTR of this virus is known to be stimulated during early T cell activation . The binding site for this complex activated a linked promoter after transfection into antigen receptor - activated T cells but not other cell types . These characteristics suggest that NFAT - 1 transmits signals initiated at the T cell antigen receptor . Characterization of thyroid hormone receptors in human IM - 9 lymphocytes . Although putatively identified more than 10 years ago , thyroid hormone receptors in human tissues remain poorly characterized . As a first step towards understanding the mechanism of thyroid hormone action in man we have characterized T3 binding sites in nuclei of the human lymphoblastoid line , IM - 9 cells . In whole cell experiments at 37 degrees C , nuclear binding of [ 125I ] T3 was saturable ( Kd 34 + / - 6 pmol / l ) and of finite capacity ( approximately equal to 350 sites / cell ) . The binding sites were extracted from a nuclear pellet by treatment with 0 . 4 mol / l KCl and sonication . Separation of bound from free [ 125I ] T3 in the extracts was achieved using the calcium phosphate matrix , hydroxyapatite at a concentration of 0 . 3 ml of a 150 g / l slurry . Rectilinear Scatchard plots were obtained only when the hydroxyapatite was washed with a buffer containing 0 . 5 % Triton X - 100 . Under these conditions T3 binding sites in the nuclear extracts were present at a concentration of 22 . 4 + / - 8 . 6 fmol / mg protein and showed an affinity of ( Kd , room temperature ) 140 + / - 10 pmol / l . The same assay system was used to determine the hierarchy of affinities for a range of natural and synthetic analogues . Calling T3 100 , the order of potencies observed was : Triac , 500 ; 3 , 5 - diiodo - 3 ' - isopropylthyronine , 89 ; T4 , 32 ; 3 , 5 - dimethyl - 3 ' isopropylthyronine 2 ; 3 , 5 - T2 , 0 . 7 , rT3 , 0 . 4 ; 3 ' 5 ' - T2 , less than 0 . 01 . These results suggest that the T3 binding sites present in human IM - 9 lymphocyte nuclei and extracts thereof are thyroid hormone receptors . These cells may be a useful tool to increase our understanding of human T3 receptors Definition of T - cell specific DNA - binding factors that interact with a 3 ' - silencer in the CD4 + T - cell gene Rpt - 1 . Analysis of the region 3 ' to the CD4 + T - cell gene Rpt - 1 ( encoding regulatory protein T - lymphocyte 1 ) led to the definition of a silencer element that inhibits heterologous gene expression in certain CD4 + T - cell lines but not in B - cell or non - lymphoid cell lines . Functional silencer activity in vivo was associated with the presence of a specific silencer - DNA - protein complex in electrophoretic mobility shift assays with T - cell extracts . Formation of this complex was selectively inhibited by the region in HIV - 1 containing a silencer element . We discuss the possibility that DNA - binding factors may coregulate HIV - 1 and Rpt - 1 gene expression through a common transcriptional silencer element . Congenital immunodeficiencies associated with absence of HLA class II antigens on lymphocytes result from distinct mutations in trans - acting factors . Coordinate regulation of HLA class II gene expression during development and coinduction of class II genes by soluble factors suggests that common trans - acting factor ( s ) control expression of these genes . In B - lymphoblastoid cell lines derived from two independent class II - deficient bare lymphocyte syndrome patients , we observed a drastic decrease in transcription rates of the class II genes . When these cell lines are fused , class II genes are reexpressed , indicating that immunodeficiencies in bare lymphocyte syndrome patients are the result of two distinct mutations . Further studies show that genes governing the expression of class II antigens fall into at least three complementation groups ; two of these were previously unidentified in mutant cell lines generated in vitro . In addition , we report the identification of two discrete complexes , NFX1 . 1 and NFX1 . 2 , that bind to the DRA X consensus element . Though the mutation in at least one mutant line generated in vitro ( RJ2 . 2 . 5 ) affects products functioning via interaction with the X box , clear alterations in either NFX1 . 1 or NFX1 . 2 are not found in any of the mutant cell lines . In vivo responsiveness to glucocorticoid correlated with glucocorticoid receptor content in peripheral blood leukocytes in normal humans . Dexamethasone loading tests ( 0 . 1 mg dexamethasone / kg , iv ) were performed in 18 normal males to evaluate the individual responsiveness to glucocorticoid . There were inter - individual differences in increase in peripheral blood polymorphonuclear leukocyte count , decrease in peripheral blood lymphocyte count , and increase in plasma free fatty acids levels after dexamethasone injection . In addition , there was a significant correlation between the maximum increase in polymorphonuclear leukocytes and the maximum decrease in lymphocytes ( r = 0 . 7514 , p less than 0 . 0003 ) . Simultaneous measurements of glucocorticoid receptor content by whole - cell assay revealed that glucocorticoid receptor content in polymorphonuclear leukocytes linearly correlated with that in the corresponding lymphocytes ( r = 0 . 9482 , p less than 0 . 0001 ) . There were also significant correlations between the maximum increase in polymorphonuclear leukocytes and glucocorticoid receptor content in polymorphonuclear leukocytes ( r = 0 . 7239 , p less than 0 . 0007 ) , and between the maximum decrease in lymphocytes and glucocorticoid receptor content in lymphocytes ( r = 0 . 7703 , p less than 0 . 0002 ) . These results suggest that individual differences are preserved both in glucocorticoid responsiveness and in glucocorticoid receptor content in peripheral blood leukocytes in normal humans . Estradiol receptors in the cytosol of peripheral blood mononuclear cells in hepatitis B virus carriers treated with interferon - alpha . Estradiol receptors in the cytosol of peripheral blood mononuclear cells and the effects of interferon - alpha ( IFN - alpha ) on estradiol receptors were studied in asymptomatic hepatitis B virus ( HBV ) carriers , patients with chronic hepatitis B and normal controls . The level of estradiol receptors in the cytosol of mononuclear cells was significantly lower in asymptomatic HBV carriers and patients with chronic hepatitis B , compared to normal controls . This low level of cytosol estradiol receptors in patients with chronic hepatitis B was increased by the administration of IFN - alpha . In addition , when peripheral blood mononuclear cells from patients with chronic hepatitis B were incubated with IFN - alpha in vitro , the level of cytosol estradiol receptors also increased by increasing the concentration of IFN - alpha . We previously reported that the response of mononuclear cells to estrogen is impaired in HBV carriers , and our present results suggested that this may be due to the low level of estradiol receptors in the cytosol of mononuclear cells . Association of increased lytic effector cell function with high estrogen receptor levels in tumor - bearing patients with breast cancer . Tumor - bearing patients with breast cancer were assayed for their natural killer ( NK ) cell activity and for the function of activated cytotoxic T - cells , as assessed by lectin - dependent cellular cytotoxicity ( LDCC ) . Tumor - bearing patients with breast cancer had a significant increase in NK activity and in LDCC , as compared with healthy control individuals . Although the enhanced NK cell activity and LDCC were closely associated with high levels ( greater than 31 fmol / mg ) of estrogen receptor ( ER ) content in the primary tumor , no other clinical or histologic correlation between the increase in either parameter of cytotoxic effector cell function could be found . Thus , ER levels greater than 31 fmol / mg might be associated with increased cytotoxic effector cell function in tumor - bearing patients with breast cancer . Properties of glucocorticoid receptors in Epstein - Barr virus - transformed lymphocytes from patients with familial cortisol resistance . In a previous report of two patients with familial glucocorticoid resistance due to reduced numbers of glucocorticoid receptors ( GR ) , we have shown decreased numbers of GR in peripheral mononuclear cells and cultured fibroblasts but normal affinity of GR in both patients . In this study , peripheral lymphocytes from these patients , one patient ' s son and daughter , and normal subjects were transformed with Epstein - Barr virus . Reduced numbers and normal affinity of GR were found in the Epstein - Barr virus - transformed lymphocytes from both patients while the son and daughter had normal numbers and affinity of GR . The thermal stability of GR and thermal activation of cytosolic receptors in both patients were found to be normal . Although the percentages of nuclear bound GR were similar in both patients and normal controls , the absolute amounts of nuclear bound GR of the patients were about one - half that of normal controls . These abnormal properties of GR ( reduced numbers of GR ) were preserved in the transformed cells from the patients . Octamer transcription factors 1 and 2 each bind to two different functional elements in the immunoglobulin heavy - chain promoter . Immunoglobulin heavy - chain genes contain two conserved sequence elements 5 ' to the site of transcription initiation : the octamer ATGCAAAT and the heptamer CTCATGA . Both of these elements are required for normal cell - specific promoter function . The present study demonstrates that both the ubiquitous and lymphoid - cell - specific octamer transcription factors ( OTF - 1 and OTF - 2 , respectively ) interact specifically with each of the two conserved sequence elements , forming either homo - or heterodimeric complexes . This was surprising , since the heptamer and octamer sequence motifs bear no obvious similarity to each other . Binding of either factor to the octamer element occurred independently . However , OTF interaction with the heptamer sequence appeared to require the presence of an intact octamer motif and occurred with a spacing of either 2 or 14 base pairs between the two elements , suggesting coordinate binding resulting from protein - protein interactions . The degeneracy in sequences recognized by the OTFs may be important in widening the range over which gene expression can be modulated and in establishing cell type specificity . Identification of a novel lymphoid specific octamer binding protein ( OTF - 2B ) by proteolytic clipping bandshift assay ( PCBA ) . The octamer sequence ATGCAAAT is found in the promoters of immunoglobulin ( Ig ) heavy and light chain genes and in the heavy chain enhancer and is a major determinant of the cell type specific expression of Ig genes in B cells . An apparent paradox is that the same sequence serves as an upstream promoter or enhancer element in a variety of housekeeping genes such as the histone H2B and U snRNA genes . The differential usage of this regulatory sequence motif is thought to be mediated by different species of octamer binding proteins . One species of 100 kd , designated OTF - 1 , is present in all cell types and may exert its activating function only when it can interact with additional adjacent transcription factors . The lymphoid cell specific octamer binding protein of 60 kd ( OTF - 2A ) specifically stimulates Ig promoters which consist essentially of a TATA - box and an octamer sequence upstream of it . Here we present evidence for yet another B cell specific octamer binding protein of 75 kd ( OTF - 2B ) . From several findings , including the absence of OTF - 2B ( but not OTF - 2A ) from a lymphocyte line that can not respond to the IgH enhancer , we propose a role of the novel octamer factor in the long range activation by the IgH enhancer . We have used the proteolytic clipping bandshift assay ( PCBA ) technique to distinguish the three different forms found in B cells . This analysis indicates that the 75 kd - species OTF - 2B is closely related to the 60 kd species OTF - 2A . Inhibition of interleukin 2 - induced proliferation of cloned murine T cells by glucocorticoids . Possible involvement of an inhibitory protein . The ability of glucocorticoids to inhibit interleukin 2 ( IL 2 ) - induced T cell proliferation in two cytotoxic T cell ( CTL ) clones has been studied . A complete inhibition of DNA synthesis by dexamethasone ( Dx ) could be observed when IL 2 - depleted cultures of CTL were either incubated for 6 h with the hormone prior to the addition of IL 2 or treated simultaneously with Dx and a low concentration of IL 2 . No significant reduction in the number and affinity of IL 2 receptors was seen after 6 h incubation with Dx . The order of potency observed with the different steroids indicated that this inhibitory effect was mediated through binding to a specific glucocorticoid receptor . The action of these hormones possibly involves the synthesis of an inhibitory protein ( s ) , since the presence of cycloheximide during the incubation with Dx prevented the inhibition of DNA synthesis . Furthermore , supernatant from Dx - treated CTL contained a nondialyzable factor which inhibited DNA synthesis and cell growth of CTL clones induced by IL 2 . Blocking of IL 2 synthesis and IL 2 receptor formation have been proposed as one of the major mechanisms of glucocorticoid - induced immunosuppression . Our results indicate that these hormones may also affect T cell proliferation by inhibiting IL 2 activity . Identification and purification of a human immunoglobulin - enhancer - binding protein ( NF - kappa B ) that activates transcription from a human immunodeficiency virus type 1 promoter in vitro . The enhancer - binding factor NF - kappa B , which is found only in cells that transcribe immunoglobulin light chain genes , has been purified from nuclear extracts of Namalwa cells ( human Burkitt lymphoma cells ) by sequence - specific DNA affinity chromatography . The purified NF - kappa B has been identified as a 51 - kDa polypeptide by UV - crosslinking analysis . ` ` Footprint ' ' and methylation - interference analyses have shown that purified NF - kappa B has a binding activity specific for the kappa light chain enhancer sequence . The purified factor activated in vitro transcription of the human immunodeficiency virus type I promoter by binding to an upstream NF - kappa B - binding site Lymphocyte glucocorticoid receptor binding in depression : normal values following recovery . The number of glucocorticoid receptor sites in lymphocytes and plasma cortisol concentrations were measured in 20 patients who had recovered from major depressive disorder and 20 healthy control subjects . The number of glucocorticoid receptor sites in lymphocytes from the recovered depressed group was not significantly different from that of the control group . Although the mean plasma cortisol concentration in recovered depressives was higher than in control subjects , the difference only just reached significance . This study shows that the reduction in glucocorticoid receptor numbers which occurs during acute depressive illness does not persist on recovery and is , therefore , state - dependent . Identification and purification of a human lymphoid - specific octamer - binding protein ( OTF - 2 ) that activates transcription of an immunoglobulin promoter in vitro . The octamer sequence 5 ' - ATGCAAAT , in either orientation , serves as an upstream element in a variety of promoters and also occurs as a modular enhancer element . It is of particular interest in immunoglobulin genes since it is found in the upstream regions of all heavy and light chain promoters and in the heavy chain enhancer , both of which are known to be necessary for cell - specific expression . We report here the chromatographic separation of ubiquitous and B cell - specific octamer - binding proteins . The B cell factor was purified to homogeneity using affinity chromatography and consists of three peptides of 62 , 61 , and 58 . 5 + / - 1 . 5 kd . Each of the polypeptides was renatured after SDS - PAGE and shown to bind to the octamer sequence . The specific DNA binding activity of the pure B cell - specific factor was indistinguishable from that of the affinity - purified ubiquitous factor . This B cell - specific octamer - binding factor , in pure form , activated transcription from a kappa light chain promoter in vitro , thus demonstrating that it is indeed a B cell - specific transcription factor for this gene . In addition to the ubiquitous and B cell - specific octamer - binding factors , we identified several additional proteins , one of which is B cell - specific , that interact with the kappa promoter . Decreased deoxyribonucleic acid binding of glucocorticoid - receptor complex in cultured skin fibroblasts from a patient with the glucocorticoid resistance syndrome . A patient with the syndrome of glucocorticoid resistance was studied . A 27 - yr - old woman initially was diagnosed as having Cushing ' s disease , based on the findings of high plasma ACTH and serum cortisol levels , increased urinary cortisol secretion , resistance to adrenal suppression with dexamethasone , and bilateral adrenal hyperplasia by computed tomography and scintigraphy of the adrenal glands . However , she had no signs or symptoms of Cushing ' s syndrome . During a 5 - yr follow - up , no clinical abnormalities developed , although hypercortisolism persisted . End - organ resistance to cortisol was suspected . To explain the end - organ resistance to cortisol , the glucocorticoid receptors ( GR ) in peripheral mononuclear leukocytes and cultured skin fibroblasts from a forearm skin biopsy were characterized and compared with the results of similar studies in normal subjects . The patient ' s GR in whole cell assays had an increased dissociation constant ( Kd ) . In the cytosol of cultured skin fibroblasts from the patient , there was also decreased binding capacity . The thermal stability and the sedimentation coefficient in a sucrose density gradient of the receptors in the cytosol of cultured skin fibroblasts from the patient and normal subjects were similar . GR complex activation , analyzed by DEAE - cellulose chromatography , was decreased in the patient . DNA binding of the GR complex after temperature - induced activation was lower in the patient than in normal subjects . Nuclear translocation of GR complexes from the patient was also slightly decreased . These results suggest that the patient ' s glucocorticoid resistance was due to a decrease in the affinity of the receptor for glucocorticoids and a decrease in the binding of the GR complex to DNA . Granulocyte - macrophage colony - stimulating factor . Sensitive and receptor - mediated regulation by 1 , 25 - dihydroxyvitamin D3 in normal human peripheral blood lymphocytes . We show that 1 , 25 - dihydroxyvitamin D3 ( 1 , 25 [ OH ] 2D3 ) , the most hormonally active metabolite of vitamin D3 , modulates sensitively and specifically both the protein and messenger RNA accumulation of the multilineage growth factor granulocyte - macrophage colony - stimulating factor ( GM - CSF ) . The regulation of GM - CSF expression is seen in both normal human mitogen - activated T lymphocytes and T lymphocytes from a line ( S - LB1 ) transformed with human T cell lymphotropic virus 1 ( HTLV - 1 ) . In contrast , cells from a HTLV - 1 transformed T lymphocyte line ( Ab - VDR ) established from a patient with vitamin D - resistant rickets type II with undetectable 1 , 25 ( OH ) 2D3 cellular receptors are resistant to the action of 1 , 25 ( OH ) 2D3 . Inhibition of GM - CSF expression by 1 , 25 ( OH ) 2D3 can occur independently of interleukin 2 regulation and is probably mediated through cellular 1 , 25 ( OH ) 2D3 receptors . We conclude that 1 , 25 ( OH ) 2D3 may be important in the physiology of hematopoiesis . Altered interaction between triiodothyronine and its nuclear receptors in absence of cortisol : a proposed mechanism for increased thyrotropin secretion in corticosteroid deficiency states . Thyroid hormones occasionally appear less effective when administered alone to patients with panhypopituitarism , and manifestations suggestive of hypothyroidism have been reported in patients suffering from untreated Addison ' s disease . In the latter condition , thyrotropin secretion is increased : this occurs already after as little as 2 days of temporary withdrawal of therapy with substitution doses of corticosteroids while circulating levels of thyroid hormones remain within normal limits . Therefore , a possible role of cortisol in interaction between triiodothyronine and its nuclear receptors was examined at the level of circulating lymphocytes obtained from patients with primary or secondary adrenocortical failure . The affinity of these receptors was found to be decreased , by more than 50 % on average , in the absence of cortisol treatments . This change was promptly corrected upon resumption of therapy . The number of binding sites was not significantly modified . The influence of cortisol on thyroid hormone receptors discussed here might account for the clinical observations mentioned above . Inhibition by cortisol of human natural killer ( NK ) cell activity . The effects of cortisol on the natural killer ( NK ) activity of human peripheral blood mononuclear ( PBM ) cells were studied in vitro using a direct 4 - h 51Cr - release assay and K 562 cell line as a target . Preincubation for 20 h of PBM cells drawn from healthy donors with 1 X 10 ( - 8 ) to 1 X 10 ( - 5 ) M cortisol resulted in a significant decrease of NK cell activity . The magnitude of the suppression was directly related to the steroid concentration and inversely related to the number of effector cells . Cortisol was able to minimize the enhancement of NK cytotoxicity obtainable in the presence of immune interferon ( IFN - gamma ) . A significantly higher suppression was achieved after sequential exposure of PBM cells to cortisol and equimolar levels of prostaglandin E2 ( PgE2 ) . The concomitant incubation with theophylline and isobutyl - methylxanthine failed to enhance the cortisol - induced suppression , whereas PgE2 - dependent inhibition significantly increased after exposure of PBM cells to methyl - xanthines . The inhibitory effect of cortisol was partially or totally prevented by the concomitant incubation with equimolar amounts of 11 - deoxycortisol and RU 486 but not of progesterone . Treatment of NK effectors with a monoclonal anti - human corticosteroid - binding globulin ( CBG ) antibody produced an enhancement of the spontaneous NK activity and a partial suppression of cortisol - mediated effects . Our results suggest that endogenous glucocorticoids play a role in the regulation of NK cell - mediated cytotoxicity . Since the effect of cortisol was additive to that of PgE2 and was not changed by phosphodiesterase inhibitors , it is conceivable that the hormone acts at a level different from the adenylate cyclase - phosphodiesterase system . Data obtained with the use of antiglucocorticoids and the anti - CBG antibody are compatible with a role both of high - affinity glucocorticoid receptors and of CBG in mediating cortisol action on the human NK cell activity . Interaction of cell - type - specific nuclear proteins with immunoglobulin VH promoter region sequences . All human and murine immunoglobulin heavy chain variable region ( VH ) genes contain the sequence ATGCAAAT approximately 70 nucleotides 5 ' from the site of transcription initiation . This octanucleotide , in reverse orientation , is also found in all light chain variable region ( VL ) genes , and in the immunoglobulin heavy chain transcriptional enhancer . Transfection studies have established that this octamer is involved in the lymphoid - specific transcription of immunoglobulin genes . Octamer - containing fragments have been reported to bind a factor present in nuclear extracts of human cell lines ; however , identical binding activity was detected in both B lymphoid and non - lymphoid cells . Here we establish that nuclear extracts from distinct cell types differ in their ability to interact with octamer - containing fragments . We have also detected a DNA - protein interaction that may be involved in the cell - type specificity of immunoglobulin expression , and we have determined that a sequence upstream of the octamer participates in an interaction with a nuclear protein ( s ) . Preferential transcription of HTLV - I LTR in cell - free extracts of human T cells producing HTLV - I viral proteins . The promoters of the adenovirus 2 major late gene , the mouse beta - globin gene , the mouse immunoglobulin VH gene and the LTR of the human T - lymphotropic retrovirus type I were tested for their transcription activities in cell - free extracts of four cell lines ; HeLa , CESS ( Epstein - Barr virus - transformed human B cell line ) , MT - 1 ( HTLV - I - infected human T cell line without viral protein synthesis ) , and MT - 2 ( HTLV - I - infected human T cell line producing viral proteins ) . LTR was preferentially transcribed in the extracts of MT - 2 although the other three genes were transcribed with relatively constant efficiencies in different extracts . The results agree well with the previous in vivo studies on the promoter activity of HTLV - I LTR . Mixing of HeLa and MT - 2 extracts revealed the presence of a LTR - specific stimulating activity in MT - 2 extracts . A nuclear factor that binds to a conserved sequence motif in transcriptional control elements of immunoglobulin genes . Trans - acting factors that mediate B - cell specific transcription of immunoglobulin genes have been postulated based on an analysis of the expression of exogenously introduced immunoglobulin gene recombinants in lymphoid and non - lymphoid cells . Two B - cell - specific , cis - acting transcriptional regulatory elements have been identified . One element is located in the intron between the variable ( V ) and constant ( C ) regions of both heavy and kappa light - chain genes and acts as a transcriptional enhancer . The second element is found upstream of both heavy and kappa light - chain gene promoters . This element directs lymphoid - specific transcription even in the presence of viral enhancers . We have sought nuclear factors that might bind specifically to these two regulatory elements by application of a modified gel electrophoresis DNA binding assay . We report here the identification of a human B - cell nuclear factor ( IgNF - A ) that binds to DNA sequences in the upstream regions of both the mouse heavy and kappa light - chain gene promoters and also to the mouse heavy - chain gene enhancer . This sequence - specific binding is probably mediated by a highly conserved sequence motif , ATTTGCAT , present in all three transcriptional elements . Interestingly , a factor showing similar binding specificity to IgNF - A is also present in human HeLa cells . The new world primates as animal models of glucocorticoid resistance . Many New World primate species have greatly increased plasma cortisol concentrations , decreased plasma cortisol binding globulin capacity and affinity , marked resistance of the hypothalamic - pituitary - adrenal axis to suppression by dexamethasone , and no biological evidence of glucocorticoid excess . These primates also have high levels of circulating progesterone , estrogen , mineralocorticoid , androgen and vitamin D . The glucocorticoid target tissues that have been examined ( circulating mononuclear lymphocytes and cultured skin fibroblasts ) have normal concentrations of glucocorticoid receptors with decreased affinity for dexamethasone . Transformation of B - lymphocytes with the Epstein - Barr virus leads to glucocorticoid receptor induction that is less than that observed with cells from Old World primates . The receptor in these cells has a low affinity for dexamethasone . The low affinity leads to an increased loss of specific bound ligand during thermal activation . Meroreceptor generation is normal . The molecular weight of the receptor , determined by SDS - PAGE , is similar to that of Old World primates ( approximately 92 , 000 ) and the activation pattern per se , examined in vitro by heating cytosol and performing phosphocellulose chromatography , appears similar to that of human controls . The ratios of nuclear to cytosolic hormone - receptor - complexes and of cytosolic activated to unactivated receptor complexes in intact cells are similar to Old World primates . Results from mixing studies do not support the hypothesis that a binding inhibitor ( s ) or a deficient cytosolic positive modifier ( s ) of binding underlies the findings in these primates . The New World primates , unlike men with the syndrome of primary cortisol resistance , have compensated for their condition with intra - adrenal and mineralocorticoid receptor adaptations . Thus , unlike Old World primates , cortisol in New World primates has only weak sodium - retaining potency because the aldosterone receptor has a low affinity for cortisol . The common element that would explain the apparent resistance to six steroid hormones in New World primates Acetylation and modulation of erythroid Kruppel - like factor ( EKLF ) activity by interaction with histone acetyltransferases . Erythroid Kruppel - like factor ( EKLF ) is a red cell - specific transcriptional activator that is crucial for consolidating the switch to high levels of adult beta - globin expression during erythroid ontogeny . EKLF is required for integrity of the chromatin structure at the beta - like globin locus , and it interacts with a positive - acting factor in vivo . We find that EKLF is an acetylated transcription factor , and that it interacts in vivo with CBP , p300 , and P / CAF . However , its interactions with these histone acetyltransferases are not equivalent , as CBP and p300 , but not P / CAF , utilize EKLF as a substrate for in vitro acetylation within its trans - activation region . The functional effects of these interactions are that CBP and p300 , but not P / CAF , enhance EKLF ' s transcriptional activation of the beta - globin promoter in erythroid cells . These results establish EKLF as a tissue - specific transcription factor that undergoes post - translational acetylation and suggest a mechanism by which EKLF is able to alter chromatin structure and induce beta - globin expression within the beta - like globin cluster . Recognition of herpes simplex virus type 2 tegument proteins by CD4 T cells infiltrating human genital herpes lesions . The local cellular immune response to herpes simplex virus ( HSV ) is important in the control of recurrent HSV infection . The antiviral functions of infiltrating CD4 - bearing T cells may include cytotoxicity , inhibition of viral growth , lymphokine secretion , and support of humoral and CD8 responses . The antigens recognized by many HSV - specific CD4 T cells localizing to genital HSV - 2 lesions are unknown . T cells recognizing antigens encoded within map units 0 . 67 to 0 . 73 of HSV DNA are frequently recovered from herpetic lesions . Expression cloning with this region of DNA now shows that tegument protein VP22 and the viral dUTPase , encoded by genes UL49 and UL50 , respectively , are T - cell antigens . Separate epitopes in VP22 were defined for T - cell clones from each of three patients . Reactivity with the tegument protein encoded by UL21 was identified for an additional patient . Three new epitopes were identified in VP16 , a tegument protein associated with VP22 . Some tegument - specific CD4 T - cell clones exhibited cytotoxic activity against HSV - infected cells . These results suggest that herpes simplex tegument proteins are processed for antigen presentation in vivo and are possible candidate compounds for herpes simplex vaccines . Fibrinogen activates NF - kappa B transcription factors in mononuclear phagocytes . Adhesion to extracellular matrices is known to modulate leukocyte activation , although the mechanisms are not fully understood . Mononuclear phagocytes are exposed to fibrinous provisional matrix throughout migration into inflammatory foci , so this study was undertaken to determine whether fibrinogen triggers activation of NF - kappa B transcription factors . U937 cells differentiated with PMA in nonadherent culture were shown to express two fibrinogen - binding integrins , predominately CD11b / CD18 , and to a lesser extent , CD11c / CD18 . Cells stimulated with fibrinogen ( 10 - 100 microg / ml ) / Mn2 + ( 50 microM ) for 2 h were examined by electrophoretic mobility shift assay . NF - kappa B activation , minimal in unstimulated cells , was substantially up - regulated by fibrinogen . Fibrinogen also caused activation of AP - 1 , but not SP1 or cAMP response element - binding protein ( CREB ) factors . Blocking mAbs against CD18 and CD11b abrogated fibrinogen - induced NF - kappa B activation . To determine the effects on transcriptional regulation , U937 cells were transfected with a plasmid containing the HIV - 1 enhancer ( bearing two NF - kappa B sites ) coupled to a chloramphenicol acetyltransferase ( CAT ) reporter . Cells were subsequently stimulated with 1 ) PMA for 24 h , inducing CAT activity by 2 . 6 - fold , 2 ) fibrinogen / Mn2 + for 2 h , inducing CAT activity by 3 . 2 - fold , or 3 ) costimulation with fibrinogen and PMA , inducing 5 . 7 - fold the CAT activity induced by PMA alone . We conclude that contact with fibrinogen - derived proteins may contribute to mononuclear phagocyte activation by signaling through CD11b / CD18 , resulting in selective activation of transcriptional regulatory factors , including NF - kappa B . Peripheral blood T cells and monocytes and B cell lines derived from patients with lupus express estrogen receptor transcripts similar to those of normal cells . OBJECTIVE : To identify and characterize estrogen receptor ( ER ) transcripts expressed in immune cells of patients with systemic lupus erythematosus ( SLE ) and healthy donors . METHODS : Peripheral blood monocytes and T cells were prepared from patients with SLE ( n = 6 ) and healthy donors ( n = 8 ) . T cells were separated into CD4 and CD8 . Some monocytes and T cells were stimulated with estradiol , PMA , and ionomycin . Epstein - Barr virus - transformed B cell lines ( n = 7 ) and B cell hybridomas ( n = 2 ) established from patients with SLE and a healthy individual were used as a B cell source . These cells were examined for ER mRNA by reverse transcription nested polymerase chain reaction . Amplified cDNA were sequenced by standard methods . RESULTS : In all cells tested , ER mRNA was expressed without prior in vitro stimulation . Partial sequences from exons 1 - 8 were nearly identical to the published sequence of the human ER mRNA . There were no notable differences in the ER transcripts between patients and healthy controls . Variant receptor transcripts lacking exon 5 or exon 7 , which encodes the hormone binding domain , were identified in the majority of the cells . Precise deletion of the exons suggests that they are alternatively spliced transcripts . Whether the detected transcripts are translated into functional receptor proteins remains to be determined . In vitro stimulation did not affect ER mRNA expression . The presence of variants did not correlate with disease activity or medication . CONCLUSION : Monocytes , T cells , and B cells in patients express transcripts of the normal wild type ER and the hormone binding domain variants in vivo . DNA damaging agents induce expression of Fas ligand and subsequent apoptosis in T lymphocytes via the activation of NF - kappa B and AP - 1 . Apoptosis induced by DNA damage and other stresses can proceed via expression of Fas ligand ( FasL ) and ligation of its receptor , Fas ( CD95 ) . We report that activation of the two transcription factors NF - kappa B and AP - 1 is crucially involved in FasL expression induced by etoposide , teniposide , and UV irradiation . A nondegradable mutant of I kappa B blocked both FasL expression and apoptosis induced by DNA damage but not Fas ligation . These stimuli also induced the stress - activated kinase pathway ( SAPK / JNK ) , which was required for the maximal induction of apoptosis . A 1 . 2 kb FasL promoter responded to DNA damage , as well as coexpression with p65 Rel or Fos / Jun . Mutations in the relevant NF - kappa B and AP - 1 binding sites eliminated these responses . Thus , activation of NF - kappa B and AP - 1 contributes to stress - induced apoptosis via the expression of FasL . A small , nonpeptidyl mimic of granulocyte - colony - stimulating factor [ see commetns ] A nonpeptidyl small molecule SB 247464 , capable of activating granulocyte - colony - stimulating factor ( G - CSF ) signal transduction pathways , was identified in a high - throughput assay in cultured cells . Like G - CSF , SB 247464 induced tyrosine phosphorylation of multiple signaling proteins and stimulated primary murine bone marrow cells to form granulocytic colonies in vitro . It also elevated peripheral blood neutrophil counts in mice . The extracellular domain of the murine G - CSF receptor was required for the activity of SB 247464 , suggesting that the compound acts by oligomerizing receptor chains . The results indicate that a small molecule can activate a receptor that normally binds a relatively large protein ligand . Minimal residual disease in acute myelogenous leukemia with PML / RAR alpha or AML1 / ETO mRNA and phenotypic analysis of possible T and natural killer cells in bone marrow . Here we studied minimal residual disease ( MRD ) of patients with acute myeloid leukemia ( AML ) who have PML / RAR alpha or AML1 / ETO as well as the phenotypic analysis of lymphocyte subsets involved in antitumor immunity . Eight patients in long - term ( LT ; 3 to 15 years ) and 15 patients in short - term ( ST ; up to 3 years ) remission were studied . Using the reverse transcription - polymerase chain reaction ( RT ) assay , the limit of detection was 10 ( - 5 ) to 10 ( - 6 ) for PML / RAR alpha transcript and 10 ( - 4 ) to 10 ( - 5 ) for the AML1 / ETO transcript . Simultaneously , T lymphocyte subsets and NK cells from the peripheral blood ( PB ) and bone marrow ( BM ) were investigated by flow cytometric analysis . Four of the eight patients in LT and 7 of the 15 patients in ST remission were MRD - positive . Although all MRD - positive patients in LT remission are still until now event - free , 3 of the 7 MRD - positive ( MRD + ) patients in ST remission soon relapsed . The total populations of CD4 + , CD8 + and CD56 + [ possible T - cell and natural killer ( T / NK ) populations ] in the BM of ST patients and MRD + / LT patients were significantly ( p < . 01 ) low . The CD8 + CD28 + population showed the same tendency ( p < . 01 - . 02 ) . The T / NK subsets in the BM of MRD - negative ( MRD - ) LT ( MRD - / LT ) patients showed similar numbers of cells as normal volunteers . Basically , the total percentage of the CD4 + , CD8 + and CD56 + cell populations in the BM was increased and in the following order : MRD - / LT patients , normal volunteers , MRD + / LT patients and MRD + or - / ST patients . The percentages of the T / NK - cell subsets in the PB were not significantly different among these groups . Thus , the difference of the possible T / NK - cell phenotype in the BM may strongly influence clinical and molecular remission . These results still remain to be confirmed by further studies of the functional anti - tumor immunity of T / NK cells of AML in remission . Mycobacterium tuberculosis mannose - capped lipoarabinomannan can induce NF - kappaB - dependent activation of human immunodeficiency virus type 1 long terminal repeat in T cells . Tuberculosis has emerged as an epidemic , extended by the large number of individuals infected with human immunodeficiency virus type 1 ( HIV - 1 ) . The major goal of this study was to determine whether the mycobacterial cell wall component mannose - capped lipoarabinomannan ( ManLAM ) of Mycobacterium tuberculosis ( M . tuberculosis ) could activate transcription of HIV - 1 in T cells with the use of an in vitro cell culture system . These experiments are of prime importance considering that CD4 - expressing T lymphocytes represent the major virus reservoir in the peripheral blood of infected individuals . Using the 1G5 cell line harbouring the luciferase reporter gene under the control of the HIV - 1 LTR , it was first found that culture protein filtrates ( CFP ) from M . tuberculosis or purified ManLAM could activate HIV - 1 LTR - dependent gene expression unlike similarly prepared CFP extracts devoid of ManLAM . The implication of protein tyrosine kinase ( s ) , protein kinase A and / or protein kinase C was highlighted by the abrogation of the ManLAM - mediated activation of HIV - 1 LTR - driven gene expression using herbimycin A and H7 . It was also determined , using electrophoresis mobility shift assays , that M . tuberculosis ManLAM led to the nuclear translocation of the transcription factor NF - kappaB . M . tuberculosis ManLAM resulted in clear induction of the luciferase gene placed under the control of the wild - type , but not the kappaB - mutated , HIV - 1 LTR region . Finally , the ManLAM - mediated activation of HIV - 1 LTR transcription was found to be independent of the autocrine or paracrine action of endogenous TNF - alpha . The results suggest that M . tuberculosis can upregulate HIV - 1 expression in T cells and could thus have the potential to influence the pathogenesis of HIV - 1 infection . Human immunodeficiency virus type 1 long terminal repeat quasispecies differ in basal transcription and nuclear factor recruitment in human glial cells and lymphocytes . The generation of genomic diversity during the course of infection has the potential to affect all aspects of HIV - 1 replication , including expression of the proviral genome . To gain a better understanding of the impact of long terminal repeat ( LTR ) sequence diversity on LTR - directed gene expression in cells of the central nervous system ( CNS ) and immune system , we amplified and cloned LTRs from proviral DNA in HIV - 1 - infected peripheral blood . Sequence analysis of nineteen LTRs cloned from 2 adult and 3 pediatric patients revealed an average of 33 nucleotide changes ( with respect to the sequence of the LAI LTR ) within the 455 - bp U3 region . Transient expression analyses in cells of neuroglial and lymphocytic origin demonstrated that some of these LTRs had activities which varied significantly from the LAI LTR in U - 373 MG cells ( an astrocytoma cell line ) as well as in Jurkat cells ( a CD4 - positive lymphocyte cell line ) . While LTRs which demonstrated the highest activities in U - 373 MG cells also yielded high activities in Jurkat cells , the LTRs were generally more active in Jurkat cells when compared to the LAI LTR . Differences in LTR sequence also resulted in differences in transcription factor recruitment to cis - acting sites within the U3 region of the LTR , as demonstrated by electrophoretic mobility shift assays . In particular , naturally occurring sequence variation impacted transcription factor binding to an activating transcription factor / cAMP response element binding ( ATF / CREB ) binding site ( located between the LEF - 1 and distal NF - kappaB transcription factor binding sites ) that we identified in previous studies of the HIV - 1 LTR . These findings suggest that LTR sequence changes can significantly affect basal LTR function and transcription factor recruitment , which may , in turn , alter the course of viral replication in cells of CNS and immune system origin . HMG box containing transcription factors in lymphocyte differentiation . The identification of the mammalian sex - determining gene Sry has led to the discovery of a large family of related ( ' HMG box ' ) transcription factors that control developmental events in yeast , C . elegans , Drosophila and vertebrates . In lymphocyte differentiation , several HMG box proteins play a decisive role . Sox - 4 is important for very early B - cell differentiation , while TCF - 1 / LEF - 1 play a crucial role in early thymocyte development . TCF / LEF proteins have recently been found to constitute a downstream component of the Wingless / Wnt signal transduction pathway . In flies , this pathway controls segment polarity ; in Xenopus it controls the definition of the body axis . Deregulation of the pathway occurs in several human tumors . These insights in the molecular events that are involved in TCF / LEF function in these organisms may eventually lead to the understanding of the function of these HMG box proteins in lymphoid development Transcriptional regulation by C / EBP alpha and - beta in the expression of the gene for the MRP14 myeloid calcium binding protein . Transcriptional regulation of the gene for the myeloid calcium binding protein , MRP14 , was investigated in human monocytic leukemia cell lines . The MRP14 gene was not expressed in monoblastic ML - 1 cells , promonocytic U - 937 cells , or promyelocytic HL - 60 cells . On the other hand , the gene was expressed in monocytic THP - 1 cells and in the HL - 60 cells treated with 1 , 25 - dihydroxyvitamin D3 ( VD3 ) . The level of MRP14 in VD3 - treated HL - 60 cells was two - fold higher than that in THP - 1 cells . Among several known transcription factor binding motifs , nuclear protein ( s ) of VD3 - treated HL - 60 cells and THP - 1 cells bound to the CCAAT / enhancer binding protein ( C / EBP ) - binding motif that was located in the upstream region of the MRP14 gene ( - 81 ) , as evidenced by the competitive gel mobility - shift assay . An antibody for C / EBP alpha super - shifted the nucleoprotein complex in THP - 1 cells but not in the VD3 - treated HL - 60 cells , whereas an antibody for C / EBP beta blocked the formation of the complex with the nuclear factor of the HL - 60 cells but not with that of THP - 1 cells . An anti - C / EBP delta antibody had no effect on the complex in either cell . Thus , it was concluded that C / EBP alpha and - beta were able to bind to the C / EBP motif , and that C / EBP alpha bound to the motif in THP - 1 cells and C / EBP beta bound to that in the VD3 - treated HL - 60 cells . Furthermore , to examine the transcriptional activity of the C / EBP motif , we transfected several constructed luciferase reporter DNAs into HL - 60 cells and THP - 1 cells . The luciferase activity of the C / EBP motif in HL - 60 cells was increased by VD3 treatment . The C / EBP motif in the MRP14 gene was confirmed to function as a regulatory region in VD3 - treated HL - 60 cells and THP - 1 cells by the assay . Since C / EBP beta was also detected in VD3 - untreated HL - 60 cells by immunoblotting , VD3 activated C / EBP beta to bind to the motif , probably through post - translational modification . Patients with high - risk myelodysplastic syndrome can have polyclonal or clonal haemopoiesis in complete haematological remission . The clonality of mature peripheral blood - derived myeloid and lymphoid cells and bone marrow haemopoietic progenitors from 18 females with myelodysplasia ( MDS ) ( five refractory anaemia , RA ; one RA with ringed sideroblasts , RARS ; three chronic myelomonocytic leukaemia , CMML ; four RA with excess of blasts , RAEB ; five RAEB in transformation , RAEB - t ) was studied by X - chromosome inactivation analysis . Using the human androgen - receptor ( HUMARA ) assay , we analysed the clonal patterns of highly purified immature CD34 + 38 - and committed CD34 + 38 + marrow - derived progenitors , and CD16 + 14 - granulocytes , CD14 + monocytes , CD3 + T and CD19 + B lymphocytes from peripheral blood . In high - risk patients ( RAEB , RAEB - t ) , clonality analysis was performed before and after intensive remission - induction treatment . All patients , except one with RA , had predominance of a single clone in their granulocytes and monocytes . The same clonal pattern was found in CD34 + progenitor cells . In contrast , CD3 + T lymphocytes were polyclonal or oligoclonal in 14 / 18 patients . X - chromosome inactivation patterns of CD19 + B cells were highly concordant with CD3 + T cells except for two patients ( one RA , one CMML ) with monoclonal B and polyclonal T lymphocytes , therefore suggesting a clonal mutation in a progenitor common to the myeloid and B - lymphoid lineages or the coexistence of MDS and a B - cell disorder in these particular patients . After high - dose non - myeloablative chemotherapy , polyclonal haemopoiesis was reinstalled in the mature myeloid cells and immature and committed marrow progenitors in three of four patients achieving complete haematological remission . Therefore we conclude that most haematological remissions in MDS are associated with restoration of polyclonal haemopoiesis . Prominent sex steroid metabolism in human lymphocytes . Steroid metabolism was investigated in cultured human B - lymphoblastoid cells ( B - LCL ) , and peripheral blood T and B cells . Gene expression was examined by reverse - transcription polymerase chain reaction amplification ( RT - PCR ) . Appropriate sized transcripts were detected in both cultured and fresh peripheral lymphocytes for CYP11A , CYP17 , HSD11L ( 11beta - hydroxysteroid dehydrogenase I ) , HSD17B1 ( 17beta - hydroxysteroid dehydrogenase type I ) and SRD5A1 ( 5alpha - reductase I ) . B - LCL , but not T and B cells , expressed CYP11B . There was minimal expression of HSD3B1 and HSD3B2 ( 3beta - hydroxysteroid dehydrogenase I and II ) in B - LCL and T cells . Transcripts for CYP19 and HSD11K were not detected . Corresponding enzymatic activity was detectable only for 17 - hydroxysteroid dehydrogenase and 5alpha - reductase , respectively producing testosterone and 5alpha - dihydrotestosterone . Steroid identities were confirmed by gas chromatography / mass spectrometry ( GC / MS ) . One metabolite thought to be deoxycorticosterone was identified by GC / MS as 6alpha - hydroxypregnanolone . It was concluded that sex hormone metabolism , including androgen synthesis , occurs in lymphocytes , and may modulate immune response . Human white blood cells and hair follicles are good sources of mRNA for the pterin carbinolamine dehydratase / dimerization cofactor of HNF1 for mutation detection . Pterin carbinolamine dehydratase / dimerization cofactor of HNF1 ( PCD / DCoH ) is a protein that has a dual function . It is a pterin 4alpha - carbinolamine dehydratase that is involved in the regeneration of the cofactor tetrahydrobiopterin during the phenylalanine hydroxylase - catalyzed hydroxylation of phenylalanine . In addition , it is the dimerization cofactor of HNF1 that is able to activate the transcriptional activity of HNF1 . Deficiencies in the gene for this dual functional protein result in hyperphenylalaninemi . Here we report for the first time that the PCD / DCoH mRNA is present in human white blood cells and hair follicles . Taking advantage of this finding , a sensitive , rapid and convenient method for screening mutations occurring in the coding region of this gene has been described . Copyright 1998 Academic Press . Biochemical characterization of the NF - Y transcription factor complex during B lymphocyte development . The transcription factor , NF - Y , plays a critical role in tissue - specific major histocompatibility complex class II gene transcription . In this report the biochemical properties of the heterotrimeric NF - Y complex have been characterized during stage - specific B - cell development , and in several class II - mutant B - cell lines , which represent distinct bare lymphocyte syndrome class II genetic complementation groups . The NF - Y complex derived from class II + mature B - cells bound with high affinity to anion exchangers , and eluted as an intact trimeric complex , whereas , NF - Y derived from class II - plasma B - cells , and from bare lymphocyte syndrome group II cell lines , RJ2 . 2 . 5 and RM3 , dissociated into discrete NF - YA and NF - YB : C subunit fractions . Recombination of the MPC11 plasma B - cell derived NF - Y A : B : C complex with the low molecular mass protein fraction , NF - Y - associated factors ( YAFs ) , derived from mature A20 B - cell nuclei , conferred high affinity anion exchange binding to NF - Y as an intact trimeric complex . Recombination of the native NF - YA : B : C complex with the transcriptional cofactor , PC4 , likewise conferred high affinity NF - Y binding to anion exchangers , and stabilized NF - Y interaction with CCAAT - box DNA motifs in vitro . Interaction between PC4 and NF - Y was mapped to the C - terminal region of PC4 , and the subunit interaction subdomain of the highly conserved DNA binding - subunit interaction domain ( DBD ) of NF - YA . These results suggest that in class II + mature B - cells NF - Y is associated with the protein cofactor , PC4 , which may play an important role in NF - Y - mediated transcriptional control of class II genes . Arrest of B lymphocyte terminal differentiation by CD40 signaling : mechanism for lack of antibody - secreting cells in germinal centers . Despite extensive research , the role of CD40 signaling in B cell terminal differentiation remains controversial . Here we show that CD40 engagement arrests B cell differentiation prior to plasma cell formation . This arrest is manifested at a molecular level as a reduction in mRNA levels of secretory immunoglobulin gene products such as mu ( s ) and J chain as well as the loss of the transcriptional regulator BLIMP - 1 . Furthermore , the inhibition of B cell differentiation by CD40 engagement could not be overcome by either mitogens or cytokines , but could be reversed by antibodies that interfere with the CD40 / gp39 interaction . These data suggest that secretory immunoglobulin is not produced by B cells that are actively engaged by gp39 - expressing T cells . A positively charged alpha - lipoic acid analogue with increased cellular uptake and more potent immunomodulatory activity . alpha - Lipoic acid ( LA ) is taken up by cells and reduced to its potent dithiol form , dihydrolipoate ( DHLA ) , much of which is rapidly effluxed out from cells . To improve retention in cells , the LA molecule was modified to confer a positive charge at physiological pH . N , N - dimethyl , N ' - 2 - amidoethyl - lipoate was synthesized . The protonated form of the new molecule is referred to as LA - Plus . The uptake of LA - Plus by human Wurzburg T cells was higher compared to that of LA . Several - fold higher amounts of DHLA - Plus , the corresponding reduced form of LA - Plus , were detected in LA - Plus treated cells compared to the amount of DHLA found in cells treated with LA . At 100 microM , LA did not but LA - Plus inhibited H2O2 induced NF - kappaB activation and NF - kappaB directed IL - 2 receptor expression . Both LA and LA - Plus synergised with selenium in inhibiting H2O2 induced NF - kappaB activation . At 150 microM LA - Plus , but not LA , inhibited TNFalpha induced NF - kappaB activation . At 5 microM LA - Plus , but not LA , protected against both spontaneous and etoposide induced apoptosis in rat thymocytes . LA - Plus is thus an improved form of LA with increased therapeutic potential . Copyright 1998 Academic Press . Carrier identification in X - linked immunodeficiency diseases . OBJECTIVE : Carrier identification in X - linked immunodeficiency disorders can be based on the demonstration of non - random X inactivation ( NRXI ) in affected blood cell lineages when growth is impaired in cells expressing the abnormal gene . We examined the utility of seeking evidence of NRXI to test the carrier status of women in families affected by X - linked severe combined immunodeficiency ( XSCID ) and X - linked hypogammaglobulinaem ( XLH ) , to identify as carriers the mothers of boys with SCID or hypogammaglobulinaem whose phenotype suggested X - linkage and to infer X - linkage in boys with SCID or hypogammaglobulinaem whose disease was not clearly X - linked on the basis either of family history or clinical and immunological characteristics . METHODOLOGY : A polymerase chain reaction - based method was used to amplify a polymorphic CAG repeat in the first exon of the androgen receptor gene after selective digestion of the active X chromosome with a methylation - sensitive enzyme , HpaII to distinguish between the paternal and maternal alleles and to identify their methylation status . RESULTS : Heterozygosity was found in 24 of 31 female subjects ( 77 % ) . As anticipated , NRXI could be demonstrated in all lymphoid cells studied from obligate carriers of XSCID and an obligate carrier of XLH but not on a carrier of X - linked immunodeficiency with hyper - IgM . The finding of NRXI in the mother of a boy with a SCID variant showed her to be a carrier of XSCID and establishes that her son has XSCID , not otherwise evident from available data . CONCLUSIONS : This PCR assay provides a rapid method for carrier detection of X - linked immunodeficiencies , and has allowed us to expand the phenotype of XSCID Leukocyte - endothelial interaction is augmented by high glucose concentrations and hyperglycemia in a NF - kB - dependent fashion . We addressed the role of hyperglycemia in leukocyte - endothelium interaction under flow conditions by exposing human umbilical vein endothelial cells for 24 h to normal ( 5 mM ) , high concentration of glucose ( 30 mM ) , advanced glycosylation end product - albumin ( 100 microg / ml ) , or hyperglycemic ( 174 - 316 mg / dl ) sera from patients with diabetes and abnormal hemoglobin A1c ( 8 . 1 + / - 1 . 4 % ) . At the end of incubation endothelial cells were perfused with total leukocyte suspension in a parallel plate flow chamber under laminar flow ( 1 . 5 dyn / cm2 ) . Rolling and adherent cells were evaluated by digital image processing . Results showed that 30 mM glucose significantly ( P < 0 . 01 ) increased the number of adherent leukocytes to endothelial cells in respect to control ( 5 mM glucose ; 151 + / - 19 versus 33 + / - 8 cells / mm2 ) . A similar response was induced by endothelial stimulation with IL - 1beta , here used as positive control ( 195 + / - 20 cells / mm2 ) . The number of rolling cells on endothelial surface was not affected by high glucose level . Stable adhesion of leukocytes to glucose - treated as well as to IL - 1beta - stimulated endothelial cells was preceded by short interaction of leukocytes with the endothelial surface . The distance travelled by leukocytes before arrest on 30 mM glucose , or on IL - 1beta - treated endothelial cells , was significantly ( P < 0 . 01 ) higher than that observed for leukocytes adhering on control endothelium ( 30 mM glucose : 76 . 7 + / - 3 . 5 ; IL1beta : 69 . 7 + / - 4 versus 5 mM glucose : 21 . 5 + / - 5 microm ) . Functional blocking of E - selectin , intercellular cell adhesion molecule - 1 , and vascular cell adhesion molecule - 1 on endothelial cells with the corresponding mouse mAb significantly inhibited glucose - induced increase in leukocyte adhesion ( 67 + / - 16 , 83 + / - 12 , 62 + / - 8 versus 144 + / - 21 cells / mm2 ) . Confocal fluorescence microscopy studies showed that 30 mM glucose induced an increase in endothelial surface expression of E - selectin , intercellular cell adhesion molecule - 1 , and vascular cell adhesion molecule - 1 . Electrophoretic mobility shift assay of nuclear extracts of human umbilical vein endothelial cells ( HUVEC ) exposed for 1 h to 30 mM glucose revealed an intense NF - kB activation . Treatment of HUVEC exposed to high glucose with the NF - kB inhibitors pyrrolidinedithiocar ( 100 microM ) and tosyl - phe - chloromethylketone ( 25 microM ) significantly reduced ( P < 0 . 05 ) leukocyte adhesion in respect to HUVEC treated with glucose alone . A significant ( P < 0 . 01 ) inhibitory effect on glucose - induced leukocyte adhesion was observed after blocking protein kinase C activity with staurosporine ( 5 nM ) . When HUVEC were treated with specific antisense oligodesoxynucleotid against PKCalpha and PKCepsilon isoforms before the addition of 30 mM glucose , a significant ( P < 0 . 05 ) reduction in the adhesion was also seen . Advanced glycosylation end product - albumin significantly increased the number of adhering leukocytes in respect to native albumin used as control ( 110 + / - 16 versus 66 + / - 7 , P < 0 . 01 ) . Sera from diabetic patients significantly ( P < 0 . 01 ) enhanced leukocyte adhesion as compared with controls , despite normal levels of IL - 1beta and TNFalpha in these sera . These data indicate that high glucose concentration and hyperglycemia promote leukocyte adhesion to the endothelium through upregulation of cell surface expression of adhesive proteins , possibly depending on NF - kB activation . Ikaros in hemopoietic lineage determination and homeostasis . Studies on the molecular mechanisms that control hemopoietic differentiation have focused on signaling cascades and nuclear effectors that drive this complex developmental system in a regulated fashion . Here we review the role of Ikaros , the founding member of a unique family of zinc finger transcription factors in this developmental process . Studies on an Ikaros null mutation have revealed an essential role for this factor in lymphoid cell fate determination and at subsequent branch points of the T cell differentiation pathway . Differences in the phenotypes of a null and a dominant negative ( DN ) Ikaros mutation provide insight into a regulatory network through which Ikaros proteins exert their effects in development . In addition a comparative analysis of the hemopoietic stem cell and precursor compartment resulting from the two Ikaros mutations reveals a profound yet not absolute requirement for Ikaros Induction of early B cell factor ( EBF ) and multiple B lineage genes by the basic helix - loop - helix transcription factor E12 . The transcription factors encoded by the E2A and early B cell factor ( EBF ) genes are required for the proper development of B lymphocytes . However , the absence of B lineage cells in E2A - and EBF - deficient mice has made it difficult to determine the function or relationship between these proteins . We report the identification of a novel model system in which the role of E2A and EBF in the regulation of multiple B lineage traits can be studied . We found that the conversion of 70Z / 3 pre - B lymphocytes to cells with a macrophage - like phenotype is associated with the loss of E2A and EBF . Moreover , we show that ectopic expression of the E2A protein E12 in this macrophage line results in the induction of many B lineage genes , including EBF , IL7Ralpha , lambda5 , and Rag - 1 , and the ability to induce kappa light chain in response to mitogen . Activation of EBF may be one of the critical functions of E12 in regulating the B lineage phenotype since expression of EBF alone leads to the activation of a subset of E12 - inducible traits . Our data demonstrate that , in the context of this macrophage line , E12 induces expression of EBF and together these transcription factors coordinately regulate numerous B lineage - associated genes . Activation - induced down - regulation of retinoid receptor RXRalpha expression in human T lymphocytes . Role of cell cycle regulation . A 5 . 4 - kilobase mRNA , the expression of which is down - regulated after treatment of human peripheral blood mononuclear cells ( PBMCs ) with various T cell - activating agents , was isolated using an mRNA differential display method . Nucleotide sequence analysis identified the 5 ' end of this RNA as human retinoid receptor RXRalpha mRNA . Here , we report the nucleotide sequence of 3 . 6 kilobases of this RNA , which represents the 3 ' end of RXRalpha mRNA , the sequence of which has not been previously described . Activated PBMCs also expressed lower levels of RXRalpha protein , and a DNA binding assay showed that the activation - induced loss of RXRalpha mRNA and protein expression correlated with the loss of DNA binding activity of this protein . We present evidence that the transition from G0 / G1 to S phase of the cell cycle results in the down - regulation of RXRalpha expression and that cell cycle inhibitors , which block the cells in G1 phase , prevent this down - regulation . The decrease in the levels of RXRalpha mRNA was found to be regulated at the post - transcriptional level and involved new protein synthesis . These observations indicate that the levels of RXRalpha expression in T lymphocytes are coupled to cell cycle progression , and there is tight regulatory control of RXRalpha expression during the transition from G0 / G1 to S phase of the cell cycle . Epidemiology and pathogenesis of AIDS - related lymphomas . Among patients with congenital and acquired immunodeficiencies , non - Hodgkin ' s lymphoma ( NHLs ) are the most common tumors of the immune system . In the setting of human immunodeficiency virus ( HIV ) infection , as many as 10 % to 20 % of people ultimately developed NHLs . These tumors are clinically aggressive , frequently involve extranodal sites , and often exhibit unique features that distinguish them from NHL arising in individuals with other forms of immunosuppression . Important in the development of HIV - associated NHL are cytokines and other factors that induce B - cell proliferation and increase the likelihood of mutations of c - myc , bcl - 6 , and other tumor - suppressor genes with carcinogenic potential . Specific forms of HIV - associated NHL are linked to expression of Epstein - Barr virus ( EBV ) - latent proteins ; the newly described DNA virus , Karposi ' s sarcoma - associated herpesvirus / human herpesvirus - 8 ( KSHV / HHV - 8 ) ; and perhaps HIV . Elucidation of the factors that contribute to the high incidence of NHL among patients infected with HIV provides insights into important elements of lymphomagenesis . Matrix metalloproteinase expression in human breast cancer : an immunohistochemical study including correlation with cathepsin D , type IV collagen , laminin , fibronectin , EGFR , c - erbB - 2 oncoprotein , p53 , steroid receptors status and proliferative indices . Matrix metalloproteinase s ( MMPs ) are a group of enzymes thought to be responsible for both normal connective tissue matrix remodelling and accelerated breakdown associated with tumour development . The current study aimed to investigate the immunohistochemical expression of matrix metalloproteinase 3 ( MMP - 3 , stromelysin - 1 ) in correlation with the expression of Basement Membrane ( BM ) antigen ( type IV collagen , laminin ) , fibronectin , cathepsin D , p53 , c - erbB - 2 , proliferative activity ( Ki - 67 , PCNA ) , steroid receptor content as well as to the other conventional clinicopathological parameters in breast cancer . This study was performed on a series of frozen and paraffin sections from 84 breast cancer specimens by immunohistochemistry using the monoclonal antibody MMP - 3 ( Ab - 1 ) . Stromelysin - 1 ( ST1 ) was observed in about 10 % of epithelial cells in the control groups ( cases of fibrocystic and benign proliferative breast disease ) , while expression ( > 10 % of expression ) was detected in 89 . 7 % of tumours . The expression of ST1 in carcinoma cells was strongly associated with its presence in the stroma ( p < 0 . 001 ) . A significantly positive correlation was found between ST1 expression , and p53 tumour suppressor gene product ( p = 0 . 004 ) , and a relationship with c - erbB - 2 protein and progesterone receptor status was also indicated . These findings suggest that ST1 expression in breast cancer tissue is irrespective of the expression of the extracellular matrix component , the proteolytic enzyme cathepsin D and the growth fraction of the tumour , and that it could be a potential new prognostic marker in breast cancer . Use of transfected liver cells to evaluate potential mechanisms of alcohol - induced liver injury [ see comments ] There is increased activity of the proinflammatory cytokine , tumor necrosis factor ( TNF ) in alcoholic liver disease ( ALD ) . Hepatic neutrophil infiltration is a principal injurious manifestation of ALD . TNF can induce cellular oxidative injury directly , and indirectly by inducing neutrophil chemotactic factor ( IL - 8 ) production by hepatocytes . IL - 8 activates and chemotactically attracts neutrophils to the liver where they release oxidizing substances . Patients with ALD also have decreased protective factors for cellular oxidative injury . Manganous superoxide dismutase ( MnSOD ) is an antioxidant protective factor . The objectives of these studies were to investigate mechanisms for induction of an injurious factor ( IL - 8 ) and a protective factor ( MnSOD ) in the HepG2 human hepatoma cell line . In the first set of experiments , IL - 8 gene reporter constructs were used to transiently transfect a derivative ( MVh2E1 - 9 ) of the HepG2 cell line which expresses P - 4502E1 and metabolizes ethanol . Inactivation of the NF - kappaB and 3 ' NF - IL - 6 DNA binding sites decreased IL - 8 gene transcriptional activation in response to TNF while inactivation of the 5 ' NF - IL - 6 binding site increased IL - 8 gene transcriptional activity in response to TNF . This system may be useful to assess the effects of ethanol on TNF - induced hepatocyte IL - 8 production . In the second set of experiments , HepG2 cells were cultured in 25 to 100 mmol concentrations of ethanol . Both TNF and ethanol increased HepG2 cell MnSOD activity in short - term ( 72 hr ) cultures with ethanol . However , after long - term ( 10 weeks ) culture with ethanol , there was no induction of MnSOD by ethanol and there was a diminished induction of MnSOD in response to TNF . Further studies are needed to assess the effect of this diminished induction of MnSOD with chronic ethanol culture on HepG2 cell susceptibility to TNF cytotoxicity . We conclude that transfected liver cell lines can be used to evaluate mechanisms for increased injurious factors and decreased protective factors in alcoholic liver injury . Tissue factor transcription driven by Egr - 1 is a critical mechanism of murine pulmonary fibrin deposition in hypoxia . Local hypoxemia and stasis trigger thrombosis . We have demonstrated previously that in a murine model of normobaric hypoxia pulmonary fibrin deposition is a result of expression of tissue factor , especially in oxygen - deprived mononuclear phagocytes ( MPs ) . We now show that transcription factor early - growth - response gene product ( Egr - 1 ) is rapidly activated in hypoxia , both in vitro and in vivo , and is responsible for transcription and expression of tissue factor in hypoxic lung . MPs and HeLa cells subjected to hypoxia ( pO2 approximately 13 torr ) had increased levels of tissue factor transcripts ( approximately 18 - fold ) and an increased rate of transcription ( approximately 15 - fold ) , based on nuclear run - on analysis . Gel - shift analysis of nuclear extracts from hypoxic MPs and HeLa cells demonstrated increased DNA - binding activity at the serum response region ( SRR ; - 111 / + 14 bp ) of the tissue factor promoter at Egr - 1 motifs . Using 32P - labeled Egr consensus oligonucleotide , we observed induction of DNA - binding activity in nuclear extracts from hypoxic lung and HeLa cells because of activation of Egr - 1 , by means of supershift analysis . Transient transfection of HeLa cells with chimeric plasmids containing wild - type or mutant SRR from the tissue factor promoter showed that intact Sp1 sites are necessary for basal promoter activity , whereas the integrity of Egr - 1 sites was required for hypoxia - enhanced expression . A central role for Egr - 1 in hypoxia - mediated tissue factor expression was confirmed by experiments with homozygous Egr - 1 null mice ; wild - type mice subjected to oxygen deprivation expressed tissue factor and showed fibrin deposition , but hypoxic homozygous Egr - 1 null mice displayed neither tissue factor nor fibrin . These data delineate a novel biology for hypoxia - induced fibrin deposition , in which oxygen deprivation - induced activation of Egr - 1 , resulting in expression of tissue factor , has an unexpected and central role . Kinetics of cytokine and NFAT gene expression in human interleukin - 2 - dependent T lymphoblasts stimulated via T - cell receptor . T cells respond to mitogenic or antigenic stimulation by proliferation and by turning on cytokine gene expression . Here we have analysed the kinetics and nature of cytokine production in human peripheral blood - derived T lymphoblasts stimulated with anti - CD3 antibodies or Lens culinaris lectin ( LCL ) . T cells were purified from peripheral blood mononuclear cells ( PBMC ) and primarily activated with anti - CD3 antibodies and cultured in the presence of interleukin - 2 ( IL - 2 ) . Anti - CD3 - restimulated T cells ( mainly CD8 + ) produced IL - 2 , interferon - gamma ( IFN - gamma ) and tumour necrosis factor - alpha ( TNF - alpha ) and low levels of IL - 4 and IL - 10 transcripts and proteins . No IL - 6 gene expression was observed . In LCL - stimulated cells the cytokine production pattern was very similar . Steady - state mRNA levels of IL - 2 , IL - 10 and IFN - gamma peaked at 3 hr after anti - CD3 stimulation and declined rapidly thereafter . The kinetics of TNF - alpha mRNA expression was faster , being at its peak level 1 hr after stimulation . Anti - CD3 - stimulated IL - 2 gene expression was down - regulated by protein synthesis inhibitor , whereas IL - 10 , IFN - gamma and TNF - alpha genes were readily induced independent of ongoing protein synthesis . T - cell receptor stimulation also induced a very rapid expression of c - jun , c - fos and NFATc1 ( NFATc ) genes , the gene products of which are involved in cytokine gene expression . In conclusion , the cytokines synthesized by IL - 2 - dependent T cells were predominantly IL - 2 , IFN - gamma and TNF - alpha . An animal model to study local oxidation of LDL and its biological effects in the arterial wall . Oxidized LDL ( oxLDL ) is present in atherosclerotic lesions and is believed to play a key role in atherogenesis . Mainly on the basis of cell culture studies , oxLDL has been shown to produce many biological effects that influence the atherosclerotic process . To study LDL oxidation in vivo , we have established a model in which Sprague - Dawley rats are given a single injection of unmodified human LDL ( > or = 4 mg / kg body weight ) . Within 6 hours , an accumulation of apolipoprotein B and epitopes present on oxLDL are detected in the arterial endothelium and media . The presence of oxLDL is associated with activation of the transcription factor nuclear factor - kappaB in the endothelium as well as endothelial expression of intercellular adhesion molecule - 1 . Injection of LDL enriched with the antioxidant probucol resulted in arterial accumulation of apolipoprotein B , but the expression of oxLDL - specific epitopes was reduced at 24 hours . Thus , this simple model has the potential to analyze the mechanisms behind and biological effects of LDL oxidation in vivo . Molecular mechanisms of promoter regulation of the gp34 gene that is trans - activated by an oncoprotein Tax of human T cell leukemia virus type I . We investigated the molecular mechanism of transcriptional activation of the gp34 gene by the Tax oncoprotein of human T cell leukemia virus type I ( HTLV - I ) . gp34 is a type II transmembrane molecule belonging to the tumor necrosis factor family and is constitutively expressed on HTLV - I - producing cells but not normal resting T cells . The transcriptional regulatory region of the gp34 gene was activated by HTLV - I Tax in the human T cell line Jurkat , in which endogenous gp34 is induced by Tax . Sequence analysis demonstrated that two NF - kappaB - like elements ( 1 and 2 ) were present in the regulatory region . Both NF - kappaB - like elements were able to bind to NF - kappaB or its related factor ( s ) in a Tax - dependent manner . Chloramphenicol acetyltransferase assays indicated that NF - kappaB - like element 1 was Tax - responsive , although the activity was lower than that the native promoter . NF - kappaB - like element 2 elevated promoter activity when combined with NF - kappaB - like element 1 , indicating cooperative function of the elements for maximum promoter function . Unlike typical NF - kappaB elements , the NF - kappaB - like elements in gp34 were not activated by treatment of Jurkat cells with phorbol ester despite induction of the NF - kappaB - like binding activity . Chloramphenicol acetyltransferase reporter assays using the region upstream of the NF - kappaB - like elements identified an upstream region that reduced transcription from cognate and noncognate core promoters in a Tax - independent manner . Our results imply complex regulation of expression of the gp34 gene and suggest implication of gp34 in proliferation of HTLV - I infected T cells . beta - Amyloid fibrils activate parallel mitogen - activated protein kinase pathways in microglia and THP1 monocytes . The senile plaques of Alzheimer ' s disease are foci of local inflammatory responses , as evidenced by the presence of acute phase proteins and oxidative damage . Fibrillar forms of beta - amyloid ( Abeta ) , which are the primary constituents of senile plaques , have been shown to activate tyrosine kinase - dependent signal transduction cascades , resulting in inflammatory responses in microglia . However , the downstream signaling pathways mediating Abeta - induced inflammatory events are not well characterized . We report that exposure of primary rat microglia and human THP1 monocytes to fibrillar Abeta results in the tyrosine kinase - dependent activation of two parallel signal transduction cascades involving members of the mitogen - activated protein kinase ( MAPK ) superfamily . Abeta stimulated the rapid , transient activation of extracellular signal - regulated kinase 1 ( ERK1 ) and ERK2 in microglia and ERK2 in THP1 monocytes . A second superfamily member , p38 MAPK , was also activated with similar kinetics . Scavenger receptor and receptor for advanced glycated end products ( RAGE ) ligands failed to activate ERK and p38 MAPK in the absence of significant increases in protein tyrosine phosphorylation , demonstrating that scavenger receptors and RAGE are not linked to these pathways . Importantly , the stress - activated protein kinases ( SAPKs ) were not significantly activated in response to Abeta . Downstream effectors of the MAPK signal transduction cascades include MAPKAP kinases , such as RSK1 and RSK2 , as well as transcription factors . Exposure of microglia and THP1 monocytes to Abeta resulted in the activation of RSK1 and RSK2 and phosphorylation of cAMP response element - binding protein at Ser133 , providing a mechanism for Abeta - induced changes in gene expression Regulation of cellular retinoic acid binding protein ( CRABP II ) during human monocyte differentiation in vitro . Cellular retinoic acid binding proteins ( CRABP ) are low molecular weight proteins whose precise function remains unknown . They bind retinoids and may thereby modulate the intracellular steady - state concentration of retinoids . Whereas CRABP I is ubiquitously expressed , CRABP II is mainly detected in various cell types of the skin . By representative difference analysis we found that CRABP II is also strongly expressed in human monocyte - derived macrophages ( MAC ) but not in freshly isolated monocytes ( MO ) . The CRABP II mRNA was gradually upregulated during differentiation from MO to MAC in the presence of 2 % serum . Adherence , which is important for MO differentiation , induced CRABP II expression , but the addition of 10 ( - 7 ) M retinoic acid inhibited the upregulation of CRABP II expression during MO / MAC differentiation . As MO can differentiate along the classical pathway not only to MAC but also to dendritic cells we analyzed the expression of CRABP II in MO - derived dendritic cells cultured with 10 % FCS , IL - 4 , and GM - CSF . In contrast to MAC , MO - derived dendritic cells showed an extremely low expression of CRABP II . From these results we conclude ( 1 ) that the availability and the metabolism of retinoids may be different in MAC compared to MO and dendritic cells and ( 2 ) that this may influence differentiation and activation of those cells . Transcription factor B - cell - specific activator protein ( BSAP ) is differentially expressed in B cells and in subsets of B - cell lymphomas . The paired box containing gene PAX - 5 encodes the transcription factor BSAP ( B - cell - specific activator protein ) , which plays a key role in B - lymphocyte development . Despite its known involvement in a rare subtype of non - Hodgkin ' s lymphoma ( NHL ) , a detailed examination of BSAP expression in NHL has not been previously reported . In this study , we analyzed normal and malignant lymphoid tissues and cell lines , including 102 cases of B - cell NHL , 23 cases of T - and null - cell NHL , and 18 cases of Hodgkin ' s disease . Normal lymphoid tissues showed strong nuclear BSAP expression in mantle zone B cells , less intense reactivity in follicular center B cells , and no expression in cells of the T - cell - rich zones . Monocytoid B cells showed weak expression , whereas plasma cells and extrafollicular large transformed B cells were negative . Of the 102 B - cell NHLs , 83 ( 81 % ) demonstrated BSAP expression . All of the 13 ( 100 % ) B - cell chronic lymphocytic leukemias ( B - CLLs ) , 21 of ( 100 % ) mantle cells ( MCLs ) , and 20 of 21 ( 95 % ) follicular lymphomas ( FLs ) were positive . Moderate staining intensities were found in most B - CLL and FL cases , whereas most MCLs showed strong reactions , paralleling the strong reactivity of nonmalignant mantle cells . Eight of 12 ( 67 % ) marginal zone lymphoma cases showed negative or low BSAP levels , and 17 of 24 ( 71 % ) large B - cell lymphomas displayed moderate to strong expression . None of the 23 T - and null - cell lymphomas reacted with the BSAP antisera , whereas in Hodgkin ' s disease , 2 of 4 ( 50 % ) nodular lymphocytic predominance and 5 of 14 ( 36 % ) classical cases showed weak nuclear or nucleolar BSAP reactions in a fraction of the tumor cells . Western blot analysis showed a 52 - kD BSAP band in B - cell lines , but not in non - B - cell or plasma cell lines . We conclude that BSAP expression is largely restricted to lymphomas of B - cell lineage and that BSAP expression varies in B - cell subsets and subtypes of B - cell NHL . The high levels of BSAP , especially those found in large - cell lymphomas and in some follicular lymphomas , may be a consequence of deregulated gene expression and suggest a possible involvement of PAX - 5 in certain B - cell malignancies . This is a US government work . There are no restrictions on its use . Mitogen and growth factor - induced activation of a STAT - like molecule in channel catfish lymphoid cells . This article describes the identification of a putative STAT molecule in the channel catfish ( Ictalurus punctatus ) , the first report of such a molecule in a ' lower ' vertebrate . A monoclonal antibody against human STAT6 recognizes an approximately 100 kDa molecule that becomes activated and translocates to the nucleus upon both growth factor and mitogen stimulation of catfish leukocytes . This presumed catfish STAT binds the mammalian interferon - gamma activation site , a known motif of mammalian STAT binding , as shown by electromobility shift assays . Purification of the proteins present in these DNA complexes confirms that the catfish reactive molecule binds to the interferon - gamma activation site sequence . These results suggest that STAT molecules have been highly conserved in vertebrate evolution . Isolation and analysis of a T cell clone variant exhibiting constitutively phosphorylated Ser133 cAMP response element - binding protein . In driving T cell proliferation , IL - 2 stimulates a new program of gene expression that includes proliferating cell nuclear antigen ( PCNA ) , a requisite processivity factor for DNA polymerase delta . PCNA transcription is regulated in part through tandem CRE sequences in the promoter and CRE binding proteins ; IL - 2 stimulates CREB phosphorylation in the resting cloned T lymphocyte , L2 . After culturing L2 cells for greater than 91 days , we consistently isolate a stable variant that exhibits constitutive CREB phosphorylation . L2 and L2 variant cells were tested for IL - 2 responsiveness and rapamycin sensitivity with respect to specific kinase activity , PCNA expression and proliferation . In L2 cells , IL - 2 stimulated and rapamycin inhibited the following : cAMP - independent CREB kinase activity , PCNA expression and proliferation . In L2 variant cells , CREB kinase activity was constitutively high ; IL - 2 stimulated and rapamycin blocked PCNA expression and proliferation . These results indicate that IL - 2 induces a rapamycin - sensitive , cAMP - independent CREB kinase activity in L2 cells . However , phosphorylation of CREB alone is not sufficient to drive PCNA expression and L2 cell proliferation in the absence of IL - 2 . Serotonin derivative , N - ( p - coumaroyl ) serotonin , inhibits the production of TNF - alpha , IL - 1alpha , IL - 1beta , and IL - 6 by endotoxin - stimulated human blood monocytes . We have reported that N - ( p - coumaroyl ) serotonin ( CS ) and its derivatives with antioxidative activity are present in safflower seeds . As reactive oxygen species ( ROS ) are implicated in the signaling of lipopolysaccharide ( LPS ) , we examined whether CS has a suppressive effect on inflammatory cytokine generation from human monocyte s in vitro . CS at 50 - 200 microM reduced tumor necrosis factor ( TNF ) , interleukin - 1 ( IL - 1 ) , and IL - 6 activities in the culture supernatants from LPS - stimulated human blood monocytes without cytotoxicity . ELISA assay revealed that the production of TNF - alpha , IL - 1alpha , IL - 1beta , and IL - 6 was inhibited by CS . Northern blot analysis showed that LPS - induced expression of these cytokine mRNA in monocytes was suppressed by CS . NF - kappaB activation was also inhibited by CS . These findings indicate that CS has a suppressive effect on proinflammatory cytokine production from monocytes , and this effect is based in part on the suppression of cytokine mRNA expression through inhibition of NF - kappaB activation . Elevated expression of differentiation inhibitory factor nm23 mRNA in monoblastic crisis of a patient with chronic myelogenous leukemia . Differentiation inhibitory factor nm23 gene has been found to be expressed in high quantities in acute myelogenous leukemia ( AML ) , especially in acute monocytic leukemia ( AML - M5 ) and is suggested as a new prognostic factor in AML - M5 . We report an example of elevated expression of nm23 mRNA in a patient with chronic myelogenous leukemia ( CML ) who developed monoblastic crisis . Relative levels of nm23 - H1 and - H2 mRNA extracted from the patient ' s peripheral blood mononuclear cells and bone marrow mononuclear cells were measured by quantitative reverse transcriptase polymerase chain reaction . The level of nm23 - H1 mRNA in CML cells at the chronic phase was as high as that in bone marrow cells from healthy volunteers . The mRNA level of nm23 - H2 was slightly below the normal level . At blastic crisis , however , expression of both nm23 - H1 and - H2 mRNA was elevated to about three to nine times of that at the chronic phase . Proliferated blastic cells were positive for non - specific esterase , and the serum lysozyme level was elevated and diagnosed as monoblastic crisis . The patient received combined chemotherapy but response was partial . These findings are compatible with our previous report that nm23 gene is overexpressed in monocytic leukemia . Increased transcription decreases the spontaneous mutation rate at the thymidine kinase locus in human cells . Transcription increases DNA repair efficiency and modulates the distribution of certain types of DNA damage . Furthermore , increased transcription level stimulates spontaneous mutation rate in yeast . We explored whether transcription level affects spontaneous mutation rate in human cells . We first developed two thymidine kinase ( tk ) inducible human cell lines using the Gal4 - Estrogen receptor system . In our TK6i - G3 and G9 tk heterozygous cell lines , the active tk allele is linked to an inducible promoter element . Tk mRNA is induced following treatment with estrogen . Spontaneous mutation rate was significantly decreased in human cell lines after induction in contrast to the report in yeast . Thus , humans may have evolved different or additional mechanisms to deal with transcription related spontaneous mutagenesis . Copyright 1998 Elsevier Science B . V . All rights reserved . Mutation of BCL - 6 gene in normal B cells by the process of somatic hypermutation of Ig genes . Immunoglobulin ( Ig ) genes are hypermutated in B lymphocytes that are the precursors to memory B cells . The mutations are linked to transcription initiation , but non - Ig promoters are permissible for the mutation process ; thus , other genes expressed in mutating B cells may also be subject to somatic hypermutation . Significant mutations were not observed in c - MYC , S14 , or alpha - fetoprotein ( AFP ) genes , but BCL - 6 was highly mutated in a large proportion of memory B cells of normal individuals . The mutation pattern was similar to that of Ig genes . CD28 - mediated activation in CD45RA + and CD45RO + T cells : enhanced levels of reactive oxygen intermediates and c - Rel nuclear translocation in CD45RA + cells . We have analyzed the effect of complete T cell activation ( anti - CD3 plus anti - CD28 ) on the activation of NF - kappaB in CD45RA + ( naive ) and CD45RO + ( memory / effector ) T cells . Long exposure ( 24 h ) induced stronger NF - kappaB DNA binding in CD45RA + cells than in CD45RO + cells . Analysis of the nuclear c - Rel protein indicated that after anti - CD3 + anti - CD28 stimulation the level of c - Rel was higher in CD45RA + cells . Analysis of the cytoplasmic inhibitor IkappaBalpha indicated that anti - CD3 + anti - CD28 stimulation induced a long - lasting degradation in CD45RA + cells but in CD45RO + cells the degradation process was more rapid . Because the CD28 costimulus is known to induce the production of reactive oxygen intermediates ( ROIs ) , the intracellular ROI levels in CD45RA + and CD45RO + cells were compared by flow cytometry . ROIs were produced in both cell types , but more strongly in CD45RA + cells . The data presented in this study further emphasize the differences between CD45RA + and CD45RO + T lymphocytes in ROI - dependent signaling pathways . Non - Hodgkin ' s lymphoma involving bilateral breasts [ see comments ] We describe here two cases of diffuse large cell type non - Hodgkin ' s lymphoma affecting the bilateral breasts . The contralateral tumor in one case appeared 17 months after the first mastectomy , whereas the bilateral tumors occurred concurrently in the other patient who was pregnant and showed widespread dissemination at initial presentation . Lymphoma cells from both cases showed the mature B - cell immunophenotype and had rearrangements of the BCL6 gene . Both patients developed progressive disease despite chemo - radiotherapy and died of leukemic manifestations . There were no apparent pathological features of lymphomas of mucosa - associated lymphoid tissue origin Biochemical characterization of MIP - 1 alpha nuclear protein . A family of hematopoietic specific transcription factors , MIP - 1 alpha nuclear protein ( MNP ) family , has recently been identified . They are intimately involved in regulating the transcription of the huMIP - 1 alpha gene in monocytes , T - cells , and transformed B - cells . One member of the family ( MNP - 1 ) is essential for promoter activity in monocytes and B - cells , while another ( MNP - 2 ) is required for full promotor activity in T - cells . A third member of the family ( MNP - 3 ) is expressed in PMA induced HL60 cells and probably has a role in monocyte differentiation . In this communication we demonstrate by two techniques that MNP - 1 and MNP - 2 are distinct but related factors , and we present further evidence to show that MNP - 1 acts as a heterodimer . Bcl - 3 expression and nuclear translocation are induced by granulocyte - macrophage colony - stimulating factor and erythropoietin in proliferating human erythroid precursors . Bcl - 3 is a proto - oncogene involved in the chromosomal translocation t ( 14 ; 19 ) found in some patients with chronic lymphocytic leukemia . It shares structural similarities with and is a member of the IkappaB family of proteins . In this report , involvement of Bcl - 3 in hematopoietic growth factor - stimulated erythroid proliferation and differentiation was examined . In TF - 1 cells , an erythroleukemia cell line , granulocyte - macrophage colony - stimulating factor ( GM - CSF ) and erythropoietin ( Epo ) greatly enhanced Bcl - 3 expression at both the protein and mRNA levels in association with stimulation of proliferation . Bcl - 3 protein was also highly expressed in early burst - forming unit - erythroid ( BFU - E ) - derived erythroid precursors ( day 7 ) and decreased during maturation ( days 10 and 14 ) , suggesting that Bcl - 3 is involved in normal erythroid proliferation . In these hematopoietic cells , Bcl - 3 was hyperphosphorylated . GM - CSF and Epo modulated the subcellular localization of Bcl - 3 . Upon stimulation of TF - 1 cells with GM - CSF or Epo , the nuclear translocation of Bcl - 3 was dramatically enhanced . Overexpression of Bcl - 3 in TF - 1 cells by transient transfection along with the NF - kappaB factors p50 or p52 resulted in significant induction of an human immunodeficiency virus - type 1 ( HIV - 1 ) kappaB - TATA - luceriferase reporter plasmid , demonstrating that Bcl - 3 has a positive role in transactivation of kappaB - containing genes in erythroid cells . Stimulation with GM - CSF enhanced c - myb mRNA expression in these cells . Bcl - 3 in nuclear extracts of TF - 1 cells bound to a kappaB enhancer in the c - myb promoter together with NF - kappaB2 / p52 and this binding activity was enhanced by GM - CSF stimulation . Furthermore , cotransfection of Bcl - 3 with p52 or p50 in TF - 1 cells resulted in significant activation of a c - myb kappaB - TATA - luceriferase reporter plasmid . These findings suggest that Bcl - 3 may participate in the transcriptional regulation of certain kappaB - containing genes involved in hematopoiesis , including c - myb . Copyright 1998 by The American Society of Hematology . 5 - Lipoxygenase compartmentalization in granulocytic cells is modulated by an internal bipartite nuclear localizing sequence and nuclear factor kappa B complex formation . A region of basic amino acids spanning residues 639 - 656 in the human 5 - lipoxygenase sequence resembles a consensus bipartite nuclear localizing sequence . A synthetic peptide consisting of the Kaposi fibroblast growth factor signal sequence fused to the 5 - lipoxygenase639 - 656 bipartite nuclear localizing sequence has a prominent inhibitory effect on 5 - lipoxygenase catalysis in granulocytic HL - 60 cells activated by calcium ionophor A23187 . Recombinant 5 - lipoxygenase was not affected by the peptide . The peptide also inhibited redistribution of 5 - lipoxygenase from the cytosol to the nuclear membrane of HL - 60 cells stimulated by A23187 . 5 - Lipoxygenase protein was detected in nuclear factor kappaB ( NF - kappaB ) p65 subunit immunoprecipitate fractions prepared from HL - 60 cell lysates . The amount of 5 - lipoxygenase protein coimmunoprecipitated by NF - kappaB antiserum was increased following A23187 stimulation . In cells treated with agents that block 5 - lipoxygenase translocation to the nucleus , 5 - lipoxygenase protein appearing in the NF - kappaB immunoprecipitate was diminished . Our results implicate an internal bipartite nuclear localizing sequence as a regulatory domain that modulates 5 - lipoxygenase redistribution and catalysis in granulocytic cells . Additionally , our results suggest that molecular determinants which govern 5 - lipoxygenase and NF - kappaB redistribution to the nucleus may be coordinately controlled in granulocytic cells . Copyright 1998 Academic Press . Inhibition of CD28 / CD3 - mediated costimulation of naive and memory human T lymphocytes by intracellular incorporation of polyclonal antibodies specific for the activator protein - 1 transcriptional complex . A number of indirect methods have been utilized in demonstrating activator protein - 1 transcription factor function in IL - 2 promoter activity . However , there has been no direct demonstration that activator protein - 1 is involved in CD28 - dependent costimulation of IL - 2 gene transcription in freshly isolated naive and memory human T lymphocytes . To address this issue , the method of scrape loading was applied to purified peripheral blood T lymphocytes . Since scrape loading relies on adherent cells , peripheral blood human T ( PB - T ) cells were immobilized on the nonspecific cell attachment factor poly - L - lysine . Cells scraped off poly - L - lysine in the presence of Ig FITC efficiently incorporated Ig , with relatively uniform fluorescence . T cells retained their physical parameters as measured by forward and side light scatter , and functional activity as measured by costimulation of proliferation and IL - 2 production after being scraped off this substrate . CD28 / CD3 - costimulated T cells produced intracellular IL - 2 from all subsets measured ( CD4 + , CD4 - , CD45RO + , and CD45RO - ) . IL - 2 production and intracellular accumulation in nonscraped PB - T cells activated with CD28 / CD3 coligation were skewed favoring CD45RO + and CD4 + subsets , as was IL - 2 production in scraped PB - T cells . The intracellular incorporation of Abs specific for c - Fos and c - Jun family members by scrape loading inhibited the production and intracellular accumulation of IL - 2 within 6 h of costimulation with PMA / ionomycin , or costimulation by CD28 and CD3 ligation . Scrape loading thus provides an efficient mechanism for intracellular incorporation of macromolecules , and the first direct evidence that c - Fos and c - Jun are involved in transcription of the IL - 2 gene within its correct chromosomal context , in resting human T lymphocyte subpopulations . Differential expression of Nur77 family members in human T - lymphotropic virus type 1 - infected cells : transactivation of the TR3 / nur77 gene by Tax protein . We analyzed the differential expression and regulation of three members of the Nur77 transcription factor family by the human T - lymphotropic virus type 1 ( HTLV - 1 ) Tax protein . We have demonstrated that in both HTLV - 1 - infected cells and Tax - expressing JPX - 9 cells , TR3 / nur77 is highly expressed , whereas neither NOR - 1 nor NOT expression is detectable . Transient transfection analysis further confirmed the Tax transactivation of the TR3 / nur77 promoter but not the NOR - 1 promoter in different cell types . Furthermore , expression of a luciferase reporter gene driven by the NGFI - B ( rat homolog of TR3 / Nur77 ) response element ( NBRE ) provided evidence that Tax - mediated transactivation resulted in the induction of a functional protein . Cotransfection assays with the TR3 / nur77 promoter sequence or the NBRE binding motif together with a series of Tax mutants have shown that Tax - induced TR3 / nur77 expression is mediated by CREB / ATF - related transcription factors . Negative regulation of the heat shock transcriptional response by HSBP1 . In response to stress , heat shock factor 1 ( HSF1 ) acquires rapid DNA binding and transient transcriptional activity while undergoing conformational transition from an inert non - DNA - binding monomer to active functional trimers . Attenuation of the inducible transcriptional response occurs during heat shock or upon recovery at non - stress conditions and involves dissociation of the HSF1 trimer and loss of activity . We have used the hydrophobic repeats of the HSF1 trimerization domain in the yeast two - hybrid protein interaction assay to identify heat shock factor binding protein 1 ( HSBP1 ) , a novel , conserved , 76 - amino - acid protein that contains two extended arrays of hydrophobic repeats that interact with the HSF1 heptad repeats . HSBP1 is nuclear - localized and interacts in vivo with the active trimeric state of HSF1 that appears during heat shock . During attenuation of HSF1 to the inert monomer , HSBP1 associates with Hsp70 . HSBP1 negatively affects HSF1 DNA - binding activity , and overexpression of HSBP1 in mammalian cells represses the transactivation activity of HSF1 . To establish a biological role for HSBP1 , the homologous Caenorhabditis elegans protein was overexpressed in body wall muscle cells and was shown to block activation of the heat shock response from a heat shock promoter - reporter construct . Alteration in the level of HSBP1 expression in C . elegans has severe effects on survival of the animals after thermal and chemical stress , consistent with a role for HSBP1 as a negative regulator of the heat shock response . Long - range transcriptional regulation of cytokine gene expression . Most studies on the control of cytokine gene expression have involved the functional analysis of proximal promoters . Recent work has identified distal elements that mediate long - range cytokine gene regulation and has implicated chromatin reorganization in regulation of cytokine gene loci . These studies have begun to elucidate the basis for cell - specificity and high - level expression of cytokine genes . A signaling complex of Ca2 + - calmodulin - dependent protein kinase IV and protein phosphatase 2A [ see comments ] Stimulation of T lymphocytes results in a rapid increase in intracellular calcium concentration ( [ Ca2 + ] i ) that parallels the activation of Ca2 + - calmodulin - dependent protein kinase IV ( CaMKIV ) , a nuclear enzyme that can phosphorylate and activate the cyclic adenosine monophosphate ( cAMP ) response element - binding protein ( CREB ) . However , inactivation of CaMKIV occurs despite the sustained increase in [ Ca2 + ] i that is required for T cell activation . A stable and stoichiometric complex of CaMKIV with protein serine - threonine phosphatase 2A ( PP2A ) was identified in which PP2A dephosphorylates CaMKIV and functions as a negative regulator of CaMKIV signaling . In Jurkat T cells , inhibition of PP2A activity by small t antigen enhanced activation of CREB - mediated transcription by CaMKIV . These findings reveal an intracellular signaling mechanism whereby a protein serine - threonine kinase ( CaMKIV ) is regulated by a tightly associated protein serine - threonine phosphatase ( PP2A ) . Hypoxia down - regulates MCP - 1 expression : implications for macrophage distribution in tumors . Monocyte chemoattractant protein 1 ( MCP - 1 ) is likely to contribute to the macrophage infiltrate in human ovarian carcinomas . Although MCP - 1 is predominantly expressed by the tumor parenchyma , macrophages accumulate at highest density in necrotic regions , which are associated with low oxygen tensions . Tumor necrosis factor alpha ( TNF - alpha ) can stimulate MCP - 1 production and is also present within ovarian carcinomas . We have investigated the effect of hypoxia both on MCP - 1 expression in ovarian cancer cell lines and monocyte migration . Hypoxia down - regulated TNF - alpha - induced MCP - 1 mRNA and protein production by ovarian cancer cells . The effect was mimicked by cobalt chloride and desferrioxamine , consistent with a specific oxygen - sensing mechanism . Unlike antioxidants , hypoxia did not inhibit nuclear factor KB mobilization . Monocyte migration in response to MCP - 1 was also diminished under hypoxic conditions . Down - regulation of MCP - 1 expression and the inhibition of monocyte migration are independent effects of hypoxia that may contribute to the distribution of macrophages within ovarian tumors . Activation of nuclear factor kappa B inflammatory bowel disease [ see comments ] BACKGROUND : Expression of pro - inflammatory cytokines is increased in the intestinal lamina propria of patients with inflammatory bowel disease ( IBD ) . Nuclear factor kappa B ( NF kappa B ) controls transcription of inflammation genes . On activation , NF kappa B is rapidly released from its cytoplasmic inhibitor ( I kappa B ) , transmigrates into the nucleus , and binds to DNA response elements in gene promoter regions . AIMS : To investigate whether increased activation of NF kappa B is important in IBD and may be down - regulated by anti - inflammatory treatment . METHODS : Activation of NF kappa B was determined by western blot assessment and electrophoretic mobility shift assay in nuclear extracts of colonic biopsy samples as well as lamina propria mononuclear cells . RESULTS : Nuclear levels of NF kappa B p65 are increased in lamina propria biopsy specimens from patients with Crohn ' s disease in comparison with patients with ulcerative colitis and controls . Increased activation of NF kappa B was detected in lamina propria mononuclear cells from patients with active IBD . Corticosteroids strongly inhibit intestinal NF kappa B activation in IBD in vivo and in vitro by stabilising the cytosolic inhibitor I kappa B alpha against activation induced degradation . CONCLUSIONS : In both IBDs , but particularly Crohn ' s disease , increased activation of NF kappa B may be involved in the regulation of the inflammatory response . Inhibition of NF kappa B activation may represent a mechanism by which steroids exert an anti - inflammatory effect in IBD Insufficient glycemic control increases nuclear factor - kappa B binding activity in peripheral blood mononuclear cells isolated from patients with type 1 diabetes . OBJECTIVE : The redox - sensitive transcription factor nuclear factor - kappa B ( NF - kappa B ) is believed to contribute to late diabetic complications . It is unknown whether NF - kappa B is influenced by glycemic control . RESEARCH DESIGN AND METHODS : To determine whether NF - kappa B is activated in patients with insufficient glycemic control ( HbA1c > 10 % ) , we developed a tissue culture - independent electrophoretic mobility shift assay ( EMSA ) - based semiquantitative detection system that allowed us to determine NF - kappa B activation in ex vivo - isolated peripheral blood mononuclear cells ( PBMCs ) . We included 43 patients with type 1 diabetes in this cross - sectional study . 10 of those received the antioxidant thioctic acid ( 600 mg / day p . o . ) for 2 weeks . RESULTS : Monocytes of patients with HbA1c levels > 10 % demonstrated significantly higher NF - kappa B binding activity in an EMSA and a stronger NF - kappa B staining in immunohistochemistry than monocytes of patients with HbA1c levels of 6 - 8 % . The increase in NF - kappa B activation correlated with an increase in plasmatic markers of lipid peroxidation . Treatment with the antioxidant thioctic acid decreased NF - kappa B binding activity . CONCLUSIONS : Hyperglycemia induces activation of the transcription factor NF - kappa B in ex vivo - isolated PBMCs of patients with type 1 diabetes . NF - kappa B activation is at least partially dependent on oxidative stress , since the antioxidant thioctic acid significantly lowered the extent of NF - kappa B binding activity . Synergistic activation of MAP kinase ( ERK1 / 2 ) by erythropoietin and stem cell factor is essential for expanded erythropoiesis . Stem cell factor ( SCF ) and erythropoietin ( EPO ) work synergistically to support erythropoiesis , but the mechanism for this synergism is unknown . By using purified human erythroid colony - forming cells ( ECFC ) , we have found that SCF and EPO synergistically activate MAP kinase ( MAPK , ERK1 / 2 ) , which correlates with the cell growth and thus may be responsible for the synergistic effects . Treatment of the cells with PD98059 and wortmannin , inhibitors of MEK and PI - 3 kinase , respectively , inhibited the synergistic activation of MAPK and also the cell growth , further supporting this conclusion . Wortmannin only inhibits MAPK activation induced by EPO but not that by SCF , suggesting that SCF and EPO may activate MAPK through different pathways , which would facilitate synergy . Furthermore , EPO , but not SCF , led to activation of STAT5 , whereas SCF and wortmannin had no effect on the EPO - induced STAT5 activation , suggesting that STAT5 is not involved in the synergistic action of SCF and EPO . Together , the data suggest that synergistic activation of MAPK by SCF and EPO is essential for expanded erythropoiesis . Copyright 1998 by The American Society of Hematology . The molecular and phenotypic profile of primary central nervous system lymphoma identifies distinct categories of the disease and is consistent with histogenetic derivation from germinal center - related B cells . Primary central nervous system lymphoma ( PCNSL ) is a major cause of morbidity and mortality among human immunodeficiency virus ( HIV ) - infected individuals . The precise histogenetic derivation and the molecular pathogenesis of PCNSL is poorly understood . In an attempt to clarify the histogenesis and pathogenesis of these lymphomas , 49 PCNSL ( 26 acquired immunodeficiency syndrome [ AIDS ] - related and 23 AIDS - unrelated ) were analyzed for multiple biologic markers , which are known to bear histogenetic and pathogenetic significance for mature B - cell neoplasms . PCNSL associated frequently ( 50 . 0 % ) with mutations of BCL - 6 5 ' noncoding regions , which are regarded as a marker of B - cell transition through the germinal center ( GC ) . Expression of BCL - 6 protein , which is restricted to GC B cells throughout physiologic B - cell maturation , was detected in 100 % AIDS - unrelated PCNSL and in 56 . 2 % AIDS - related cases . Notably , among AIDS - related PCNSL , expression of BCL - 6 was mutually exclusive with expression of Epstein - Barr virus ( EBV ) - encoded latent membrane protein ( LMP ) - 1 and , with few exceptions , also of BCL - 2 . All but one PCNSL expressed hMSH2 , which among mature B cells selectively stains GC B cells . These data suggest that PCNSL may be frequently related to GC B cells and may be segregated into two major biologic categories based on the expression pattern of BCL - 6 , LMP - 1 , and BCL - 2 . BCL - 6 ( + ) / LMP - 1 ( - ) / BCL - 2 ( - ) PCNSL occur both in the presence and in the absence of HIV infection and consistently display a large noncleaved cell morphology . Conversely , BCL - 6 ( - ) / LMP - 1 ( + ) / BCL - 2 ( + ) PCNSL are restricted to HIV - infected hosts and are represented by lymphomas with immunoblastic features . These data are relevant for the pathogenesis and histogenesis of PCNSL and may be helpful to segregate distinct biologic and prognostic categories of these lymphomas . Copyright 1998 by The American Society of Hematology . Antioxidant regulation of phorbol ester - induced adhesion of human Jurkat T - cells to endothelial cells . Regulation of adhesion molecule expression and function by reactive oxygen species via specific redox sensitive mechanisms have been reported . The effects of clinically safe antioxidants in the regulation of adhesion molecule expression in human endothelial cells ( ECV ) , and adherence of human Jurkat T cells to ECV cells were investigated . The thiol antioxidant , alpha - lipoate , at clinically relevant doses down - regulated phorbol 12 - myristate 13 - acetate ( PMA ) - induced adhesion molecule expression and cell - cell adhesion . Inhibition of PMA - induced ICAM - 1 and VCAM - 1 expression as well as PMA - induced adhesion of Jurkat T - cells to ECV cells by alpha - lipoate was dose dependent ( 50 - 250 microM ) . The effect was significant for ICAM - 1 ( p < . 01 ) and VCAM - 1 ( p < . 01 ) expression in cells pretreated with 100 microM alpha - lipoate compared to PMA - activated untreated cells . Inhibition of PMA - induced adhesion molecule expression and cell - cell adhesion was more pronounced when a combination of antioxidants , alpha - lipoate and alpha - tocopherol , were used compared to the use of either of these antioxidant alone . The regulation of adhesion molecule expression and function by low concentration of antioxidants investigated does not appear to be NF - kappaB regulated or transcription dependent because no change in the mRNA response was observed . Protein kinase C ( PKC ) has been suggested to regulate PMA - induced adhesion molecule expression by post - transcriptional stabilization of adhesion molecule mRNA . Alpha - lipoate pretreatment did not influence the response of PKC activity to PMA . Oxidants are known to be involved in the regulation of cell adhesion processes . Treatment of ECV cells with PMA induced generation of intracellular oxidants . Alpha - lipoate ( 100 or 250 microM ) treatment decreased PMA - induced generation of intracellular oxidants . The inhibitory effect of low concentration of alpha - lipaote alone or in combination with alpha - tocopherol on agonist - induced adhesion processes observed in this study may be of potential therapeutic value . Binding of human immunodeficiency virus type 1 to CD4 and CXCR4 receptors differentially regulates expression of inflammatory genes and activates the MEK / ERK signaling pathway . We have previously shown that binding of human immunodeficiency virus type 1 ( HIV - 1 ) virions to CD4 receptors stimulates association of Lck with Raf - 1 and results in the activation of Raf - 1 kinase in a Ras - independent manner . In the present study , we demonstrate that HIV - 1 envelope glycoproteins of both T - cell - tropic and macrophagetropic strains rapidly activate the ERK / mitogen - activated protein ( MAP ) kinase pathway and the binding of nuclear transcription factors ( AP - 1 , NF - kappaB , and C / EBP ) and stimulate expression of cytokine and chemokine genes . The activation of this signaling pathway requires functional CD4 receptors and is independent of binding to CXCR4 . Binding of the natural ligand stromal cell - derived factor 1 ( SDF - 1 ) to CXCR4 , which inhibits entry of T - cell - tropic HIV - 1 , activates also the ERK / MAP kinase pathway . However , SDF - 1 did not affect the CD4 - mediated expression of cytokine and chemokine genes . These results provide firm molecular evidence that binding of HIV - 1 envelope glycoproteins to CD4 receptor initiates a signaling pathway ( s ) independent of the binding to the chemokine receptor that leads to the aberrant expression of inflammatory genes and may contribute significantly to HIV - 1 replication as well as to deregulation of the immune system . Antigen receptor signaling induces MAP kinase - mediated phosphorylation and degradation of the BCL - 6 transcription factor . The bcl - 6 proto - oncogene encodes a POZ / zinc finger transcriptional repressor expressed in germinal center ( GC ) B and T cells and required for GC formation and antibody affinity maturation . Deregulation of bcl - 6 expression by chromosomal rearrangements and point mutations of the bcl - 6 promoter region are implicated in the pathogenesis of B - cell lymphoma . The signals regulating bcl - 6 expression are not known . Here we show that antigen receptor activation leads to BCL - 6 phosphorylation by mitogen - activated protein kinase ( MAPK ) . Phosphorylation , in turn , targets BCL - 6 for rapid degradation by the ubiquitin / proteasome pathway . These findings indicate that BCL - 6 expression is directly controlled by the antigen receptor via MAPK activation . This signaling pathway may be crucial for the control of B - cell differentiation and antibody response and has implications for the regulation of other POZ / zinc finger transcription factors in other tissues . Glucocorticoid receptors are differentially expressed in the cells and tissues of the immune system . Cytosolic glucocorticoid receptor ( GR ) binding studies on immune tissues demonstrate that the thymus exhibits three to four times higher levels of GR protein than the spleen . High levels of GR are consistent with the exquisite sensitivity of the thymus to glucocorticoid exposure . Nevertheless , whole cell binding studies reveal similar levels of GR in immature thymic T lymphocytes and more mature , splenic T lymphocytes . Moreover , whole cell binding techniques indicate that neutrophils ( which represent roughly 30 % of splenic leukocytes ) exhibit higher GR than both T and B lymphocytes , further contradicting results from cytosolic binding studies . To address these inconsistencies , GR protein was assessed in immune cells and tissues using cytosolic radioligand binding . Western blot analysis , and immunocytochemistry . Consistent with previous cytosolic receptor binding studies on immune tissue homogenates , thymic T cells were found to have higher levels of GR than T cells isolated from the spleen . In addition , neutrophils were found to have fewer GR than lymphocytes and monocytes . These results indicate a meaningful relationship between receptor expression and known sensitivity to glucocorticoids . Functional replacement of the mouse E2A gene with a human HEB cDNA . The mammalian E2A , HEB , and E2 - 2 genes encode a unique class of basic helix - loop - helix ( bHLH ) transcription factors that are evolutionarily conserved and essential for embryonic and postnatal development . While the structural and functional similarities among the gene products are well demonstrated , it is not clear why deletion of E2A , but not HEB or E2 - 2 , leads to a complete arrest in B - lymphocyte development . To understand the molecular basis of the functional specificity between E2A and HEB / E2 - 2 in mammalian development , we generated and tested a panel of E2A knockin mutations including subtle mutations in the E12 and E47 exons and substitution of both E12 and E47 exons with a human HEB cDNA . We find that the alternatively spliced E12 and E47 bHLH proteins of the E2A gene play similar and additive roles in supporting B lymphopoiesis . Further , we find that HEB driven by the endogenous E2A promoter can functionally replace E2A in supporting B - cell commitment and differentiation toward completion . Finally , the postnatal lethality associated with E2A disruption is fully rescued by the addition of HEB . This study suggests that the functional divergence among E12 , E47 , and HEB in different cell types is partially defined by the context of gene expression . Biased dependency of CD80 versus CD86 in the induction of transcription factors regulating the human IL - 2 promoter . In addition to the signals obtained by ligation of the TCR , T cells need additional , co - stimulatory signals to be activated . One such co - stimulatory signal is delivered when CD28 on T cells binds to CD80 or CD86 on antigen - presenting cells ( APC ) . In the present study , we analyzed the ability of CD80 and CD86 to co - stimulate human T cells activated by superantigen . Using the Raji B cell lymphoma , which express similar levels of CD80 and CD86 , it was found that T cell proliferation was mainly co - stimulated by CD80 . To further characterize the consequences of this biased co - stimulatory dependency , we employed a well - defined system of transfected CHO cells expressing human MHC class II together with CD80 , CD86 or CD80 and CD86 . Proliferation of freshly prepared CD4 + T cells required the presence of either CD80 or CD86 . However , IL - 2 production reached only suboptimal levels in the presence of CD86 but optimal levels with CD80 . To analyze IL - 2 transcriptional activity in CD80 and CD86 co - stimulated T cells we used Jurkat T cells transfected with luciferase reporter gene constructs . CD80 induced higher levels of IL - 2 promoter - enhancer activity compared to CD86 . Furthermore , the activity of transcription factors regulating the IL - 2 promoter - enhancer region including activation protein - 1 , CD28 response element and nuclear factor kappaB were 4 - 8 times higher after CD80 compared to CD86 ligation . Our results suggest that the eventual appearance of CD80 on recently activated CD86 + APC is important for the superinduction of IL - 2 production and to support vigorous T cell proliferation . Duplication of the DR3 gene on human chromosome 1p36 and its deletion in human neuroblastoma . The human DR3 gene , whose product is also known as Wsl - 1 / APO - 3 / TRAMP / LARD , encodes a tumor necrosis factor - related receptor that is expressed primarily on the surface of thymocytes and lymphocytes . DR3 is capable of inducing both NF - kappa B activation and apoptosis when overexpressed in mammalian cells , although its ligand has not yet been identified . We report here that the DR3 gene locus is tandemly duplicated on human chromosome band 1p36 . 2 - p36 . 3 and that these genes are hemizygously deleted and / or translocated to another chromosome in neuroblastoma ( NB ) cell lines with amplified MYCN . Duplication of at least a portion of the DR3 gene , including the extracellular and transmembrane regions but not the cytoplasmic domain , was demonstrated by both fluorescence in situ hybridization and genomic Southern blotting . In most NB cell lines , both the DR3 and the DR3L sequences are simultaneously deleted and / or translocated to another chromosome . Finally , DR3 / Wsl - 1 protein expression is quite variable among these NB cell lines , with very low or undetectable levels in 7 of 17 NB cell lines Differential protection of normal and malignant human myeloid progenitors ( CFU - GM ) from Ara - C toxicity using cycloheximide . Cycloheximide , a reversible protein synthesis inhibitor , is thought to block DNA replication in normal cells by preventing synthesis of a labile protein . In animal systems , cycloheximide protects normal cells from cytotoxic S - phase specific agents , such as cytosine arabinoside ( Ara - C ) . Malignant cells appear not to be susceptible to cycloheximide - induced cycle arrest and , subsequently , may not be protected from Ara - C cytotoxicity . The effect of cycloheximide on granulocyte / macrophage progenitors ( CFU - GM ) after in vitro Ara - C exposure was examined using normal human bone marrow , malignant progenitors from patients with chronic myelogenous leukemia ( CML ) , and clonogenic cells from the human acute nonlymphocytic leukemia cell lines HL - 60 and KG - 1 . Mononuclear or clonogenic cells were incubated for one hour with cycloheximide , followed by the addition , for three or 17 hours , of Ara - C before being plated in a methylcellulose culture system . CFU - GM survival was significantly increase if normal cells were treated with cycloheximide before Ara - C exposure . Similar cycloheximide pretreatment of CML progenitors and clonogenic HL - 60 and KG - 1 cells failed to protect CFU - GM from Ara - C - induced cytotoxicity . Primary cortisol resistance accompanied by a reduction in glucocorticoid receptors in two members of the same family . This report describes studies of a man suspected of having primary cortisol resistance . This conclusion is based on his high plasma cortisol levels and high 24 - h urinary 17 - hydroxycorticosteroi and cortisol excretion , plus the fact that he had no manifestations of Cushing ' s syndrome . Among family members tested , his mother also had hypercortisolemia . Both mother and son had high levels of unbound plasma cortisol , but their plasma ACTH concentrations were within the normal range . Both were partially resistant to dexamethasone adrenal suppression , and both had mild hypertension without hypokalemia . To study this apparent end - organ resistance to cortisol , we examined the glucocorticoid receptors in peripheral mononuclear cells . Using whole cell assays , glucocorticoid receptors in both patients were found to have reduced total binding capacity . We conclude that these two patients , members of the same family , have primary cortisol resistance accompanied by a reduced number of glucocorticoid receptors . [ Glucocorticoid receptors and response to polychemotherapy in acute lymphatic leukemia ] Glucocorticoid receptor ( GR ) levels were quantified in leukemic blasts from peripheral blood of 86 patients with acute lymphoblastic leukemia . The subsequent achievement of complete remission after combination chemotherapy was correlated with high receptor levels . Forty - seven of 50 patients with leukemic cells containing more than 6 , 000 receptor sites and 22 of 36 patients with cells containing less than 6 , 000 receptor sites achieved remission . The study of glucocorticoid receptors in leukemic cells may predict response to combination chemotherapy in patients with acute lymphoblastic leukemia . Specific uptake of 1 , 25 - dihydroxycholecalcif by human chronic myeloid leukemia cells . We have examined mononuclear cell preparations from patients with chronic myeloid leukemia [ CML ] for binding of and response to 1 , 25 - dihydroxycholecalcif [ 1 , 25 - ( OH ) 2D3 ] . Whole cells specifically took up [ 3H ] - 1 , 25 - ( OH ) 2D3 with high affinity ( Kd 3 . 6 X 10 ( - 11 ) M ) and low capacity . Subcellular fractionation of labeled cells showed that binding was restricted to cytosols and nuclei . Sucrose gradient centrifugation of cells preincubated with [ 3H ] - 1 , 25 - ( OH ) 2D3 revealed a single 3 . 6S peak which was totally displaced with 100 - fold excess nonradioactive hormone . However , we were unable to demonstrate specific binding of 1 , 25 - ( OH ) 2D3 by postlabeling standard cytosol preparations . In addition , cytosols prepared from a mixture of CML cells and 1 , 25 - ( OH ) 2D3 receptor - positive T47D ( human breast cancer ) cells had less than 10 % of the binding measured in T47D cytosol alone . However , the levels of binding in T47D cytosols were not reduced if the receptors were occupied with [ 3H ] - 1 , 25 - ( OH ) 2D3 prior to the addition of the CML cytosols . Thus , CML cells appear to contain both the receptor for 1 , 25 - ( OH ) 2D3 and an unknown substance which prevents its detection following the preparation of cytosol . Cells from patients with CML in the chronic phase specifically bound more 1 , 25 - ( OH ) 2D3 [ 18 . 0 + / - 3 . 2 ( S . E . ) fmol / 10 ( 7 ) cells ] than did those in acute myeloid transformation [ 7 . 2 + / - 1 . 5 ] or than did cells from patients with acute myeloid leukemia [ 2 . 6 + / - 0 . 8 ] . Only cells from the first group of patients responded to the addition of 1 , 25 - ( OH ) 2D3 by differentiating along the monocyte - macrophage pathway . We conclude that the differentiation - induction effect of 1 , 25 - ( OH ) 2D3 is likely to depend on adequate levels of receptor and that intact cells rather than cytosol preparations should be studied before cells of a particular tissue are designated as receptor negative . Effect of cell cycle position on dexamethasone binding by mouse and human lymphoid cell lines : correlation between an increase in dexamethasone binding during S phase and dexamethasone sensitivity . We determined the effect of cell cycle position on the amount of dexamethasone that was specifically bound by mouse and human lymphoid cell lines . Cell lines that were either sensitive or resistant to growth inhibition by dexamethasone were compared . Exponentially growing cells were separated by centrifugal elutriation into fractions that corresponded to different positions in the cell cycle . The cell cycle phase distribution of each fraction was estimated by flow cytometry and autoradiography . The amount of dexamethasone bound per cell in each fraction was measured by a whole cell binding assay . In three dexamethasone - sensitive cell lines ( two mouse and one human ) , we found that the amount of dexamethasone bound per cell increased 2 - 4 - fold between G1 phase and S phase , and then decreased during G2 / M phase . Results were the same when the amount of dexamethasone bound per milligram of cell protein was measured . Binding affinity was the same during G1 phase and S phase , but the proportion of bound dexamethasone that translocated to the nucleus was greater during S phase . In contrast , we found that the amount of dexamethasone bound per cell by three dexamethasone - resistant cell lines ( two mouse and one human ) did not increase during S phase . Our results indicate that cell cycle changes in dexamethasone binding are not simply related to changes in cell protein or cell volume during the cell cycle . An increase in dexamethasone binding during S phase may be required for dexamethasone to inhibit cell growth , and a failure of dexamethasone binding to increase during S phase might represent a new mechanism of dexamethasone resistance in lymphoid cells . Presence and steroid inducibility of glutamine synthetase in human leukemic cells . Glutamine synthetase ( EC 6 . 3 . 1 . 2 ; GS ) is present in lymphoblasts from patients with acute lymphoblastic leukemia ( ALL ) as well as in normal peripheral blood lymphocytes . In 16 out of 20 ALL patients studied exposure of the cells to physiological concentrations of dexamethasone in vitro increased enzyme activity above the control levels . The increase was specific for glucocorticoid receptor ligands . A direct correlation was found between the magnitude of glucocorticoid - mediated increase of GS activity and the cellular levels of specific glucocorticoid receptors assayed in the same cell specimen . Moreover , the basal levels of the enzyme measured in cells prior to exposure to dexamethasone correlated negatively with receptor density . It is suggested that the presence of steroid - inducible GS in ALL cells may prove to be a marker for functional receptor sites . Binding of progestins to the glucocorticoid receptor . Correlation to their glucocorticoid - like effects on in vitro functions of human mononuclear leukocytes . A number of physiological and synthetic progestins were tested for their ability to compete with [ 3H ] dexamethasone for the binding to the glucocorticoid receptor of human mononuclear leukocytes and their ability to elicit glucocorticoid - like effects on the same cells . As compared to the reference compound dexamethasone ( relative receptor binding affinity defined as 100 % ) , two potent synthetic progestins with a pregnane - type structure , megestrol acetate and medroxyprogesterone acetate , were found to display a considerable binding affinity towards the receptor ( 46 and 42 % , respectively ) . The relative binding affinity of the naturally occurring ligand , cortisol , to the receptor was clearly lower ( 25 % ) . The effective binding of medroxyprogesterone acetate to the glucocorticoid receptor was confirmed by direct binding studies utilizing a tritiated derivative of this steroid . No evidence for the existence of a specific progesterone receptor in human mononuclear leukocytes was obtained as judged by the results of competition experiments where a progesterone receptor - specific ligand [ 3H ] Org 2058 was used . Medroxyprogesterone acetate and megestrol acetate also induced glucocorticoid - like effects on the lymphocyte functions . These included inhibition of the proliferative responses to the T - cell mitogens concanavalin A and phytohaemagglutinin and an enhanced accumulation of immunoglobulin secreting cells in pokeweed mitogen - stimulated cultures . The progestin effect appears to be mediated through a radiosensitive ( suppressor ) subpopulation of T lymphocytes . In contrast , the synthetic progestins related structurally to 19 - nortestosterone , norethisterone and d - norgestrel , were virtually devoid of binding affinity towards the glucocorticoid receptor nor did they measurably influence the in vitro lymphocyte functions . These studies demonstrate that certain progestins in common clinical use probably possess inherent glucocorticoid activity and suggest that side effects attributable to this character ( e . g . suppression of the pituitary - adrenal axis ) might be expected when these compounds are used in pharmacological doses . Metabolic and ultrastructural aspects of the in vitro lysis of chronic lymphocytic leukemia cells by glucocorticoids . Human chronic lymphocytic leukemia ( CLL ) cells like prothymocytes and immunoactivated T - lymphocytes are readily lysed in vitro by pharmacological concentrations of glucocorticoids such as cortisol , whereas peripheral blood lymphocytes and thymocytes are unaffected by the hormone . In this study , metabolic and ultrastructural aspects of the cortisol - induced killing process of CLL cells are recorded . In vitro lysis was found to be temperature dependent and was detected only after 6 to 8 hr incubation with cortisol by means of the trypan blue exclusion test . However , 30 min of incubation with cortisol at either 37 degrees or 4 degrees followed by the removal of the hormone was still sufficient to induce the lytic process . Ultrastructural studies demonstrated sequential changes in the cytoplasm , including swelling of mitochondria and cytoplasmic decompartmentalizati , followed by loss of surface microvilli with the appearance of ` ` holes ' ' in the cell membrane , and subsequent condensation of nuclear chromatin . The large holes in the membrane appearing after 6 hr of incubation with the hormone may be the cause for the penetration of the viable stain into the dead cells , as seen by light microscopy . Addition of metabolic inhibitors including actinomycin D , puromycin , and cycloheximide following administration of cortisol resulted in inhibition of the cell lysis . An excess of an antagonist such as cortexolone was found to inhibit the cortisol - induced cytolysis of the CLL cells . It is suggested that the glucocorticoid - induced lysis of human CLL cells is similar to the phenomenon observed in rat or murine lymphocytes and is mediated by interaction of the steroid molecule with the cytoplasmic receptor . The resulting complex appears to activate specific gene ( s ) the products of which eventually cause cytolysis . Glucocorticoid receptors in lymphoid tumors . There is a range of levels of glucocorticoid receptor numbers seen in the various subclasses of acute lymphatic leukemia ( ALL ) . This variability can not be explained by the known correlation between active cell proliferation and an increase in the number of receptors , since the tumors with the highest growth fraction ( i . e . , Burkitt ' s lymphoma and T - cell leukemia ) tend to have lower average receptor numbers than do tumors with lower growth fractions such as common ALL . All clinical specimens from patients with lymphatic leukemia have some measurable level of glucocorticoid receptors ; therefore , the resistance seen in vivo can not be explained by the lack of receptors . However , there has been a positive correlation , in our hands , with receptor level and prognosis . On the basis of in vitro models , it is proposed that perhaps the high receptor cell lines ( i . e . , common ALL of childhood ) have relative stability of their genetic material making glucocorticoid - resistant mutations less likely to occur in patients with these cells than in low - receptor cell lines ( i . e . , T - cell leukemia ) . This greater genetic variability in the low - receptor lines could account for the earlier emergence of clinical glucocorticoid resistance in these patients . [ Tumor histology and steroid receptors in breast carcinoma ] In Specimens of 115 patients with breast cancer 4 tumorparameters ( tumorsize , tumorboder , nucleargrade , lymphocytic stromal reaction ) 3 features of regional lymphnodes ( sinushistiocytosis , T - cellreaction , lymphnode metastases ) and estrogen and progesteron receptors were determined . A strong sinushistiocytosis and T - cellreaction could be verified mainly in metastases in free lymphnodes . The steroid receptor content does not correlate with histological parameters Aldosterone - receptor deficiency in pseudohypoaldosteron . Pseudohypoaldosteron , a syndrome characterized by salt wasting and failure to thrive , usually presents in infancy as high urinary levels of sodium despite hyponatremia , hyperkalemia , hyperreninemia , and elevated aldosterone levels . We have investigated this syndrome for the possibility of abnormal Type I or ` ` mineralocorticoid - like ' ' receptors , which have intrinsic steroid specificity indistinguishable from that of renal mineralocorticoid receptors and are found in many tissues and cells , including mononuclear leukocytes . We have studied three patients with pseudohypoaldosteron : the 28 - year - old index case in Melbourne ( Patient 1 ) and two siblings in Munich , eight and two years of age ( Patients 2 and 3 ) ; clinically , Patient 3 had a less severe case than his sister . Percoll - separated control monocytes bound [ 3H ] aldosterone with high affinity ( Kd approximately 3 nM ) and limited capacity ( 150 to 600 sites per cell ) . On repeated examination , no [ 3H ] aldosterone binding was found in monocytes from Patients 1 and 2 ; in Patient 3 , the levels were 62 sites per cell , more than 2 S . D . below those of the control . Levels in the parents of the Munich patients ( first cousins ) were normal . It appears that pseudohypoaldosteron is caused by a Type I receptor defect , that the defect may be complete or partial , that transmission may be autosomal recessive , and that the study of patients with pseudohypoaldosteron may indicate physiologic roles for Type I receptors in nonepithelial tissues . Glucocorticoid inhibition of urokinase - like plasminogen activators in cultured human lymphoblasts . Two human lymphoblast cell lines , LICR - LON - HMy2 ( HMy2 cells ) and GM4672A cells , are moderately growth inhibited by dexamethasone ( 1 , 4 - pregnadien - 9 - fluoro - 16 alpha - methyl - 11 beta , 17 alpha , 21 - triol - 3 , 20 - dione ) ( Dex ) . Both cell types secrete a urokinase ( UK ) - like plasminogen activator ( PA ) . Treatment of both HMy2 and GM4672A cells with Dex for 1 - 4 days inhibits extracellular PA activity in a concentration - dependent manner , being half - maximal at approximately 1 X 10 ( - 9 ) M . Inhibition of PA in both cell types is specific for active glucocorticoids , and this specificity parallels the ability of various steroids to bind to glucocorticoid receptors . HMy2 cell PA is fully suppressible by Dex , whereas up to one third of the activator expressed by GM4672A cells is resistant to glucocorticoid inhibition . Mixing experiments using a UK standard and conditioned media from Dex - treated cells suggest an absence of glucocorticoid - inducible inhibitors to UK or plasmin in both cell types . However , conditioned media from Dex - treated GM4672A cells inhibits a portion of the homologous cellular activator in conditioned media from control GM4672A cells . Thus , low levels of glucocorticoid - inducible inhibitors may contribute to , but can not fully account for , Dex inhibition of GM4672A PA activity . Glucocorticoid - inducible inhibitors in HMy2 cells are either totally absent or are present at undetectable levels . Thus , regulation of UK - like PAs in HMy2 and GM4672A cells differs with respect to the extent to which glucocorticoids inhibit constitutively expressed activator levels , as well as the possible contribution of glucocorticoid - inducible inhibitors to the regulatory process in GM4672A cells . Characterization of aldosterone binding sites in circulating human mononuclear leukocytes . Aldosterone binding sites in human mononuclear leukocytes were characterized after separation of cells from blood by a Percoll gradient . After washing and resuspension in RPMI - 1640 medium , cells were incubated at 37 degrees C for 1 h with different concentrations of [ 3H ] aldosterone plus a 100 - fold concentration of RU - 26988 ( 11 alpha , 17 alpha - dihydroxy - 17 beta - propynylandrost - 1 , 4 , 6 - trien - 3 - one ) , with or without an excess of unlabeled aldosterone . Aldosterone binds to a single class of receptors with an affinity of 2 . 7 + / - 0 . 5 nM ( means + / - SD , n = 14 ) and a capacity of 290 + / - 108 sites / cell ( n = 14 ) . The specificity data show a hierarchy of affinity of desoxycorticosterone = corticosterone = aldosterone greater than hydrocortisone greater than dexamethasone . The results indicate that mononuclear leukocytes could be useful for studying the physiological significance of these mineralocorticoid receptors and their regulation in humans . Mineralocorticoid and glucocorticoid receptors in circulating mononuclear leukocytes of patients with primary hyperaldosteronism . Mineralocorticoid and glucocorticoid receptors were measured in circulating mononuclear leukocytes in 5 patients affected by Conn ' s syndrome ( 3 cases of bilateral adrenal hyperplasia and 2 cases of adenoma plus unilateral hyperplasia ) . The number of the binding sites per cell resulted significantly lower ( 189 + / - 114 , mean + / - SD ) , as compared with the normal controls ( 298 + / - 105 ) . The affinity of aldosterone for the receptor was found to be not different than that of healthy control subjects . The capacity and the affinity of dexamethasone for glucocorticoid receptors ranged in the normal values . These data suggest a possible down - regulation of mineralocorticoid receptors in humans . Short - term and long - term effects of estrogen on lymphoid tissues and lymphoid cells with some remarks on the significance for carcinogenesis . Estrogens have long been thought to play a role in regulating the immune system . The difference in some types of immune responses between males and females is well - known , as is the pronounced thymic involution induced by exogenous estrogens . Estrogens stimulate some aspects of macrophage activity and , depending on dose and mitogen , inhibit or stimulate lymphocyte proliferative response in vitro . Another example is the estrogen effect on the delayed type hypersensitivity response . A broad review is given of such estrogen effects on lymphoid tissue and immune response . Most of the studies published so far are phenomenological . However , the recent description of estrogen receptors in the thymus and in some lymphocyte subpopulations , as well as a deeper understanding of regulating factors in the immune system , open the possibility of a more detailed understanding of the estrogen mechanism of interference . Estrogen effects in adults are reversible . After treating neonatal mice with the synthetic estrogen diethylstilbestrol ( DES ) , disturbances are induced in lymphocyte populations and lymphocyte functions which are permanent and irreversible . Lymphocytes from adult , neonatally DES - treated female mice have a reduced mitogen response to ConA and LPS ( T and B cell mitogen ) and the delayed type hypersensitivity response is depressed . A detailed analysis demonstrated a decreased T helper cell population . The activity of Natural Killer cells is permanently reduced and this functional impairment is related to a decreased number of these cells , in turn determined at the bone marrow level . The same animals have an increased sensitivity to chemical carcinogens ( methylcholanthrene ) and they spontaneously develop epithelial changes in the uterine cervix which morphologically are similar to adenocarcinoma . The association between estrogen - associated malignancy and estrogen effects in lymphocyte functions deserves further study . Drugs affecting the hormonal receptors of normal and leukaemic peripheral leucocytes . The authors investigated the behaviour of steroid hormone uptake in leukaemic cells ( CML , CLL , AML , ALL ) , in basal conditions and after incubation with drugs which modify the cellular concentration of cAMP , PGE and PGF . The results demonstrated the presence in leukaemic cells of an alteration in the incorporation of steroid hormones . This alteration was scarcely modified by incubation with theophylline , which increases cellular concentration of cAMP . On the other hand , it was moderately counteracted by thioproline and was evidently inhibited by flurbiprofen , which also reduced cellular concentrations of prostaglandins , particularly PGE2 , with the exception of PGF2 which showed a poor response . Differences were observed in the behavior of hormonal uptake of CML , in contrast to that of AML , CLL and ALL peripheral leucocytes . Human breast cancer and impaired NK cell function . Recent advances in tumor immunology have led to the discovery of a new lymphoid cell with unique antitumor activity . Natural killer ( NK ) cells form an antitumor surveillance system and appear to be vital in preventing tumor growth and metastasis in animal models . We studied NK activity in patients with benign and malignant breast disease , using a chromium - 51 release microtiter cytotoxicity assay with K562 cells as targets . Compared with benign controls , patients with malignancies had significantly depressed NK - mediated lysis ( P less than 0 . 01 ) . Furthermore , lysis in those with advanced disease ( stages II , III , and IV ) was significantly less than in those with limited disease ( stage I ) ( P less than 0 . 01 ) . NK activity was not correlated to estrogen or progesterone receptor states . Positive correlation of a depressed natural killer activity with the extent of tumor spread supports the concept of an NK cell immune surveillance system in breast cancer and emphasizes its importance in this malignancy . Immunosuppressive effect of serum progesterone during pregnancy depends on the progesterone binding capacity of the lymphocytes . Cytotoxic activity and progesterone binding capacity of the lymphocytes , together with serum progesterone concentrations , were determined in women with normal pregnancy or with a clinical diagnosis of threatened abortion or threatened premature labour . The lymphocytes of women with threatened abortion or threatened premature labour showed significantly higher cytotoxic activity ( P less than 0 . 001 ) and significantly lower progesterone binding capacity ( P less than 0 . 001 ) than did lymphocytes obtained from the healthy pregnant women . Significant inverse correlation was found between progesterone binding capacity and cytotoxic activity of the lymphocytes ( P less than 0 . 001 ) , but the progesterone concentration of the pregnancy serum appeared to have no influence on the other two parameters . The findings indicate that intact progesterone binding capacity of the lymphocytes is an essential factor for the manifestation of the blocking effect exerted by pregnancy serum on lymphocyte cytotoxicity in vitro . Serum sex steroid and peptide hormone concentrations , and endometrial estrogen and progestin receptor levels during administration of human leukocyte interferon . Five normally cycling healthy women were given daily subcutaneous injections of human leukocyte interferon ( 3 X 10 ( 6 ) units / day ) from the 3rd through 23rd day of the menstrual cycle , and serum steroid and peptide hormone concentrations monitored at 3 - day intervals during the treatment and the preceding control cycle . Concentrations of cytosol and nuclear estrogen receptors ( ERC and ERN , respectively ) and progestin receptors ( PRC and PRN ) were also measured from endometrial biopsies taken on the 24th day of the control and treatment cycle . In addition , an extensive monitoring of clinical chemical and hematological tests from the blood samples were performed . Serum estradiol and progesterone concentrations were significantly decreased during the treatment cycle , suggesting that interferon interacts in vivo with the function of both FSH and LH . No significant changes were observed in the serum peptide hormone concentrations measured ( FSH , LH , prolactin , insulin , growth hormone and TSH ) ; neither were the levels of endometrial ERC , ERN , PRC and PRN affected by interferon administration . As expected , interferon administration resulted in decreased leukocyte counts . Moreover , an increasing tendency in the activities of serum alkaline phosphatase and gamma - glutamyltransferase during the interferon therapy shows that interferon may slightly interfere with the liver function . These results suggest that one of the mechanisms by which interferon treatment may affect the growth of hormone - dependent neoplasms could be the interaction with production and / or function of circulating hormonal compounds . [ Glucocorticoid receptor level in the blood leukocytes in different acute diseases ] Content of glucocorticoid receptors in cytosol of blood leukocytes , concentration of cortisol and amount of leukocytes in blood were studied in 20 patients with acute impairments within the second day of the disease . Content of receptors in cytosol of blood leukocytes was studied using 3H - triamcinolone acetonide . Distinct increase in amount of the leukocyte glucocorticoid receptors was found in patients with poisoning by dichlorethane and hypnotic drugs under conditions of acute myocardial infarction . In acute pancreatitis content of the leukocyte receptors was not altered as compared with controls . Concentration of endogenous cortisol was increased in blood of all the patients , except of the cases of acetate intoxication . Reverse correlation was observed between concentration of cortisol in blood and content of glucocorticoid receptors in leukocytes . But in the patients with acute pancreatitis the decrease in content of leukocyte glucocorticoid receptors was not observed although there was an increase in cortisol concentration in blood . The role of glucocorticoid receptors in immunological processes under conditions of purulent complications and possibility to regulate the metabolism in leukocytes Therapeutic concentrations of glucocorticoids suppress the antimicrobial activity of human macrophages without impairing their responsiveness to gamma interferon . By exposing human blood - derived macrophages and alveolar macrophages in vitro to dexamethasone , we showed in these studies that glucocorticoids markedly suppress the antimicrobial activity of macrophages but not macrophage activation by lymphokines . As little as 2 . 5 X 10 ( - 8 ) mol / liter of dexamethasone prevented macrophages from inhibiting germination of Aspergillus spores or from eliminating ingested bacteria such as Listeria , Nocardia , or Salmonella . Damage to macrophage function was inhibited by progesterone and appeared to be receptor - mediated . In accordance with in vivo observations , dexamethasone required 24 - 36 h to suppress antimicrobial activity . While glucocorticoids interfered with base - line activity of macrophages , dexamethasone concentrations comparable to drug levels in patients had no effect on macrophage activation . Proliferating lymphocytes and gamma - interferon thus increased the antimicrobial activity of phagocytes exposed to glucocorticoids over that of control cells . Macrophage activation and correction of the dexamethasone effect by gamma - interferon , however , was dependent on the pathogen . The lymphokine enhanced the antimicrobial activity of dexamethasone - treated macrophages against Listeria and Salmonella but not against Aspergillus or Nocardia . Dexamethasone - induced damage to the antimicrobial activity of human macrophages in vitro parallels observations that glucocorticoids render laboratory animals susceptible to listeriosis and aspergillosis by damaging resident macrophages . Suppression of macrophage antimicrobial activity should thus be considered when treating patients with glucocorticoids ; its prevention by gamma - interferon might be beneficial for some but not all pathogens . Interleukin 2 receptor ( Tac antigen ) expression in HTLV - I - associated adult T - cell leukemia . Interleukin - 2 ( IL - 2 ) is a lymphokine synthesized by some T - cells following activation . Resting T - cells do not express IL - 2 receptors , but receptors are rapidly expressed on T - cells following interaction of antigens , mitogens , or monoclonal antibodies with the antigen - specific T - cell receptor complex . Using anti - Tac , a monoclonal antibody that recognizes the IL - 2 receptor , the receptor has been purified and shown to be a Mr 33 , 000 peptide that is posttranslationally glycosylated to a Mr 55 , 000 mature form . Normal resting T - cells and most leukemic T - cell populations do not express IL - 2 receptors ; however , the leukemic cells of the 11 patients examined who had human T - cell lymphotropic virus - associated adult T - cell leukemia expressed the Tac antigen . In human T - cell lymphotropic virus - I infected cells , the Mr 42 , 000 long open reading frame protein encoded in part by the pX region of this virus may act as a transacting transcriptional activator that induces IL - 2 receptor gene transcription , thus providing an explanation for the constant association of IL - 2 receptor expression with adult T - cell lymphotropic virus - I infection of lymphoid cells . The constant expression of large numbers of IL - 2 receptors which may be aberrant may play a role in the uncontrolled growth of adult T - cell leukemia cells . Two patients with Tac - positive adult T - cell leukemia have been treated with the anti - Tac . One of the patients had 6 - and 3 - mo remissions of his leukemia following two courses of therapy with this monoclonal antibody directed toward this growth factor receptor . Lymphocyte glucocorticoid receptor binding in depressed patients with hypercortisolemia . Despite elevated levels of serum and urinary cortisol , patients with depressive illness manifest none of the clinical stigmata of glucocorticoid excess . This hypercortisolemia in the absence of clinical effects suggests a state of hormone resistance and could be mediated by alterations in the glucocorticoid receptor . Earlier studies have shown that small doses of glucocorticoids cause a decrease in glucocorticoid receptor binding in normal human lymphocytes . White cells from depressed patients with significant hypercortisolemia would be expected to show a similar change in receptor concentration if peripheral tissues are adequately exposed to and sensitive to the hormone . In this study we compared the binding of [ 3H ] dexamethasone to lymphocytes from normal subjects and depressed patients with hypercortisolemia . Lymphocytes from normal subjects had a mean receptor concentration of 10 . 2 + / - 0 . 66 fm / 10 ( 6 ) cells ( S . E . M . ) and a dissociation constant of 4 . 8 + / - 0 . 47 nM . Lymphocytes from depressed patients with abnormal 0800 h serum cortisol after dexamethasone had a mean receptor concentration of 8 . 8 + / - 0 . 75 fm / 10 ( 6 ) cells , which was not significantly different from that in lymphocytes from normal subjects or from depressed subjects with normal post - dexamethasone cortisol levels ( 9 . 4 + / - 0 . 95 fm / 10 ( 6 ) cells ) . Lymphocytes from depressed patients with elevated urinary free cortisol excretion ( UFC ) also had normal receptor concentration and binding affinity for dexamethasone . The lack of a change in lymphocyte glucocorticoid receptor concentration in the presence of cortisol excess suggests the possibility that hypercortisolemia in depressive illness represents a state of peripheral glucocorticoid resistance . Structure and regulation of the glucocorticoid hormone receptor . The glucocorticoid receptor is an intracellular protein which possesses three distinct domains , one that binds agonist and antagonist steroids , one that binds DNA , and one that binds anti - receptor antibodies and is required for glucocorticoid modulation of gene expression . In intact cells , receptor number , affinity and activity can change in response to factors that bind to the receptor , or that act indirectly through ill - defined mechanisms which may include resumption or arrest of cell cycling and variations in intracellular calcium ion concentrations . Some of these factors appear to exert their effect by controlling critical receptor properties such as ATP - dependent phosphorylation , integrity of thiol groups , and exposure of key amino acid residues . Glucocorticoid agonists promote the ' transformation ' of the receptor into the DNA - binding state , which is competent for modulating gene expression . Glucocorticoid antagonists are steroids that interact with the receptor but either fail to produce a stable complex or produce a stable but inefficient complex . Although substituent groups that confer agonist or antagonist activity to the steroid have been identified , the molecular determinants of this difference at the receptor level remain unknown . Most in vitro and in vivo data on receptor regulation can be accommodated by postulating the existence of an intracellular cycle that involves five states of the receptor . The active free receptor is phosphorylated , reduced , and presumably oligomeric ( state A ) . Following binding of an agonist ( state B ) , it can become transformed by dissociation into its subunits and dephosphorylation ( state C ) . The transformed receptor then interacts with chromatin ( state D ) . Dissociation of the steroid and oxidation of receptor thiol group ( s ) lead to the inactive receptor form ( state E ) . Reduction and rephosphorylation of the receptor enable it to bind steroids again so that the cycle is closed . Thermodynamics of steroid binding to the human glucocorticoid receptor . The thermodynamics of the interaction of glucocorticoids with their receptor were studied in cytosol from human lymphoblastoid cells . The rate and affinity constants of dexamethasone and cortisol between 0 degree and 25 degrees C were calculated by curve - fitting from time - course and equilibrium kinetics . The data were consistent with a simple reversible bimolecular interaction . Arrhenius and Va n ' t Hoff plots were curvilinear for both steroids . At equilibrium , the solution for the equation delta G = delta H - T X delta S ( eqn . 1 ) was ( in kJ X mol - 1 ) - 47 = 36 - 83 ( dexamethasone ) and - 42 = - 9 - 33 ( cortisol ) at 0 degree C . Enthalpy and entropy changes decreased quasi - linearly with temperature such that , at 25 degrees C , the respective values were - 50 = - 75 + 25 and - 43 = - 48 + 5 . Thus , for both steroids , the interaction was entropy - driven at low temperature and became entirely enthalpy - driven at 20 degrees C . Thermodynamic values for the transition state were calculated from the rate constants . For the forward reaction , eqn . ( 1 ) gave 45 = 84 - 39 ( dexamethasone ) and 46 = 60 - 14 ( cortisol ) at 0 degree C , and 44 = 24 + 20 ( dexamethasone ) and 46 = 28 + 18 ( cortisol ) at 25 degrees C . These data fit quite well with a two - step model [ Ross & Subramanian ( 1981 ) Biochemistry 20 , 3096 - 3102 ] proposed for ligand - protein interactions , which involves a partial immobilization of the reacting species governed by hydrophobic forces , followed by stabilization of the complex by short - range interactions . On the basis of this model , an analysis of the transition - state thermodynamics led to the conclusion that no more than half of the steroid molecular area is engaged in the binding process . Cell cycle - related changes in number of T - lymphocyte receptors for glucocorticoids and insulin . Enriched human peripheral T - lymphocytes were stimulated with PHA and examined for variations in insulin and glucocorticoid ( dexamethasone ) receptor numbers during the early phases of the cell cycle . Cells in G0 , G1a and G1b phases , where the G1a - G1b transition is an Interleukin 2 dependent event , were quantitated by flow cytometry . Few but significant numbers of glucocorticoid receptors ( 2700 / cell ) and no insulin receptors ( - 1 / cell ) were found in the resting ( G0 ) phase . As cells entered the G1a phase the specific binding of dexamethasone increased and of insulin took place . Although the specific binding further increased as T - cells entered the G1b phase ( as measured at 44 h of incubation and using hydroxyurea - treated cells ) , the major changes in the specific binding of dexamethasone took place during the period 16 - 20 h after stimulation . Based on these findings , it is concluded that both receptor types ( cell membrane and cytoplasmic receptors ) are being formed and increased at G1 phase prior to cell proliferation , indicating the importance of G1 phase in immunoregulation . Glucocorticoid receptors and cortico - sensitivity in a human clonal monocytic cell line , CM - SM . CM - SM is a clonal line of human precursor mononuclear phagocytes inducible to macrophage differentiation in response to the tumor promoter phorbol ester 12 - O - tetradecanoyl - phorbol - 13 - acetate ( TPA ) . Untreated CM - SM cells contain single class , high - affinity ( KD = 4 . 0 X 10 ( - 9 ) M ) glucocorticoid - specific receptor sites ( approximately 60 , 000 per cell ) , as measured by a whole cell assay , at 37 degrees C , using [ 3H ] triamcinolone acetonide ( TA ) . Exposure of CM - SM to dexamethasone ( DEX ) produced a progressive , dose - and time - related series of changes in CM - SM cell growth , saturation density , morphology , and functional properties , with half - maximal effects at about 10 ( - 9 ) M for DEX . TA - receptor sites rapidly decreased ( about 70 % ) after DEX treatment , without any apparent change in steroid specificity and affinity . After 5 days in culture with a saturating concentration ( 3 . 6 X 10 ( - 8 ) M ) of hormone , the cells reached a saturation density of about 9 . 0 X 10 ( 6 ) viable cells / ml ( about 4 . 0 X 10 ( 6 ) viable cells / ml in the controls ) , while the modal volume of the resulting cell population was approximately 60 % , as compared to the volume of untreated cells . DEX - treated cells appeared less differentiated than controls , as assessed by combined morphologic , antigenic , and cytoenzymatic analyses . DEX almost completely inhibited TPA activation of the following macrophage functions : adherency to the culture plate , expression of lysosomal enzymes , Fc and C3 receptors , and stimulation of phagocytosis . After removal of DEX , the cells , within a few passages , returned to a state apparently identical to the untreated controls and could be induced to macrophage differentiation in response to TPA . Acute lymphoblastic leukemia in children : current status , controversies , and future perspective . Disease - free survival ( DFS ) in childhood ALL is 60 % , and survival in good , average , and poor prognostic groups defined by initial WBC and age is 90 , 60 , and 45 % , respectively . Additional immunological , morphological , biochemical , cytokinetic , and cytogenetic factors have been identified , illustrating the heterogeneity of ALL and its derivation from malignant clones at various stages of differentiation and with varying rates of proliferation . Of biologic importance , these factors may refine further the characteristic features of clinically - determined prognostic groups . Multivariate analysis of large prospective trials with homogeneous therapy will be required to determine the independent prognostic importance of these factors . Current treatment strategies in ALL include ( 1 ) tailoring therapy and its intensity to prognostic groups ; ( 2 ) multiple - drug combinations in induction ; ( 3 ) early use of intrathecal ( IT ) methotrexate ( MTX ) ; ( 4 ) CNS prophylaxis with IT MTX alone in good prognosis patients and combined cranial radiation ( CXRT ) , 1800 rads plus IT MTX , in average and poor prognosis patients . Current studies show a CNS relapse rate of 5 % in all prognostic groups . Late neuropsychological defects caused by cranial XRT and IT MTX have prompted programs designed to reduce the potential late toxicity of CNS prophylaxis . More pronounced in younger children , these abnormalities include decreased IQ , visual - motor incoordination , poor performance in mathematics , and memory dysfunction . Until 1980 , more intensive induction , consolidation , and maintenance therapy had failed to prolong DFS in children with a poor prognosis . In West Germany ( Berlin - Frankfurt - Muenster protocol ) a 70 to 75 % DFS is seen in all patients regardless of initial WBC , suggesting that effective therapy will override prognostic factors . Ultra - high - dose MTX , without cranial radiation , is also showing promise in poor prognosis patients . Other issues include the optimal duration of therapy , the role of testicular biopsies , and prophylactic testicular radiation . Recent studies suggest that prognostic factors lose their significance after 2 years of continuous complete remission and that 2 years of maintenance therapy is adequate . Bilateral open - wedge testicular biopsies have identified occult testicular disease in 8 to 10 % of males . A unified approach to children with leukemia / lymphoma , a group with a particularly poor prognosis , utilizing NHL - type therapy may be more effective than conventional ALL therapy . ( ABSTRACT TRUNCATED AT 400 WORDS ) Glucocorticoid receptor and in vitro sensitivity to steroid hormones in human lymphoproliferative diseases and myeloid leukemia . The glucocorticoid receptor ( GR ) quantitation by a whole - cell assay and / or cytosol technique and the in vitro sensitivity to steroids have been assessed in peripheral blood cells from normal donors and patients with chronic lymphatic leukemia ( CLL ) , acute lymphoblastic leukemia ( ALL ) , lymphosarcoma cell leukemia ( LSCL ) , acute nonlymphatic leukemia ( ANLL ) , and chronic myeloid leukemia ( CML ) . Within the lymphoproliferative diseases , ALL cells exhibited the highest GR concentration ( regardless of the method used ) and the highest in vitro inhibition of spontaneous [ 3H ] thymidine ( [ 3H ] TdR ) uptake by glucocorticoids . A significant relationship between GR concentration ( whole - cell assay ) and in vitro sensitivity to dexamethasone was also found . On the contrary , CLL cells presented the highest sensitivity to glucocorticoids in PHA - stimulated cell cultures . Cells from the only two ALL patients who did not undergo a remission after glucocorticoid - inclusive chemotherapy had both the lowest in vitro sensitivity to dexamethasone and the lowest GR concentration with whole - cell assay . Concerning myeloid leukemia , ANLL patients had GR concentrations slightly higher than those found in the ALL group but exhibited the lowest degree of inhibition of spontaneous [ 3H ] TdR uptake by dexamethasone ( stimulatory effects occurred in some cases ) . CML cells exhibited an inhibition degree by in vitro glucocorticoids significantly higher than that of ANLL cells but not different from that of lymphoproliferative diseases . No clear relationship among GR pattern , in vitro cell sensitivity to glucocorticoids , and clinicohematologic parameters was observed in myeloid leukemia - bearing patients . Glucocorticoid receptors and in vitro corticosensitivity of peanut - positive and peanut - negative human thymocyte subpopulations . In 6 human thymus glands , the immature subset of thymocytes was separated from the more mature one , by differential peanut lectin agglutination . These 2 cell subpopulations were analyzed for glucocorticoid receptor content by using a whole cell assay , with ( 3H ) - triamcinolone acetonide as tracer . The unagglutinated thymocytes ( peanut negative ) contained about 2 times more receptor sites per cell than agglutinated ( peanut positive ) ones ( 7650 + / - 1550 S . D . verus 3195 + / - 896 S . D . ) . The affinity for steroid was similar in both cell subsets , as was the stereospecificity for glucocorticoids , the time - course of steroid - receptor association , and cytoplasmic to nuclear translocation . Despite the greater number of glucocorticoid receptor sites , the peanut - negative thymocyte subpopulation did not differ from the peanut - positive one in its sensitivity to the inhibitory effects of triamcinolone acetonide , as determined by measurements of the incorporation of radiolabeled precursors of protein and DNA . Moreover , the peanut - negative subset appeared more resistant in vitro to the steroid - induced cell lysis as compared to the peanut - positive one . Thus , our data suggest that glucocorticoid receptor density and corticosensitivity are not directly correlated and that the number of glucocorticoid receptor sites may be dependent on the degree of immunologic maturation Defective binding and function of 1 , 25 - dihydroxyvitamin D3 receptors in peripheral mononuclear cells of patients with end - organ resistance to 1 , 25 - dihydroxyvitamin D . Lectin - induced DNA synthesis by peripheral mononuclear cells from 17 normal donors was inhibited ( 40 - 60 % ) by 1 , 25 - dihydroxyvitamin D3 ( 1 , 25 [ OH ] 2D3 ) at physiological concentrations ( 10 ( - 10 ) - 10 ( - 9 ) M ) . The lymphocytes acquire specific receptors for 1 , 25 ( OH ) 2D3 upon activation by the lectins . This process precedes the inhibitory effect of 1 , 25 ( OH ) 2D3 . We studied lymphocytes from six patients from four different kindreds with the syndrome of hereditary end - organ resistance to 1 , 25 ( OH ) 2D ( the so - called vitamin D - dependent rickets type II ) . In five patients ( three kindreds ) peripheral blood mononuclear cells did not acquire receptors for 1 , 25 ( OH ) 2D3 upon phytohemagglutinin - induced activation . Moreover , in contrast to normal lymphocytes , the mitogenic stimulation of these patients ' lymphocytes by phytohemagglutinin and concanavalin A was not inhibited by 1 , 25 ( OH ) 2D3 . Activated lymphocytes of the sixth patient from a fourth kindred exhibited normal binding of [ 3H ] 1 , 25 ( OH ) 2D3 but the hormone failed to inhibit the mitogenic stimulation . A similar pattern of the vitamin D effector system was previously observed in fibroblasts cultured from skin biopsies of the same group of patients . The conclusions from these findings are : ( a ) the inhibition of mitogenic stimulation by 1 , 25 ( OH ) 2D3 is mediated by specific functional receptors to the hormone ; and ( b ) the receptors for 1 , 25 ( OH ) 2D3 in mononuclear cells are probably controlled genetically by the same mechanisms as the effector system in well - characterized target organs of the hormone , such as intestine and kidney . Glucocorticoid receptors of mononuclear leukocytes from myasthenia gravis patients . The present study was performed to analyse glucocorticoid receptor ( GR ) binding in peripheral blood mononuclear leukocytes ( MNL ) from 39 myasthenia gravis ( MG ) patients ( unoperated patients ( n = 13 ) , thymectomized patients ( n = 14 ) and patients receiving glucocorticoids : thymectomized ( n = 11 ) and unoperated ( n = 6 ] . A whole cell binding assay with 3 ( H ) dexamethasone was used . GR mean values were significantly higher in the MNL of MG patients ( thymectomized or not ) not receiving glucocorticoid than in the MNL of healthy donors . Affinity was within the normal range . Sex , age or clinical forms of illness did not influence the results . In patients receiving prednisone ( Pd ) the GR values were significantly lower than in MG patients without Pd therapy , independent of Pd dose or time of administration . No differences in receptor binding between normal subjects and MG patients receiving Pd have been found . Immunological interference of high dose corticosteroids . High - dose corticosteroids ( HDC ) will influence cellular as well as humoral participants of the immune response . The lymphoid tissue will decrease in size and weight after prolonged treatment with HDC . Lymphocyte functions will be impaired . Reduced synthesis of B - as well as T - lymphocytes will be seen . The inhibitory effect on B - cell function can be observed both as decreased serum levels of immunoglobulins and as impaired binding of antibodies and complement to the cellular surface . Reduced T - cell function indicated by impaired stimulation by PHA and porkweed as well as by impaired lymphokinin effects on leukocyte migration inhibition has been reported . Reduced lymphocyte adherence to antigen and suppressed lymphocyte reaction have also been observed . Humoral factors involved in chemotaxis , opsonisation , phagocytosis , vascular permeability leading to leakage of fluid and cells and factors involved in lysis of antigens are impaired . This can be explained partly by the observed reduced complement activation via the alternative as well as the classical pathway in association with HDC therapy . Acute processes with increased vascular permeability and accumulation of leukocytes as impairing factors could be influenced beneficially by HDC therapy . This positive effect can be seen in treatment of septic shock or rejection of a transplant . However , if sepsis or rejection is not rapidly reversed , complications such as multisystem organ failure and bacteremia are prone to appear . Identification of human leukemic glucocorticoid receptors using affinity labeling and anti - human glucocorticoid receptor antibodies . Antisera raised against human lymphoid glucocorticoid receptors were used in combination with the glucocorticoid receptor affinity label [ 3H ] dexamethasone 21 - mesylate [ ( 3H ] DM ) to identify the glucocorticoid receptors of the human B - lymphoblastoid cell line IM - 9 and the human T - cell leukemic cell line CEM - C7 . Antisera were obtained following immunization of New Zealand White rabbits with [ 3H ] triamcinolone acetonide [ ( 3H ] TA ) - glucocorticoid receptor complexes partially purified by two - stage DNA - cellulose chromatography . The presence of anti - human glucocorticoid receptor antibodies was verified by : ( a ) adsorption of [ 3H ] TA - receptor - antibody complexes to Protein A ; ( b ) a shift to higher apparent molecular weight in the elution position from Sephacryl S300 of [ 3H ] TA - receptor complexes incubated with immune serum ; and ( c ) the ability of immune serum to displace [ 3H ] TA - receptor complexes on sucrose gradients . These antibodies also recognized rat liver and murine S49 cell glucocorticoid receptors . Sodium dodecyl sulfate - polyacrylamide gel electrophoresis of [ 3H ] DM - labeled IM - 9 cytosol identified a major competable band with a molecular weight of approximately 90 , 000 , three minor competable components with molecular weights of approximately 78 , 000 , approximately 51 , 000 , and approximately 38 , 500 , and at least 21 other noncompetable components . Following immunoprecipitation of [ 3H ] DM - labeled cytosol with immune serum , only the Mr 90 , 000 and 78 , 000 components were seen . Sodium dodecyl sulfate - polyacrylamide gel electrophoresis of [ 3H ] DM - labeled CEM - C7 cytosol revealed a larger number of [ 3H ] DM - labeled components . However , after immunoprecipitation of [ 3H ] DM - labeled CEM - C7 cytosol , a predominant competable component with a molecular weight of 90 , 000 was easily identified . This component was markedly diminished when cytosols from the glucocorticoid receptor - deficient cell line ICR - 27 were used . Thus , the combination of affinity labeling and anti - human glucocorticoid receptor antibodies is capable of providing direct physical identification of human lymphoid glucocorticoid receptors . Effect of thymosin on glucocorticoid receptor activity and glucocorticoid sensitivity of human thymocytes . Incubation with thymosin fraction 5 , ( TMS F5 at 300 micrograms / ml ) a partially purified thymic factor , reduced the steroid binding activity of human infant thymocytes from 9 . 6 + / - 2 . 1 fmole / ml to 5 . 0 + / - 2 . 0 fmole / ml . The glucocorticoid receptor activity in normal infant thymocytes was found to be 2 , 146 + / - 726 ( s . d . ) sites per cell with dissociation constant of 1 . 4 + / - 0 . 6 X 10 ( - 8 ) M . TMS F5 also increased the resistance of human thymocytes to the cytolytic effect of dexamethasone ( 2 . 5 X 10 ( - 8 ) M ) to 168 . 6 + / - 30 . 2 % of control ( P less than 0 . 01 ) . In animals , medullary and peripheral blood T cells are more resistant to glucocorticoids than immature thymic T cells . The results show that thymosin can induce changes consistent with differentiation in human thymocytes . These in vitro results are consistent with a physiological role of thymosin in intrathymic T cell maturation in man . Incubation of a human malignant thymus derived T cell line ( MOLT 3 ) with TMS F5 also resulted in a significant reduction of the number of steroid binding sites to 44 . 2 + / - 15 . 3 % of control ( P less than 0 . 05 ) , but TMS F5 did not significantly reduce the glucocorticoid sensitivity of MOLT 3 cells . Specific high - affinity receptors for 1 , 25 - dihydroxyvitamin D3 in human peripheral blood mononuclear cells : presence in monocytes and induction in T lymphocytes following activation . Human peripheral blood monocytes have high affinity binding sites for 1 , 25 - ( OH ) 2D3 ( Kd 0 . 14 nM , sedimentation coefficient 3 . 7S ) . Resting human peripheral blood T lymphocytes , however , do not have a demonstrable 1 , 25 - ( OH ) 2D3 receptor . After activation with phytohemagglutinin the T cells exhibit the receptor within 24 h , and this expression is blocked by cycloheximide . The receptor in activated T lymphocytes has a sedimentation coefficient of 3 . 7S and a high affinity ( Kd 0 . 10 nM ) for the ligand . Effects of chronic glucocorticoid excess in man on insulin binding to circulating cells : differences between endogenous and exogenous hypercorticism . We measured [ 125I ] insulin binding to circulating monocytes or erythrocytes from 16 patients with chronic glucocorticoid excess , 9 chronically treated with prednisone and 7 with adrenocortical hyperfunction . With monocytes , [ 125I ] insulin binding was iincreased in all patients . Analysis of binding data indicated that increased binding in patients treated with prednisone was due to an ncrease in receptor concentration , whereas in patients with adrenocortical hyperfunction , it was due to an increase in receptor affinity . With erythrocytes from patients with adrenocortical hyperfunction there was an increase in receptor affinity and a decrease in receptor concentration , so that the binding of [ 125I ] insulin was normal . The disparity of results between endogenous and exogenous hypercorticism , between the two cell types , and between the present studies and previous studies suggest that the effects of glucocorticoid excess on the insulin receptor are extremely complex and wide - ranging and that in this condition , extrapolations in humans from data with circulating cells to liver and muscle may not be appropriate . Reduced level of cellular glucocorticoid receptors in patients with anorexia nervosa . Specific glucocorticoid receptors were measured in circulating mononuclear leukocytes from 12 patients with anorexia nervosa and 21 healthy control subjects . Cells from patients were found to contain a significantly ( p less than 0 . 01 ) lower level of glucocorticoid receptor ( 3830 + / - 210 sites / cell , mean + / - SE ) than those from controls ( 4930 + / - 250 sites / cell ) . A partial glucocorticoid receptor defect may well explain the abnormal cortisol metabolism and glucocorticoid resistance commonly found in patients with anorexia nervosa . Regulation of the glucocorticoid receptor in human lymphocytes . The presence of a glucocorticoid receptor in human lymphocytes is well established , but factors affecting its regulation have not been described . Using a competitive binding whole cell assay , we have examined the binding of [ 3H ] - dexamethasone at 24 and 37 degrees C in untreated normal subjects and in healthy subjects taking various glucocorticoid preparations . At 24 degrees C normal human lymphocytes had 6000 binding sites / cell and a dissociation constant of 4 x 10 ( - 9 ) M . The administration of 1 mg of dexamethasone , 5 mg of prednisone , and 37 . 5 mg of cortisone acetate resulted in a 30 % decrease in binding sites after 1 week with no change in binding affinity . No changes in the number of binding sites was noted before 1 week and the diminished number persisted for 1 week after discontinuation of glucocorticoid treatment . Lymphocytes from hospitalized patients taking 40 - 60 mg of dexamethasone daily demonstrated the same change in number of binding sites that was seen in normal subjects taking 1 mg of dexamethasone . When binding assays were carried out at physiologic temperature there was the same decrease in number of binding sites after dexamethasone administration , and in addition , there was a two - fold increase in binding affinity . Glucocorticoid administration results in a time - dependent decrease in the number of lymphocyte glucocorticoid binding sites that is independent of the type of glucocorticoid administered . This is the first in vivo demonstration that glucocorticoids modulate their own receptors in man . Immunoglobulin localization in benign and malignant lesions of the human mammary gland . Using direct imunofluorescence , lesions from 266 human breast specimens were studied for the presence of IgA , IgM , or IgG localization . The lesions included benign elements from 66 subcutaneous mastectomy specimens in which the absence of simultaneous breast malignancy was documented , primary breast carcinomas from 153 mastectomy specimens , and 47 biopsies containing metastatic breast cancer . A statistically significant association of IgA and IgM with benign lesions was contrasted to the association of IgG with malignant lesions . In both primary and metastatic lesions , IgG localization was associated with estrogen - receptor - poor primary cancers as compared with estrogen - receptor - rich primary cancers . Among primary breast cancer patients , IgG localization in the tumor correlated with relative lymphopenia . A shorter disease - free interval was noted in association with IgG localization among the metastatic breast lesions . No statistically significant association between stage of disease and immunoglobulin presence was demonstrable . Moderate - to - severe intraductal epithelial hyperplasias were more often associated with immunoglobulin G localization that were other benign lesions Correlation of steroid receptors with histologic differentiation in mammary carcinoma . A Singapore experience . Cancer of the breast is the most common tumor in females in Singapore , with the rate of 20 . 7 per 100 , 000 per year ( 1977 estimate ) , which is predicted to increase to 29 . 8 per 100 , 000 women per year by 1995 . A detailed histopathologic review of 50 primary breast cancer tumors analyzed for estrogen receptor ( ER ) level was carried out and a variety of morphologic features correlated with ER results to identify any factors that will improve the management and prognosis for breast cancer . Cytosol was incubated with 3H - estradiol in the presence and absence of cold diethylstilbestrol , and bound and free hormone were separated by Dextran - coated charcoal method . Tumors binding more than 5 fmol / mg cytosol protein were classified as ER - positive . Progesterone receptor ( PR ) level was analyzed in some specimens with the use of a similar method . Most of the patients were Chinese ( 90 % ) . Three patients were Malays , one was Indian , and one was European in this series . Results indicated that there was strong correlation between ER level , age , and histologic grade of the tumors . No correlation existed between absence or presence of lymph node metastases and ER . Although there was a trend for ER - positive tumors to have a low - grade lymphocytic infiltration , the difference was not statistically significant . Mononuclear cells infiltrating human mammary carcinomas : immunohistochemical analysis with monoclonal antibodies . Breast carcinomas were examined by the immunoperoxidase technique using antisera specific for lymphocyte subsets , monocytes , NK cells and major histocompatibility antigens ( HLA - A , - B , - C ; Ia - like ) . Sixty - four per cent of the patients had a moderate or strong mononuclear cell infiltration , 77 % of the patients without mononuclear cell infiltration had receptors for estrogens as compared to 51 % of the patients with infiltration . The majority of the infiltrating mononuclear cells were T cells ; generally the OKT8 cells were predominant . The Leu 3A / OKT8 cell ratio was not related to histological type , tumor size , age of the patient or presence of metastases . Some of the T cells had the Ia antigen and were thus probably activated . The B cells were either absent or less numerous than the T cells . There was no relation between their distribution and the various parameters studied . A few monocytes were heterogeneous according to their markers ( OKM I and acid phosphatase ) . In 6 cases only there was a strong infiltration of mononuclear cells positive for acid phosphatase . The number of the natural killer cells was also low . Only a few mononuclear infiltrating cells had receptors for transferrin . There was a positive correlation between the inflammatory infiltration and the presence of HLA class - I antigens on tumor cell s . Some of the antisera specific for lymphocyte subsets also stained the breast carcinoma cells . The great variations in the subsets of mononuclear cells in breast carcinomas may correspond to various systems of defense against neoplasm . A case of male pseudohermaphroditis with normal androgen receptor binding and 47 , XYY karyotype . A case of male pseudohermaphroditis with 47 , XYY karyotype in blood and cutaneous fibroblasts is described . The plasma testosterone response to HCG stimulation was slightly below the normal range on two occasions suggesting a deficit of gonadal function . A study of the receptors for dihydrotestosterone in fibroblasts of genital and nongenital skin showed a normal concentration of receptors in genital skin ; 5 - alpha - reductase activity in fibroblasts of the genital skin was low , but the plasma relationship testosterone / dihydrotestosterone under HCG stimulation was normal . The diagnostic possibility of a complete testicular feminization syndrome with normal receptors for dihydrotestosterone is commented on . 1 , 25 - Dihydroxyvitamin D3 inhibits antigen - induced T cell activation . The proliferative response of murine spleen and thymus cells to antigen but not to lectin was inhibited by the active metabolite of vitamin D3 , 1 , 25 - ( OH ) 2D3 . To directly examine the effect of 1 , 25 - ( OH ) 2D3 on T cell activation in the absence of other complicating interactions , we utilized a panel of cloned Ia - restricted T cell hybridomas that secrete IL 2 on activation by cloned Ia - bearing stimulator cells ( TA3 ) or when stimulated by mitogen . Physiologic concentrations of 1 , 25 - ( OH ) 2D3 ( 0 . 01 to 0 . 1 nm ) inhibited the antigen - induced secretion of IL 2 by several of these T cell hybridomas . This inhibition was dependent on the concentration of the free hormone and could be overcome by increasing the number of Ia - bearing stimulator cells used . Pretreatment of the T hybridoma but not the TA3 stimulator cell with 1 , 25 - ( OH ) 2D3 resulted in inhibition of activation . These results are consistent with the finding that specific 1 , 25 - ( OH ) 2D3 receptors are present on the T cell hybridomas but are lacking in TA3 cells . 1 , 25 - ( OH ) 2D3 failed , however , to inhibit the activation of the T cell hybridomas by lectin or by an anti - Thy - 1 antibody . These findings suggest that 1 , 25 - ( OH ) 2D3 may be interfering with early events of antigen - induced T cell activation , perhaps by hindering T cell recognition of the relevant antigen on stimulator cell surfaces . This system should prove useful in studying the molecular mechanisms by which 1 , 25 - ( OH ) 2D3 acts to inhibit T cell activation and subsequent IL 2 production . Glucocorticoid receptors and steroid sensitivity in normal and neoplastic human lymphoid tissues : a review . The determination of estrogen and progesterone receptors in breast cancer has been shown to be useful in predicting the response to endocrine therapy . Given their well - known inhibitory effects on lymphoid tissue , glucocorticoids have been used widely in the treatment of leukemia . Given these facts , over the last 10 years , several investigators have measured the number of glucocorticoid receptors in normal and neoplastic lymphoid tissue to see whether their number correlated with glucocorticoid responsiveness in vitro or in vivo . No clear correlation could be established between the level of glucocorticoid receptor and the in vitro action of steroids in normal and neoplastic lymphoid tissue . In contrast , attempts to correlate glucocorticoid receptor levels in acute lymphocytic leukemia to in vivo steroid responsiveness and immunological type using the whole - cell - binding assay for receptor determination and selecting the patients according to age and immunological criteria have been more successful . [ Glucocorticoid receptors in normal human lymphocytes ] Glucocorticoid ( GC ) receptors were studied in intact lymphocytes from 11 donors . GC binding parameters were found to be highly reproducible in repeated experiments with lymphocytes . It was shown that GC receptors in donors ' lymphocytes could be distributed into two different classes similarly to the pattern seen in skin fibroblasts . Human lymphocytes are an adequate object for studying genetically determined variability of GC receptors and its clinical importance . Specific estrogen binding sites in human lymphoid cells and thymic cells . The binding of estrogen in preparations of human peripheral blood mononuclear cells , as well as by splenic and thymic cells is demonstrated by three different approaches ( Dextran - coated charcoal method , whole cell assay , and gel filtration on a sepharose 4B column ) . Scatchard ' s analysis of [ 3H ] - moxestrol ( R2858 ) and [ 3H ] - estradiol binding proves the existence of a single class of receptor sites having a dissociation constant of 0 . 18 - 2 . 4 X 10 ( - 9 ) M . Physicochemical properties of the binder , including binding capacity and steroid specificity , are quite similar to those reported for the thymus of small mammalian species or human thymoma . Administration of fibroblast interferon to patients with advanced breast cancer : possible effects on skin metastasis and on hormone receptors . Eleven patients with metastasized breast cancer received 8 intramuscular injections of 6 x 10 ( 6 ) units of human fibroblast interferon over a period of 40 days . The injections did not cause local irritation or inflammation . Fever occurred in only 1 of the 11 patients . Although several types of metastases were monitored , only skin nodules consistently ( 10 out of 11 patients ) exhibited changes that were suggestive of a therapeutic effect of the treatment regimen : either a simple decrease in size of some nodules or central necrosis accompanied by an inflammatory reaction . NK - activity of peripheral blood leukocytes was significantly increased after administration of the first dose ; the effect of subsequent injections was less clear . Receptors for estrogens and progestogens were increased in the tumor biopsies of 2 out of 2 and 5 out of 6 patients tested respectively . Decreased glucocorticoid receptor binding in adrenal insufficiency . To examine the effect of glucocorticoid deficiency on the glucocorticoid receptor , we examine the binding of [ 3H ] dexamethasone to lymphocytes in normal subjects and patients with adrenal insufficiency before and after glucocorticoid replacement therapy . Using a whole cell competitive binding assay , normal human lymphocytes had 5977 + / - 1487 ( mean + / - SD ) binding sites / cell and a dissociation constant of 10 + / - 2 nM . Lymphocytes from patients with untreated adrenal insufficiency had fewer binding sites ( 3364 + / - 322 ) and a 2 - fold increase in binding affinity ( 5 . 4 + / - 0 . 9 mM ) . The administration of conventional replacement doses of cortisone acetate for 6 months caused no change in receptor number , but was associated with a decrease in binding affinity toward normal . After long term glucocorticoid replacement therapy , binding parameters were similar to those in patients before treatment . The physiological implications of the decreased receptor number and increased binding affinity in adrenal insufficiency remain to be elucidated . Glucocorticoid receptor concentrations and terminal transferase activity as indicators of prognosis in acute non - lymphocytic leukaemia . Activity of terminal deoxynucleotidyl transferase ( TdT ) , adenosine deaminase , and 5 ' nucleotidase and the cellular concentration of glucocorticoid ( dexamethasone ) receptor were determined in 25 patients with acute non - lymphocytic leukaemia . All patients were treated according to a common protocol . Increased activity of TdT ( greater than 0 . 1 unit / microgram DNA ) was found in 11 patients . This group of patients was shown to have higher remission and survival rates ( p = 0 . 06 ) compared with patients with low activity of TdT . The glucocorticoid receptor concentration of the leukaemic blast cells ranged from 0 to 0 . 94 fmol / microgram DNA . Thirteen patients had blast cells with a glucocorticoid receptor concentration over 0 . 22 fmol / microgram DNA . These patients had significantly increased remission and survival rates ( p = 0 . 006 ) compared with those with a low receptor concentration . This finding can not be explained by a difference in sensitivity to glucocorticoids since these were not used as therapeutic agents . Adenosine deaminase and 5 ' nucleotidase activities both varied within two orders of magnitude . No correlation could be found between activities of these enzymes and remission or survival rate . These results show that measurements of TdT activity and the glucocorticoid receptor concentration yield valuable prognostic information in acute non - lymphocytic leukaemia [ 3H ] cortivazol : a unique high affinity ligand for the glucocorticoid receptor . Cortivazol ( CVZ ) and deacylcortivazol ( DAC ) are pyrazolosteroids with potent glucocorticoid activity . In previous work we showed that DAC is 40 - fold more potent than dexamethasone ( DEX ) in lysing leukemic lymphoblasts . To assess the interaction between these atypical steroids and the glucocorticoid receptor , we examined the binding of [ 3H ] CVZ to cytosol from glucocorticoid - sensitive and - resistant variants of the human leukemic cell line CEM C7 . In glucocorticoid - sensitive cells [ 3H ] CVZ causes a 2 - fold induction of glutamine synthetase and binds to a protein in the 4 . 6 S region of high salt sucrose gradients . On DEAE - cellulose chromatography , [ 3H ] CVZ - receptor complexes show a shift from high ( 0 . 25 M KP ) to low salt ( 0 . 09 M KP ) eluting forms upon activation . CVZ competes for a 97 , 000 - dalton protein labeled by [ 3H ] dexamethasone mesylate . Scatchard analysis of the binding of [ 3H ] CVZ in glucocorticoid - sensitive cells revealed a curvilinear plot which resolved into high ( 0 . 4 nM ) and low ( 11 nM ) affinity components . The receptor concentration of the low affinity site ( 0 . 30 pmol / mg protein ) was approximately twice that of the high affinity site ( 0 . 14 pmol / mg protein ) . Dissociation experiments with dilution and / or excess unlabeled CVZ supported the presence of independent sites . In contrast , the binding of [ 3H ] DEX to C7 cytosol revealed a single class of binding sites ( Kd = 1 . 9 nM ; receptor concentration , 0 . 46 pmol / mg protein ) . Examination of the binding of [ 3H ] CVZ using 10 ( - 5 ) M DEX as the competing ligand showed that DEX binds only to the low affinity site detected by [ 3H ] CVZ . In cytosol from a glucocorticoid - resistant cell line with virtually no [ 3H ] DEX binding , [ 3H ] CVZ detected a single high affinity binding site that was similar in dissociation constant ( 0 . 8 nM ) and receptor concentration ( 0 . 13 pmol / mg protein ) to the high affinity site detected in the glucocorticoid - sensitive cell line C7 . A controlled pore glass bead assay for the measurement of cytoplasmic and nuclear glucocorticoid receptors . An assay for the quantitation of cytoplasmic and nuclear glucocorticoid receptors in lymphoid tissue has been developed using controlled pore glass ( CPG ) beads . Soluble receptor - - 3H - steroid complex ( cytosol or nuclear extract ) is adsorbed quantitatively within the crevasses of porous glass beads . Excess labeled steroid as well as most non - specifically bound steroid is easily washed away , leaving the hormone - receptor complex retained by the beads . Bound 3H - steroid is eluted with ethanol and measured for radioactivity . This procedure which is simple , rapid , and highly reproducible is carried out using frozen samples ( stable for many months ) containing as few as 1 X 10 ( 7 ) cells . A comparison of the CPG assay to dextran coated charcoal and a whole cell assay demonstrates that CPG and dextran coated charcoal give equivalent measurements of cytosolic receptor concentration , while the CPG and whole cell assays provide equivalent values for total receptor content . Plasmacytoid blast crisis in B - cell chronic lymphocytic leukemia : effect of estradiol on growth and differentiation in vitro . Evolution of a case of chronic lymphocytic leukemia ( CLL ) into blast crisis was found to be characterized by three unusual features ( 1 ) the phenotype of the emerging blast cells was that of pre - plasmacytoid cells as shown by plasma cell morphology and an immunological phenotype corresponding partially with CLL - or intermediate B - cells , partially with plasma cells ( terminal transferase - , common acute lymphocytic leukemia antigen - , Ia + , surface immunoglobulin heavy chains - , surface kappa light chains + , intracytoplasmic immunoglobulin A + and G + , BA - 1 + , polyclonal gammaglobulin production ) ; ( 2 ) cytogenetic analysis of spontaneous metaphases revealed that in addition to the typical CLL abnormality , trisomy 12 , in all of the cells , an additional translocation between chromosomes 14 and 17 was present in 40 % with a presumptive breakpoint on chromosome 14 ( q12 - 3 ) never described before ( commonly q32 ) and ( 3 ) the progression of the disease was associated with a striking increase in the expression by the transformed cells of specific binding sites for estradiol ( E2 ) due to an actual increase in total cellular receptor proteins and not to a change in receptor affinity for E2 . The functional status of the steroid receptors was confirmed by nuclear transfer of the cytoplasmic hormone - receptor complex upon temperature activation . Since the rise in E2 - receptor display paralleled a large increase in the proliferative activity of the cells as well as a change in their maturation status the question was raised as to whether the E2 - receptor should be considered as a physiological marker of growth rate or of cellular differentiation . Exposure of the patient ' s blast cells to E2 in vitro resulted in cessation of cell growth following at least one mitosis after addition of the inducer as seen from the replacement of the large blasts by small CLL - like cells without definite signs of alteration of the differentiation status . This suggests the association of E2 - receptor expression with control of growth rather than cell maturation . Multiple forms and fragments of cytosolic glucocorticoid receptors from human leukemic cells and normal lymphocytes . Therapy with glucocorticoids is generally more effective in acute lymphoblastic leukemia than in other types of human leukemia . Previous studies , however , have not revealed any consistent relationship between clinical responsiveness and the cellular or cytosolic concentration of glucocorticoid - binding sites . The objectives of this study were to determine whether there are intrinsic structural differences among the glucocorticoid receptors in various types of leukemic cells and normal lymphocytes and to investigate the role of endogenous peptidases in receptor degradation . Cytosols were prepared from fresh or rapidly frozen leukocytes from 6 healthy adults and 35 high - risk leukemia patients ( median white blood cell count , 150 , 000 cells / microliter ; median age , 13 years ) . Receptors were labeled with [ 3H ] triamcinolone acetonide and quantitated by charcoal - dextran treatment or Sephadex LH - 20 chromatography . Mean and median cytosolic receptor concentrations in 12 acute lymphoblastic leukemia specimens lacking the standard B - cell or T - cell markers ( ` ` null cells ' ' ) were approximately 4 - fold higher than in 23 other leukemic cell specimens . No other consistent differences in receptor content were observed . Agarose filtration and ultracentrifugation in hypotonic buffers containing 20 mM Na2MoO4 revealed complexes of similar size and shape in all clinical specimens tested and two established leukemic cell lines . They had Stokes radii ( Rs ) of 8 . 1 + / - 0 . 5 ( S . D . ) nm ( n = 50 ) , sedimentation coefficients of 9 . 5 + / - 0 . 3S ( n = 40 ) , molecular weights of approximately 330 , 000 , and axial ratios ( a / b ) of approximately 12 . In hypertonic , molybdate - free buffer , these oligomeric complexes were dissociated into subunits with Rs of 5 . 9 + / - 0 . 3 nm ( n = 12 ) and a / b of 11 to 12 , as observed previously for other receptors . Fragmentation of the oligomer and the subunit was evident in some cytosols . High activities of peptidases of various specificities were detected in leukemic cell cytosols , as in other cytosols , by fluorometric assays with derivatives of 7 - amino - 4 - methylcoumarin . Receptor cleavage by these and other endogenous enzymes may account for previous observations of ` ` abnormal ' ' receptors in cytosols from some leukemic specimens . We conclude that intrinsic structural defects in the receptors are unlikely explanations for the unresponsiveness of some types of leukemia to steroid therapy . Glucocorticoid receptor number and intracellular water space . In order to elucidate the relationship between cell water content and number of glucocorticoid receptors , eleven normal and malignant lymphoid or myelomonocytic cell types originating from mouse , rat and man were investigated . The cellular water space was measured with 3H2O , and glucocorticoid receptor number was measured in a whole - cell binding assay with [ 3H ] dexamethasone at 30 and 37 degrees C . The intracellular water phase concentration of glucocorticoid receptors ( around 40 nmol / l cell water ) , and the dependence of receptor affinity on temperature were similar in normal and malignant rodent and human cells . It is concluded that comparisons of glucocorticoid receptor levels are best made on the basis of intracellular receptor concentrations . Covalent labeling of rat thymocyte and human lymphoid glucocorticoid receptor . Lymphoid cells contain specific receptors for glucocorticoids . We have used [ 3H ] dexamethasone - 21 - mesylate to label covalently glucocorticoid receptors in rat thymic lymphocytes and in neoplastic cells obtained from patients with acute lymphoblastic leukemia and malignant lymphoma . The covalently labeled glucocorticoid receptors were identified by polyacrylamide gel electrophoresis ( in the presence of 0 . 1 % sodium dodecyl sulfate ) . In cytosolic fractions prepared from rat thymic lymphocytes , [ 3H ] - dexamethasone - 21 - mesylate labels a protein ( Mr approximately equal to 95 , 000 ) which was identified as the glucocorticoid receptor by the following criteria : ( a ) labeling of this moiety is inhibited by treatment with a 100 - fold molar excess of glucocorticoids , such as dexamethasone and triamcinolone acetonide ; and ( b ) the covalently labeled Mr approximately equal to 95 , 000 protein is activated ( by heating at 20 degrees for 30 min ) to a form that binds to DNA - cellulose . When intact thymocytes are treated with [ 3H ] dexamethasone - 21 - mesylate , an Mr approximately equal to 95 , 000 moiety is also labeled covalently . Approximately 35 % of the glucocorticoid receptors can be labeled covalently when intact thymocytes are treated with 100 nM [ 3H ] dexamethasone - 21 - mesylate for 30 min at 4 degrees . Neoplastic cells from acute lymphoblastic leukemia and malignant lymphoma were treated with [ 3H ] dexamethasone - 21 - mesylate . In all samples , an Mr approximately equal to 95 , 000 moiety was labeled covalently ; labeling was inhibited by excess glucocorticoid . Smaller moieties were also identified by competition experiments ; these may represent proteolytic fragments of the Mr approximately equal to 95 , 000 receptor . Thus , in rat and human lymphoid cells , [ 3H ] dexamethasone - 21 - mesylate can be used to label covalently the glucocorticoid receptor . The association of cytosol oestrogen and progesterone receptors with histological features of breast cancer and early recurrence of disease . Two hundred and eighty - eight primary breast tumours were examined for the presence or absence of oestrogen ( REc ) and progesterone ( RPc ) receptors . Analysis has shown a relative interdependence between the steroid receptor status of primary breast cancer and other prognostic variables such as histological grade , lymphocytic infiltration and tumour elastosis . There were significant associations between epithelial cellularity , stromal fibrosis and the value of REc in those tumours in which the receptor was present . Cellularity and fibrosis were unrelated to the presence or absence of oestrogen receptor . By contrast , neither the presence or absence nor the value of RPc could be related to cellularity or fibrosis . The value of REc and RPc analysis as an indicator of prognosis was examined in a sub - group of 175 patients receiving no additional treatment following mastectomy . Overall relapse - free survival ( RFS ) was no different for those patients with receptors compared to those without them ( REc P = 0 . 11 , RPc P = 0 . 7 ) . There was no difference in RFS of receptor positive and negative tumours when the axillary node status was taken into account . Clinical implications of glucocorticoid receptors in human leukemia . Normal lymphoid cells contain glucocorticoid receptor . A variety of stimuli that activate these cells also induce increases in receptor concentration . Similar glucocorticoid receptors can be detected in lymphoid cells from patients with acute lymphoblastic leukemia ( ALL ) . Absence of the glucocorticoid receptor ( usually found in treated patients ) predicts lack of glucocorticoid responsiveness . Furthermore , in our hands , glucocorticoid receptor levels correlate with the duration of complete remission in ALL ( though not in other forms of leukemia ) . This association is independent of cell type , age , sex , or initial leukocyte count . The level of receptor shows a negative correlation with increasing aggressiveness of the tumor ( null - cell leukemia greater than T - cell leukemia greater than Burkitt ' s lymphoma ) . Corticosteroid - mediated immunoregulation in man . Glucocorticoids have profound and complex effects on the human immune response . However , the precise mechanisms of the corticosteroid - induced immunoregulation in man have not been precisely defined . Intracytoplasmic corticosteroid - specific receptors appear to be an important common pathway for steroid - induced changes , but variations of receptor parameters do not account for the multifaceted effects on the immune system . Human circulating mononuclear cells redistribute out of the intravascular compartment following treatment with corticosteroids . Although certain components at this redistribution phenomenon have been well - characterized , the importance of this compartmental cellular shift with respect to the mechanisms of corticosteroid - induced immunoregulation are less well - defined . Recent observations that activated lymphocytes may be sensitive to the lytic effects of glucocorticoids suggest that under certain situations the elimination of selected subsets of cells may be a relevant mechanism of corticosteroid - mediated immunoregulation in man . Corticosteroid - mediated effects on monocyte function may be an important mechanism of drug - induced immunoregulation in monocyte - dependent responses . In some experimental conditions , corticosteroids inhibit Interleukin 1 production by monocytes . The immunoregulatory effects of corticosteroids on lymphocyte immune responses are complex . In vitro corticosteroids appear to selectively affect early immunoregulatory events as opposed to altering an established response . Multiple sites of steroid - induced modulations of human B cell responses have been defined . Human lymphoid cell lines and glucocorticoids : II . Whole cell and cytoplasmic binding properties of lymphoblastoid , leukaemia and lymphoma lines . The glucocorticoid binding properties of 18 human lymphoid cell lines ( HLCL ) have been investigated . The specificity of steroid binding was confirmed with various glucocorticoid agonists and antagonists . A gradation in whole cell and cytoplasmic glucocorticoid binding capacity was observed in the different cell line types : lymphoblastoid greater than lymphoma greater than leukaemia . The cytoplasmic receptors of leukaemia and lymphoblastoid lines appeared to contain both proteinaceous and phospholipid components . Cytoplasmic steroid - receptor complexes exhibited a wide range of sedimentation coefficients ( 8 . 5 - 11 . 3S ) in low ionic strength buffer but there was no correlation with cell line type or glucocorticoid sensitivity . Activation of these complexes by heat ( 37 degrees C ) or exposure to high ionic strength buffer ( 0 . 3 M NaCl ) induced nuclear binding of steroid but only complexes in high ionic strength buffer manifested changes in sedimentation coefficient . No correlation was observed between the level or nature of glucocorticoid binding and the cytolethal or cytostatic responsiveness of HLCL to glucocorticoid treatment in vitro . The resistance to cytolethal effects can not be ascribed to a failure of cells to take up and bind steroid or to significant differences in the molecular species of cytoplasmic receptors present . The molecular mechanisms by which glucocorticoids achieve cytolethal responses in human lymphoid cells CD28 - mediated activation in CD45RA + and CD45RO + T cells : enhanced levels of reactive oxygen intermediates and c - Rel nuclear translocation in CD45RA + cells . We have analyzed the effect of complete T cell activation ( anti - CD3 plus anti - CD28 ) on the activation of NF - kappaB in CD45RA + ( naive ) and CD45RO + ( memory / effector ) T cells . Long exposure ( 24 h ) induced stronger NF - kappaB DNA binding in CD45RA + cells than in CD45RO + cells . Analysis of the nuclear c - Rel protein indicated that after anti - CD3 + anti - CD28 stimulation the level of c - Rel was higher in CD45RA + cells . Analysis of the cytoplasmic inhibitor IkappaBalpha indicated that anti - CD3 + anti - CD28 stimulation induced a long - lasting degradation in CD45RA + cells but in CD45RO + cells the degradation process was more rapid . Because the CD28 costimulus is known to induce the production of reactive oxygen intermediates ( ROIs ) , the intracellular ROI levels in CD45RA + and CD45RO + cells were compared by flow cytometry . ROIs were produced in both cell types , but more strongly in CD45RA + cells . The data presented in this study further emphasize the differences between CD45RA + and CD45RO + T lymphocytes in ROI - dependent signaling pathways . Ikaros in hemopoietic lineage determination and homeostasis . Studies on the molecular mechanisms that control hemopoietic differentiation have focused on signaling cascades and nuclear effectors that drive this complex developmental system in a regulated fashion . Here we review the role of Ikaros , the founding member of a unique family of zinc finger transcription factors in this developmental process . Studies on an Ikaros null mutation have revealed an essential role for this factor in lymphoid cell fate determination and at subsequent branch points of the T cell differentiation pathway . Differences in the phenotypes of a null and a dominant negative ( DN ) Ikaros mutation provide insight into a regulatory network through which Ikaros proteins exert their effects in development . In addition a comparative analysis of the hemopoietic stem cell and precursor compartment resulting from the two Ikaros mutations reveals a profound yet not absolute requirement for Ikaros in the production and differentiation of these populations . Overexpression of p65 and c - Jun substitutes for B7 - 1 costimulation by targeting the CD28RE within the IL - 2 promoter . The role of Rel and activation protein - 1 ( AP - 1 ) in IL - 2 promoter activity in B7 - 1 - and leukocyte function - associated Ag - 3 ( LFA . 3 ) - costimulated T cells has been evaluated . We demonstrate that overexpression of c - Jun but not c - Fos increases IL - 2 promoter activity in both B7 - 1 - and LFA - 3 - costimulated Jurkat T cells . Cotransfection of both c - Jun and c - Fos substitutes for B7 - 1 costimulation in driving an activation protein - 1 response element but not for the IL - 2 promoter . Overexpression of Rel proteins demonstrated that p65 - expressing Jurkat cells transcribed equally well a nuclear factor kappabeta reporter construct when costimulated with B7 - 1 or LFA - 3 , but transcription of IL - 2 promoter or CD28 response element ( CD28RE ) - driven reporters was superior in B7 - 1 - costimulated cells . Combined expression of c - Jun and p65 induced vigorous transcription of IL - 2 promoter - and CD28RE - driven reporter constructs in both LFA - 3 - and B7 - 1 - costimulated Jurkat cells . Mutating the CD28RE but not the upstream nuclear factor kappabeta - binding site in the IL - 2 promoter reduced B7 - 1 - driven transcription > 90 % . The results implicates a major role of the CD28RE in the integration of p65 / c - Jun - mediated transcription within the IL - 2 promoter . We suggest that the transition from an autocrine LFA - 3 - driven immune response to a B7 - - induced paracrine immune response involves the activation of c - Jun and p65 , which target the CD28RE region of the IL - 2 promoter . Defects in actin - cap formation in Vav - deficient mice implicate an actin requirement for lymphocyte signal transduction . BACKGROUND : Antigen - receptor interactions on lymphocytes result in local clustering of actin , receptors and signaling molecules into an asymmetric membrane structure termed a cap . Although actin polymerization is known to be required , the mechanisms underlying cap formation are unclear . We have studied the events underlying cap formation using mice bearing a null mutation in vav ( vav - / - ) , a gene that encodes a guanine - nucleotide exchange factor for the GTPase Rac . RESULTS : Lymphocytes from vav - / - mice failed to form T - cell receptor caps following activation and had a defective actin cytoskeleton . The vav - / - T cells were deficient in interleukin - 2 ( IL - 2 ) production and proliferation , and the peak of Ca2 + mobilization was reduced although of normal duration . Activation of Jun N - terminal kinase or stress - activated kinase ( JNK or SAPK ) and mitogen - activated protein kinase ( MAPK ) and the induction of the transcription factor NF - ATc1 and egr - 1 genes was normal . Despite the reduced Ca2 + mobilization , translocation of cytoplasmic NF - ATc to the nucleus was normal , reflecting that the lower levels of Ca2 + in vav - / - cells were still sufficient to activate calcineurin . Treatment of lymphocytes with cytochalasin D , which blocks actin polymerization , inhibited cap formation and produced defects in signaling and IL - 2 transcriptional induction in response to antigen - receptor signaling that were nearly identical to those seen in vav - / - cells . In transfection studies , either constitutively active Vav or Rac could complement constitutively active calcineurin to activate NF - AT - dependent transcription . CONCLUSIONS : These results indicate that Vav is required for cap formation in lymphocytes . Furthermore , the correlation between cap formation , IL - 2 production and proliferation supports the hypothesis that an actin - dependent pathway is a source of specialized growth regulatory signals . CD14 - dependent activation of human endothelial cells by Bacteroides fragilis outer membrane . We studied the capacity of isolated Bacteriodes fragilis outer membrane , B . fragilis NCTC9343 lipopolysaccharide ( LPS ; endotoxin ) , and B . fragilis NCTC9343 capsular polysaccharides to activate human umbilical vein endothelial cell ( HUVEC ) monolayers . To assess HUVEC activation , E - selectin expression was measured by enzyme - linked immunosorbent assay ( ELISA ) , Northern blot analysis for E - selectin - specific mRNA , and electrophoretic gel mobility shift assay ( EMSA ) for NF - kappa B , a transcription factor necessary for E - selectin gene activation . Exposure of HUVECs to B . fragilis outer membrane fractions , separated from other components of the B . fragilis cell wall by isopycnic , sucrose gradient centrifugation , significantly increased surface expression of E - selectin and induced functional endothelial cell - dependent leukocyte adhesion . B . fragilis outer membranes induced translocation of NF - kappa B to HUVEC nuclei and accumulation of E - selectin mRNA in HUVEC cytoplasm . E - selectin expression induced by B . fragilis outer membranes was not blocked by polymixin B . In contrast , E - selectin expression induced by outer membrane fractions purified from E . coli was competitively inhibited by polymixin B . Neither purified B . fragilis LPS , a prominent constituent of the outer membrane , nor purified B . fragilis capsular polysaccharides induced HUVEC activation . Two different monoclonal antibodies directed against human CD14 completely inhibited B . fragilis outer membrane - induced NF - kappa B activation , E - selectin transcription , and E - selectin surface expression . We conclude that the outer membrane component of the B . fragilis cell wall contains a proinflammatory factor ( s ) , that is not LPS , which induces human endothelial cell activation by a soluble CD14 - dependent mechanism . NF - kappaB protects HIV - 1 - infected myeloid cells from apoptosis . HIV - 1 infection of primary monocytic cells and myeloid cell lines results in sustained NF - kappaB activation . Recently , NF - kappaB induction has been shown to play a role in protecting cells from programmed cell death . In the present study , we sought to investigate whether constitutive NF - kappaB activity in chronically HIV - 1 - infected promonocytic U937 ( U9 - IIIB ) and myeloblastic PLB - 985 ( PLB - IIIB ) cells affects apoptotic signaling . TNFalpha and cycloheximide caused infected cells to undergo apoptosis more rapidly than parental U937 and PLB - 985 cells . Inhibition of TNFalpha - induced NF - kappaB activation using the antioxidant N - acetylcysteine ( NAC ) resulted in increased apoptosis in both U937 and U9 - IIIB cells , while preactivation of NF - kappaB with the non - apoptotic inducer IL - 1beta caused a relative decrease in apoptosis . Inhibition of constitutive NF - kappaB activity in U9 - IIIB and PLB - IIIB cells also induced apoptosis , suggesting that NF - kappaB protects cells from a persistent apoptotic signal . TNFalpha plus NAC treatment resulted in a marked decrease in Bcl - 2 protein levels in HIV - 1 - infected cells , coupled with an increase in Bax protein compared to uninfected cells , suggesting that the difference in susceptibility to TNFalpha - induced apoptosis may relate to the differences in relative levels of Bcl - 2 and Bax . The protective role of NF - kappaB in blocking TNFalpha - and HIV - 1 - induced apoptosis was supported by studies in Jurkat T cells engineered to express IkappaB alpha repressor mutants ( TD - IkappaB ) under the control of a tetracycline - responsive promoter . Cells underwent apoptosis in response to TNFalpha only when NF - kappaB activation was inhibited by TD - IkappaB expression . As was observed for the U9 - IIIB cells , TNFalpha treatment also induced a marked decrease in Bcl - 2 protein levels in TD - IkappaB expressing cells . These experiments demonstrate that apoptotic signaling is perturbed in HIV - 1 - infected U9 - IIIB cells and indicate that NF - kappaB activation may play an additional protective role against HIV - 1 - induced apoptosis in myeloid cells . Human normal peripheral blood B - lymphocytes are deficient in DNA - dependent protein kinase activity due to the expression of a variant form of the Ku86 protein . The heterodimeric Ku protein , which comprises a 86 kDa ( Ku86 ) amd a 70 kDa ( Ku70 ) subunits , is an abundant nuclear DNA - binding protein which binds in vitro to DNA termini without sequence specificity . Ku is the DNA - targeting component of the large catalytic sub - unit of the DNA - dependent protein kinase complex ( DNA - PK [ CS ] ) , that plays a critical role in mammalian double - strand break repair and lymphoid V ( D ) J recombination . By using electrophoretic mobility shift assays , we demonstrated that in addition to the major Ku x DNA complex usually detected in cell line extracts , a second complex with faster electrophoretic mobility was observed in normal peripheral blood lymphocytes ( PBL ) extracts . The presence of this faster migrating complex was restricted to B cells among the circulating lymphocyte population . Western blot analysis revealed that B cells express a variant form of the Ku86 protein with an apparent molecular weight of 69 kDa , and not the 86 kDa - full - length protein . Although the heterodimer Ku70 / variant - Ku86 binds to DNA - ends , this altered form of the Ku heterodimer has a decreased ability to recruit the catalytic component of the complex , DNA - PK ( CS ) , which contributes to an absence of detectable DNA - PK activity in B cells . These data provide a molecular basis for the increased sensitivity of B cells to ionizing radiation and identify a new mechanism of regulation of DNA - PK activity that operates in vivo . Co - stimulation of human peripheral blood mononuclear cells with IL - 2 and anti - CD3 monoclonal antibodies induces phosphorylation of CREB . Phosphorylation of the cAMP - response element binding protein CREB within 1 h of CD2 but not CD3 cross - linking of human PBMC was recently demonstrated . The absence of P - CREB following CD3 cross - linking was unexpected , as other laboratories reported increased phosphorylation of CREB following CD3 cross - linking of the Jurkat lymphocyte cell line . Due to Jurkat T - cells being IL - 2 - independent , it was postulated that IL - 2 might provide a necessary co - stimulus for phosphorylation of CREB in primary lymphocytes . Therefore , P - CREB was evaluated following co - stimulation of human PBMC through the IL - 2 and CD2 or CD3 receptors . IL - 2 did not further augment phosphorylation of CREB following CD2 cross - linking . However , while neither IL - 2 nor CD3 cross - linking alone induced P - CREB , a 4 . 5 - fold increase in phosphorylation of CREB within 1 h of IL - 2 / CD3 co - stimulation was observed . Phosphorylation was not associated with the induction of cAMP , and inhibition of PKA signaling had no effect on P - CREB . Consistent with signal transduction through p56lck or p59fyn , inhibition of PTK signaling reduced phosphorylation 50 % . Interestingly , inhibiting PKC signaling with calphostin C further increased P - CREB levels 3 - fold over that observed in IL - 2 / CD3 co - stimulated cells not pretreated with a PKC inhibitor . In contrast to previous studies performed in the absence of exogenous IL - 2 , no increase in binding of CREB to a 32P - labeled oligonucleotide probe was observed by electrophoretic mobility shift assay . These data suggest that the IL - 2 and CD3 signaling pathways provide a necessary and co - operative stimulus promoting phosphorylation of CREB following receptor cross - linking . HIV - 1 infection induces a selective reduction in STAT5 protein expression . HIV - 1 infection is accompanied by qualitative and quantitative defects in CD4 + T lymphocytes . Loss of immune function in HIV patients is usually associated with a profound dysregulation of cytokine production . To investigate whether cytokine signaling defects occur during HIV infection , PHA blasts from healthy human donors were infected with two strains of HIV - 1 and screened for the expression of STAT proteins used in cytokine signaling . A selective decrease in STAT5B was seen 8 days after infection with the BZ167 dual - tropic HIV isolate , but not with the Ba - L , M - tropic strain . Based on these findings , purified T cells from HIV - infected patients in different stages of disease were also tested for STAT expression ; decreases in STAT5A , STAT5B , and STAT1alpha were observed in all patients . The reduction in STATs seen in vivo and in vitro after HIV infection may contribute to the loss of T cell function in HIV disease . Transcription factors that regulate monocyte / macrophage differentiation . Although all the cells in an organism contain the same genetic information , differences in the cell phenotype arise from the expression of lineage - specific genes . During myelopoiesis , external differentiating signals regulate the expression of a set of transcription factors . The combined action of these transcription factors subsequently determines the expression of myeloid - specific genes and the generation of monocytes and macrophages . In particular , the transcription factor PU . 1 has a critical role in this process . We review the contribution of several transcription factors to the control of macrophage development Transcription factor LKLF is sufficient to program T cell quiescence via a c - Myc - - dependent pathway . T lymphocytes circulate in a quiescent state until they encounter cognate antigen bound to the surface of an antigen - presenting cell . The molecular pathways that regulate T cell quiescence remain largely unknown . Here we show that forced expression of the lung Kruppel - like transcription factor ( LKLF ) in Jurkat T cells is sufficient to program a quiescent phenotype characterized by decreased proliferation , reduced cell size and protein synthesis and decreased surface expression of activation markers . Conversely , LKLF - deficient peripheral T cells produced by gene targeting showed increased proliferation , increased cell size and enhanced expression of surface activation markers in vivo . LKLF appeared to function , at least in part , by decreasing expression of the proto - oncogene encoding c - Myc . Forced expression of LKLF was associated with markedly decreased c - Myc expression . In addition , many effects of LKLF expression were mimicked by expression of the dominant - negative MadMyc protein and rescued by overexpression of c - Myc . Thus , LKLF is both necessary and sufficient to program quiescence in T cells and functions , in part , by negatively regulating a c - Myc - - dependent pathway . HTLV - 1 p12 ( I ) protein enhances STAT5 activation and decreases the interleukin - 2 requirement for proliferation of primary human peripheral blood mononuclear cells . The p12 ( I ) protein , encoded by the pX open reading frame I of the human T - lymphotropic virus type 1 ( HTLV - 1 ) , is a hydrophobic protein that localizes to the endoplasmic reticulum and the Golgi . Although p12 ( I ) contains 4 minimal proline - rich , src homology 3 - binding motifs ( PXXP ) , a characteristic commonly found in proteins involved in signaling pathways , it has not been known whether p12 ( I ) has a role in modulating intracellular signaling pathways . This study demonstrated that p12 ( I ) binds to the cytoplasmic domain of the interleukin - 2 receptor ( IL - 2R ) beta chain that is involved in the recruitment of the Jak1 and Jak3 kinases . As a result of this interaction , p12 ( I ) increases signal transducers and activators of transcription 5 ( STAT5 ) DNA binding and transcriptional activity and this effect depends on the presence of both IL - 2R beta and gamma ( c ) chains and Jak3 . Transduction of primary human peripheral blood mononuclear cells ( PBMCs ) with a human immunodeficiency virus type 1 - based retroviral vector expressing p12 ( I ) also resulted in increased STAT5 phosphorylation and DNA binding . However , p12 ( I ) could increase proliferation of human PBMCs only after stimulation of T - cell receptors by treatment of cells with low concentrations of alphaCD3 and alphaCD28 antibodies . In addition , the proliferative advantage of p12 ( I ) - transduced PBMCs was evident mainly at low concentrations of IL - 2 . Together , these data indicate that p12 ( I ) may confer a proliferative advantage on HTLV - 1 - infected cells in the presence of suboptimal antigen stimulation and that this event may account for the clonal proliferation of infected T cells in vivo . ( Blood . 2001 ; 98 : 823 - 829 ) Single dose intranasal administration of retinal autoantigen generates a rapid accumulation and cell activation in draining lymph node and spleen : implications for tolerance therapy . BACKGROUND / AIMS : A single intranasal delivery of retinal autoantigen suppresses effectively experimental autoimmune uveoretinitis ( EAU ) . To further unravel underlying mechanisms the authors wished to determine , firstly , the kinetics of antigen delivery and , secondly , the early cellular responses involved in the initial stages of nasal mucosal tolerance induction . METHODS : Flow cytometry , cell proliferation assays , and microscopy were used to track antigen following a single , intranasal dose of Alexa - 488 labelled retinal antigen . RESULTS : A rapid accumulation of antigen within both superficial cervical lymph nodes ( SCLN ) and spleen was observed after 30 minutes . Significant proliferative responses to IRBP were elicited by 48 hours indicating that systemic priming of naive T cells to retinal antigen had occurred . Cell activation was further confirmed by immunoprecipitation studies , which demonstrated phosphorylation of STAT4 but not STAT6 in both lymph nodes and spleen . However , at 24 hours , STAT4 heterodimerisation with STAT 3 was only observed in spleen . CONCLUSIONS : The results provide novel evidence that following a single intranasal application rapid transfer of antigen occurs . Resulting T cell proliferation develops consequent to differential cell signalling in SCLN and spleen . Further understanding of these underlying cellular mechanisms , in particular as is inferred by the results the contribution of local versus systemic tolerance induction , may assist in strategies to clinically apply mucosal tolerance therapy successfully . Regulation of interleukin ( IL ) - 18 receptor alpha chain expression on CD4 ( + ) T cells during T helper ( Th ) 1 / Th2 differentiation . Critical downregulatory role of IL - 4 . Interleukin ( IL ) - 18 has been well characterized as a costimulatory factor for the induction of IL - 12 - mediated interferon ( IFN ) - gamma production by T helper ( Th ) 1 cells , but also can induce IL - 4 production and thus facilitate the differentiation of Th2 cells . To determine the mechanisms by which IL - 18 might regulate these diametrically distinct immune responses , we have analyzed the role of cytokines in the regulation of IL - 18 receptor alpha chain ( IL - 18Ralpha ) expression . The majority of peripheral CD4 ( + ) T cells constitutively expressed the IL - 18Ralpha . Upon antigen stimulation in the presence of IL - 12 , marked enhancement of IL - 18Ralpha expression was observed . IL - 12 - mediated upregulation of IL - 18Ralpha required IFN - gamma . Activated CD4 ( + ) T cells that expressed low levels of IL - 18Ralpha could produce IFN - gamma when stimulated with the combination of IL - 12 and IL - 18 , while CD4 ( + ) cells which expressed high levels of IL - 18Ralpha could respond to IL - 18 alone . In contrast , T cell stimulation in the presence of IL - 4 resulted in a downregulation of IL - 18Ralpha expression . Both IL - 4 ( - / ) - and signal transducer and activator of transcription ( Stat ) 6 ( - / ) - T cells expressed higher levels of IL - 18Ralpha after TCR stimulation . Furthermore , activated T cells from Stat6 ( - / ) - mice produced more IFN - gamma in response to IL - 18 than wild - type controls . Thus , positive / negative regulation of the IL - 18Ralpha by the major inductive cytokines ( IL - 12 and IL - 4 ) determines the capacity of IL - 18 to polarize an immune response . Glucocorticoid - regulated transcription factors . Glucocorticoids are the most effective antiinflammatory drugs used in the treatment of asthma . They act by binding to a specific receptor ( GR ) that , upon activation , translocates to the nucleus and either increases ( transactivates ) or decreases ( transrepresses ) gene expression . Inhibition of pro - inflammatory transcription factors such as activator protein ( AP ) - 1 , signal transducers and activators of transcription ( STATs ) , nuclear factor of activated T cells ( NFAT ) and nuclear factor ( NF ) - kappa B is thought to be a major action of glucocorticoids . Acetylation of histones allows unwinding of the local DNA structure and enables RNA polymerase II to enhance gene transcription . Histone acetylation is regulated by a balance between the activity of histone acetyltransferases ( HATs ) and histone deacetylases ( HDACs ) . GR acts as a direct inhibitor of NF - kappa B - induced HAT activity and also by recruiting HDAC2 to the NF - kappa B / HAT complex . A sub - group of patients with glucocorticoid - insensitive asthma have an inability to induce histone acetylation in response to dexamethasone suggesting reduced expression of a GR - specific HAT . This suggests that pharmacological manipulation of specific histone acetylation status is a potentially useful approach for the treatment of inflammatory diseases . Identification of the precise mechanism by which activated GR recruits HDAC2 may reveal new targets for the development of drugs that may dissociate the antiinflammatory actions of glucocorticoids from their side effects that are largely due to gene induction . Copyright Academic Press . Differential ultraviolet - B - induced immunomodulation in XPA , XPC , and CSB DNA repair - deficient mice . Ultraviolet B irradiation has serious consequences for cellular immunity and can suppress the rejection of skin tumors and the resistance to infectious diseases . DNA damage plays a crucial role in these immunomodulatory effects of ultraviolet B , as impaired repair of ultraviolet - B - induced DNA damage has been shown to cause suppression of cellular immunity . Ultraviolet - B - induced DNA damage is repaired by the nucleotide excision repair mechanism very efficiently . Nucleotide excision repair comprises two subpathways : transcription - coupled and global genome repair . In this study the immunologic consequences of specific nucleotide excision repair defects in three mouse models , XPA , XPC , and CSB mutant mice , were investigated . XPA mice carry a total nucleotide excision repair defect , whereas XPC and CSB mice only lack global genome and transcription - coupled nucleotide excision repair , respectively . Our data demonstrate that cellular immune parameters in XPA , XPC , and CSB mice are normal compared with their wild - type ( control ) littermates . This may indicate that the reported altered cellular responses in xeroderma pigmentosum patients are not constitutive but could be due to external factors , such as ultraviolet B . Upon exposure to ultraviolet B , only XPA mice are very sensitive to ultraviolet - B - induced inhibition of Th1 - mediated contact hypersensitivity responses and interferon - gamma production in skin draining lymph nodes . Lipopolysaccharide - stimulated tumor necrosis factor alpha and interleukin - 10 production are significantly augmented in both XPA and CSB mice after ultraviolet B exposure . Lymph node cell numbers were increased very significantly in XPA , mildly increased in CSB , and not in XPC mice . In general XPC mice do not exhibit any indication of enhanced ultraviolet B susceptibility with regard to the immune parameters analyzed . These data suggest that both global genome repair and transcription - coupled repair are needed to prevent immunomodulation by ultraviolet B , whereas transcription - coupled repair is the major DNA repair subpathway of nucleotide excision repair that prevents the acute ultraviolet - B - induced effects such as erythema . Biomechanical strain induces class a scavenger receptor expression in human monocyte / macrophages and THP - 1 cells : a potential mechanism of increased atherosclerosis in hypertension . BACKGROUND : Although hypertension is an important risk factor for the development of atherosclerosis , the mechanisms for this interaction are incompletely described . Previous studies have suggested that biomechanical strain regulates macrophage phenotype . We tested the hypothesis that biomechanical strain can induce expression of the class A scavenger receptor ( SRA ) , an important lipoprotein receptor in atherogenesis . METHODS AND RESULTS : Human monocyte / macrophages or THP - 1 cells were cultured in a device that imposes uniform biaxial cyclic 1 - Hz strains of 0 % , 1 % , 2 % , or 3 % , and SRA expression was analyzed . Mechanical strains induced SRA mRNA ( 3 . 5 + / - 0 . 6 - fold at 3 % strain for 48 hours , P < 0 . 01 ) and SRA protein in THP - 1 cells in an amplitude - dependent manner . This induction was accompanied by augmented expression of the class B scavenger receptor CD36 ( 2 . 8 + / - 0 . 3 - fold , P < 0 . 001 ) but not by increased peroxisome proliferator - activated receptor - gamma expression . To evaluate this effect in vivo , apolipoprotein E ( - / - ) mice were randomly assigned to receive standard chow , a high - cholesterol diet , or a high - cholesterol diet with hypertension induced by angiotensin II infusion for 8 weeks . Immunohistochemistry revealed that among macrophages in atherosclerotic lesions of the aorta , the proportion of macrophages with SRA expression was highest in hypertensive animals on a high - cholesterol diet ( 43 . 9 + / - 0 . 7 % , versus 12 . 0 + / - 2 . 0 % for normotensive animals on a high - cholesterol diet and 4 . 7 + / - 4 . 7 % for animals on standard chow ; P < 0 . 001 ) . CONCLUSIONS : Biomechanical strain induces SRA expression by monocyte / macrophages , suggesting a novel mechanism for promotion of atherosclerosis in hypertensive patients . High glucose induces MCP - 1 expression partly via tyrosine kinase - AP - 1 pathway in peritoneal mesothelial cells . BACKGROUND : High glucose in peritoneal dialysis solutions has been implicated in the pathogenesis of peritoneal fibrosis in chronic ambulatory peritoneal dialysis ( CAPD ) patients . However , the mechanisms are not very clear . Peritoneal macrophages seem to participate in the process of peritoneal fibrosis and monocyte chemoattractant protein - 1 ( MCP - 1 ) plays a key role in the recruitment of monocytes toward the peritoneal cavity . However , little is known about the effect of high glucose on MCP - 1 expression and its signal transduction pathway in human peritoneal mesothelial cells . METHODS : Mesothelial cells were cultured with glucose ( 5 to 100 mmol / L ) or mannitol chronically for up to seven days . MCP - 1 expression of mRNA and protein was measured by Northern blot analysis and enzyme - linked immunosorbent assay ( ELISA ) . Chemotactic activity of high - glucose - conditioned culture supernatant was measured by chemotactic assay . To examine the roles of the transcription factors activator protein - 1 ( AP - 1 ) and nuclear factor - kappaB ( NF - kappaB ) , electrophoretic mobility shift assay ( EMSA ) was performed . RESULTS : Glucose induced MCP - 1 mRNA expression in a time - and dose - dependent manner . MCP - 1 protein in cell culture supernant was also increased . Equivalent concentrations of mannitol had no significant effect . High - glucose - conditioned supernatant possessed an increased chemotactic activity for monocytes , which was neutralized by anti - MCP - 1 antibody . EMSA revealed that glucose increased the AP - 1 binding activity in a time - and dose - dependent manner , but not NF - kappaB . Curcumin , an inhibitor of AP - 1 , dose - dependently suppressed the induction of MCP - 1 mRNA by high glucose . Tyrosine kinase inhibitors such as genistein ( 12 . 5 to 50 micromol / L ) and herbimycin A ( 0 . 1 to 1 micromol / L ) inhibited the high - glucose - induced MCP - 1 mRNA expression in a dose - dependent manner , and also suppressed the high - glucose - induced AP - 1 binding activity . CONCLUSIONS : : High glucose induced mesothelial MCP - 1 expression partly via the tyrosine kinase - AP - 1 pathway . Signal thresholds and modular synergy during expression of costimulatory molecules in B lymphocytes . We analyzed intracellular pathways modulating surface densities of CD80 and CD86 in B cells activated through ligation of the Ag receptor , and the adhesion molecule CD54 . Whereas B cell Ag receptor ( BCR ) cross - linking alone stimulated increased expression of CD86 , up - regulation of CD80 required dual stimulation with anti - IgM and anti - CD54 . The principal downstream component contributed by BCR signaling , toward both CD80 and CD86 induction , was the elevated concentration of free cytoplasmic Ca ( 2 + ) , recruited by way of capacitative influx . This alone was sufficient to generate an increase in CD86 levels . However , CD80 enhancement required the concerted action of both intracellular Ca ( 2 + ) concentration and CD54 - initiated pathways . The nexus between anti - IgM and anti - CD54 stimulation , in the context of CD80 regulation , was identified to involve a self - propagating process of sequential synergy . The first step involved amplified accumulation of intracellular cAMP , as a result of cross - talk between BCR - mobilized Ca ( 2 + ) and CD54 - derived signals . This then facilitated a second synergistic interaction between Ca ( 2 + ) and cAMP , culminating in CD80 expression . Our findings of distinct signal transducer requirements , with the added consequences of cross - talk , offers an explanation for variable modulation of costimulatory molecule expression in response to diverse physiological stimuli . Importantly , these results also reveal how concentration threshold barriers for recruitment of individual second messengers can be overcome by constructive convergence of signaling modules . The role of Epstein - Barr virus in neoplastic transformation . In this review , we focus on new data from basic , translational and clinical research relating to the Epstein - Barr virus ( EBV ) . Beside its well - known tropism for B lymphocytes and epithelial cells , EBV also infects T lymphocytes , monocytes and granulocytes . After primary infection , EBV persists throughout the life span in resting memory B cells , from where it is reactivated upon breakdown of cellular immunity . In the process of neoplastic transformation , the EBV - encoded latent membrane protein 1 ( LMP1 ) oncogene represents the major driving force . LMP1 acts like a constitutively activated receptor of the tumor necrosis factor receptor family and allows the amplification or bypassing of physiological regulatory signals through direct and indirect interactions with proteins of the tumor necrosis factor receptor - associated factor ( TRAF ) family . TRAF2 - mediated NF - kappaB activation , AP - 1 induction and JAK3 / STAT activation may result in sustained proliferation leading to lymphoma . The ability of LMP1 to suppress germinal center formation and its capacity to mediate its own transcriptional activation shed new light on the pathogenesis of EBV - associated latency type II lymphoproliferations like Hodgkin ' s disease and angioimmunoblastic lymphadenopathy . The carboxy terminus of LMP1 is also a reliable marker for individual EBV strain identification and thus offers new possibilities in tracing the molecular events leading to posttransplant lymphoproliferative disorders ( PTLDs ) . Cytotoxic T lymphocytes directed against well - characterized epitopes of EBV latency genes represent an already successful and promising therapeutic approach to EBV - associated lymphomas , in particular PTLDs Interferon - alpha drives T cell - mediated immunopathology in the intestine . The ability of interferon ( IFN ) - alpha to induce autoimmunity and exacerbate Th1 diseases is well known . We have recently described enhanced expression of IFN - alpha in the mucosa of patients with celiac disease ( CD ) , a gluten - sensitive Th1 - mediated enteropathy , characterized by villous atrophy and crypt cell hyperplasia . Previous studies from this laboratory have shown that T cell activation in explant cultures of human fetal gut can also result in villous atrophy and crypt cell hyperplasia . We have , therefore , examined changes that take place in explant cultures of human fetal gut after activation of T cells with anti - CD3 and / or IFN - alpha . We show that activation of T cells with anti - CD3 alone elicits a small IFN - gamma and TNF - alpha response with no tissue injury . Similarly , no changes are seen in explants cultured with IFN - alpha alone . However , addition of IFN - alpha with anti - CD3 results in enhanced Th1 response and crypt cell hyperplasia . This is associated with enhanced phosphorylation of STAT1 , STAT3 , and Fyn , a Src homology tyrosine kinase , which interacts with both TCR and IFN - alpha signal components . Together these data indicate that IFN - alpha can facilitate activation of Th1 - reactive cells in the gut and drive immunopathology . Suppression of tumor necrosis factor alpha production by cAMP in human monocytes : dissociation with mRNA level and independent of interleukin - 10 . BACKGROUND : Elevation of cellular cAMP inhibits lipopolysaccharide ( LPS ) - stimulated tumor necrosis factor alpha ( TNF - alpha ) production and increases the expression of interleukin ( IL ) - 10 in mononuclear cells . TNF - alpha gene expression obligates activation of the transcription factor nuclear factor kappaB ( NF - kappaB ) . Exogenous IL - 10 inhibits NF - kappaB in monocytes and thus attenuates TNF - alpha production . We examined the role of endogenous IL - 10 in the regulation of NF - kappaB activation and TNF - alpha production in human monocytes by cAMP . METHODS : Human monocytes were stimulated with Escherichia coli LPS ( 100 ng / ml ) with and without forskolin ( FSK , 50 microM ) or dibutyryl cyclic AMP ( dbcAMP , 100 microM ) . Cytokine ( TNF - alpha and IL - 10 ) release was measured by immunoassay . TNF - alpha mRNA was measured by reverse transcription polymerase chain reaction , and NF - kappaB DNA binding activity was assessed by gel mobility shift assay . RESULTS : cAMP - elevating agents inhibited LPS - stimulated TNF - alpha release ( 0 . 77 + / - 0 . 13 ng / 10 ( 6 ) cells in LPS + dbcAMP and 0 . 68 + / - 0 . 19 ng / 10 ( 6 ) cells in LPS + FSK , both P < 0 . 05 vs 1 . 61 + / - 0 . 34 ng / 10 ( 6 ) cells in LPS alone ) . Conversely , cAMP enhanced LPS - stimulated IL - 10 release ( 100 + / - 21 . 5 pg / 10 ( 6 ) cells in LPS + dbcAMP and 110 + / - 25 . 2 pg / 10 ( 6 ) cells in LPS + FSK , both P < 0 . 05 vs 53 . 3 + / - 12 . 8 pg / 10 ( 6 ) cells in LPS alone ) . Neither TNF - alpha mRNA expression nor NF - kappaB activation stimulated by LPS was inhibited by the cAMP - elevating agents . Neutralization of IL - 10 with a specific antibody did not attenuate the effect of cAMP - elevating agents on TNF - alpha production . CONCLUSION : The results indicate that cAMP inhibits LPS - stimulated TNF - alpha production through a posttranscriptional mechanism that is independent of endogenous IL - 10 . Copyright 2001 Academic Press . Activation of the p21 ( CIP1 / WAF1 ) promoter by bone morphogenetic protein - 2 in mouse B lineage cells . BMPs exert a negative growth effect on various types of cells . We have previously reported that BMP - 2 inhibited the growth of HS - 72 mouse hybridoma cells by inducing p21 ( CIP1 / WAF1 ) expression . In the present study , we demonstrated that BMP - 2 activated the mouse p21 ( CIP1 / WAF1 ) promoter in HS - 72 cells , and that a 29 - base pair ( b ) region of the promoter ( - 1928 / - 1900 relative to the TATA box ) , conserved between mice and humans , was responsive to BMP - 2 as well as expression of Smad1 , Smad4 , and constitutively active mutants of BMP type I receptors . Furthermore , an oligonucleotide containing the 29 - b region was found to be associated with Smad4 and phosphorylated Smad1 in the nuclear extract of BMP - 2 - stimulated HS - 72 cells . These results suggested that BMP - 2 might activate p21 ( CIP1 / WAF1 ) transcription by inducing a binding of Smad4 and Smad1 to the 29 - b region in HS - 72 cells . Dendritic cell development from common myeloid progenitors . Dendritic cells ( DCs ) are professional antigen - presenting cells which both initiate adaptive immune responses and control tolerance to self - antigens . It has been suggested that these different effects on responder cells depend on subsets of DCs arising from either myeloid or lymphoid hematopoietic origins . In this model , CD8 alpha + Mac - 1 - DCs are supposed to be of lymphoid while CD8 alpha - Mac - 1 + DCs are supposed to be of myeloid origin . Here we summarize our findings that both CD8 alpha + and CD8 alpha - DCs can arise from clonogenic common myeloid progenitors ( CMPs ) in both thymus and spleen . Therefore CD8 alpha expression DCs does not indicate a lymphoid origin and differences among CD8 alpha + and CD8 alpha - DCs might rather reflect maturation status than ontogeny . On the basis of transplantation studies , it seems likely that most of the DCs in secondary lymphoid organs and a substantial fraction of thymic DCs are myeloid - derived . Macrophage stimulation with Murabutide , an HIV - suppressive muramyl peptide derivative , selectively activates extracellular signal - regulated kinases 1 and 2 , C / EBPbeta and STAT1 : role of CD14 and Toll - like receptors 2 and 4 . The smallest unit of bacterial peptidoglycans known to be endowed with biological activities is muramyl dipeptide ( MDP ) . A clinically acceptable synthetic derivative of MDP , namely murabutide ( MB ) , has been found to present interesting pharmacological properties and to suppress HIV - 1 replication in monocyte - derived macrophages ( MDM ) . We have addressed the signaling events activated in MDM following stimulation with either MB or the potent immunostimulant LPS . We also examined whether signaling by muramyl peptides involves the use of cell surface receptors , including CD14 and Toll - like receptor 2 ( TLR2 ) or TLR4 that are known to be signal - transducing receptors for other bacterial cell wall components . We demonstrate that , unlike LPS , the safe immunomodulator MB selectively activates extracellular signal - regulated kinases ( Erk ) 1 / 2 , in the absence of detectable Jun N - terminal kinase ( JNK ) or p38 mitogen - activated kinase activation . Furthermore , STAT1 activation but weak or no activation of STAT3 or STAT5 respectively , could be detected in MB - stimulated MDM . Using MonoMac6 cells , we observed high C / EBPbeta and AP - 1 but weaker and transient NF - kappaB activation by MB . Moreover , the truncated form of C / EBPbeta , known to repress HIV - 1 transcription , was detected in extracts from MB - treated THP - 1 cells . Surprisingly , neither MB nor MDP were able to transduce signals via CD14 and TLR2 or 4 . These findings present major differences in the early cell activation process between LPS and muramyl peptides , and strongly argue for the implication of co - receptors other than TLR2 and TLR4 in mediating the signaling events induced by defined subunits of bacterial peptidoglycans . Nuclear peroxisome proliferator - activated receptors alpha and gamma have opposing effects on monocyte chemotaxis in endometriosis . The peroxisome proliferator - activated receptors ( PPARs ) alpha and gamma are nuclear receptors that play important roles in inflammatory diseases like ulcerative colitis and arthritis . In this study , we examined the possible role of PPARs in macrophage attraction into the peritoneal cavity of patients with endometriosis . We identified PPAR - alpha and - gamma messenger RNA by RT - PCR and protein by immunoblotting of lysates of peritoneal macrophages and monocytic U937 cells . Using immunocytochemistry , we localized PPAR - alpha and - gamma within the nuclei of both cell types . Monocyte chemotactic activity of peritoneal fluid from patients with endometriosis was quantified in Boyden chambers . Migration of U937 cells was increased by WY 14643 and reduced by rosiglitazone . Peritoneal fluid from patients with endometriosis activated U937 cells transiently transfected with a PPAR - alpha / GAL4 luciferase reporter . By contrast , peritoneal fluid did not cause significant activation of PPAR - gamma / GAL4 constructs . The U937 cells transiently transfected with a PPAR response element luciferase reporter showed disease stage - dependent up - regulation when treated with peritoneal fluid from patients with endometriosis . Treatment with peritoneal fluid from healthy controls down - regulated PPAR response element transactivation . We conclude that peritoneal fluid of endometriosis patients contains activators of PPAR - alpha that stimulate macrophage chemotaxis . Inhibitors of PPAR - alpha or activators of PPAR - gamma could be developed for the treatment of inflammation associated with endometriosis . Long - term - impaired expression of nuclear factor - kappa B and I kappa B alpha in peripheral blood mononuclear cells of trauma patients . Nuclear factor ( NF ) - kappa B expression and dimer characteristics were studied in peripheral blood mononuclear cells ( PBMCs ) of major - trauma patients and healthy controls . Analysis of PBMCs on days 1 , 3 , 5 , and 10 after trauma revealed that expression of both p65p50 heterodimers and p50p50 homodimers was significantly reduced compared with that in controls . In vitro lipopolysaccharide ( LPS ) stimulation of PBMCs induced NF - kappa B translocation . However , throughout the survey , p65p50 activation remained significantly lower in trauma patients than in controls . After LPS stimulation in vitro , the p65p50 / p50p50 ratio was significantly lower in PBMCs from trauma patients than from healthy controls . The ex vivo expression of I kappa B alpha was higher in PBMCs of controls than of trauma patients . LPS did not induce I kappa B expression in PBMCs from trauma patients , but strong induction was obtained with staphylococci , suggesting that this defect is not universal and depends on the nature of the activating signal . Although no direct correlation was found between levels of interleukin - 10 or transforming growth factor - beta and NF - kappa B , these immunosuppressive cytokines were significantly elevated in trauma patients by 10 days after admission . The long - term low - basal and LPS - induced nuclear translocation of NF - kappa B recalled long - term immunoparalysis observed in patients with severe inflammatory stress such as trauma . Hepatic ischemia - reperfusion injury . BACKGROUND : The morbidity associated with liver transplantation and major hepatic resections is partly a result of ischemia - reperfusion injury . DATA SOURCES : The entire world literature on the subject was searched via Medline . Keywords included reperfusion injury , transplantation , liver resection , nitric oxide , endothelin , cytokines , Kupffer cells , ischemic / ischaemic preconditioning , and nuclear factor - kappa B . CONCLUSIONS : An imbalance between endothelin and nitric oxide levels results in failure of the hepatic microcirculation at the onset of reperfusion . Activation of nuclear factor - kappa B in the liver promotes proinflammatory cytokine and adhesion molecule synthesis . These result in oxygen - derived free radical production and neutrophil recruitment , further contributing to cellular injury . Various therapeutic modalities acting on the above mediators have been successfully used to attenuate reperfusion injury in animal models of hepatic transplantation and resection . Application of the knowledge gained from animal models of hepatic ischemia - reperfusion to the clinical setting will improve the outcome of hepatic surgery . Down - regulation of IL - 12 p40 gene in Plasmodium berghei - infected mice . We analyzed the mechanism that causes suppression of IL - 12 p40 gene induction during Plasmodium berghei infection . Although IL - 12 together with IFN - gamma plays an important role in protection against pathogenic infection , the IL - 12 p70 protein production of infected macrophages is lower than that by the uninfected macrophages . We showed in the present study that the induction of IL - 12 p40 gene but not IL - 12 p35 gene in macrophages of P . berghei - infected mice was profoundly inhibited . The inhibition was induced by interaction with macrophages that had contacted with P . berghei - infected erythrocytes and was mediated by a soluble factor , IL - 10 . There was comparable activation of NF - kappaB in uninfected and infected cells . The induction of IFN - regulatory factor - 1 gene was comparable in transcription level in uninfected and infected cells , while the unidentified complex formation of IFN - regulatory factor - 1 was observed in infected cells . Therefore , the inhibition of the IL - 12 p40 gene induction appeared to be regulated at transcriptional regulation level of the gene . The Friend of GATA proteins U - shaped , FOG - 1 , and FOG - 2 function as negative regulators of blood , heart , and eye development in Drosophila . Friend of GATA ( FOG ) proteins regulate GATA factor - activated gene transcription . During vertebrate hematopoiesis , FOG and GATA proteins cooperate to promote erythrocyte and megakaryocyte differentiation . The Drosophila FOG homologue U - shaped ( Ush ) is expressed similarly in the blood cell anlage during embryogenesis . During hematopoiesis , the acute myeloid leukemia 1 homologue Lozenge and Glial cells missing are required for the production of crystal cells and plasmatocytes , respectively . However , additional factors have been predicted to control crystal cell proliferation . In this report , we show that Ush is expressed in hemocyte precursors and plasmatocytes throughout embryogenesis and larval development , and the GATA factor Serpent is essential for Ush embryonic expression . Furthermore , loss of ush function results in an overproduction of crystal cells , whereas forced expression of Ush reduces this cell population . Murine FOG - 1 and FOG - 2 also can repress crystal cell production , but a mutant version of FOG - 2 lacking a conserved motif that binds the corepressor C - terminal binding protein fails to affect the cell lineage . The GATA factor Pannier ( Pnr ) is required for eye and heart development in Drosophila . When Ush , FOG - 1 , FOG - 2 , or mutant FOG - 2 is coexpressed with Pnr during these developmental processes , severe eye and heart phenotypes result , consistent with a conserved negative regulation of Pnr function . These results indicate that the fly and mouse FOG proteins function similarly in three distinct cellular contexts in Drosophila , but may use different mechanisms to regulate genetic events in blood vs . cardial or eye cell lineages The RING finger protein Siah - 1 regulates the level of the transcriptional coactivator OBF - 1 . The transcriptional coactivator OBF - 1 , which interacts with Oct - 1 and Oct - 2 and the octamer site DNA , has been shown to be critical for development of a normal immune response and the formation of germinal centers in secondary lymphoid organs . Here we have identified the RING finger protein Siah - 1 as a protein interacting specifically with OBF - 1 . This interaction is mediated by the C - terminal part of Siah - 1 and by residues in the N - terminus of OBF - 1 , partly distinct from the residues required for formation of a complex with the Oct POU domains and the DNA . Interaction between Siah - 1 and OBF - 1 leads to downregulation of OBF - 1 protein level but not mRNA , and to a corresponding reduction in octamer site - dependent transcription activation . Inhibition of the ubiquitin - proteasome pathway in B cells leads to elevated levels of OBF - 1 protein . Furthermore , in immunized mice , OBF - 1 protein amounts are dramatically increased in primary activated B cells , without concomitant increase in OBF - 1 mRNA . These data suggest that Siah - 1 is part of a novel regulatory loop controlling the level of OBF - 1 protein in B cells . The beta - catenin - - TCF - 1 pathway ensures CD4 ( + ) CD8 ( + ) thymocyte survival . The association of trans - acting T cell factors ( TCFs ) or lymphoid enhancer factor 1 ( LEF - 1 ) with their coactivator beta - catenin mediates transient transcriptional responses to extracellular Wnt signals . We show here that T cell maturation depends on the presence of the beta - catenin - - binding domain in TCF - 1 . This domain is necessary to mediate the survival of immature CD4 ( + ) CD8 ( + ) double - positive ( DP ) thymocytes . Accelerated spontaneous thymocyte death in the absence of TCF - 1 correlates with aberrantly low expression of the anti - apoptotic protein Bcl - x ( L ) . Increasing anti - apoptotic effectors in thymocytes by the use of a Bcl - 2 transgene rescued TCF - 1 - deficient DP thymocytes from apoptosis . Thus , TCF - 1 , upon association with beta - catenin , transiently ensures the survival of immature T cells , which enables them to generate and edit T cell receptor ( TCR ) alpha chains and attempt TCR - mediated positive selection . TRAIL / Apo2L ligand selectively induces apoptosis and overcomes drug resistance in multiple myeloma : therapeutic applications . Multiple myeloma ( MM ) remains incurable and novel treatments are urgently needed . Preclinical in vitro and in vivo evaluations were performed to assess the potential therapeutic applications of human recombinant tumor necrosis factor ( TNF ) - related apoptosis - inducing ligand / Apo2 ligand ( TRAIL / Apo2L ) in MM . TRAIL / Apo2L potently induced apoptosis of MM cells from patients and the majority of MM cell lines , including cells sensitive or resistant to dexamethasone ( Dex ) , doxorubicin ( Dox ) , melphalan , and mitoxantrone . TRAIL / Apo2L also overcame the survival effect of interleukin 6 on MM cells and did not affect the survival of peripheral blood and bone marrow mononuclear cells and purified B cells from healthy donors . The status of the TRAIL receptors ( assessed by immunoblotting and flow cytometry ) could not predict TRAIL sensitivity of MM cells . The anti - MM activity of TRAIL / Apo2L was confirmed in nu / xid / bg mice xenografted with human MM cells ; TRAIL ( 500 microg intraperitoneally daily for 14 days ) was well tolerated and significantly suppressed the growth of plasmacytomas . Dox up - regulated the expression of the TRAIL receptor death receptor 5 ( DR5 ) and synergistically enhanced the effect of TRAIL not only against MM cells sensitive to , but also against those resistant to , Dex - or Dox - induced apoptosis . Nuclear factor ( NF ) - kappaB inhibitors , such as SN50 ( a cell - permeable inhibitor of the nuclear translocation and transcriptional activity of NF - kappaB ) or the proteasome inhibitor PS - 341 , enhanced the proapoptotic activity of TRAIL / Apo2L against TRAIL - sensitive MM cells , whereas SN50 reversed the TRAIL resistance of ARH - 77 and IM - 9 MM cells . Importantly , normal B lymphocytes were not sensitized to TRAIL by either Dox , SN50 , or PS - 341 . These preclinical studies suggest that TRAIL / Apo2L can overcome conventional drug resistance and provide the basis for clinical trials of TRAIL - based treatment regimens to improve outcome in patients with MM . ( Blood . 2001 ; 98 : 795 - 804 ) CD28 costimulation is required not only to induce IL - 12 receptor but also to render janus kinases / STAT4 responsive to IL - 12 stimulation in TCR - triggered T cells . The activation of resting T cells for the acquisition of various functions depends on whether CD28 costimulatory signals are provided upon T cell receptor stimulation . Here , we investigated how CD28 costimulation functions to allow TCR - triggered resting T cells to acquire IL - 12 responsiveness . When T cells are stimulated with low doses of anti - CD3 mAb , CD28 costimulation was required for the optimal levels of IL - 12 receptor ( IL - 12R ) expression . However , stimulation of T cells with high doses of anti - CD3 alone induced comparable levels of IL - 12R expression to those induced upon CD28 costimulation . Nevertheless , there was a substantial difference in IL - 12 responsiveness between these two groups of T cells : compared to anti - CD28 - costimulated T cells , T cells that were not costimulated with anti - CD28 exhibited decreased levels of Janus kinases ( JAK ) JAK2 / TYK2 and STAT4 phosphorylation and IFN - y production following IL - 12 stimulation . Importantly , STAT6 phosphorylation following IL - 4 stimulation was not decreased in anti - CD28 - uncostimulated T cells . These resutls indicate that CD28 costimulation not only contributes to up - regulating IL - 12R expression but is also required to render JAKs / STAT4 responsive to IL - 12 stimulation . Constitutively activated Akt - 1 is vital for the survival of human monocyte - differentiated macrophages . Role of Mcl - 1 , independent of nuclear factor ( NF ) - kappaB , Bad , or caspase activation . Recent data from mice deficient for phosphatase and tensin homologue deleted from chromosome 10 or src homology 2 domain - containing 5 ' inositol phosphatase , phosphatases that negatively regulate the phosphatidylinositol 3 - kinase ( PI3K ) pathway , revealed an increased number of macrophages in these animals , suggesting an essential role for the PI3K pathway for macro - phage survival . Here , we focused on the role of the PI3K - regulated serine / threonine kinase Akt - 1 in modulating macrophage survival . Akt - 1 was constitutively activated in human macrophages and addition of the PI3K inhibitor , LY294002 , suppressed the activation of Akt - 1 and induced cell death . Furthermore , suppression of Akt - 1 by inhibition of PI3K or a dominant negative ( DN ) Akt - 1 resulted in loss of mitochondrial transmembrane potential , activation of caspases - 9 and - 3 , and DNA fragmentation . The effects of PI3K inhibition were reversed by the ectopic expression of constitutively activated Akt - 1 or Bcl - x ( L ) . Inhibition of PI3K / Akt - 1 pathway either by LY294002 or DN Akt - 1 had no effect on the constitutive or inducible activation of nuclear factor ( NF ) - kappaB in human macrophages . However , after inhibition of the PI3K / Akt - 1 pathway , a marked decrease in the expression of the antiapoptotic molecule Mcl - 1 , but not other Bcl - 2 family members was observed , and Mcl - 1 rescued macrophages from LY294002 - induced cell death . Further , inhibition of Mcl - 1 by antisense oligonucleotides , also resulted in macrophage apoptosis . Thus , our findings demonstrate that the constitutive activation of Akt - 1 regulates macrophage survival through Mcl - 1 , which is independent of caspases , NF - kappaB , or Bad . GRbeta expression in nasal polyp inflammatory cells and its relationship to the anti - inflammatory effects of intranasal fluticasone . BACKGROUND : Nasal polyposis disease is an inflammatory disorder with intense eosinophilic infiltration of respiratory mucosa that is often difficult to control with topical steroids . Recent evidence suggests that overexpression of the glucocorticoid receptor splice variant GRbeta in inflammatory cells might contribute to steroid insensitivity in diseases such as asthma . OBJECTIVE : The purposes of this investigation were to determine whether nasal polyp ( NP ) inflammatory cells overexpress GRbeta and to examine whether GRbeta overexpression is associated with insensitivity to the potent topical steroid fluticasone propionate ( FP ) . METHODS : Biopsies were obtained from 10 subjects with NPs before and 4 weeks after treatment with intranasal FP . Middle turbinates biopsies from 6 healthy , nonallergic subjects served as normal controls . Biopsies were immunostained for inflammatory cell markers as well as GRbeta and probed for various cytokine mRNA . The anti - inflammatory response to FP was examined in relation to pretreatment levels of GRbeta expression . RESULTS : The total numbers of inflammatory cells were increased in NPs . The percentage of inflammatory cells expressing GRbeta was also increased ( 40 . 5 % + / - 19 . 2 % vs 16 . 1 % + / - 4 . 0 % , P = . 009 ) . GRbeta expression in NPs was almost exclusive to T lymphocytes , eosinophils , and macrophages . An inverse correlation was observed between the baseline inflammatory cell GRbeta expression and the reduction after FP treatment in EG2 - positive eosinophils , CD4 - positive T lymphocytes , endothelial VCAM - 1 expression , and IL - 4 mRNA - positive cells . NPs that were ` ` FP - insensitive ' ' in terms of suppression of eosinophil numbers ( major basic protein - positive ) had a significantly greater percentage of GRbeta - positive inflammatory cells , a higher ratio of GRbeta - positive / GRalpha - positive cells , and increased numbers of GRbeta - positive eosinophils and macrophages in comparison with those that were ` ` FP - sensitive . ' ' ` ` FP - insensitive ' ' NPs also demonstrated a higher percentage of IL - 5 - positive inflammatory cells expressing GRbeta before and after FP treatment . CONCLUSION : GRbeta expression appears to be a marker of steroid insensitivity in NPs . Expression of GRbeta by NP inflammatory cells , particularly T cells and eosinophils , might render them resistant to suppression by topical steroids and thereby contribute to persistent NP inflammation . Transcriptional regulation of galectin - 10 ( eosinophil Charcot - Leyden crystal protein ) : a GC box ( - 44 to - 50 ) controls butyric acid induction of gene expression . Galectin - 10 ( gal - 10 , also known as Charcot - Leyden crystal protein ) is a member of the galectin family of beta - galactoside binding proteins that is expressed uniquely in eosinophilic and basophilic leukocytes . To gain a better understanding of galectin gene expression , we present an analysis of the transcriptional regulation of the gene encoding gal - 10 . Analysis of the minimal promoter revealed nine consensus - binding sites for transcription factors , including several that are also found in the minimal promoters of galectins - 1 , - 2 , and - 3 . The decrease in gal - 10 promoter activity after disruption of either the GC box ( - 44 to - 50 ) or the Oct site ( - 255 to - 261 ) suggests that these sites , along with the previously characterized GATA and EoTF sites , are necessary for full promoter activity . By supershift analysis , we demonstrate binding of the transcription factors Sp1 and Oct1 to the consensus GC box and the Oct site , respectively . Similar to gal - 1 , gal - 10 expression is induced by butyric acid , an effect that is lost upon ablation of the GC box . Additionally , we demonstrate AML3 binding to the consensus AML site and YY1 binding to the Inr sequence , both elements functioning as silencers in the gal - 10 promoter . Tumour - stromal interactions . Role of the stroma in mammary development . Mammary development depends on branching morphogenesis , namely the bifurcation and extension of ductal growth points ( end buds ) and secretory lobules into a more or less fatty stroma . Because breast carcinomas are overwhelmingly ductal in origin , this review focuses on stromal influences guiding postnatal ductal development and there is only the briefest account of the role of embryonic stroma ( mesenchyme ) . The stroma as the necessary target for endocrine mammogens and the source of stimulatory growth factors is described and the importance of mammary epithelium - induced modifications of the periductal stroma is emphasized . Evidence is presented that if they are to grow , end buds must condition proximal fatty stroma by recruiting white blood cells as well as inducing stromal cell division and , possibly , estrogen receptors . The induction of a fibrous stromal tunic around the end bud is described and its likely role as a complex ductal morphogen is discussed ; a possible role in growth inhibition is also considered . Although the signals governing fibrotic induction , ductal morphogenesis , and growth inhibition are unknown , a role for transforming growth factor - beta is highly likely and is discussed . Finally , a need for new conceptual and experimental approaches to understanding stromal - epithelial signaling is discussed . Adipophilin is a sensitive marker for lipid loading in human blood monocytes . Adipophilin , a marker of lipid accumulation initially described in adipocytes , was recently shown to be induced in macrophage foam cells . We found that even freshly isolated blood monocytes express adipophilin and that the amount of adipophilin protein is variable in monocytes from different healthy individuals . However , the physiological expression of adipophilin does not correlate with the levels of free fatty acids , cholesterylesters or free cholesterol . Enzymatically modified low - density lipoprotein ( E - LDL ) induces rapid foam cell formation in monocytes and upregulates adipophilin mRNA and protein within 2 h of incubation . This rapid induction of adipophilin is accompanied by a significant increase of free fatty acids in monocytes incubated with E - LDL . Adipophilin facilitates the uptake of free fatty acids , and here we demonstrate that free fatty acids increase is related to the early upregulation of adipophilin expression in blood monocytes . Fatty acids are ligands for peroxisome proliferator - activated receptor - gamma ( PPARgamma ) , and the upregulation of adipophilin mRNA by PPARgamma agonists like 15d - PGJ ( 2 ) and ciglitazone indicates that PPARgamma may mediate the induction of adipophilin expression in human blood monocytes . Constitutive expression of MHC class II genes in melanoma cell lines results from the transcription of class II transactivator abnormally initiated from its B cell - specific promoter . In melanoma cell lines , two different patterns of MHC class II expression have been described , either an IFN gamma - inducible expression of HLA - DR and HLA - DP , with a faint or null expression of HLA - DQ , resembling that described for melanocytes , or a constitutive expression , i . e . , IFN - gamma independent , of all three HLA - D isotypes . As this latter phenotype has been associated with a more rapid progression of melanoma tumors , we have analyzed in different melanoma cell lines the molecular mechanisms leading to this abnormal pattern of MHC class II expression . In agreement with the evidence of a coordinate transcription of the HLA - D genes in these cell lines , we have shown the constitutive expression of CIITA ( class II transactivator ) transcripts , CIITA being known as the master switch of MHC class II expression . Unexpectedly , these transcripts initiate from promoter III of the CIITA gene , a promoter that is mainly used constitutively in B lymphocytes . This expression was further shown to occur through factor ( s ) acting on the enhancer located upstream of CIITA promoter III , which was previously described in epithelioid cells as an IFN - gamma - response sequence . The hypothesis of a general abnormality of the IFN - gamma transduction pathway was dismissed . Constitutive transcription of CIITA from promoter III having been observed in unrelated melanoma cell lines , we propose the hypothesis that this phenomenon might not be a random event , but could be linked to the neoplasic state of the melanoma cells Caspase - mediated calcineurin activation contributes to IL - 2 release during T cell activation . Calcineurin , a Ca ( 2 + ) / calmodulin - dependent Ser / Thr phosphatase ( protein phosphatase 2B ) , plays a critical role in IL - 2 production during T cell activation . It has been previously reported that IL - 2 release in activated Jurkat T requires caspase - like activity ( Posmantur et al . ( 1998 ) Exp . Cell . Res . 244 , 302 - 309 ) . We report here that the 60 - kDa catalytic subunit of calcineurin A ( Cn A ) was partially cleaved to a 45 - kDa form in phytohemagglutinin A ( PHA ) or phorbol ester + ionomycin ( P + I ) - activated Jurkat cells . In parallel , proteolytic activation of upstream caspases ( caspase - 8 and - 9 ) as well as effector caspase - 3 was also observed . Cn A cleavage was caspase mediated , since it was inhibitable by pan - caspase inhibitor Cbz - Asp - CH ( 2 ) OC ( O ) - 2 , 6 - dichlorobenzene ( Z - D - DCB ) . Cn A cleavage was also observed when purified calcineurin was digested in vitro with caspase - 3 . Truncated Cn A was associated with enhanced phosphatase activity and reduced calmodulin sensitivity . Furthermore , in PHA or P + I - activated Jurkat cells , dephosphorylation of calcineurin substrate NFATc ( a transcription factor known to be involved in transactivation of the IL - 2 gene ) , was also suppressed by Z - D - DCB . Taken together , our results suggest that caspase - mediated cleavage of Cn A contributes to IL - 2 production during T cell activation . Copyright 2001 Academic Press . Maturation of human dendritic cells as sulfasalazine target . AIM : Sulfasalazine , a nonsteroidal anti - inflammatory drug , is effective in treating some autoimmune diseases , but its mechanism of action is unclear . To determine whether dendritic cells could be a possible target of the drug , we studied the effects of sulfasalazine and its metabolites , aminosalicylate and sulfapyridine , on in vitro maturation ( terminal differentiation ) of human myeloid dendritic cells . METHODS : We prepared immature dendritic cells by incubating CD14 - positive cells in the presence of granulocyte - macrophage colony - stimulating factor and interleukin ( IL ) - 4 . The cells were matured by addition of tumor necrosis factor ( TNF ) - a , IL - 1 beta , and prostaglandin E2 in the presence of sulfasalazine or its metabolites - - aminosalicylate and sulfapyridine , or their combinations . We quantified the effect of drugs on the dendritic cell characteristics , such as stimulation of autologous and allogeneic pan - T cell proliferation , surface marker phenotype , IL - 12 p40 subunit secretion , and activation of nuclear transcription factor ( NF ) - kappa B . RESULTS : Dendritic cells treated with sulfasalazine ( 1 . 25 micromol / L or 2 . 5 micromol / L ) could not stimulate T cells ( p < 0 . 028 , two - sided paired t - test ) . In distinction to drug - free maturing dendritic cells , 2 . 5 micromol / L sulfasalazine upregulated the levels of CD14 and CD68 and downregulated the levels of CD40 , CD80 , and CD83 ( for all CD markers , p < 0 . 03 for difference between measurements in the absence and the presence of sulfasalazine ) . From concentration - dependent changes in CD83 expression , we found an apparent ID50 > > 1 . 5 micromol / L sulfasalazine . The apparent ID50 value for aminosalicylate - inhibited maturation was 4 micromol / L . Sulfapyridine had no effect . At 1 . 25 micromol / L , sulfasalazine largely inhibited NF - kB activation in dendritic cells . CONCLUSION : Maturing human dendritic cells are hundred - fold more sensitive to sulfasalazine than T cells and NK cells and the most sensitive human cells described so far . Thus , dendritic cell maturation is an important target of sulfasalazine . Because of the role of dendritic cells in ( auto ) immunity , inhibition of their maturation might provide a target for further optimization of sulfasalazine therapy . Defective function of the proteasome in autoimmunity : involvement of impaired NF - kappaB activation . Type 1 diabetes ( also known as insulin - dependent diabetes mellitus or juvenile - onset diabetes ) is usually caused by T cell - mediated autoimmunity , with a prediabetic state characterized by the production of autoantibodies specific for proteins expressed by pancreatic beta cells . The nonobese patient with diabetes ( NOD ) mouse is a spontaneous model of type 1 diabetes with a strong genetic component that maps to the major histocompatibility complex ( MHC ) region of the genome . A specific proteasome defect has been identified in NOD mouse in select lymphocytic and monocytic lineages that results from down - regulation of expression of the proteasome subunit LMP2 , which is encoded by a gene in the MHC genomic region . This defect prevents the proteolytic processing required for the production and activation of the transcription factor nuclear factor - kappaB ( NF - kappaB ) , which plays important roles in immune and inflammatory responses , as well as increases the susceptibility of the affected cells to apoptosis induced by tumor necrosis factor - alpha ( TNF - alpha ) . The novel role of the proteasome in dysfunction in autoimmunity is presented and documented to be both tissue and developmental stage specific . We propose a role of the proteasome as a step in disease pathogenesis and tissue targeting . Down - regulation of TDT transcription in CD4 ( + ) CD8 ( + ) thymocytes by Ikaros proteins in direct competition with an Ets activator . Ikaros is a unique regulator of lymphopoiesis that associates with pericentromeric heterochromatin and has been implicated in heritable gene inactivation . Binding and competition experiments demonstrate that Ikaros dimers compete with an Ets activator for occupancy of the lymphocyte - specific TdT promoter . Mutations that selectively disrupt Ikaros binding to an integrated TdT promoter had no effect on promoter function in a CD4 ( + ) CD8 ( + ) thymocyte line . However , these mutations abolished down - regulation on differentiation , providing evidence that Ikaros plays a direct role in repression . Reduced access to restriction enzyme cleavage suggested that chromatin alterations accompany down - regulation . The Ikaros - dependent down - regulation event and the observed chromatin alterations appear to precede pericentromeric repositioning . Current models propose that the functions of Ikaros should be disrupted by a small isoform that retains the dimerization domain and lacks the DNA - binding domain . Surprisingly , in the CD4 ( + ) CD8 ( + ) thymocyte line , overexpression of a small Ikaros isoform had no effect on differentiation or on the pericentromeric targeting and DNA - binding properties of Ikaros . Rather , the small isoform assembled into multimeric complexes with DNA - bound Ikaros at the pericentromeric foci . The capacity for in vivo multimer formation suggests that interactions between Ikaros dimers bound to the TdT promoter and those bound to pericentromeric repeat sequences may contribute to the pericentromeric repositioning of the inactive gene . Type I interferons and IL - 12 : convergence and cross - regulation among mediators of cellular immunity . Therapeutic use of type I IFN ( IFN - alpha / beta ) has become common . Many of the diverse diseases targeted are marked by pathogenetic abnormalities in cell - mediated immunity ( CMI ) , these cellular immune responses either causing injury to the host , lacking sufficient vigor for virus or tumor clearance , or both . In general , therapeutic efficacy is limited . It is thus notable that the pleiotropic effects of type I IFN on CMI remain poorly understood . We characterized the effects of type I IFN on the production of IL - 12 , the central immunoregulatory cytokine of the CD4 ( + ) T cell arm of CMI . We show that type I IFN are potent inhibitors of IL - 12 production by human monocytes / macrophages . The underlying mechanism involves transcriptional inhibition of the IL - 12p40 gene , marked by down - regulation of PU . 1 binding activity at the upstream Ets site of the IL - 12p40 promoter . Type I IFN have previously been shown to be able to substitute for IL - 12 in driving IFN - gamma production from T and NK cells . The ability of IFN - alpha / beta to suppress IL - 12 production while up - regulating IFN - gamma production suggests a possible mechanistic basis for the difficulties of employing these cytokines in diseases involving abnormalities of CMI . Nuclear factor - kappaB suppressive and inhibitor - kappaB stimulatory effects of troglitazone in obese patients with type 2 diabetes : evidence of an antiinflammatory action ? It has been shown recently that troglitazone exerts an anti - inflammatory effect , in vitro , and in experimental animals . To test these properties in humans , we investigated the effect of troglitazone on the proinflammatory transcription factor nuclear factor - kappaB and its inhibitory protein IkappaB in mononuclear cells ( MNC ) and plasma soluble intracellular adhesion molecule - 1 , monocyte chemoattractant protein - 1 , plasminogen activator inhibitor - 1 , and C - reactive protein . We also examined the effect of troglitazone on reactive oxygen species generation , p47 ( phox ) subunit expression , 9 - hydroxyoctadecadieno acid ( 9 - HODE ) , 13 - HODE , o - tyrosine , and m - tyrosine in obese patients with type 2 diabetes . Seven obese patients with type 2 diabetes were treated with troglitazone ( 400 mg / day ) for 4 weeks . Blood samples were obtained at weekly intervals . Nuclear factor - kappaB binding activity in MNC nuclear extracts was significantly inhibited after troglitazone treatment at week 1 and continued to be inhibited up to week 4 . On the other hand , IkappaB protein levels increased significantly after troglitazone treatment at week 1 , and this increase persisted throughout the study . Plasma monocyte chemoattractant protein - 1 and soluble intracellular adhesion molecule - 1 concentrations did not decrease significantly after troglitazone treatment , although there was a trend toward inhibition . Reactive oxygen species generation by polymorphonuclear cells and MNC , p47 ( phox ) subunit protein quantities , plasminogen activator inhibitor - 1 , and C - reactive protein levels decreased significantly after troglitazone intake . 13 - HODE / linoleic acid and 9 - HODE / linoleic acid ratios also decreased after troglitazone intake . However , o - tyrosine / phenylalanine and m - tyrosine / phenylalanine ratios did not change significantly . These data show that troglitazone has profound antiinflammatory effects in addition to antioxidant effects in obese type 2 diabetics ; these effects may be relevant to the recently described beneficial antiatherosclerotic effects of troglitazone at the vascular level . OX40 stimulation by gp34 / OX40 ligand enhances productive human immunodeficiency virus type 1 infection . OX40 is a member of the tumor necrosis factor ( TNF ) receptor superfamily and known to be an important costimulatory molecule expressed on activated T cells . To investigate the role of costimulation of OX40 in human immunodeficiency virus type 1 ( HIV - 1 ) infection by its natural ligand , gp34 , the OX40 - transfected ACH - 2 cell line , ACH - 2 / OX40 , chronically infected with HIV - 1 , was cocultured with paraformaldehyde ( PFA ) - fixed gp34 - transfected mouse cell line , SV - T2 / gp34 . The results showed that HIV - 1 production was strongly induced . This was followed by apparent apoptosis , and both processes were specifically inhibited by the gp34 - specific neutralizing monoclonal antibody 5A8 . Endogenous TNF alpha ( TNF - alpha ) and TNF - beta production were not involved in the enhanced HIV - 1 production . Furthermore , enhanced HIV - 1 transcription in gp34 - stimulated ACH - 2 / OX40 cells was dependent on the kappa B site of the HIV - 1 long terminal repeat , and the OX40 - gp34 interaction activated NF - kappa B consisting of p50 and p65 subunits . When primary activated CD4 ( + ) T cells acutely infected with HIV - 1 ( NL4 - 3 ) ( CXCR4 - using T - cell - line - tropic ) were cocultured with PFA - fixed gp34 ( + ) human T - cell leukemia virus type 1 - bearing MT - 2 cells or SV - T2 / gp34 cells , HIV - 1 production was also markedly enhanced . The enhancement was again significantly inhibited by 5A8 . The present study first shows that OX40 - gp34 interaction stimulates HIV - 1 expression and suggests that OX40 triggering by gp34 may play an important role in enhancing HIV - 1 production in both acutely and latently infected CD4 ( + ) T cells in vivo . Troglitazone , a PPARgamma ligand , inhibits osteopontin gene expression in human monocytes / macrophage THP - 1 cells . Peroxizome proliferator - activated receptor - gamma ( PPARgamma ) is a member of the nuclear receptor family of transcription factors that regulate adipocyte differentiation . Recent studies indicate that liganded PPARgamma not only promotes differentiation but also inhibits the activation of macrophages . Osteopontin , a component of extracellular matrix , is synthesized by macrophages in atherosclerotic plaques . In this study , we examined whether PPARgamma ligand regulates osteopontin gene expression in THP - 1 cells , a cell line derived from human monocytic leukemia cells which can differentiate to macrophage upon stimulation with phorbol ester PMA . Northern blot analysis showed that osteopontin expression is markedly induced in response to PMA . Troglitazone , a PPARgamma ligand , dramatically attenuated the PMA - induced osteopontin expression . Transient transfection assays of the human osteopontin promoter / luciferase construct which contains a 5 ' - flanking region between - 1500 and + 87 relative to the transcription start site demonstrate that either treatment with troglitazone or cotransfection of PPARgamma expression vector inhibits osteopontin promoter activity . These data indicate that troglitazone reduces osteopontin gene expression at transcriptional level through PPARgamma activation , and suggest the role of troglitazone in inhibiting the ability of macrophages to produce extracellular matrix , which is particularly relevant to atherosclerotic plaque formation . Transcription factor NF - kappa B regulates Ig lambda light chain gene rearrangement . The tissue - and stage - specific assembly of Ig and TCR genes is mediated by a common V ( D ) J recombinase complex in precursor lymphocytes . Directed alterations in the accessibility of V , D , and J gene segments target the recombinase to specific Ag receptor loci . Accessibility within a given locus is regulated by the functional interaction of transcription factors with cognate enhancer elements and correlates with the transcriptional activity of unrearranged gene segments . As demonstrated in our prior studies , rearrangement of the Igkappa locus is regulated by the inducible transcription factor NF - kappaB . In contrast to the Igkappa locus , known transcriptional control elements in the Iglambda locus lack functional NF - kappaB binding sites . Consistent with this observation , the expression of assembled Iglambda genes in mature B cells has been shown to be NF - kappaB independent . Nonetheless , we now show that specific repression of NF - kappaB inhibits germline transcription and recombination of Iglambda gene segments in precursor B cells . Molecular analyses indicate that the block in NF - kappaB impairs Iglambda rearrangement at the level of recombinase accessibility . In contrast , the activities of known Iglambda promoter and enhancer elements are unaffected in the same cellular background . These findings expand the range of NF - kappaB action in precursor B cells beyond Igkappa to include the control of recombinational accessibility at both L chain loci . Moreover , our results strongly suggest the existence of a novel Iglambda regulatory element that is either directly or indirectly activated by NF - kappaB during the early stages of B cell development . Transcription factor STAT5A is a substrate of Bruton ' s tyrosine kinase in B cells . STAT5A is a molecular regulator of proliferation , differentiation , and apoptosis in lymphohematopoietic cells . Here we show that STAT5A can serve as a functional substrate of Bruton ' s tyrosine kinase ( BTK ) . Purified recombinant BTK was capable of directly binding purified recombinant STAT5A with high affinity ( K ( d ) = 44 nm ) , as determined by surface plasmon resonance using a BIAcore biosensor system . BTK was also capable of tyrosine - phosphorylating ectopically expressed recombinant STAT5A on Tyr ( 694 ) both in vitro and in vivo in a Janus kinase 3 - independent fashion . BTK phosphorylated the Y665F , Y668F , and Y682F , Y683F mutants but not the Y694F mutant of STAT5A . STAT5A mutations in the Src homology 2 ( SH2 ) and SH3 domains did not alter the BTK - mediated tyrosine phosphorylation . Recombinant BTK proteins with mutant pleckstrin homology , SH2 , or SH3 domains were capable of phosphorylating STAT5A , whereas recombinant BTK proteins with SH1 / kinase domain mutations were not . In pull - down experiments , only full - length BTK and its SH1 / kinase domain ( but not the pleckstrin homology , SH2 , or SH3 domains ) were capable of binding STAT5A . Ectopically expressed BTK kinase domain was capable of tyrosine - phosphorylating STAT5A both in vitro and in vivo . BTK - mediated tyrosine phosphorylation of ectopically expressed wild type ( but not Tyr ( 694 ) mutant ) STAT5A enhanced its DNA binding activity . In BTK - competent chicken B cells , anti - IgM - stimulated tyrosine phosphorylation of STAT5 protein was prevented by pretreatment with the BTK inhibitor LFM - A13 but not by pretreatment with the JAK3 inhibitor HI - P131 . B cell antigen receptor ligation resulted in enhanced tyrosine phosphorylation of STAT5 in BTK - deficient chicken B cells reconstituted with wild type human BTK but not in BTK - deficient chicken B cells reconstituted with kinase - inactive mutant BTK . Similarly , anti - IgM stimulation resulted in enhanced tyrosine phosphorylation of STAT5A in BTK - competent B cells from wild type mice but not in BTK - deficient B cells from XID mice . In contrast to B cells from XID mice , B cells from JAK3 knockout mice showed a normal STAT5A phosphorylation response to anti - IgM stimulation . These findings provide unprecedented experimental evidence that BTK plays a nonredundant and pivotal role in B cell antigen receptor - mediated STAT5A activation in B cells Role of T - bet in commitment of TH1 cells before IL - 12 - dependent selection . How cytokines control differentiation of helper T ( TH ) cells is controversial . We show that T - bet , without apparent assistance from interleukin 12 ( IL - 12 ) / STAT4 , specifies TH1 effector fate by targeting chromatin remodeling to individual interferon - gamma ( IFN - gamma ) alleles and by inducing IL - 12 receptor beta2 expression . Subsequently , it appears that IL - 12 / STAT4 serves two essential functions in the development of TH1 cells : as growth signal , inducing survival and cell division ; and as trans - activator , prolonging IFN - gamma synthesis through a genetic interaction with the coactivator , CREB - binding protein . These results suggest that a cytokine does not simply induce TH fate choice but instead may act as an essential secondary stimulus that mediates selective survival of a lineage . Stat6 is necessary and sufficient for IL - 4 ' s role in Th2 differentiation and cell expansion . IL - 4 plays a critical role in the differentiation of T CR - stimulated naive CD4 T cells to the Th2 phenotype . In response to IL - 4 , the IL - 4R activates a set of phosphotyrosine binding domain - containing proteins , including insulin receptor substrate 1 / 2 , Shc , and IL - 4R interacting protein , as well as Stat6 . Stat6 has been shown to be required for Th2 differentiation . To determine the roles of the phosphotyrosine binding adaptors in Th2 differentiation , we prepared a retrovirus containing a mutant of the human ( h ) IL - 4R alpha - chain , Y497F , which is unable to recruit these adaptors . The mutant hIL - 4Ralpha , as well as the wild - type ( WT ) hIL - 4Ralpha , was introduced into naive CD4 T cells . Upon hIL - 4 stimulation , Y497F worked as well as the WT hIL - 4Ralpha in driving Th2 differentiation , as measured by Gata3 up - regulation and IL - 4 production . Furthermore , IL - 4 - driven cell expansion was also normal in the cells infected with Y497F , although cells infected with Y497F were not capable of phosphorylating insulin receptor substrate 2 . These results suggest that the signal pathway mediated by Y497 is dispensable for both IL - 4 - driven Th2 differentiation and cell expansion . Both WT and Y497F hIL - 4Ralpha lose the ability to drive Th2 differentiation and cell expansion in Stat6 - knockout CD4 T cells . A constitutively activated form of Stat6 introduced into CD4 T cells resulted in both Th2 differentiation and enhanced cell expansion . Thus , activated Stat6 is necessary and sufficient to mediate both IL - 4 - driven Th2 differentiation and cell expansion in CD4 T cells . The effect of HIV - 1 regulatory proteins on cellular genes : derepression of the IL - 2 promoter by Tat . In HIV - infected individuals dysregulation of the immune system is characterized by severe disorders of the cytokine network . Increase secretion of IL - 2 , the major T cell growth and differentiation cytokine , may play a decisive role in sensitization of T cells for activation induced apoptosis and indirect death of activated T cells through augmented virus replication . We investigated the cause of enhanced IL - 2 secretion and found that the HIV Tat induces this effect . We demonstrate that increased IL - 2 secretion is due to Tat - enhanced IL - 2 promoter activation . Tat derepresses and activates the distal AP - 1 site ( position - 185 to - 177 ) in the IL - 2 promoter . In nonstimulated T cells a repressor complex containing NF - IL6 , JunB , c - Fos and Fra - 1 is formed on the AP - 1 ( IL - 2 / d ) site and represses IL - 2 promoter activity . After T cell activation , a heterodimeric activator containing p65 and c - Jun binds to the AP - 1 ( IL - 2 / d ) site . HIV Tat enhances activation of NF - kappaB and consequently , activates the AP - 1 ( IL - 2 / d ) site . Our data provide evidence for a novel mechanism by which HIV Tat dysregulates IL - 2 production and therefore may contribute to the HIV - 1 infection in a way yet to be clarified . Transforming growth factor - beta1 interferes with thrombopoietin - induced signal transduction in megakaryoblastic and erythroleukemic cells . OBJECTIVE : Thrombopoietin ( TPO ) and transforming growth factor - beta ( 1 ) ( TGF - beta ( 1 ) ) have been shown to exert opposite effects on proliferation and megakaryocytic differentiation of hematopoietic cells . To determine whether TGF - beta ( 1 ) interferes directly with TPO - induced signal transduction in hematopoietic cells , we compared the regulatory effects in the TPO - responsive cell lines Mo - 7e and HEL . MATERIALS AND METHODS : The cells were stimulated by 100 ng / mL TPO and / or 100 ng / mL TGF - beta1 and analyzed for proliferation ( 3H thymidine incorporation ) , viability ( trypan blue exclusion ) , and protein expression and phosphorylation ( Western blot ) . RESULTS : TPO enhanced the proliferation of Mo - 7e cells as determined by 3H - thymidine incorporation , whereas TGF - beta1 suppressed baseline cell growth and antagonized the proliferative effect of TPO . TPO - induced proliferation also was reduced by a specific inhibitor of the mitogen - activated protein kinase ( MAPK ) pathway ( PD098059 ) , which inhibits activation of the MAPK extracellular signal - regulated kinases ( ERK ) ERK1 and ERK2 , and AG490 , an inhibitor of Janus kinase - 2 , which completely blocked TPO - induced proliferation . As demonstrated by Western blotting , TGF - beta1 reduced the TPO - stimulated ERK1 / ERK2 and STAT5 phosphorylation in Mo - 7e and HEL cells . This effect was completely reversed by preincubation with a tyrosine phosphatase inhibitor ( Na3VO4 ) , which suggests that TGF - beta1 activated a phosphatase . Although STAT3 also was activated by TPO , STAT3 activation remained unaltered by TGF - beta1 . CONCLUSION : Taken together , these data suggest that TGF - beta1 modulates TPO - mediated effects on megakaryocytic proliferation by interfering with TPO - induced signal transduction , particularly by reducing the activities of MAPK ERK1 / ERK2 and STAT5 . Invariant chain induces B cell maturation by activating a TAF ( II ) 105 - NF - kappaB - dependent transcription program . Early stages of B cell development occur in the bone marrow , resulting in formation of immature B cells . From there these immature cells migrate to the spleen where they differentiate to mature cells . This final maturation step is crucial for the B cells to become responsive to antigens and to participate in the immune response . Recently , invariant chain ( Ii ) , a major histocompatibility complex class II chaperone , as well as the transcription factors c - Rel and p65 / RelA , were found to play a role in the final antigen - independent differentiation stage of B cells in the spleen . In this study , we investigated a possible link between Ii - dependent B cell maturation and the NF - kappaB pathway . Our studies indicate that Ii - induced B cell maturation involves activation of transcription mediated by the NF - kappaB p65 / RelA homodimer and requires the B cell - enriched coactivator TBP - associated factor ( II ) 105 . Androgens indirectly accelerate thymocyte apoptosis . Apoptotic processes , or the disturbance of the natural regulation of these processes , may be involved in the pathogenesis of autoimmune diseases ( AID ) . Women are , in general , more susceptible than men to develop AID like rheumatoid arthritis . Androgens and glucocorticoids , in contrast to oestrogens , have favourable effects in AID models as well as in human AID . It is known that glucocorticoids ( GC ) , used for treatment of AID , increase apoptosis in the thymus resulting in decreased numbers of CD4 + CD8 + thymocytes . It was asked whether androgens , in contrast to oestrogens , exert their favourable effects in the treatment of AID by a mechanism comparable to that described for GC by eliminating the apoptosis prone CD4 + CD8 + population in the thymus . Although both androgens and oestrogens proved thymolytic , a significantly decreased percentage of CD4 + CD8 + thymocytes was observed by flow cytometry after treatment of mice with the androgen methyltestosterone , but not with the oestrogen ethinylestradiol . To investigate whether the observed thymolytic effects were due to the presence of hormone receptors on thymocytes , cells were isolated from the thymus and incubated with androgens or oestrogens to measure apoptosis . Several techniques were used to determine thymocyte apoptosis in vitro , but no enhanced apoptotic signal was observed . Using the very sensitive TUNEL assay , no direct effect of androgens on thymocytes in vitro could be observed . This is in sharp contrast to the high signal observed with GC . Therefore , upon in vivo androgen treatment , other cells containing androgen receptors than thymocytes are probably involved in inducing the increase in thymic apoptosis . To study the role of the androgen receptor on thymocyte apoptosis , androgen receptor mutant ( Tfm / Y ) mice were treated with androgens . No alterations of thymocyte subpopulations were seen , suggesting that changes in the percentage of CD4 + CD8 + thymocytes after administration of androgens depend on the presence of functional androgen receptors . Thus , it is concluded that androgens indirectly accelerate thymocyte apoptosis in vivo . Inhibition of the transcription factors AP - 1 and NF - kappaB in CD4 T cells by peroxisome proliferator - activated receptor gamma ligands . The peroxisome proliferator - activated receptor gamma ( PPARgamma ) , a member of the nuclear hormone receptor superfamily , is essential for adipocyte differentiation and glucose homeostasis . PPARgamma has been found recently to regulate macrophage activation in response to mitogens and inflammation . Our study shows PPARgamma to be preferentially expressed in the nuclei of resting T cells and to increase upon activation of T cells by either anti - CD3 and anti - CD28 or phorbol myristyl acetate ( PMA ) . We also found the PPARgamma ligand ciglitizone to attenuate the activation of T cells by inhibiting cytokine gene expression and anti - CD3 and anti - CD28 or PMA - induced proliferative responses . Inhibition of both the proliferative response and inflammatory cytokine expression in CD4 T cells was correlated with suppression of the activated transcription factors AP1 and NF - kappaB . PPARgamma ligands also strongly inhibited SEA - induced Vbeta3 T cell activation in vivo . These results , together with previous findings of the inhibitory effect of PPARgamma ligands on activated macrophages , provide clear evidence for PPARgamma as a negative regulator of the inflammatory activation of both macrophage and T cells . PPARgamma may thus be a potential therapeutic target for the treatment of autoimmunity . A prominent role for activator protein - 1 in the transcription of the human 2B4 ( CD244 ) gene in NK cells . The cell surface glycoprotein 2B4 ( CD244 ) of the Ig superfamily is involved in the regulation of NK and T lymphocyte functions . We have recently identified CD48 as the high affinity counterreceptor for 2B4 in both mice and humans . The cytoplasmic domain of 2B4 associates with src homology 2 domain - containing protein or signaling lymphocyte activation molecule - associated protein , whose mutation is the underlying genetic defect in the X - linked lymphoproliferative syndrome . In this study , we report the molecular cloning and characterization of the human 2B4 ( h2B4 ) promoter . Through primer extension analysis , we found that the transcription of the h2B4 gene initiates at multiple start sites . We isolated h2B4 genomic clones and PCR amplified the 5 ' untranslated region containing the promoter elements . We have identified a functional AP - 1 site that lies between ( - 106 to - 100 ) through transient transfection analysis in YT cells , a human NK cell line . EMSAs with Abs specific for various protein factors of the AP - 1 family revealed that multiple members of the Jun family are involved in the regulation of the h2B4 gene . Mutation of the AP - 1 site not only abolishes protein / DNA interactions but also promoter activity . These results demonstrate a significant role for AP - 1 in the transcriptional regulation of the h2B4 gene . Functional correction of FA - C cells with FANCC suppresses the expression of interferon gamma - inducible genes . Because hematopoietic cells derived from Fanconi anemia ( FA ) patients of the C - complementation group ( FA - C ) are hypersensitive to the inhibitory effects of interferon gamma ( IFNgamma ) , the products of certain IFNgamma - inducible genes known to influence hematopoietic cell survival were quantified . High constitutive expression of the IFNgamma - inducible genes , IFN - stimulated gene factor 3 gamma subunit ( ISGF3gamma ) , IFN regulatory factor - 1 ( IRF - 1 ) , and the cyclin - dependent kinase inhibitor p21 ( WAF1 ) was found in FANCC mutant B lymphoblasts , low - density bone marrow cells , and murine embryonic fibroblasts . Paradoxically , these cells do not activate signal transducer and activator of transcription ( STAT ) 1 properly . In an attempt to clarify mechanisms by which FA - C cells overexpress IFNgamma - inducible genes in the face of defective STAT1 phosphorylation , it was reasoned that decreased levels of activated STAT1 might result in reduced expression of a hematopoietic IFNgamma - responsive protein that normally modulates expression of other IFNgamma - responsive genes . Levels of the IFNgamma - inducible factor IFN consensus sequence binding protein ( ICSBP ) , a negative trans - acting regulator of some IFNgamma - inducible genes , were quantified . ICSBP levels were reduced in FA - C B lymphoblasts and MEFs . However , enforced expression of ICSBP failed to down - regulate IRF - 1 , ISGF3gamma , and p21 ( WAF1 ) . Thus , the FANCC protein functions to modulate expression of a family of genes that in normal cells are inducible only by specific environmental cues for apoptosis or mitogenic inhibition , but it does so independently of the classic IFN - STAT1 pathway and is not the direct result of reduced ICSBP expression . A genetic investigation of E2A function in lymphocyte development . Lymphocytes are derived from hematopoietic stem cells ( HSC ) following a series of regulated differentiation events . Multipotent HSCs become committed to the B cell lineage in bone marrow and the T cell lineage in the thymus after receiving appropriate signals from the corresponding microenvironment . These committed lymphoid cells must then undergo V ( D ) J recombination at the immunoglobulin gene or T cell receptor gene locus resulting in clonal production of functional B or T lymphocytes , respectively . Lymphocyte commitment and differentiation are accompanied by programmed gene expression or repression events which are driven by lineage and stage specific transcription factors . The basic - helix - loop - helix ( bHLH ) transcription factors encoded by the E2A gene are involved in several differentiation events during B and T cell development , including lineage commitment , initiation of V ( D ) J recombination , and antigen receptor mediated proliferation and differentiation . Several recent reviews have provided a comprehensive discussion of biochemical , cellular , and genetic research on E2A function in lymphocyte development ( 1 , 2 ) . Here , we only discuss some of the genetic approaches our laboratory ( except where it is noted ) has undertaken to investigate the molecular pathways mediated by E2A transcription factors in lymphocyte development D609 inhibits ionizing radiation - induced oxidative damage by acting as a potent antioxidant . Tricyclodecan - 9 - yl - xanthogenate ( D609 ) has been extensively studied in biological systems and exhibits a variety of biological functions , including antiviral , antitumor , and anti - inflammatory activities . Most of these activities have been largely attributed to the inhibitory effect of D609 on phosphatidylcholine - specific phospholipase C . However , as a xanthate derivative , D609 is a strong electrolyte and readily dissociates to xanthate anions and cations of alkali metals in solution . Xanthate anions and protonated xanthic acid contain a free thiol moiety and are highly reductive . This implies that D609 and other xanthate derivatives may function as potent antioxidants . Indeed , we found that D609 inhibited the Fenton reaction - induced oxidation of dihydrorhodamine 123 in a dose - dependent manner similar to that of pyrrolidinedithiocar , a well known antioxidant . In addition , D609 inhibited the formation of the alpha - phenyl - tert - butylnitrone - free radical spin adducts and lipid peroxidation of synaptosomal membranes by the Fenton reagents . Furthermore , preincubation of lymphocytes with D609 resulted in a significant diminution of ionizing radiation ( IR ) - induced 1 ) production of reactive oxygen species ; 2 ) decrease in intracellular reduced glutathione ; 3 ) oxidative damage to proteins and lipids ; and 4 ) activation of nuclear factor - kappaB . Moreover , when D609 ( 50 mg / kg i . v . ) was administered to mice 10 min prior to total body IR ( 6 . 5 and 8 . 5 Gy ) , it protected the mice from IR - induced lethality . Thus , these results indicate that D609 is a potent antioxidant and has the ability to inhibit IR - induced cellular oxidative stress . Inhibition of AP - 1 by the glucocorticoid - inducible protein GILZ . The immunosuppressive effects of glucocorticoids arise largely by inhibition of cytokine gene expression , which has been ascribed to interference between the glucocorticoid receptor and transcription factors such as AP - 1 and NF - kappa B as well as by competition for common coactivators . Here we show that glucocorticoid - induced inhibition of interleukin - 2 mRNA expression in activated normal T cells required new protein synthesis , suggesting that this phenomenon is secondary to expression of glucocorticoid - regulated genes . One of the most prominent glucocorticoid - induced genes is glucocorticoid - induced leucine zipper ( GILZ ) , which has been reported to inhibit activation - induced up - regulation of Fas ligand ( FasL ) mRNA . Indeed , transient expression of GILZ in Jurkat T cells blocked induction of a reporter construct driven by the FasL promoter . This could be accounted for by GILZ - mediated inhibition of Egr - 2 and Egr - 3 , NFAT / AP - 1 - inducible transcription factors that bind a regulatory element in the FasL promoter and up - regulate FasL expression . GILZ also potently inhibited AP - 1 - driven and IL - 2 promoter - driven reporter constructs , and recombinant GILZ specifically interacted with c - Fos and c - Jun in vitro and inhibited the binding of active AP - 1 to its target DNA . Whereas homodimerization of GILZ required the presence of its leucine zipper , the interaction with c - Fos and c - Jun occurred through the N - terminal 60 - amino acid region of GILZ . Thus , GILZ represents a glucocorticoid - induced gene product that can inhibit a variety of activation - induced events , at least in part by direct interference with AP - 1 , and is therefore a candidate for a mediator of glucocorticoid - induced immunosuppression . Pharmacokinetic differences between a T cell - tolerizing and a T cell - activating peptide . Vaccination with a peptide representing a CTL epitope from the human papillomavirus ( HPV ) 16 E7 protein induces a specific CTL response that prevents the outgrowth of HPV16 E7 - expressing tumors . In contrast , vaccination with a peptide encoding an adenovirus type 5 ( Ad5 ) E1A CTL epitope results in CTL tolerance and enhanced growth of an Ad5 E1A - expressing tumor . It is unclear why these peptides induce such opposite effects . To determine whether a difference in pharmacokinetics can explain the functional contrasts , tritiated Ad5 E1A and HPV16 E7 peptides were injected into mice . Results show that the tolerizing peptide spread through the body 16 times faster than the activating peptide and was cleared at least 2 times faster . The HPV16 E7 peptide kinetics correlated with the kinetics of HPV16 E7 - specific CTL induction . In contrast , Ad5 E1A peptide injection resulted in physical deletion of preexisting Ad5 E1A - specific CTLs within 24 h after injection . This tolerization occurred at the time when the peptide reached its maximum peptide concentration in the organs . These data suggest that ubiquitous expression of the tolerizing Ad5 E1A peptide within a short period of time causes activation - induced cell death of Ad5 E1A - specific CTLs . Therefore , information on the pharmacokinetics of peptides is vital for the safety and efficacy of peptide - based vaccines . Smad3 and Smad4 mediate transforming growth factor - beta1 - induced IgA expression in murine B lymphocytes . Transforming growth factor ( TGF ) - beta1 is well established as a critical IgA isotype switching factor and Smad molecules have been reported to act as transducers and transcriptional factors in the expression of TGF - beta1 - targeted genes . We examined the involvement of Smad proteins in TGF - beta1 - induced IgA expression . First , we found that TGF - beta1 significantly increases endogenous germ - line ( GL ) alpha transcripts by LPS - stimulated CH12 . LX . 4933 ( mu ( + ) ) B lymphoma cells . To investigate its signaling mechanisms , the lymphoma cell line was transfected with pFL3 that contains the TGF - beta - responsive element of the GLalpha promoter , and stimulated with TGF - beta1 . Similar to endogenous GLalpha transcripts , TGF - beta1 induces GLalpha promoter activity and overexpression of Smad3 markedly enhances the promoter activity . This activity is further augmented by cotransfected Smad4 . On the other hand , Smad7 substantially abrogates the synergistic effect of Smad3 / 4 on GLalpha promoter activity . In addition , overexpression of Smad3 / 4 enhances TGF - beta1 - induced endogenous GLalpha transcripts in normal spleen B cell s . Finally , in the presence of TGF - beta1 , overexpression of Smad3 / 4 selectively increases both surface IgA expression and IgA production . The results from the present study indicate that Smad3 , Smad4 , and Smad7 , at least in part , serve as mediators linking TGF - beta1 to transcriptional regulation of IgA switching related gene and regulation of IgA class switching . The translesion DNA polymerase zeta plays a major role in Ig and bcl - 6 somatic hypermutation . Ig somatic mutations would be introduced by a polymerase ( pol ) while repairing DNA outside main DNA replication . We show that human B cells constitutively express the translesion pol zeta , which effectively extends DNA past mismatched bases ( mispair extender ) , and pol eta , which bypasses DNA lesions in an error - free fashion . Upon B cell receptor ( BCR ) engagement and coculture with activated CD4 + T cells , these lymphocytes upregulated pol zeta , downregulated pol eta , and mutated the Ig and bcl - 6 genes . Inhibition of the pol zeta REV3 catalytic subunit by specific phosphorothioate - modified oligonucleotides impaired Ig and bcl - 6 hypermutation and UV damage - induced DNA mutagenesis , without affecting cell cycle or viability . Thus , pol zeta plays a critical role in Ig and bcl - 6 hypermutation , perhaps facilitated by the downregulation of pol eta . Molecular mechanism of cell cycle progression induced by the oncogene product Tax of human T - cell leukemia virus type I . The trans - activator protein Tax of human T - cell leukemia virus type I ( HTLV - I ) plays an important role in the development of adult T - cell leukemia through , at least in part , its ability to stimulate cell growth . We previously reported that Tax induced cell cycle progression from G0 / G1 phase to S and G2 / M phases in human T - cell line Kit 225 cells . To elucidate molecular mechanism of Tax - induced cell cycle progression , we systematically examined the effects of Tax on biochemical events associated with cell cycle progression . Introduction of Tax into resting Kit 225 cells induced activation of the G1 / S transition regulation cascade consisting of activation of cyclin dependent kinase 2 ( CDK2 ) and CDK4 , phosphorylation of the Rb family proteins and an increase in free E2F . The kinase activation was found to result from Tax - induced expression of genes for cell cycle regulatory molecules including cyclin D2 , cyclin E , E2F1 , CDK2 , CDK4 and CDK6 , and Tax - induced reduction of CDK inhibitors p19 ( INK4d ) and p27 ( Kip1 ) . These modulations by Tax always paralleled the ability of Tax to activate the NF - kappaB transcription pathway . These results indicate the important role of Tax - mediated trans - activation of the genes for cell cycle regulatory molecules in Tax - induced cell cycle progression . Cot kinase induces cyclooxygenase - 2 expression in T cells through activation of the nuclear factor of activated T cells . Cyclooxygenase - 2 ( COX - 2 ) is induced in human T lymphocytes upon T cell receptor triggering . Here we report that Cot kinase , a mitogen - activated protein kinase kinase kinase involved in T cell activation , up - regulates COX - 2 gene expression in Jurkat T cells . Induction of COX - 2 promoter activity by Cot kinase occurred mainly through activation of the nuclear factor of activated T cells ( NFAT ) . Mutation of the distal ( - 105 / - 97 ) and proximal ( - 76 / - 61 ) NFAT response elements in the COX - 2 promoter abolished the activation induced by Cot kinase . Even more , coexpression of a dominant negative version of NFAT inhibited Cot kinase - mediated COX - 2 promoter activation , whereas cotransfection of a constitutively active version of the calcium - dependent phosphatase calcineurin synergizes with Cot kinase in the up - regulation of COX - 2 promoter - driven transcription . Strikingly , Cot kinase increased transactivation mediated by a GAL4 - NFAT fusion protein containing the N - terminal transactivation domain of NFATp . In contrast to phorbol ester plus calcium ionophore A23187 , Cot kinase increases both COX - 2 promoter activity and NFAT - mediated transactivation in a cyclosporin A - independent manner . These data indicate that Cot kinase up - regulates COX - 2 promoter - driven transcription through the NFAT response elements , being the Cot kinase - induced NFAT - dependent transactivation presumably implicated in this up - regulation . Positive and negative roles of the trans - acting T cell factor - 1 for the acquisition of distinct Ly - 49 MHC class I receptors by NK cells . Members of the Ly - 49 gene family code for class I MHC - specific receptors that regulate NK cell function . Due to a combinatorial distribution of Ly - 49 receptors , NK cells display considerable clonal heterogeneity . The acquisition of one Ly - 49 receptor , Ly - 49A is strictly dependent on the transcriptional trans - acting factor T cell - specific factor - 1 ( TCF - 1 ) . Indeed , TCF - 1 binds to two sites in the Ly - 49a promoter and regulates its activity , suggesting that the Ly - 49a gene is a direct TCF - 1 target . TCF - 1 deficiency resulted in the altered usage of additional Ly - 49 receptors . We show in this study , using TCF - 1 beta ( 2 ) - microglobulin double - deficient mice , that these repertoire alterations are not due to Ly - 49 / MHC class I interactions . Our findings rather suggest a TCF - 1 - dependent , cell autonomous effect on the acquisition of multiple Ly - 49 receptors . Besides reduced receptor usage ( Ly - 49A and D ) , we also observed no effect ( Ly - 49C ) and significantly expanded ( Ly - 49G and I ) receptor usage in the absence of TCF - 1 . These effects did not in all cases correlate with the presence of TCF binding sites in the respective proximal promoter . Therefore , besides TCF - 1 binding to the proximal promoter , Ly - 49 acquisition may also be regulated by TCF - 1 binding to more distant cis - acting elements and / or by regulating the expression of additional trans - acting factors . Consistent with the observed differential , positive or negative role of TCF - 1 for Ly - 49 receptor acquisition , reporter gene assays revealed the presence of an inducing as well as a repressing TCF site in certain proximal Ly - 49 promoters . These findings reveal an important role of TCF - 1 for the formation of the NK cell receptor repertoire . Ligation of CD11b and CD11c beta ( 2 ) integrins by antibodies or soluble CD23 induces macrophage inflammatory protein 1alpha ( MIP - 1alpha ) and MIP - 1beta production in primary human monocytes through a pathway dependent on nuclear factor - kappaB . Chemokines and adhesion molecules such as integrins play a major part in the trafficking , extravasation , and recruitment of leukocytes to inflammatory sites . This study investigated the effects of beta ( 2 ) integrin engagement on chemokine production by freshly isolated human monocytes . We found that ligation of CD11b or CD11c but not CD11a alpha chains of beta ( 2 ) integrins by antibodies or soluble CD23 ( sCD23 ) fusion proteins rapidly induced transcription and secretion of interleukin 8 , macrophage inflammatory protein ( MIP ) 1alpha , and MIP - 1beta . Because the promoters of these chemokine genes contain kappaB binding sites , we assessed the possible role of nuclear factor - kappaB ( NF - kappaB ) in controlling induction of the genes through beta ( 2 ) integrin engagement . Electrophoretic mobility shift assays showed that sCD23 or antibodies to CD11b or to CD11c up - regulated DNA - binding activity of NF - kappaB . Activation of NF - kappaB was accompanied by degradation of its cytosolic inhibitor IkappaB - alpha . Blockade of depletion of IkappaB - alpha by proteasome inhibitors ( proteasome inhibitor I or acetyl - leucinyl - leucinyl - norleucinal ) led to concomitant inhibition of NF - kappaB DNA - binding activity and expression of MIP - 1alpha and MIP - 1beta messenger RNA induced by beta ( 2 ) integrin ligation . These results suggest that triggering of CD11b or CD11c beta ( 2 ) integrin on primary human monocytes provides activation signals leading to nuclear translocation of NF - kappaB and subsequent secretion of MIP - 1alpha and MIP - 1beta that may have an important role in recruitment of other inflammatory cells during initiation of an inflammatory response Synergistic transcriptional activation of human Acyl - coenzyme A : cholesterol acyltransterase - 1 gene by interferon - gamma and all - trans - retinoic acid THP - 1 cells . Acyl - coenzyme A : cholesterol acyltransferase ( ACAT ) is an intracellular enzyme involved in cellular cholesterol homeostasis and in atherosclerotic foam cell formation . Human ACAT - 1 gene contains two promoters ( P1 and P7 ) , each located in a different chromosome ( 1 and 7 ) ( Li , B . L . , Li , X . L . , Duan , Z . J . , Lee , O . , Lin , S . , Ma , Z . M . , Chang , C . C . , Yang , X . Y . , Park , J . P . , Mohandas , T . K . , Noll , W . , Chan , L . , and Chang , T . Y . ( 1999 ) J . Biol Chem . 274 , 11060 - 11071 ) . Interferon - gamma ( IFN - gamma ) , a cytokine that exerts many pro - atherosclerotic effects in vivo , causes up - regulation of ACAT - 1 mRNA in human blood monocyte - derived macrophages and macrophage - like cells but not in other cell types . To examine the molecular nature of this observation , we identified within the ACAT - 1 P1 promoter a 159 - base pair core region . This region contains 4 Sp1 elements and an IFN - gamma activated sequence ( GAS ) that overlaps with the second Sp1 element . In the monocytic cell line THP - 1 cell , the combination of IFN - gamma and all - trans - retinoic acid ( a known differentiation agent ) enhances the ACAT - 1 P1 promoter but not the P7 promoter . Additional experiments showed that all - trans - retinoic acid causes large induction of the transcription factor STAT1 , while IFN - gamma causes activation of STAT1 such that it binds to the GAS / Sp1 site in the ACAT - 1 P1 promoter . Our work provides a molecular mechanism to account for the effect of IFN - gamma in causing transcriptional activation of ACAT - 1 in macrophage - like cells . Inhaled nitric oxide down - regulates intrapulmonary nitric oxide production in lipopolysaccharide - induced acute lung injury . OBJECTIVE : To examine whether inhaled nitric oxide ( NO ) affected the intrapulmonary production of NO , reactive oxygen species , and nuclear factor - kappaB in a lipopolysaccharide ( LPS ) - induced model of acute lung injury . DESIGN : Prospective , randomized , laboratory study . SETTING : Experimental laboratory at a biomedical institute . SUBJECTS : Twenty male rabbits weighing 2 . 5 - 3 . 5 kg . INTERVENTIONS : Saline or LPS ( 5 mg / kg of body weight ) was administered intravenously with or without NO inhalation ( 10 ppm ) in each group of five rabbits . MEASUREMENTS AND MAIN RESULTS : LPS increased the lung leak index , the neutrophils and NO levels in bronchoalveolar lavage fluid , and NO levels produced by resting and stimulated alveolar macrophages . Inhaled NO decreased the lung leak index , the neutrophils and NO levels as measured by nitrite levels in the lavage fluid , and NO produced by the resting and stimulated alveolar macrophages . Inhaled NO also blocked the activities of reactive oxygen species and nuclear factor - kappaB binding to DNA in lavage cells and in alveolar macrophages . CONCLUSION : Inhaled NO attenuates LPS - induced acute lung injury , possibly by decreasing NO production in the lungs . The mechanism of reducing NO production resulting from inhaled NO may involve , in part , the activities of reactive oxygen species and / or nuclear factor - kappaB . Treatment of allergic airway inflammation and hyperresponsiveness by antisense - induced local blockade of GATA - 3 expression . Recent studies in transgenic mice have revealed that expression of a dominant negative form of the transcription factor GATA - 3 in T cells can prevent T helper cell type 2 ( Th2 ) - mediated allergic airway inflammation in mice . However , it remains unclear whether GATA - 3 plays a role in the effector phase of allergic airway inflammation and whether antagonizing the expression and / or function of GATA - 3 can be used for the therapy of allergic airway inflammation and hyperresponsiveness . Here , we analyzed the effects of locally antagonizing GATA - 3 function in a murine model of asthma . We could suppress GATA - 3 expression in interleukin ( IL ) - 4 - producing T cells in vitro and in vivo by an antisense phosphorothioate oligonucleotide overlapping the translation start site of GATA - 3 , whereas nonsense control oligonucleotides were virtually inactive . In a murine model of asthma associated with allergic pulmonary inflammation and hyperresponsiveness in ovalbumin ( OVA ) - sensitized mice , local intranasal administration of fluorescein isothiocyanate - labeled GATA - 3 antisense oligonucleotides led to DNA uptake in lung cells associated with a reduction of intracellular GATA - 3 expression . Such intrapulmonary blockade of GATA - 3 expression caused an abrogation of signs of lung inflammation including infiltration of eosinophils and Th2 cytokine production . Furthermore , treatment with antisense but not nonsense oligonucleotides induced a significant reduction of airway hyperresponsiveness in OVA - sensitized mice to levels comparable to saline - treated control mice , as assessed by both enhanced pause ( PenH ) responses and pulmonary resistance determined by body plethysmography . These data indicate a critical role for GATA - 3 in the effector phase of a murine asthma model and suggest that local delivery of GATA - 3 antisense oligonucleotides may be a novel approach for the treatment of airway hyperresponsiveness such as in asthma . This approach has the potential advantage of suppressing the expression of various proinflammatory Th2 cytokines simultaneously rather than suppressing the activity of a single cytokine . T helper - cell phenotype regulates atherosclerosis in mice under conditions of mild hypercholesterolemia . BACKGROUND : T cells are implicated in atherosclerosis , but little is known about the genetic control or molecular pathways , especially under conditions of mild hypercholesterolemia . METHODS AND RESULTS : BALB / c mice , making a CD4 + Th2 ( IL - 4 + ) cell response , express both MHC class II antigens ( IA ( d ) , IE ( d ) ) and are atherosclerosis - resistant . C57Bl / 6 mice produce a CD4 + Th1 ( interferon [ IFN ] gamma + ) response , express IA ( b ) but no IE , and are atherosclerosis - prone . To evaluate T helper - cell phenotype in fatty streak formation , wild - type C57Bl / 6 mice ( IA ( b ) + IE - ) and transgenic mice , either AB ( o ) , IA ( b ) - IE - ; ABEalpha , IA - IE ( k ) + ; or BL : TG : Ealpha , IA ( b ) + IE ( k ) + , were fed a high - cholesterol diet for 16 weeks and evaluated histomorphometricall for aortic lesions . Lesion size in AB ( o ) , ABEalpha , and BL : TG : Ealpha strains was decreased by 54 % , 79 % , and 82 % , respectively , compared with wild - type , correlating with decreased Th1 and increased Th2 expression and suggesting that T helper - cell phenotype is important in fatty lesion development . Decreasing Th1 cells by antibodies ( alpha - CD4 ) or cytokines ( IL - 4 ) also caused > / = 80 % reductions in lesion size . Immunohistology revealed IFN - gamma , but not IL - 4 , colocalized with activated macrophages . Confirming these findings in a different mouse strain , BALB / c Stat 6 knockout mice ( Th2 cell - deficient ) developed aortic lesions comparable to C57Bl / 6 mice on the same diet . CONCLUSIONS : In mildly hypercholesterolemic C57Bl / 6 mice , presence of IA ( b ) and absence of IE regulated CD4 + T helper - cell phenotype ; fatty lesions were proportional to IFNgamma + Th1 cells in both C57Bl / 6 and BALB / c strains . IFN - gamma may participate through macrophage activation , whereas IL - 4 may act to limit Th1 - cell response . Requirement for p38 and p44 / p42 mitogen - activated protein kinases in RAGE - mediated nuclear factor - kappaB transcriptional activation and cytokine secretion . Advanced glycation end product ( AGE ) activation of the signal - transducing receptor for AGE ( RAGE ) has been linked to a proinflammatory phenotypic change within cells . However , the precise intracellular signaling pathways involved have not been elucidated . We demonstrate here that human serum albumin modified with N ( varepsilon ) - ( carboxymethyl ) lysine ( CML ) , a major AGE adduct that progressively accumulates with aging , diabetes , and renal failure , induced nuclear factor ( NF ) - kappaB - driven reporter gene expression in human monocytic THP - 1 cells . The NF - kappaB response was blocked with a synthetic peptide corresponding to the putative ligand - binding domain of RAGE , with anti - RAGE antiserum , and by coexpression of truncated receptors lacking the intracellular domain . Signal transduction from RAGE to NF - kappaB involved the generation of reactive oxygen species , since reporter gene expression was blocked with the antioxidant N - acetyl - L - cysteine . CML - modified albumin produced rapid transient activation of tyrosine phosphorylation , extracellular signal - regulated kinase 1 and 2 , and p38 mitogen - activated protein kinase ( MAPK ) , but not c - Jun NH ( 2 ) - terminal kinase . RAGE - mediated NF - kappaB activation was suppressed by the selective p38 MAPK inhibitor SB203580 and by coexpression of a kinase - dead p38 dominant - negative mutant . Activation of NF - kappaB by CML - modified albumin increased secretion of proinflammatory cytokines ( tumor necrosis factor - alpha , interleukin - 1beta , and monocyte chemoattractant protein - 1 ) severalfold , and inhibition of p38 MAPK blocked these increases . These results indicate that p38 MAPK activation mediates RAGE - induced NF - kappaB - dependent secretion of proinflammatory cytokines and suggest that accelerated inflammation may be a consequence of cellular activation induced by this receptor . Antigen - receptor cross - linking and lipopolysaccharide trigger distinct phosphoinositide 3 - kinase - dependent pathways to NF - kappa B activation in primary B cells . The NF - kappaB / Rel transcription factors play an important role in the expression of genes involved in B cell development , differentiation and function . Nuclear NF - kappaB is induced in B cells by engagement of either the BCR or CD40 or by stimulation with lipopolysaccharide ( LPS ) . Despite the importance of NF - kappaB to B cell function , little is known about the signaling pathways leading to NF - kappaB activation . In this report we address the role of phosphoinositide 3 ' - kinase ( PI 3 - kinase ) in BCR - and LPS - induced NF - kappaB activation using populations of primary murine resting B cells . Using the specific pharmacological inhibitors of PI 3 - kinase , Wortmannin and LY294002 , we demonstrate that PI 3 - kinase activity is vital for BCR - induced NF - kappaB DNA - binding activity . Furthermore , we show that this is achieved via protein kinase C - dependent degradation of IkappaBalpha . Similar analyses reveal that PI 3 - kinase is also critical in triggering NF - kappaB DNA - binding activity and IkappaBalpha degradation following LPS stimulation . Interestingly , a PKC inhibitor which blocked the BCR - induced IkappaBalpha degradation had no effect on the degradation of IkappaBalpha after LPS stimulation . Taken together , our results indicate the involvement of PI 3 - kinase in at least two distinct signaling pathways leading to activation of NF - kappaB in B cells . Tetramer - guided epitope mapping : rapid identification and characterization of immunodominant CD4 + T cell epitopes from complex antigens . T cell responses to Ags involve recognition of selected peptide epitopes contained within the antigenic protein . In this report , we describe a new approach for direct identification of CD4 + T cell epitopes of complex Ags that uses human class II tetramers to identify reactive cells . With a panel of 60 overlapping peptides covering the entire sequence of the VP16 protein , a major Ag for HSV - 2 , we generated a panel of class II MHC tetramers loaded with peptide pools that were used to stain peripheral lymphocytes of an HSV - 2 infected individual . With this approach , we identified four new DRA1 * 0101 / DRB1 * 0401 - and two DRA1 * 0101 / DRB1 * 0404 - restricted , VP16 - specific epitopes . By using tetramers to sort individual cells , we easily obtained a large number of clones specific to these epitopes . Although DRA1 * 0101 / DRB1 * 0401 and DRA1 * 0101 / DRB1 * 0404 are structurally very similar , nonoverlapping VP16 epitopes were identified , illustrating high selectivity of individual allele polymorphisms within common MHC variants . This rapid approach to detecting CD4 + T cell epitopes from complex Ags can be applied to any known Ag that gives a T cell response . Localized pancreatic NF - kappaB activation and inflammatory response in taurocholate - induced pancreatitis . Transcription factor nuclear factor - kappaB ( NF - kappaB ) is activated in cerulein pancreatitis and mediates cytokine expression . The role of transcription factor activation in other models of pancreatitis has not been established . Here we report upregulation of NF - kappaB and inflammatory molecules , and their correlation with local pancreatic injury , in a model of severe pancreatitis . Rats received intraductal infusion of taurocholate or saline , and the pancreatic head and tail were analyzed separately . NF - kappaB and activator protein - 1 ( AP - 1 ) activation were assessed by gel shift assay , and mRNA expression of interleukin - 6 , tumor necrosis factor - alpha , KC , monocyte chemoattractant protein - 1 , and inducible nitric oxide synthase was assessed by semiquantitative RT - PCR . Morphological damage and trypsin activation were much greater in the pancreatic head than tail , in parallel with a stronger activation of NF - kappaB and cytokine mRNA . Saline infusion mildly affected these parameters . AP - 1 was strongly activated in both pancreatic segments after either taurocholate or saline infusion . NF - kappaB inhibition with N - acetylcysteine ameliorated the local inflammatory response . Correlation between localized NF - kappaB activation , cytokine upregulation , and tissue damage suggests a key role for NF - kappaB in the development of the inflammatory response of acute pancreatitis . CD45 tyrosine phosphatase controls common gamma - chain cytokine - mediated STAT and extracellular signal - related kinase phosphorylation in activated human lymphoblasts : inhibition of proliferation without induction of apoptosis . The objective of this study was to test whether CD45 signals can influence signaling processes in activated human lymphoblasts . To this end , we generated lymphoblasts which proliferate in response to common gamma - chain cytokines , but readily undergo apoptosis after cytokine withdrawal . In experiments with the CD45R0 mAb UCHL - 1 , but not control CD45 mAbs , we found significant inhibition of proliferation . Interestingly , the pan - CD45 mAb GAP8 . 3 , which is most effective in inhibition of OKT - 3 - mediated proliferation in quiescent lymphocytes , was ineffective in lymphoblasts . Addition of CD3 mAb OKT - 3 had no influence on IL - 2 - mediated proliferation ( with or without UCHL - 1 ) . In contrast , after addition of OKT - 3 to IL - 4 - and IL - 7 - stimulated proliferation assays , UCHL - 1 signals could not significantly alter cellular proliferation . We did not find induction of apoptosis following CD45R0 signaling . In Western blots using mAbs detecting phosphorylated STAT - 3 , STAT - 5 , STAT - 6 , or extracellular signal - related kinase 1 / 2 , we found that CD45R0 signaling could effectively diminish phosphorylation of these intracellular signaling components . Using RT - PCR , we found that CD45R0 signaling inhibited IL - 2 mRNA production without major influence on IL - 13 , IL - 5 , or IFN - gamma mRNA levels . Costimulation with OKT - 3 and IL - 2 optimally induced secretion of IFN - gamma , TNF - alpha , and IL - 5 , which was not decreased by CD45 signals . In conclusion , we illustrate that CD45R0 signals control early cytokine receptor - associated signaling processes and mRNA and DNA synthesis in activated human lymphoblasts . Furthermore , we show the existence of CD45 epitopes ( GAP8 . 3 ) , which are active and critical for signaling in quiescent lymphocytes , but are nonfunctional in activated human lymphoblasts . Pax5 determines the identity of B cells from the beginning to the end of B - lymphopoiesis . Despite being one of the most intensively studied cell types , the molecular basis of B cell specification is largely unknown . The Pax5 gene encoding the transcription factor BSAP is required for progression of B - lymphopoiesis beyond the pro - B cell stage . Pax5 - deficient pro - B cells are , however , not yet committed to the B - lymphoid lineage , but instead have a broad lymphomyeloid developmental potential . Pax5 appears to mediate B - lineage commitment by repressing the transcription of non - B - lymphoid genes and by simultaneously activating the expression of B - lineage - specific genes . Pax5 thus functions both as a transcriptional repressor and activator , depending on its interactions with corepressors of the Groucho protein family or with positive regulators such as the TATA - binding protein . Once committed to the B - lineage , B cells require Pax5 function to maintain their B - lymphoid identity throughout B cell development Partners in transcription : NFAT and AP - 1 . Combinatorial regulation is a powerful mechanism that enables tight control of gene expression , via integration of multiple signaling pathways that induce different transcription factors required for enhanceosome assembly . The four calcium - regulated transcription factors of the NFAT family act synergistically with AP - 1 ( Fos / Jun ) proteins on composite DNA elements which contain adjacent NFAT and AP - 1 binding sites , where they form highly stable ternary complexes to regulate the expression of diverse inducible genes . Concomitant induction of NFAT and AP - 1 requires concerted activation of two different signaling pathways : calcium / calcineurin , which promotes NFAT dephosphorylation , nuclear translocation and activation ; and protein kinase C ( PKC ) / Ras , which promotes the synthesis , phosphorylation and activation of members of the Fos and Jun families of transcription factors . A fifth member of the NFAT family , NFAT5 , controls the cellular response to osmotic stress , by a mechanism that requires dimer formation and is independent of calcineurin or of interaction with AP - 1 . Pharmacological interference with theNFAT : AP - 1 interaction may be useful in selective manipulation of the immune response . Balanced activation of NFAT and AP - 1 is known to be required for productive immune responses , but the role of NFAT : AP - 1 interactions in other cell types and biological processes remains to be understood . Cytokine production by Vgamma ( + ) - T - cell subsets is an important factor determining CD4 ( + ) - Th - cell phenotype and susceptibility of BALB / c mice to coxsackievirus B3 - induced myocarditis . Two coxsackievirus B3 ( CVB3 ) variants ( H3 and H310A1 ) differ by a single amino acid mutation in the VP2 capsid protein . H3 induces severe myocarditis in BALB / c mice , but H310A1 is amyocarditic . Infection with H3 , but not H310A1 , preferentially activates Vgamma4 Vdelta4 cells , which are strongly positive for gamma interferon ( IFN - gamma ) , whereas Vgamma1 Vdelta4 cells are increased in both H3 and H310A1 virus - infected animals . Depletion of Vgamma1 ( + ) cells using monoclonal anti - Vgamma1 antibody enhanced myocarditis and CD4 ( + ) - , IFN - gamma ( + ) - cell responses in both H3 - and H310A1 - infected mice yet decreased the CD4 ( + ) - , IL - 4 ( + ) - cell response . Depleting Vgamma4 ( + ) cells suppressed myocarditis and reduced CD4 ( + ) IFN - gamma ( + ) cells but increased CD4 ( + ) IL - 4 ( + ) T cells . The role of cytokine production by Vgamma1 ( + ) and Vgamma4 ( + ) T cells was investigated by adoptively transferring these cells isolated from H3 - infected BALB / c Stat4 knockout ( Stat4ko ) ( defective in IFN - gamma expression ) or BALB / c Stat6ko ( defective in IL - 4 expression ) mice into H3 virus - infected wild - type BALB / c recipients . Vgamma4 and Vgamma1 ( + ) T cells from Stat4ko mice expressed IL - 4 but no or minimal IFN - gamma , whereas these cell populations derived from Stat6ko mice expressed IFN - gamma but no IL - 4 . Stat4ko Vgamma1 ( + ) cells ( IL - 4 ( + ) ) suppress myocarditis . Stat6ko Vgamma1 ( + ) cells ( IFN - gamma ( + ) ) were not inhibitory . Stat6ko Vgamma4 ( + ) cells ( IFN - gamma ( + ) ) significantly enhanced myocarditis . Stat4ko Vgamma4 ( + ) cells ( IL - 4 ( + ) ) neither inhibited nor enhanced disease . These results show that distinct gammadelta - T - cell subsets control myocarditis susceptibility and bias the CD4 ( + ) - Th - cell response . The cytokines produced by the Vgamma subpopulation have a significant influence on the CD4 ( + ) - Th - cell phenotype . Plasmin - induced expression of cytokines and tissue factor in human monocytes involves AP - 1 and IKKbeta - mediated NF - kappaB activation . It was previously shown that plasmin activates human peripheral monocytes in terms of lipid mediator release and chemotactic migration . Here it is demonstrated that plasmin induces proinflammatory cytokine release and tissue factor ( TF ) expression by monocytes . Plasmin 0 . 043 to 1 . 43 CTA U / mL , but not active site - blocked plasmin , triggered concentration - dependent expression of mRNA for interleukin - 1alpha ( IL - 1alpha ) , IL - 1beta , tumor necrosis factor - alpha ( TNF - alpha ) , and TF with maximum responses after 4 hours . Plasmin - mediated mRNA expression was inhibited in a concentration - dependent manner by the lysine analogue trans - 4 - ( aminomethyl ) cyclohexane - 1 - carboxylic acid ( t - AMCA ) . Increases in mRNA levels were followed by concentration - and time - dependent release of IL - 1alpha , IL - 1beta and TNF - alpha and by TF expression on monocyte surfaces . Neither cytokines nor TF could be detected when monocytes were preincubated with actinomycin D or cycloheximide . Electrophoretic mobility shift assays indicated plasmin - induced activation of NF - kappaB ; DNA - binding complexes were composed of p50 , p65 , and c - Rel , as shown by supershift experiments . Nuclear translocation of NF - kappaB / Rel proteins coincided with IkappaBalpha degradation . At variance with endotoxic lipopolysaccharide , plasmin elicited the rapid degradation of another cytoplasmic NF - kappaB inhibitor , p105 . Proteolysis of NF - kappaB inhibitors was apparently due to transient activation of IkappaB kinase ( IKK ) beta that reached maximum activity at 1 hour after plasmin stimulation . In addition , AP - 1 binding was increased in plasmin - treated monocytes , with most complexes composed of JunD , c - Fos , and FosB . These findings further substantiate the role of plasmin as a proinflammatory activator of human monocytes and reveal an important new link between the plasminogen - plasmin system and inflammation . ( Blood . 2001 ; 97 : 3941 - 3950 ) STAT3 is constitutively active in some patients with Polycythemia rubra vera . OBJECTIVE : Polycythemia vera is a clonal stem cell disorder characterized by hyperproliferation of the erythroid , myeloid , and megakaryocytic lineages . While it has been shown that progenitor cells of P . vera patients are hypersensitive to several growth factors including erythropoietin , insulin - like growth factor - 1 , thrombopoietin , interleukin - 3 , and granulocyte / monocyte colony - stimulating factor , the molecular pathogenesis of this disease remains unknown . Growth factor hypersensitivity could be mediated by changes in signal transduction pathways . We therefore investigated a common downstream effector of cytokines , the signal transducers and activators of transcription ( STATs ) . A constitutive activation of STAT factors could explain the increased proliferation of P . vera cells even in the absence of growth factor stimulation . METHODS : Peripheral granulocytes from patients with P . vera and from healthy volunteers were assayed for STAT1 , 3 , and 5 DNA binding by electrophoretic mobility shift assay . RESULTS : Four of 14 P . vera patients analyzed showed constitutive STAT3 DNA binding in unstimulated peripheral granulocytes , while none of the 17 healthy volunteers tested did . None of the subjects showed constitutive STAT1 or STAT5 activity . Western blotting demonstrated that , in the three patients , STAT3 is constitutively phosphorylated on Tyr 705 , whereas it is unphosphorylated in the other patients and in controls . Interestingly , constitutive STAT3 activity did not correlate with the duration of disease or the treatment regimen . It was observed in a recently diagnosed patient and in two patients treated only with phlebotomy . CONCLUSION : Our data suggest that constitutive phosphorylation and activation of STAT3 is not a secondary event induced by mutagenizing agents or by prolonged hyperproliferation of hematopoietic cells , but rather represents a primary molecular aberration . Constitutively active STAT3 may contribute to the growth factor hypersensitivity of P . vera cells . Identification of phosphorylation sites for Bruton ' s tyrosine kinase within the transcriptional regulator BAP / TFII - I . Bruton ' s tyrosine kinase ( Btk ) , a member of the Tec family of cytosolic kinases , is essential for B cell development and function . BAP / TFII - I , a protein implicated in transcriptional regulation , is associated with Btk in B cells and is transiently phosphorylated on tyrosine following B cell receptor engagement . BAP / TFII - I is a substrate for Btk in vitro and is hyperphosphorylated on tyrosine upon coexpression with Btk in mammalian cells . In an effort to understand the physiologic consequences of BAP / TFII - I tyrosine phosphorylation following B cell receptor stimulation , site - directed mutagenesis and phosphopeptide mapping were used to locate the predominant sites of BAP / TFII - I phosphorylation by Btk in vitro . These residues , Tyr248 , Tyr357 , and Tyr462 , were also found to be the major sites for Btk - dependent phosphorylation of BAP / TFII - I in vivo . Residues Tyr357 and Tyr462 are contained within the loop regions of adjacent helix - loop - helix - like repeats within BAP / TFII - I . Mutation of either Tyr248 , Tyr357 , or Tyr462 to phenylalanine reduced transcription from a c - fos promoter relative to wild - type BAP / TFII - I in transfected COS - 7 cells , consistent with the interpretation that phosphorylation at these sites contributes to transcriptional activation . Phosphorylation of BAP / TFII - I by Btk may link engagement of receptors such as surface immunoglobulin to modulation of gene expression . Expression of interferon consensus sequence binding protein induces potent immunity against BCR / ABL - induced leukemia . Mice deficient in the interferon consensus sequence binding protein ( ICSBP ) develop a disease resembling chronic myeloid leukemia ( CML ) , which in humans is caused by the BCR / ABL oncoprotein . Interferon - alpha ( IFN - alpha ) induces ICSBP expression and is an effective therapy for CML . This study examined whether enforced expression of ICSBP might antagonize BCR / ABL - induced leukemia ; results demonstrated that ICSBP - modified cells generated a protective CD8 ( + ) cytotoxic T - cell response against BCR / ABL - transformed BaF3 cells in a murine leukemia model . ICSBP expression represents a novel means of stimulating a host immune response to BCR / ABL ( + ) leukemia cells and a potential strategy for immunotherapy of CML . ( Blood . 2001 ; 97 : 3491 - 3497 ) A transcriptional block in the IL - 2 promoter at the - 150 AP - 1 site in effector CD8 + T cells . Both CD4 + and CD8 + T cells that produce IL - 2 in response to Ag recognition have been isolated . However , most effector CD8 + T cells recovered after exposure to Ag do not produce sufficient IL - 2 to sustain growth , and depend on CD4 + T helper cells for this obligate growth factor . IL - 2 expression in CD4 + T cells is primarily controlled at the level of transcription , but mechanisms restricting IL - 2 production in CD8 + T cells have not been elucidated . To evaluate transcriptional regulation of the IL - 2 gene in CD8 + T cells , we stably transfected reporter genes into Ag - specific CD8 + T cell clones . CD28 + CD8 ( + ) T cells unable to transcribe the IL - 2 gene in response to antigenic stimulation had a block in transactivation of the - 150 CD28 response element ( CD28RE ) / AP - 1 site of the IL - 2 promoter , but did transactivate the composite NFAT / AP - 1 and OCT / AP - 1 sites , and a consensus AP - 1 motif . Mutation of the nonconsensus - 150 AP - 1 site to a consensus AP - 1 site , or insertion of a CD28RE / AP - 1 consensus site upstream of the native - 150 CD28RE / AP - 1 site restored transactivation of the altered promoter . These results suggest that the defect at the - 150 site may reflect the absence or inactivity of a required factor rather than repression of the IL - 2 promoter . Stem cell factor and interleukin - 3 induce stepwise generation of erythroid precursor cells from a basic fibroblast growth factor - dependent hematopoietic stem cell line , A - 6 . A m ultipotent immature myeloid cell population was produced from a basic fibroblast growth factor ( bFGF ) - dependent hematopoietic stem cell line , A - 6 , when cultured with stem cell factor ( SCF ) replacing bFGF . Those cells were positive for stem cell markers , c - kit and CD34 , and a myeloid cell marker , F4 / 80 . Some cell fractions were also positive for Mac - 1 , a macrophage marker or Gr - 1 , a granulocytic maker , but negative for an erythroid marker TER119 . They also showed the expression of mRNA for the myeloid - specific PU . 1 but did not that for the erythroid - specific GATA - 1 . Among various cytokines , interleukin - 3 ( IL - 3 ) induced erythroid precursor cells that expressed the erythroid - specific GATA - 1 and beta - major globin . The quantitative analysis showed that erythroid precursor cells were newly produced from the immature myeloid cells by cultivation with IL - 3 . SCF and IL - 3 induced stepwise generation of erythroid precursor cells from an A - 6 hematopoietic stem cell line . Copyright 2001 Academic Press . Distinct BMI - 1 and EZH2 expression patterns in thymocytes and mature T cells suggest a role for Polycomb genes in human T cell differentiation . BMI - 1 and EZH2 Polycomb - group ( PcG ) proteins belong to two distinct protein complexes involved in the regulation of hematopoiesis . Using unique PcG - specific antisera and triple immunofluorescence , we found that mature resting peripheral T cells expressed BMI - 1 , whereas dividing blasts were EZH2 ( + ) . By contrast , subcapsular immature double - negative ( DN ) ( CD4 ( - ) / CD8 ( - ) ) T cells in the thymus coexpressed BMI - 1 and EZH2 or were BMI - 1 single positive . Their descendants , double - positive ( DP ; CD4 ( + ) / CD8 ( + ) ) cortical thymocytes , expressed EZH2 without BMI - 1 . Most EZH2 ( + ) DN and DP thymocytes were dividing , while DN BMI - 1 ( + ) / EZH2 ( - ) thymocytes were resting and proliferation was occasionally noted in DN BMI - 1 ( + ) / EZH2 ( + ) cells . Maturation of DP cortical thymocytes to single - positive ( CD4 ( + ) / CD8 ( - ) or CD8 ( + ) / CD4 ( - ) ) medullar thymocytes correlated with decreased detectability of EZH2 and continued relative absence of BMI - 1 . Our data show that BMI - 1 and EZH2 expression in mature peripheral T cells is mutually exclusive and linked to proliferation status , and that this pattern is not yet established in thymocytes of the cortex and medulla . T cell stage - specific PcG expression profiles suggest that PcG genes contribute to regulation of T cell differentiation . They probably reflect stabilization of cell type - specific gene expression and irreversibility of lineage choice . The difference in PcG expression between medullar thymocytes and mature interfollicular T cells indicates that additional maturation processes occur after thymocyte transportation from the thymus . Stepwise lineage restriction of progenitors in lympho - myelopoiesis . It has long been controversial whether hematopoiesis progresses through ordered stages of determination as in embryonic development . This is due to the absence of a methodology capable of exactly determining the developmental potential of hematopoietic stem / progenitor cells . The multilineage progenitor ( MLP ) assay enabled us to discriminate among seven types of hematopoietic progenitors , which are multipotent progenitor p - MTB ( capable of generating myeloid , T and B cells ) , bipotent progenitors p - MT , p - MB and p - TB , and unipotent progenitors p - M , p - T and p - B . Among these seven types , the p - TB type progenitor was found to be absent . These findings indicate that the process of lineage commitment proceeds through an ordered but not random process . By extending the area of investigation to include the erythroid lineage , more convincing evidence for the ordered process was obtained . Detailed and exact illustration of the process of hematopoiesis will provide an opportunity to revive hematopoiesis as one of the most fascinating targets of research in developmental biology Epstein - Barr Virus and its glycoprotein - 350 upregulate IL - 6 in human B - lymphocytes via CD21 , involving activation of NF - kappaB and different signaling pathways . Epstein - Barr virus ( EBV ) is a ubiquitous and highly immunotropic gamma herpesvirus that infects more than 90 % of humans worldwide . Its pathogenicity leads to a number of diseases including tumors that result from EBV ' s ability to readily transform B - lymphocytes and , to a lesser extent , epithelial cells . EBV utilizes CD21 / CR2 as its receptor on B cells to initiate the infection process . EBV binds to CR2 through its major envelope glycoprotein - 350 ( gp350 ) and is also a remarkable immunomodulating agent . We had previously shown that EBV is capable of modulating the synthesis of a number of cytokines . We now show that while both purified recombinant gp350 ( rgp350 ) and EBV upregulate IL - 6 mRNA synthesis in B cells , EBV - induced IL - 6 gene activation occurs for a significantly longer period of time ( i . e . 12 hours for EBV as compared to 6 hours for rgp350 ) . Moreover , the half - life of EBV - induced IL - 6 mRNA was also significantly longer ( 10 hours ) than that of mRNA induced by rgp350 ( about 6 hours ) . Both EBV and gp350 enhance the binding of the NF - kappaB transcription factor , as determined by band - shift and augment NF - kappaB - mediated activation of a CAT reporter plasmid . Furthermore , we demonstrate that while the activation of IL - 6 gene expression by gp350 is mediated primarily by the protein kinase C pathway , EBV can mediate its effects through multiple signaling pathways . To our knowledge this is the first report showing that the binding of a herpesvirus envelope glycoprotein to CR2 on human B cells results in the activation of the NF - kappaB transcription factor leading to the upregulation of IL - 6 gene expression in these lymphocytes . Copyright 2001 Academic Press . Gene - and tissue - specificity of mutation in Big Blue rats treated with the hepatocarcinogen N - hydroxy - 2 - acetylaminofluorene . In a previous study , we found that treating transgenic Big Blue rats with the hepatocarcinogen N - hydroxy - 2 - acetylaminofluorene ( N - OH - AAF ) produced the same major DNA adduct in the target liver and the nontarget spleen lymphocytes and bone marrow cells , induced lacI mutants in the liver , and induced much lower frequencies of l acI and hprt mutants in spleen lymphocytes . In the present study , sequence analysis was conducted on lacI DNA and hprt cDNA from the mutants , to determine the mutational specificity of N - OH - AAF in the rat . All the mutation spectra from N - OH - AAF - treated rats differed significantly from corresponding mutation profiles from untreated animals ( P = 0 . 02 to P < 0 . 0001 ) . Although there were similarities among the mutational patterns derived from N - OH - AAF - treated rats ( e . g . , G : C - - > T : A transversion was the most common mutation in all mutation sets ) , there were significant differences in the patterns of basepair substitution and frameshift mutation between the liver and spleen lymphocyte lacI mutants ( P = 0 . 02 ) and between the spleen lymphocyte lacI and hprt mutants ( P = 0 . 04 ) . Also , multiplex PCR analysis of genomic DNA from the hprt mutants indicated that 12 % of mutants from treated rats had major deletions in the hprt gene ; no corresponding incidence of large deletions was evident among lacI mutations . All the mutation profiles reflect the general mutational specificity of the major DNA adduct formed by N - OH - AAF . The differences between N - OH - AAF mutation in the endogenous gene and transgene can be partially explained by the structures of the two genes . The tissue - specificity of the mutation spectra may contribute to targeting tumor formation to the liver . Environ . Mol . Mutagen . 37 : 203 - 214 , 2001 . Published 2001 Wiley - Liss , Inc . Caspase - dependent cleavage of the hematopoietic specific adaptor protein Gads alters signalling from the T cell receptor . Gads is a SH2 and SH3 domain - containing , hematopoietic - specific adaptor protein that functions in signalling from the T cell receptor . Gads acts by linking SLP - 76 , bound by the carboxy - terminal Gads SH3 domain , to tyrosine phosphorylated LAT which contains binding sites for the Gads SH2 domain . Gads is distinguished from Grb2 and the closely related Grap protein by the presence of a 120 amino acid unique region between the SH2 domain and the carboxy terminal SH3 domain . Here we demonstrate that the unique region of Gads contains a capase cleavage site . Induction of apoptosis in lymphocytes results in detectable Gads cleavage by 60 min . Gads cleavage is blocked in vivo by treating cells with a caspase 3 inhibitor . A putative caspase 3 cleavage site was identified within the unique region and mutation of this site prevented Gads cleavage in vitro , and in vivo . The Gads cleavage products retained the predicted binding specificity for SLP - 76 and LAT . Expression of the Gads cleavage products in Jurkat T cells inhibited NFAT activation following TCR cross linking . These findings indicate that cleavage of Gads in vivo could function to alter signalling downstream of the T cell receptor by disrupting cross talk between SLP - 76 and LAT . Targeting of p300 to the interleukin - 2 promoter via CREB - Rel cross - talk during mitogen and oncogenic molecular signaling in activated T - cells . In this report , we explore the mechanisms of targeting of p300 to the interleukin - 2 ( IL - 2 ) promoter in response to mitogenic and oncogenic molecular signals . Recruitment of p300 by cAMP - responsive element - binding protein - Rel cross - talk at the composite CD28 response element ( CD28RE ) - TRE element of the IL - 2 promoter is essential for promoter inducibility during T - cell activation , and CD28RE - TRE is the exclusive target of the human T - cell lymphotropic virus type I oncoprotein Tax . The intrinsic histone acetyltransferase activity of p300 is dispensable for activation of the IL - 2 promoter , and the N - terminal 743 residues contain the minimal structural requirements for synergistic transactivation of the CD28RE - TRE , the IL - 2 promoter , and endogenous IL - 2 gene expression . Mutational analysis of p300 reveals differential structural requirements for the N - terminal p300 module by individual cis - elements within the IL - 2 promoter . These findings provide evidence that p300 assembles at the IL - 2 promoter to form an enhanceosome - like signal transduction target that is centrally integrated at the CD28RE - TRE element of the IL - 2 promoter through specific protein module - targeted associations in activated T - cells . Regulation of cytokine production in T - cell responses to inhalant allergen : GATA - 3 expression distinguishes between Th1 - and Th2 - polarized immunity . BACKGROUND : The precise nature of allergen - specific cytokine responses in atopics versus non - atopics , in particular the ' Th1 polarity ' of responses in non - atopics , remains controversial . This is due in part to the relative insensitivity of cytokine detection systems , and associated variations in kinetics of cytokine production and catabolism in in vitro culture systems . As an alternative to cytokine measurement , this study focuses on expression of the transcription factor GATA - 3 for analysis of allergen - specific Th cell responses . METHODS : Cord blood mononuclear cells were Th1 - or Th2 - polarized by culture in IL - 12 - or IL - 4 - employing established methods ; PBMC from house dust mite ( HDM ) - sensitive atopics and controls were stimulated overnight with HDM ; cytokine production was measured by ELISA and GATA - 3 mRNA expression by PCR . RESULTS : Cytokine - driven Th2 polarization of naive T cells is associated with marked upregulation of GATA - 3 expression , whereas a reciprocal expression pattern accompanies differentiation towards the Th1 cytokine phenotype . In T cells from HDM skin prick test - positive ( HDM - SPT + / HDM - IgE + ) volunteers , overnight stimulation results in marked upregulation of GATA - 3 expression , compared to an equally marked downregulation of expression in T cells from SPT - / IgE - subjects . In subjects who are HDM - SPT + but IgE - , GATA - 3 expression levels remained relatively stable during culture with HDM . CONCLUSIONS : Upregulation of GATA - 3 expression in PBMC is a hallmark of the early phase of Th2 recall responses to specific allergen in atopics . The reciprocal expression pattern observed in HDM - specific recall responses of non - atopics provides independent confirmation of the presence of underlying Th1 - like immunity in these subjects . The parallel findings in neonatal T cells suggest that the same approach may be utilized for monitoring the progress of allergen - specific Th1 / Th2 memory development during early childhood , and hence in assessment of risk for future allergic disease . Copyright 2001 S . Karger AG , Basel The heat shock response reduces myelin oligodendrocyte glycoprotein - induced experimental autoimmune encephalomyelitis in mice . The stress response ( SR ) can block inflammatory gene expression by preventing activation of transcription factor nuclear factor - kappa B ( NF - kappaB ) . As inflammatory gene expression contributes to the pathogenesis of demyelinating diseases , we tested the effects of the SR on the progression of the demyelinating disease experimental autoimmune encephalomyelitis ( EAE ) . EAE was actively induced in C57BL / 6 mice using an encephalitogenic myelin oligodendrocyte glycoprotein ( MOG ( 35 - 55 ) ) peptide . Whole body hyperthermia was used to induce a heat shock response ( HSR ) in immunized mice 2 days after the booster MOG ( 35 - 55 ) peptide injection . The HSR reduced the incidence of EAE by 70 % , delayed disease onset by 6 days , and attenuated disease severity . The HSR attenuated leukocyte infiltration into CNS assessed by quantitation of perivascular infiltrates , and by reduced staining for CD4 and CD25 immunopositive T - cells . T - cell activation , assessed by the production of interferon gamma ( IFNgamma ) in response to MOG ( 35 - 55 ) , was also decreased by the HSR . The HSR reduced inflammatory gene expression in the brain that normally occurs during EAE , including the early increase in RANTES ( regulated on activation of normal T - cell expressed and secreted ) expression , and the later expression of the inducible form of nitric oxide synthase . The early activation of transcription factor NF - kappaB was also blocked by the HSR . The finding that the SR reduces inflammation in the brain and the clinical severity of EAE opens a novel therapeutic approach for prevention of autoimmune diseases . In vivo detection of intracellular signaling pathways in developing thymocytes . Information regarding the intracellular signaling processes that occur during the development of T cells has largely been obtained with the use of transgenic mouse models , which although providing invaluable information are time consuming and costly . To this end , we have developed a novel system that facilitates the in vivo analysis of signal transduction pathways during T - lymphocyte development . This approach uses reporter - plasmids for the detection of intracellular signals mediated by the mitogen - activated protein kinase or cyclic AMP - dependent protein kinase . Reporter - plasmids are transfected into thymocytes in fetal thymic organ culture by accelerated DNA / particle bombardment ( gene gun ) , and the activation of a signaling pathway is determined in the form of a standard luciferase assay . Importantly , this powerful technique preserves the structural integrity of the thymus , and will provide an invaluable tool to study how thymocytes respond to normal environmental stimuli encountered during differentiation within the thymic milieu . Thus , this method allows for the monitoring of signals that occur in a biological time frame , such as during differentiation , and within the natural environment of differentiating cells . Core - binding factor beta ( CBFbeta ) , but not CBFbeta - smooth muscle myosin heavy chain , rescues definitive hematopoiesis in CBFbeta - deficient embryonic stem cells . Core - binding factor beta ( CBFbeta ) is the non - DNA - binding subunit of the heterodimeric CBFs . Genes encoding CBFbeta ( CBFB ) , and one of the DNA - binding CBFalpha subunits , Runx1 ( also known as CBFalpha2 , AML1 , and PEBP2alphaB ) , are required for normal hematopoiesis and are also frequent targets of chromosomal translocations in acute leukemias in humans . Homozygous disruption of either the Runx1 or Cbfb gene in mice results in embryonic lethality at midgestation due to hemorrhaging in the central nervous system , and severely impairs fetal liver hematopoiesis . Results of this study show that Cbfb - deficient mouse embryonic stem ( ES ) cells can differentiate into primitive erythroid colonies in vitro , but are impaired in their ability to produce definitive erythroid and myeloid colonies , mimicking the in vivo defect . Definitive hematopoiesis is restored by ectopic expression of full - length Cbfb transgenes , as well as by a transgene encoding only the heterodimerization domain of CBFbeta . In contrast , the CBFbeta - smooth muscle myosin heavy chain ( SMMHC ) fusion protein generated by the inv ( 16 ) associated with acute myeloid leukemias ( M4Eo ) can not rescue definitive hematopoiesis by Cbfb - deficient ES cells . Sequences responsible for the inability of CBFbeta - SMMHC to rescue definitive hematopoiesis reside in the SMMHC portion of the fusion protein . Results also show that the CBFbeta - SMMHC fusion protein transdominantly inhibits definitive hematopoiesis , but not to the same extent as homozygous loss of Runx1 or Cbfb . CBFbeta - SMMHC preferentially inhibits the differentiation of myeloid lineage cells , while increasing the number of blastlike cells in culture . The latency pattern of Epstein - Barr virus infection and viral IL - 10 expression in cutaneous natural killer / T - cell lymphomas . The nasal type , extranodal natural killer or T ( NK / T ) - cell lymphoma is usually associated with latent Epstein - Barr virus ( EBV ) infection . In order to elucidate the EBV gene expression patterns in vivo , we examined eight patients with cutaneous EBV - related NK / T - cell lymphomas , including six patients with a NK - cell phenotype and two patients with a T - cell phenotype . The implication of EBV in the skin lesions was determined by the presence of EBV - DNA , EBV - encoded nuclear RNA ( EBER ) and a clonality of EBV - DNA fragments containing the terminal repeats . Transcripts of EBV - encoded genes were screened by reverse transcription - polymerase chain reaction ( RT - PCR ) , and confirmed by Southern blot hybridization . The expression of EBV - related antigens was examined by immunostaining using paraffin - embedded tissue sections and cell pellets of EBV - positive cell lines . Our study demonstrated that all samples from the patients contained EBV nuclear antigen ( EBNA ) - 1 mRNA which was transcribed using the Q promoter , whereas both the Q promoter and another upstream promoter ( Cp / Wp ) were used in EBV - positive cell lines , B95 . 8 , Raji and Jiyoye . Latent membrane protein - 1 ( LMP - 1 ) mRNA was detected in seven of eight patients and all cell lines , whereas EBNA - 2 transcripts were found only in the cell lines . Immunostaining showed no LMP - 1 , EBNA - 2 or ZEBRA antigens in the paraffin - embedded tissue sections , although they were positive in the cell line cells . Latent BHRF1 transcripts encoding bcl - 2 homologue and BCRF1 transcripts encoding viral interleukin ( vIL ) - 10 were detected in one and two of eight patients , respectively . A patient with NK - cell lymphoma expressing both transcripts died of rapid progression of the illness . Our results indicate that the restricted expression of the latency - associated EBV genes and the production of vIL - 10 and bcl - 2 homologue may favour tumour growth , evading the host immune surveillance . Copyright 2001 Cancer Research Campaign . Oxidized alkyl phospholipids are specific , high affinity peroxisome proliferator - activated receptor gamma ligands and agonists . Synthetic high affinity peroxisome proliferator - activated receptor ( PPAR ) agonists are known , but biologic ligands are of low affinity . Oxidized low density lipoprotein ( oxLDL ) is inflammatory and signals through PPARs . We showed , by phospholipase A ( 1 ) digestion , that PPARgamma agonists in oxLDL arise from the small pool of alkyl phosphatidylcholines in LDL . We identified an abundant oxidatively fragmented alkyl phospholipid in oxLDL , hexadecyl azelaoyl phosphatidylcholine ( azPC ) , as a high affinity ligand and agonist for PPARgamma . [ ( 3 ) H ] azPC bound recombinant PPARgamma with an affinity ( K ( d ) ( ( app ) ) approximately 40 nm ) that was equivalent to rosiglitazone ( BRL49653 ) , and competition with rosiglitazone showed that binding occurred in the ligand - binding pocket . azPC induced PPRE reporter gene expression , as did rosiglitazone , with a half - maximal effect at 100 nm . Overexpression of PPARalpha or PPARgamma revealed that azPC was a specific PPARgamma agonist . The scavenger receptor CD36 is encoded by a PPRE - responsive gene , and azPC enhanced expression of CD36 in primary human monocytes . We found that anti - CD36 inhibited azPC uptake , and it inhibited PPRE reporter induction . Results with a small molecule phospholipid flippase mimetic suggest azPC acts intracellularly and that cellular azPC accumulation was efficient . Thus , certain alkyl phospholipid oxidation products in oxLDL are specific , high affinity extracellular ligands and agonists for PPARgamma that induce PPAR - responsive genes Regulation of the human MAT2B gene encoding the regulatory beta subunit of methionine adenosyltransferase , MAT II . Methionine adenosyltransferase ( MAT ) catalyzes the biosynthesis of S - adenosylmethionine ( AdoMet ) , a key molecule in transmethylation reactions and polyamine biosynthesis . The MAT II isozyme consists of a catalytic alpha2 and a regulatory beta subunit . Down - regulation of the MAT II beta subunit expression causes a 6 - 10 - fold increase in intracellular AdoMet levels . To understand the mechanism by which the beta subunit expression is regulated , we cloned the MAT2B gene , determined its organization , characterized its 5 ' - flanking sequences , and elucidated the in vitro and in vivo regulation of its promoter . Transcription of the MAT2B gene initiates at position - 203 relative to the translation start site . Promoter deletion analysis defined a minimal promoter between positions + 52 and + 93 base pairs , a GC - rich region . Inclusion of the sequences between - 4 and + 52 enhanced promoter activity ; this was primarily because of an Sp1 recognition site at + 9 / + 15 . The inclusion of sequences up to position - 115 provided full activity ; this was attributed to a TATA at - 32 . The Sp1 site at position + 9 was key for the formation of protein . DNA complexes . Mutation of both the Sp1 site at + 9 and the TATA at - 32 reduced promoter activity to its minimal level . Supershift assays showed no effect of the anti - Sp1 antibody on complex formation , whereas the anti - Sp3 antibody had a strong effect on protein . DNA complex formation , suggesting that Sp3 is one of the main factors binding to this Sp1 site . Chromatin immunoprecipitation assays supported the involvement of both Sp1 and Sp3 in complexes formed on the MAT2B promoter . The data show that the 5 ' - untranslated sequences play an important role in regulating the MAT2B gene and identifies the Sp1 site at + 9 as a potential target for modulating MAT2B expression , a process that can have a major effect on intracellular AdoMet levels . Molecular pathogenesis of influenza A virus infection and virus - induced regulation of cytokine gene expression . Despite vaccines and antiviral substances influenza still causes significant morbidity and mortality world wide . Better understanding of the molecular mechanisms of influenza virus replication , pathogenesis and host immune responses is required for the development of more efficient means of prevention and treatment of influenza . Influenza A virus , which replicates in epithelial cells and leukocytes , regulates host cell transcriptional and translational systems and activates , as well as downregulates apoptotic pathways . Influenza A virus infection results in the production of chemotactic ( RANTES , MIP - 1 alpha , MCP - 1 , MCP - 3 , and IP - 10 ) , pro - inflammatory ( IL - 1 beta , IL - 6 , IL - 18 , and TNF - alpha ) , and antiviral ( IFN - alpha / beta ) cytokines . Cytokine gene expression is associated with the activation of NF - kappa B , AP - 1 , STAT and IRF signal transducing molecules in influenza A virus - infected cells . In addition of upregulating cytokine gene expression , influenza A virus infection activates caspase - 1 enzyme , which is involved in the proteolytic processing of proIL - 1 beta and proIL - 18 into their biologically active forms . Influenza A virus - induced IFN - alpha / beta is essential in host ' s antiviral defence by activating the expression of antiviral Mx , PKR and oligoadenylate synthetase genes . IFN - alpha / beta also prolongs T cell survival , upregulates IL - 12 and IL - 18 receptor gene expression and together with IL - 18 stimulates NK and T cell IFN - gamma production and the development of Th1 - type immune response . Comparison of hprt and lacI mutant frequency with DNA adduct formation in N - hydroxy - 2 - acetylaminofluorene - treated Big Blue rats . N - Hydroxy - 2 - acetylaminofluorene ( N - OH - AAF ) is the proximate carcinogenic metabolite of the powerful rat liver carcinogen 2 - acetylaminofluorene . In this study , transgenic Big Blue ( R ) rats were used to examine the relationship between in vivo mutagenicity and DNA adduct formation by N - OH - AAF in the target liver compared with that in nontarget tissues . Male rats were given one , two , or four doses of 25 mg N - OH - AAF / kg body weight by i . p . injection at 4 - day intervals , and groups of treated and control rats were euthanized up to 10 weeks after beginning the dosing . Mutant frequencies were measured in the spleen lymphocyte hprt gene , and lacI mutant frequencies were determined in the liver and spleen lymphocytes . At 6 weeks after beginning the dosing , the hprt mutant frequency in spleen lymphocytes from the four - dose group was 16 . 5 x 10 ( - 6 ) compared with 3 . 2 x 10 ( - 6 ) in control animals . Also at 6 weeks , rats given one , two , or four doses of N - OH - AAF had lacI mutant frequencies in the liver of 97 . 6 , 155 . 6 , and 406 . 8 x 10 ( - 6 ) , respectively , compared with a control frequency of 25 . 7 x 10 ( - 6 ) ; rats given four doses had lacI mutant frequencies in spleen lymphocytes of 55 . 8 x 10 ( - 6 ) compared with a control frequency of 20 . 4 x 10 ( - 6 ) . Additional rats were evaluated for DNA adduct formation in the liver , spleen lymphocytes , and bone marrow by ( 32 ) P - postlabeling . Adduct analysis was conducted 1 day after one , two , and four treatments with N - OH - AAF , 5 days after one treatment , and 9 days after two treatments . N - ( Deoxyguanosin - 8 - yl ) - 2 - aminofluorene was the major DNA adduct identified in all the tissues examined . Adduct concentrations increased with total dose to maximum values in samples taken 1 day after two doses , and remained essentially the same after four doses . In samples taken after four doses , adduct levels were 103 , 28 , and 7 fmol / microg of DNA in liver , spleen lymphocytes , and bone marrow , respectively . The results indicate that the extent of both DNA adduct formation and mutant induction correlates with the organ specificity for N - OH - AAF carcinogenesis in the rat . Environ . Mol . Mutagen . 37 : 195 - 202 , 2001 . Published 2001 Wiley - Liss , Inc . Expression of Mad1 in T cells leads to reduced thymic cellularity and impaired mitogen - induced proliferation . To investigate Mad1 function in vivo , transgenic mice were generated that express a Mad1 transgene in T lineage cells under the control of the proximal lck promoter . Thymus size in lck - Mad1 transgenic mice is drastically reduced although representation of the various thymocyte sub populations appears normal . To investigate more closely any effects of Mad1 expression on thymocytes , we examined thymic selection using MHC class I - restricted H - Y - TCR transgenic mice . Mad1 expression in vivo reduces the efficiency of positive selection . Furthermore , thymocytes and splenic T cells from lck - Mad1 transgenic mice display a profound proliferative defect in response to activation with either PMA / Ionomycin or immobilized anti - CD3 / CD28 antibody . This proliferative defect is not reversed by addition of exogenous IL - 2 and is p53 - independent . The growth inhibition caused by Mad1 is overcome by expression of active c - Myc . Differential requirement for the transcription factor PU . 1 in the generation of natural killer cells versus B and T cells . PU . 1 is a member of the Ets family of transcription factors required for the development of various lymphoid and myeloid cell lineages , but its role in natural killer ( NK ) cell development is not known . The study shows that PU . 1 is expressed in NK cells and that , on cell transfer into alymphoid Rag2 / gammac ( - / - ) mice , hematopoietic progenitors of PU . 1 ( - / - ) fetal liver cells could generate functional NK cells but not B or T cells . Nevertheless , the numbers of bone marrow NK cell precursors and splenic mature NK cells were reduced compared to controls . Moreover , PU . 1 ( - / - ) NK cells displayed reduced expression of the receptors for stem cell factor and interleukin ( IL ) - 7 , suggesting a nonredundant role for PU . 1 in regulating the expression of these cytokine receptor genes during NK cell development . PU . 1 ( - / - ) NK cells also showed defective expression of inhibitory and activating members of the Ly49 family and failed to proliferate in response to IL - 2 and IL - 12 . Thus , despite the less stringent requirement for PU . 1 in NK cell development compared to B and T cells , PU . 1 regulates NK cell differentiation and homeostasis . Benzene - extracted components are important for the major activity of diesel exhaust particles : effect on interleukin - 8 gene expression in human bronchial epithelial cells . Epidemiologic and experimental studies suggest that diesel exhaust particles ( DEPs ) may be related to increasing respiratory mortality and morbidity . We have shown that DEPs augmented the production of inflammatory cytokines by human airway epithelial cells in vitro . To better understand the mechanisms of their proinflammatory activities , we studied the effects of several components extracted from DEPs on interleukin ( IL ) - 8 expression in human bronchial epithelial cell line BEAS - 2B and normal human airway epithelial cells obtained from very peripheral airways by an ultrathin bronchoscope . We used several agents active on signal transduction pathways in cytokine expression , such as the protein kinase C inhibitor staurosporin , antioxidant agents including N - acetyl cysteine ( NAC ) and pyrrolidine dithiocarbamate ( PDTC ) , and p38 mitogen - activated protein kinase ( MAPK ) inhibitor SB203580 . Benzene - extracted components showed effects mimicking DEPs on IL - 8 gene expression , release of several cytokines ( IL - 8 ; granulocyte macrophage colony - stimulating factor ; and regulated on activation , normal T cells expressed and secreted ) and nuclear factor ( NF ) - kappa B activation . We also found that NAC , PDTC , and SB203580 suppressed the activities of DEPs and their benzene extracts , suggesting the roles of oxidants - mediated NF - kappa B activation and p38MAPK pathways . Finally , benzo [ a ] pyrene , one of the important compounds included in the benzene component , replicated the activities shown by DEPs . The nuclear receptor PPAR gamma is expressed by mouse T lymphocytes and PPAR gamma agonists induce apoptosis . Peroxisome proliferator - activated receptor ( PPAR ) - gamma is a nuclear hormone receptor that serves as a trans factor to regulate lipid metabolism . Intense interest is focused on PPAR - gamma and its ligands owing to its putative role in adipocyte differentiation . Little is known , however , about the functions of PPAR - gamma in the immune system , especially in T lymphocytes . We demonstrate that both naive and activated ovalbumin - specific T cells from DO11 . 10 - transgenic mice express PPAR - gamma mRNA and protein . In order to determine the function of PPAR - gamma , T cells were stimulated with phorbol 12 - myristate 13 - acetate and ionomycin or antigen and antigen - presenting cells . Simultaneous exposure to PPAR - gamma ligands ( e . g . 15 - deoxy - Delta ( 12 , 14 ) - prostaglandin J ( 2 ) , troglitazone ) showed drastic inhibition of proliferation and significant decreases in cell viability . The decrease in cell viability was due to apoptosis of the T lymphocytes , and occurred only when cells were treated with PPAR - gamma , and not PPAR - alpha agonists , revealing specificity of this response for PPAR - gamma . These observations suggest that PPAR - gamma agonists play an important role in regulating T cell - mediated immune responses by inducing apoptosis . T cell death via PPAR - gamma ligation may act as a potent anti - inflammatory signal in the immune system , and ligands could possibly be used to control disorders in which excessive inflammation occurs . Suppression of lung inflammation in rats by prevention of NF - kappaB activation in the liver . Activation of NF - kappaB and production of NF - kappaB - dependent chemokines are thought to be involved in the pathogenesis of neutrophilic lung inflammation . Calpain - 1 inhibitor ( CI - 1 ) blocks activation of NF - kappaB by preventing proteolysis of the inhibitory protein IkappaB - alpha by the ubiquitin / proteasome pathway . We hypothesized that inhibition of proteasome function with CI - 1 would block NF - kappaB activation in vivo after intraperitoneal ( i . p . ) treatment with bacterial lipopolysaccharide ( LPS ) , and that NF - kappaB inhibition would be associated with suppression of chemokine gene expression and attenuation of neutrophilic alveolitis . We treated rats with a single i . p . injection of CI - 1 ( 10 mg / kg ) two hours prior to i . p . LPS ( 7 mg / kg ) . Treatment with Cl - 1 prevented degradation of IkappaB - alpha and activation of NF - kappaB in the liver in response to LPS ; however , Cl - 1 treatment had no detected effect on NF - kappaB activation in lung tissue . CI - 1 treatment prior to LPS resulted in 40 % lower MIP - 2 concentration in lung lavage fluid compared to rats treated with vehicle prior to LPS ( 502 + / - 112 pg / ml vs . 859 + / - 144 pg / ml , P < 0 . 05 ) . In addition , CI - 1 treatment substantially inhibited LPS - induced neutrophilic alveolitis ( 2 . 7 + / - 1 . 2 x 10 ( 5 ) vs . 43 . 7 + / - 12 . 2 x 10 ( 5 ) lung lavage neutrophils , P < 0 . 01 ) . These data indicate that NF - kappaB inhibition in the liver can alter lung inflammation induced by systemic LPS treatment and suggest that a liver - lung interaction contributes to the inflammatory response of the lung . Notch1 regulates maturation of CD4 + and CD8 + thymocytes by modulating TCR signal strength . Notch signaling regulates cell fate decisions in multiple lineages . We demonstrate in this report that retroviral expression of activated Notch1 in mouse thymocytes abrogates differentiation of immature CD4 + CD8 + thymocytes into both CD4 and CD8 mature single - positive T cells . The ability of Notch1 to inhibit T cell development was observed in vitro and in vivo with both normal and TCR transgenic thymocytes . Notch1 - mediated developmental arrest was dose dependent and was associated with impaired thymocyte responses to TCR stimulation . Notch1 also inhibited TCR - mediated signaling in Jurkat T cells . These data indicate that constitutively active Notch1 abrogates CD4 + and CD8 + maturation by interfering with TCR signal strength and provide an explanation for the physiological regulation of Notch expression during thymocyte development . Expression of SART3 antigen and induction of CTLs by SART3 - derived peptides in breast cancer patients . We recently reported the SART3 tumour - rejection antigen as possessing tumour epitopes capable of inducing HLA - class I - restricted cytotoxic T lymphocytes ( CTLs ) . This study investigated expression of the SART3 antigen in breast cancer to explore an appropriate molecule for use in specific immunotherapy of breast cancer patients . The SART3 antigen was detected in all of the breast cancer cell lines tested , 30 of 40 ( 75 % ) breast cancer tissue samples , and 0 of 3 non - tumourous breast tissue samples . SART3 derived peptides at positions 109 - 118 and 315 - 323 induced HLA - A24 restricted CTLs that reacted to breast cancer cells from the peripheral blood mononuclear cells ( PBMCs ) of breast cancer patients . Therefore , the SART3 antigen and its peptides could be an appropriate molecule for use in specific immunotherapy of the majority of HLA - A24 - positive breast cancer patients Autostimulation of the Epstein - Barr virus BRLF1 promoter is mediated through consensus Sp1 and Sp3 binding sites . As an essential step in the lytic cascade , the Rta homologues of gammaherpesviruses all activate their own expression . Consistent with this biologic function , the Epstein - Barr virus ( EBV ) Rta protein powerfully stimulates the promoter of its own gene , Rp , in EBV - positive B cells in transient - transfection reporter - based assays . We analyzed the activity of RpCAT in response to Rta by deletional and site - directed mutagenesis . Two cognate Sp1 binding sites located at - 279 and - 45 relative to the transcriptional start site proved crucial for Rta - mediated activation . Previously described binding sites for the cellular transcription factor Zif268 and the viral transactivator ZEBRA were found to be dispensable for activation of RpCAT by Rta . Gel shift analysis , using extracts of B cells in latency or induced into the lytic cycle , identified Sp1 and Sp3 as the predominant cellular proteins bound to Rp near - 45 . During the lytic cycle , ZEBRA bound Rp near the Sp1 / Sp3 site . The binding of Sp1 and Sp3 to Rp correlated with the reporter activities in the mutagenesis study , establishing a direct link between transcriptional activation of Rp by Rta and DNA binding by Sp1 and / or Sp3 . The relative abundance or functional state of the cellular Sp1 and Sp3 transcription factors may be altered in response to stimuli that induce the BRLF1 promoter and thereby contribute to the activation of the viral lytic cycle . Gene transfer of antisense hypoxia inducible factor - 1 alpha enhances the therapeutic efficacy of cancer immunotherapy . Solid tumors meet their demands for nascent blood vessels and increased glycolysis , to combat hypoxia , by activating multiple genes involved in angiogenesis and glucose metabolism . Hypoxia inducible factor - 1 ( HIF - 1 ) is a constitutively expressed basic helix - loop - helix transcription factor , formed by the assembly of HIF - 1alpha and HIF - 1beta ( Arnt ) , that is stablized in response to hypoxia , and rapidly degraded under normoxic conditions . It activates the transcription of genes important for maintaining oxygen homeostasis . Here , we demonstrate that engineered down - regulation of HIF - 1alpha by intratumoral gene transfer of an antisense HIF - 1alpha plasmid leads to the down - regulation of VEGF , and decreased tumor microvessel density . Antisense HIF - 1alpha monotherapy resulted in the complete and permanent rejection of small ( 0 . 1 cm in diameter ) EL - 4 tumors , which is unusual for an anti - angiogenic agent where transient suppression of tumor growth is the norm . It induced NK cell - dependent rejection of tumors , but failed to stimulate systemic T cell - mediated anti - tumor immunity , and synergized with B7 - 1 - mediated immunotherapy to cause the NK cell and CD8 T cell - dependent rejection of larger EL - 4 tumors ( 0 . 4 cm in diameter ) that were refractory to monotherapies . Mice cured of their tumors by combination therapy resisted a rechallenge with parental tumor cells , indicating systemic antitumor immunity had been achieved . In summary , whilst intensive investigations are in progress to target the many HIF - 1 effectors , the results herein indicate that blocking hypoxia - inducible pathways and enhancing NK - mediated antitumor immunity by targeting HIF - 1 itself may be advantageous , especially when combined with cancer immunotherapy . Runx2 : a novel oncogenic effector revealed by in vivo complementation and retroviral tagging . The Runx2 ( Cbfa1 , Pebp2alphaA , Aml3 ) gene was previously identified as a frequent target for transcriptional activation by proviral insertion in T - cell lymphomas of CD2 - MYC transgenic mice . We have recently shown that over - expression of the full - length , most highly expressed Runx2 isoform in the thymus perturbs T - cell development , leads to development of spontaneous lymphomas at low frequency and is strongly synergistic with Myc . To gain further insight into the relationship of Runx2 to other lymphomagenic pathways , we tested the effect of combining the CD2 - Runx2 transgene either with a Pim1 transgene ( E ( mu ) - Pim1 ) or with the p53 null genotype , as each of these displays independent synergy with Myc . In both cases we observed synergistic tumour development . However , Runx2 appeared to have a dominant effect on the tumour phenotype in each case , with most tumours conforming to the CD3 ( + ) , CD8 ( + ) , CD4 ( + / - ) phenotype seen in CD2 - Runx2 mice . Neonatal infection of CD2 - Runx2 mice with Moloney murine leukaemia virus ( Moloney MLV ) also led to a dramatic acceleration of tumour onset . Analysis of known Moloney MLV target genes in these lymphomas showed a high frequency of rearrangement at c - Myc or N - Myc ( 82 % ) , and a significant number at Pim1 or Pim2 ( 23 % ) , and at Pal1 / Gfi1 ( 18 % ) . These results indicate that Runx2 makes a distinct contribution to T - cell lymphoma development which does not coincide with any of the oncogene complementation groups previously identified by retroviral tagging . The involvement of TNF - alpha - related apoptosis - inducing ligand in the enhanced cytotoxicity of IFN - beta - stimulated human dendritic cells to tumor cells . TNF - alpha - related apoptosis - inducing ligand ( TRAIL ) is characterized by its preferential induction of apoptosis of tumor cells but not normal cells . Dendritic cells ( DCs ) , besides their role as APCs , now have been demonstrated to exert cytotoxicity or cytostasis on some tumor cells . Here , we report that both human CD34 ( + ) stem cell - derived DCs ( CD34DCs ) and human CD14 ( + ) monocyte - derived DCs ( MoDCs ) express TRAIL and exhibit cytotoxicity to some types of tumor cells partially through TRAIL . Moderate expression of TRAIL appeared on CD34DCs from the 8th day of culture and was also seen on freshly isolated monocytes . The level of TRAIL expression remained constant until DC maturation . TRAIL expression on immature CD34DCs or MoDCs was greatly up - regulated after IFN - beta stimulation . Moreover , IFN - beta could strikingly enhance the ability of CD34DCs or MoDCs to kill TRAIL - sensitive tumor cells , but LPS did not have such an effect . The up - regulation of TRAIL on IFN - beta - stimulated DCs partially contributed to the increased cytotoxicity of DCS : Pretreatment of TRAIL - sensitive tumor cells with caspase - 3 inhibitor could significantly increase their resistance to the cytotoxicity of IFN - beta - stimulated DCS : In contrast , NF - kappaB inhibitor could significantly increase the sensitivity of tumor cells to the killing by nonstimulated or LPS - stimulated DCS : Our studies demonstrate that IFN - beta - stimulated DCs are functionally cytotoxic . Thus , an innate mechanism of DC - mediated antitumor immunity might exist in vivo in which DCs act as effectors to directly kill tumor cells partially via TRAIL . Subsequently , DCs act as APCs involved in the uptake , processing , and presentation of apoptotic tumor Ags to cross - prime CD8 ( + ) CTL cells . Tumor cells regulate the lytic activity of tumor - specific cytotoxic t lymphocytes by modulating the inhibitory natural killer receptor function . Tumor - infiltrating p58 + T cells from a renal tumor were specifically expanded in response to tumor cell stimulation and cloned . These p58 + T cells were found to express a memory phenotype and corresponded to clonal TCRBV3 T - cell expansion . Functionally , p58 ( + ) CTLs displayed a low lytic activity for HLA - A2 tumor and normal cells . However , this lytic activity was significantly increased after blockade of p58 with specific monoclonal antibodies . Interestingly , we demonstrated that stimulation by tumor cells was required to trigger the inhibitory effect of p58 on the lytic activity of antigen - specific CTLs and that stimulation of the inhibitory function of p58 by tumor cells correlated with an inhibition of nuclear factor - kappaB activation in p58 + tumor - specific CTLS . T - cell factor - 1 expression during human natural killer cell development and in circulating CD56 ( + ) bright natural killer cells . Transcription factors are essential to govern differentiation along the lymphoid lineage from uncommitted hematopoietic stem cells . Although many of these transcription factors have putative roles based on murine knockout experiments , their function in human lymphoid development is less known and was studied further . Transcription factor expression in fresh and cultured adult human bone marrow and umbilical cord blood progenitors was evaluated . We found that fresh CD34 ( + ) Lin ( - ) cells that are human leukocyte antigen ( HLA ) - DR ( - ) or CD38 ( - ) constitutively express GATA - 3 but not T - cell factor - 1 ( TCF - 1 ) or Id - 3 . Culture with the murine fetal liver cell line AFT024 and defined cytokines was capable of inducing TCF - 1 mRNA . However , no T - cell receptor gene rearrangement was identified in cultured progeny . Id - 3 , a basic helix loop helix factor with dominant negative function for T - cell differentiation transcription factors , also was upregulated and may explain unsuccessful T - cell maturation . To better understand the developmental link between natural killer ( NK ) cells derived from progenitors , we studied NK cell subsets circulating in blood . CD56 ( + bright ) , but not CD56 ( + dim ) , NK cells constitutively express TCF - 1 by reverse transcriptase polymerase chain reaction and Western blot analysis . The TCF - 1 isoform found in CD56 ( + bright ) cells , which express lectin but not immunoglobulin class I recognizing inhibitory receptors , was identical to that induced in NK cell differentiation culture and was distinctly different from isoforms in T cells . These results suggest that TCF - 1 does not target human killer immunoglobulin receptor genes , TCF - 1 is uniquely expressed in circulating CD56 ( + bright ) NK cells , and specific TCF - 1 isoforms may play an important role in regulating NK differentiation from a common NK / T - cell progenitor . Transcriptional activation by a matrix associating region - binding protein . contextual requirements for the function of bright . Bright ( B cell regulator of IgH transcription ) is a B cell - specific , matrix associating region - binding protein that transactivates gene expression from the IgH intronic enhancer ( E mu ) . We show here that Bright has multiple contextual requirements to function as a transcriptional activator . Bright can not transactivate via out of context , concatenated binding sites . Transactivation is maximal on integrated substrates . Two of the three previously identified binding sites in E mu are required for full Bright transactivation . The Bright DNA binding domain defined a new family , which includes SWI1 , a component of the SWI . SNF complex shown to have high mobility group - like DNA binding characteristics . Similar to one group of high mobility group box proteins , Bright distorts E mu binding site - containing DNA on binding , supporting the concept that it mediates E mu remodeling . Transfection studies further implicate Bright in facilitating spatially separated promoter - enhancer interactions in both transient and stable assays . Finally , we show that overexpression of Bright leads to enhanced DNase I sensitivity of the endogenous E mu matrix associating regions . These data further suggest that Bright may contribute to increased gene expression by remodeling the immunoglobulin locus during B cell development . Analysis of BCL - 6 mutations in classic Hodgkin disease of the B - and T - cell type . BCL - 6 is essential for germinal center formation and thus for affinity maturation of immunoglobulin ( Ig ) genes by somatic mutations . The 5 ' - noncoding region of the BCL - 6 gene is even a target for the mutation machinery . Translocations of the BCL - 6 gene to heterologous promoters and mutations of its 5 ' - noncoding regulatory region were reported to be potential mechanisms for deregulating BCL - 6 expression and for playing a role in the genesis of non - Hodgkin lymphoma . In line with this hypothesis is the observation that B - cell lymphoma with somatic mutations , such as diffuse large B - cell lymphoma and follicular lymphoma , also carry BCL - 6 mutations , some of which are recurrently detectable . Classic Hodgkin disease ( cHD ) is also derived from B cells with high loads of somatic mutations and thus a further candidate for BCL - 6 mutations . To determine the presence and potential role of BCL - 6 mutations in cHD , the 5 ' - noncoding BCL - 6 proportion of single Hodgkin and Reed - Sternberg ( HRS ) cells from 6 cases of cHD and 6 cases of HD - derived cell lines was analyzed . All B - cell - derived HD cases and cell lines harbored BCL - 6 mutations . In contrast , both T - cell - derived HD cases and cell lines were devoid of BCL - 6 mutations . With only one exception , there were no lymphoma - specific recurrent BCL - 6 mutations detected , and BCL - 6 protein was absent from the HRS cells of most cases . In conclusion , ( 1 ) somatic BCL - 6 mutations are restricted to cHD cases of B - cell origin , and ( 2 ) the BCL - 6 mutations represent mostly irrelevant somatic base substitutions without consequences for BCL - 6 protein expression and the pathogenesis of cHD . Gadd45gamma is dispensable for normal mouse development and T - cell proliferation . Gadd45gamma , a family member of the growth arrest and DNA damage - inducible gene family 45 ( Gadd45 ) , is strongly induced by interleukin - 2 ( IL - 2 ) in peripheral T cells . While in most tissues all Gadd45 family members are expressed , Gadd45gamma is the only member that is induced by IL - 2 . Here we show that the IL - 2 - induced expression of Gadd45gamma is dependent on a signaling pathway mediated by the tyrosine kinase Jak3 and the transcription factors Stat5a and Stat5b ( signal transducer and activator of transcription ) . Previous studies with ectopically overexpressed Gadd45gamma in various cell lines implicated its function in negative growth control . To analyze the physiological role of Gadd45gamma we used homologous recombination to generate mice lacking Gadd45gamma . Gadd45gamma - deficient mice develop normally , are indistinguishable from their littermates , and are fertile . Furthermore , hematopoiesis in mice lacking Gadd45gamma is not impaired and Gadd45gamma - deficient T lymphocytes show normal responses to IL - 2 . These data demonstrate that Gadd45gamma is not essential for normal mouse development and hematopoiesis , possibly due to functional redundancy among the Gadd45 family members . Gadd45gamma is also dispensable for IL - 2 - induced T - cell proliferation . Decreased expression of c - myc family genes in thymuses from myasthenia gravis patients . The thymus is a critical organ for the elimination of autoreactive T cells by apoptosis . We studied the expression of apoptosis - associated genes , bcl - xL , bad , caspase - 3 , and c - myc family genes in myasthenia gravis ( MG ) thymuses . We observed that the mRNA levels of myc family genes , c - myc and max , were markedly reduced in MG thymuses . These results indicate that c - myc - mediated signaling is abnormal in MG thymuses . The levels of molecules whose expressions are associated with myc , such as STAM , prothymosin - alpha , and NFkappaB Immunohistochemical detection of interferon - gamma - producing cells in dermatophytosis . Skin lesions of dermatophytosis are thought to be a result of a T cell - dependent inflammatory response that is mediated by various cytokines . We examined whether IFN - gamma - positive cells ( as expression of Th1 response ) were present in the skin lesions of dermatophytosis in situ by immunohistochemical techniques . Mixtures of CD4 - positive T cells and CD8 - positive T cells were found to be present in the dermal infiltrates of the lesions . Considerable numbers of CD1a - positive cells were detected in the upper dermis and epidermis . A marked accumulation of CD68 - positive cells was found in the upper dermis . IFN - gamma - positive cells were present in the upper dermis of the lesions . The pattern of IFN - gamma staining appeared to be intracellular in mononuclear lymphoid cells . The staining was considered to be highly specific because it could be completely blocked by preabsorption with recombinant IFN - gamma . Our data support the hypothesis that the skin lesions of dermatophytosis may be associated with a Th1 response . Th1 response , which is characterized by IFN - gamma release , is thought to be involved in the host defense against dermatophytes and to reflect cutaneous reaction in dermatophytosis . Regulation of the helix - loop - helix proteins , E2A and Id3 , by the Ras - ERK MAPK cascade . Activation of mitogen - activated protein kinase ( MAPK ) pathways leads to cellular differentiation and / or proliferation in a wide variety of cell types , including developing thymocytes . The basic helix - loop - helix ( bHLH ) proteins E12 and E47 and an inhibitor HLH protein , Id3 , play key roles in thymocyte differentiation . We show here that E2A DNA binding is lowered in primary immature thymocytes consequent to T cell receptor ( TCR ) - mediated ligation . Whereas expression of E2A mRNA and protein are unaltered , Id3 transcripts are rapidly induced upon signaling from the TCR . Activation of Id3 transcription is regulated in a dose - dependent manner by the extracellular signal - regulated kinase ( ERK ) MAPK module . These observations directly connect the ERK MAPK cascade and HLH proteins in a linear pathway . Retinoic acid up - regulates myeloid ICAM - 3 expression and function in a cell - specific fashion - - evidence for retinoid signaling pathways in the mast cell lineage . Investigation of mast cell responsiveness toward retinoic acid ( RA ) revealed selective promotion of ICAM - 3 expression in the human mast cell line HMC - 1 . This process was dose - and time - dependent and detectable by flow cytometry , Western blot analysis , ELISA , and Northern blot analysis . ICAM - 3 modulation was found to be cell - type dependent , detectable also for HL - 60 cells and monocytes but not U - 937 and only weakly for KU812 cells . Terminally differentiated skin mast cells also failed to up - modulate their ICAM - 3 , suggesting the requirement for some degree of immaturity for the process . RA - mediated effects on ICAM - 1 expression , studied in parallel , were clearly distinct from those on ICAM - 3 . Investigation of retinoid receptor expression , known to mediate intracellular RA signaling , revealed presence of RAR alpha , RAR gamma , RXR beta , and RXR gamma transcripts in all cell lines studied , and HMC - 1 cells were the only line lacking RXR alpha . RAR beta , not expressed at baseline , was induced by RA in a fashion obviously correlating with ICAM - 3 up - regulation . Increased ICAM - 3 expression was of functional significance , such that processes stimulated or co - stimulated via ICAM - 3 ( homotypic aggregation , IL - 8 secretion ) were clearly enhanced upon RA pretreatment , suggesting that RA may contribute via hitherto unrecognized pathways to immune function and host defense . CD28 and T cell co - stimulation . Over the last decade the concept of T cell co - stimulation has emerged to take a central role in the process of T cell activation . However , the exact definition of co - stimulation is still unclear . In this review , we re - examine the concept of co - stimulation . We suggest that while co - stimulation is important , there is little evidence to link co - stimulation with T cell anergy . We then suggest a framework for studying co - stimulation . Focusing on recent advances in our understanding of CD28 , we discuss four areas of T cell activation where co - stimulation may play a role . Regulation of activator protein - 1 and NF - kappa B in CD8 + T cells exposed to peripheral self - antigens . The transcriptional events that control T cell tolerance to peripheral self Ags are still unknown . In this study , we analyzed the regulation of AP - 1 - and NF - kappa B - mediated transcription during in vivo induction of tolerance to a self Ag expressed exclusively on hepatocytes . Naive CD8 ( + ) Desire ( Des ) ( + ) T cells isolated from the Des TCR - transgenic mice that are specific for the H - 2K ( b ) class I Ag were transferred into Alb - K ( b ) - transgenic mice that express the H - 2K ( b ) Ag on hepatocytes only . Tolerance develops in these mice . We found that the self - reactive CD8 ( + ) Des ( + ) T cells were transiently activated , then became unresponsive and were further deleted . In contrast to CD8 ( + ) Des ( + ) T cells activated in vivo with APCs , which express high AP - 1 and high NF - kappa B transcriptional activity , the unresponsive CD8 ( + ) Des ( + ) T cells expressed no AP - 1 and only weak NF - kappa B transcriptional activity . The differences in NF - kappa B transcriptional activity correlated with the generation of distinct NF - kappa B complexes . Indeed , in vivo primed T cells predominantly express p50 / p50 and p65 / p50 dimers , whereas these p50 - containing complexes are barely detectable in tolerant T cells that express p65 - and c - Rel - containing complexes . These observations suggest that fine regulation of NF - kappa B complex formation may determine T cell fate . Transcriptional regulation in lymphocytes . Lymphocytes have been used to investigate many cellular processes , including lineage commitment , differentiation , proliferation and apoptosis . The transcription factors that mediate these processes are often expressed broadly in many cell types . The emerging theme is one of cell - type - specific regulation , affecting not only the functional activation of transcription factors but also their access to appropriate regions of DNA . Existence of retinoic acid - receptor - independent retinoid X - receptor - dependent pathway in myeloid cell function . We previously reported that ER - 27191 ( 4 - [ 4 , 5 , 7 , 8 , 9 , 10 - hexahydro - 7 , 7 , 10 , 10 - tetramethyl - 1 - ( 3 - pyridylmethyl ) anthra [ 1 , 2 - b ] pyrrol - 3 - yl ] benzoic acid ) is a potent antagonist of retinoic acid receptor ( RAR ) , and ER - 35795 ( ( 2E , 4E , 6E ) - 7 - [ 1 - ( 1 - methylethyl ) - 8 - chloro - 1 , 2 , 3 , 4 - tetrahydroquinolin - 6 - yl ] - 6 - fluoro - 3 - methyl - 2 , 4 , 6 - nonatrienoic acid ) is a novel retinoid X receptor ( RXR ) - specific agonist . By using these compounds , we investigated whether distinct RAR - dependent and RXR - dependent pathways operate to mediate the diverse activities of retinoids , particularly , the effects of the RXR pathway on cellular function . ER - 27191 completely antagonized HL60 cell differentiation induced by all - trans - retinoic acid ( atRA ) . However , the differentiation induced by the ER - 35795 was not antagonized at all by the RAR antagonist , but was inhibited by an RXR homodimer antagonist ( LGD100754 , ( 2E , 4E , 6Z ) - 7 - ( 3 - n - propoxy - 5 , 6 , 7 , 8 - tetrahydro - 5 , 5 , 8 , 8 - tetramethylnaphthale - 2 - yl ) - 3 - methylocta - 2 , 4 , 6 - trienoic acid ) . Its agonistic action on RXR / RAR heterodimer , on the other hand , was neutralized by the RAR antagonist . During HL60 cell differentiation , atRA induced RARbeta mRNA , while the RXR had no effect . Interestingly , a functional RXR - pathway was also seen in lipopolysaccharide - induced inhibition of mouse splenocyte proliferation . These results strongly suggest the existence of a pharmacological RXR - dependent pathway that is activated by a ligand that can bind to RXR . Targeting Src homology 2 domain - containing tyrosine phosphatase ( SHP - 1 ) into lipid rafts inhibits CD3 - induced T cell activation . To study the mechanism by which protein tyrosine phosphatases ( PTPs ) regulate CD3 - induced tyrosine phosphorylation , we investigated the distribution of PTPs in subdomains of plasma membrane . We report here that the bulk PTP activity associated with T cell membrane is present outside the lipid rafts , as determined by sucrose density gradient sedimentation . In Jurkat T cells , approximately 5 - - 10 % of Src homology 2 domain - containing tyrosine phosphatase ( SHP - 1 ) is constitutively associated with plasma membrane , and nearly 50 % of SHP - 2 is translocated to plasma membrane after vanadate treatment . Similar to transmembrane PTP , CD45 , the membrane - associated populations of SHP - 1 and SHP - 2 are essentially excluded from lipid rafts , where other signaling molecules such as Lck , linker for activation of T cells , and CD3 zeta are enriched . We further demonstrated that CD3 - induced tyrosine phosphorylation of these substrates is largely restricted to lipid rafts , unless PTPs are inhibited . It suggests that a restricted partition of PTPs among membrane subdomains may regulate protein tyrosine phosphorylation in T cell membrane . To test this hypothesis , we targeted SHP - 1 into lipid rafts by using the N - terminal region of Lck ( residues 1 - - 14 ) . The results indicate that the expression of Lck / SHP - 1 chimera inside lipid rafts profoundly inhibits CD3 - induced tyrosine phosphorylation of CD3 zeta / epsilon , IL - 2 generation , and nuclear mobilization of NF - AT . Collectively , these results suggest that the exclusion of PTPs from lipid rafts may be a mechanism that potentiates TCR / CD3 activation An instructive component in T helper cell type 2 ( Th2 ) development mediated by GATA - 3 . Although interleukin ( IL ) - 12 and IL - 4 polarize naive CD4 ( + ) T cells toward T helper cell type 1 ( Th1 ) or Th2 phenotypes , it is not known whether cytokines instruct the developmental fate in uncommitted progenitors or select for outgrowth of cells that have stochastically committed to a particular fate . To distinguish these instructive and selective models , we used surface affinity matrix technology to isolate committed progenitors based on cytokine secretion phenotype and developed retroviral - based tagging approaches to directly monitor individual progenitor fate decisions at the clonal and population levels . We observe IL - 4 - dependent redirection of phenotype in cells that have already committed to a non - IL - 4 - producing fate , inconsistent with predictions of the selective model . Further , retroviral tagging of naive progenitors with the Th2 - specific transcription factor GATA - 3 provided direct evidence for instructive differentiation , and no evidence for the selective outgrowth of cells committed to either the Th1 or Th2 fate . These data would seem to exclude selection as an exclusive mechanism in Th1 / Th2 differentiation , and support an instructive model of cytokine - driven transcriptional programming of cell fate decisions . In vitro - activated human lupus T cells express normal estrogen receptor proteins which bind to the estrogen response element . We have shown that estrogen receptor ( ERalpha , ERbeta ) transcripts are expressed in SLE and normal T cells . In this study , T cell nuclear extracts from female lupus patients and normal donors were tested for biologically active ER proteins capable of binding to the human estrogen response element ( hERE ) by electrophoretic mobility shift assays . When peripheral blood T cells were stimulated with 17beta - estradiol ( E2 ) , PMA and ionomycin , two major retarded bands in T cell nuclear extracts exhibited a migration pattern similar to slow migrating protein - ERE complexes in human breast cancer cell extracts . T cells cultured only with E2 did not have these complexes . The formation of the complexes was inhibited by competition with the hERE cold oligonucleotide and partially with anti - ERalpha antibodies . There was no notable difference in the migration pattern of ERE - binding proteins between the SLE and normal T cell extracts . Together , these results suggest that activated human T cells , whether lupus - derived or normal - derived , contain biologically active ERalpha proteins . Other factors may be responsible for differential sensitivity of lupus T cells to estrogen . Mechanism of the inhibitory effect of protease inhibitor on tumor necrosis factor alpha production of monocytes . If the inflammatory response becomes excessive or uncontrolled by some stimuli , inappropriate inflammatory responses occur . Monocytes are extremely important cells for regulating the cytokine network and tumor necrosis factor alpha ( TNFalpha ) and interleukin - ( IL ) 10 , which are mainly synthesized by monocytes , are representative cytokines that play a central role in the cytokine network . Protease inhibitors such as gabexate mesilate ( GM ) and ulinastatin ( UTI ) have been shown to have various beneficial effects by inhibiting the activation of leukocytes , but the mechanism for this has yet to be fully elucidated . In this study we investigated the mechanism of the inhibitory effect of protease inhibitors on the proinflammatory cytokine production of lipopolysaccharide - ( LPS ) stimulated monocytes . LPS - stimulated monocytes were treated with GM or UTI . The value of TNFalpha and IL - 10 in the culture medium of monocytes was measured and each mRNA expression was assayed . The inhibitory effect of protease inhibitors on the activity of intracellular signal transduction pathways such as protein kinase C ( PKC ) and nuclear factor kappa B ( NFkappaB ) were also evaluated . GM decreased the TNFalpha production of LPS - stimulated monocytes as shown by the inhibition of mRNA expression and increased the IL - 10 production of LPS - stimulated monocytes . GM also suppressed the NFkappaB activity of LPS - stimulated monocytes . UTI decreased the TNFalpha production of LPS - stimulated monocytes , but did not inhibit the TNFalpha mRNA expression . The present study shows that the inhibitory effect of GM on the TNFalpha production of activated human monocytes is mediated by the suppression of NFkappaB activation , while the mechanism of UTI inhibiting TNFalpha production of human monocytes may be due to the inhibition of either the translation or secretion of TNFalpha . Homocysteine stimulates the expression of monocyte chemoattractant protein - 1 in endothelial cells leading to enhanced monocyte chemotaxis . Hyperhomocysteinemia has been identified as an independent risk factor for atherosclerosis . The infiltration of monocytes into the arterial wall is one of the key events during atherogenesis . Monocyte chemoattractant protein - 1 ( MCP - 1 ) is a potent chemokine that stimulates the migration of monocytes into the intima of the arterial wall . The mechanism by which increased monocyte infiltration occurs in atherosclerotic lesions in patients with hyperhomocysteinemia has not been delineated . The objective of the present study was to investigate the effect of homocysteine on MCP - 1 production in endothelial cells . Cells were incubated with homocysteine . The secretion of MCP - 1 protein was significantly increased ( 195 % as compared to the control ) in cells treated with pathological concentrations of homocysteine . Such effect was accompanied by an increased expression of MCP - 1 mRNA ( 176 % as compared to the control ) in endothelial cells which resulted in enhanced monocyte chemotaxis . The p38 MAP kinase as well as other members of the p38 MAP kinase pathway , including MKK3 , MKK6 , ATF - 2 and Elk - 1 , were activated in homocysteine - treated cells . Homocysteine - induced MCP - 1 expression and subsequent monocyte chemotaxis were blocked by a p38 MAP kinase inhibitor ( SB203580 ) suggesting that the p38 MAP kinase pathway might be involved in homocysteine - induced MCP - 1 expression in endothelial cells . In contrast , staurosporine , a protein kinase C inhibitor , had no effect on homocysteine - induced MCP - 1 expression . In conclusion , our results indicate that homocysteine stimulates MCP - 1 expression in endothelial cells leading to enhanced monocyte chemotaxis . Inducible resistance to Fas - mediated apoptosis in B cells . Apoptosis produced in B cells through Fas ( APO - 1 , CD95 ) triggering is regulated by signals derived from other surface receptors : CD40 engagement produces upregulation of Fas expression and marked susceptibility to Fas - induced cell death , whereas antigen receptor engagement , or IL - 4R engagement , inhibits Fas killing and in so doing induces a state of Fas - resistance , even in otherwise sensitive , CD40 - stimulated targets . Surface immunoglobulin and IL - 4R utilize at least partially distinct pathways to produce Fas - resistance that differentially depend on PKC and STAT6 , respectively . Further , surface immunoglobulin signaling for inducible Fas - resistance bypasses Btk , requires NF - kappaB , and entails new macromolecular synthesis . Terminal effectors of B cell Fas - resistance include the known anti - apoptotic gene products , Bcl - xL and FLIP , and a novel anti - apoptotic gene that encodes FAIM ( Fas Apoptosis Inhibitory Molecule ) . faim was identified by differential display and exists in two alternatively spliced forms ; faim - S is broadly expressed , but faim - L expression is tissue - specific . The FAIM sequence is highly evolu - tionarily conserved , suggesting an important role for this molecule throughout phylogeny . Inducible resistance to Fas killing is hypothesized to protect foreign antigen - specific B cells during potentially hazardous interactions with FasL - bearing T cells , whereas autoreactive B cells fail to become Fas - resistant and are deleted via Fas - dependent cytotoxicity . Inadvertent or aberrant acquisition of Fas - resistance may permit autoreactive B cells to escape Fas deletion , and malignant lymphocytes to impede anti - tumor immunity . Stromal cell - derived factor 1 alpha - induced chemotaxis in T cells is mediated by nitric oxide signaling pathways . Stromal cell - derived factor 1 alpha ( SDF1 alpha ) and its cognate chemokine receptor CXCR4 act as potent chemoattractants and regulate trafficking and homing of hematopoietic progenitor cells and lymphocytes . However , the molecular mechanisms regulating SDF1 alpha - driven cell migration are not well defined . In this study , we have explored the roles of the second messenger NO and the transcription factor NF - kappa B in SDF1 alpha - induced T cell migration . SDF1 alpha treatment of Jurkat T cells increased the activity of NO synthase , which catalyzes the generation of NO . We observed that pretreatment of Jurkat cells or activated PBLs with several NO donors significantly enhanced the SDF1 alpha - induced migration , whereas various inhibitors of NO synthase markedly abrogated the chemotactic response in a concentration - dependent manner . Furthermore , we observed that inhibitors of the transcription factor NF - kappa B , which is linked to NO signaling pathways , also significantly blocked the SDF1 alpha - induced chemotactic response . However , these compounds did not have a significant effect on SDF1 alpha - induced mitogen - activated protein kinase activity . In addition , the MAP / Erk kinase kinase inhibitor PD98059 did not abrogate SDF1 alpha - induced chemotaxis . AKT , which has been shown to mediate NO production , was also phosphorylated upon SDF1 alpha stimulation . These studies suggest that NO - related signaling pathways may mediate SDF1 alpha - induced chemotaxis , but not mitogen - activated protein kinase activation . The lack of NF - kappa B transactivation and PKC epsilon expression in CD4 ( + ) CD8 ( + ) thymocytes correlates with negative selection . Deletion of autoreactive thymocytes at the DP stage is the basis for tolerance to thymus - expressed self antigens . In this study we investigated whether distinct signalling pathways are induced in DP thymocytes as compared to mature T cells upon stimulation with antigen . Using triple transgenic mice expressing a TCR transgene , dominant negative ras / Mek proteins and a reporter gene construct with AP - 1 or NF - kappa B binding sites , we showed a complete lack of transcriptional activity of NF - kappa B but not AP - 1 in DP thymocytes , whereas both were transcriptionally active in mature T cells after antigenic stimulation . Lack of NF - kappa B induction correlated with increased death in response to antigen . AP - 1 induction was dependent on the integrity of the ras / Mek pathway indicating that this pathway was activated in the DP thymocytes . In contrast , we found a complete lack of constitutive expression of the epsilon isoform of Protein Kinase C ( PKC ) in DP thymocytes , although it was present in mature thymocytes and peripheral T cells . Taken together the results suggest that the lack of PKC epsilon in DP thymocytes could lead to the absence of NF - kappa B activity after antigenic stimulation contributing to negative selection . Cell Death and Differentiation ( 2000 ) 7 , 1253 - 1262 . CD2 stimulation leads to the delayed and prolonged activation of STAT1 in T cells but not NK cells . OBJECTIVE : T lymphocytes can be activated by soluble factors such as cytokines or through direct cell - cell interactions . Although cytokine receptors are known to signal through STAT family transcription factors , the mechanisms by which other cell - surface molecules , such as CD2 , transduce signals is unclear . The goal of this study was to determine whether stimulation of T cells through CD2 recapitulates aspects of cytokine - induced T - cell activation by use of STAT transcription factors . MATERIALS AND METHODS : T cells were treated with anti - CD2 antibodies or cells bearing the natural CD2 ligand CD58 , after which signaling through STAT transcription factors was assessed . RESULTS : Stimulation of CD2 on primary T lymphocytes leads to the tyrosine phosphorylation , nuclear translocation , and DNA binding of STAT1 . In contrast to stimulation by cytokines , the activation of STAT1 in response to CD2 ligation is delayed and does not involve Jak kinases . Furthermore , while STAT phosphorylation induced by cytokines is generally transient , STAT1 phosphorylation following CD2 stimulation persists for a period of days . Transcription of key target genes such as IRF1 and c - fos proceeds with delayed kinetics following CD2 stimulation , suggesting that this unique pattern of STAT activation may lead to a distinct cellular response following CD2 ligation . This pathway appears to be restricted to T cells , as stimulation of CD2 on NK cells does not lead to STAT1 activation . CONCLUSION : Stimulation of T cells through cell - surface molecules such as CD2 involves activation of STAT transcription factors , thus recapitulating elements of cytokine signaling . NFATc1 and NFATc2 together control both T and B cell activation and differentiation . NFAT transcription factors play critical roles in gene transcription during immune responses . To investigate further the two most prominent NFAT family members , NFATc1 and NFATc2 , we generated mice bearing lymphoid systems devoid of both . Doubly deficient T cells displayed cell surface markers of activation yet were significantly deficient in the development of multiple effector functions , including Th cytokine production , surface effector molecule expression , and cytolytic activity . Nevertheless , doubly deficient B cells were hyperactivated , as evidenced by extremely elevated serum IgG1 and IgE , as well as plasma cell expansion and infiltration of end organs . Thus , in T cells , NFATc1 and NFATc2 are dispensable for inflammatory reactivity but are required for effector differentiation , while in B cells , NFATs regulate both normal homeostasis and differentiation . Epstein - barr virus immediate - early protein BZLF1 is SUMO - 1 modified and disrupts promyelocytic leukemia bodies . Although the immediate - early proteins of both herpes simplex virus ( HSV ) and cytomegalovirus ( CMV ) are known to modify promyelocytic leukemia ( PML ) ( ND10 ) bodies in the nucleus of the host cell , it has been unclear whether lytic infection with gamma herpesviruses induces a similar effect . The PML protein is induced by interferon , involved in major histocompatibility complex class I presentation , and necessary for certain types of apoptosis . Therefore , it is likely that PML bodies function in an antiviral capacity . SUMO - 1 modification of PML is known to be required for the formation of PML bodies . To examine whether Epstein - Barr virus ( EBV ) lytic replication interferes with PML bodies , we expressed the EBV immediate - early genes BZLF1 ( Z ) and BRLF1 ( R ) in EBV - positive cell lines and examined PML localization . Both Z and R expression resulted in PML dispersion in EBV - positive cells . Z but not R expression is sufficient to disrupt PML bodies in EBV - negative cell lines . We show that dispersion of PML bodies by Z requires a portion of the transcriptional activation domain of Z but not the DNA - binding function . As was previously reported for the HSV - 1 ICP0 and CMV IE1 proteins , Z reduces the amount of SUMO - 1 - modified PML . We also found that Z itself is SUMO - 1 modified ( through amino acid 12 ) and that Z competes with PML for limiting amounts of SUMO - 1 . These results suggest that disruption of PML bodies is important for efficient lytic replication of EBV . Furthermore , Z may potentially alter the function of a variety of cellular proteins by inhibiting SUMO - 1 modification Suppression of nuclear factor - kappaB and stimulation of inhibitor kappaB by troglitazone : evidence for an anti - inflammatory effect and a potential antiatherosclerotic effect in the obese . To elucidate whether troglitazone exerts an antiinflammatory effect in humans , in vivo , we investigated the suppression of nuclear factor kappaB ( NFkappaB ) in mononuclear cells ( MNC ) by this drug . We measured intranuclear NFkappaB , total cellular NFkappaB , inhibitor kappaB ( IkappaB ) alpha , reactive oxygen species ( ROS ) generation , and p47 ( phox ) subunit ( a key component protein of nicotinamide adenine dinucleotide phosphate oxidase ) in MNC . Plasma tumor necrosis factor ( TNF ) - alpha , soluble intercellular adhesion molecule - 1 ( sICAM - 1 ) , monocyte chemoattractant protein - 1 ( MCP - 1 ) , plasminogen activator inhibitor type 1 ( PAI - 1 ) , C - reactive protein ( CRP ) , and interleukin ( IL ) - 10 ( antiinflammatory cytokine ) concentrations were also measured as mediators of inflammatory activity that are regulated by the proinflammatory transcription factor NFkappaB . Seven nondiabetic obese patients were given 400 mg troglitazone daily for 4 weeks . Blood samples were collected before and at weekly intervals thereafter . MNC were separated ; and the levels of intranuclear NFkappaB , total cellular NFkappaB , IkappaBalpha , and p47 ( phox ) subunit and ROS generation were determined . Plasma was used to measure insulin glucose , TNFalpha , sICAM , MCP - 1 , PAI - 1 , CRP , and IL - 10 . Plasma insulin concentrations fell significantly at week 1 , from 31 . 2 + / - 29 . 1 to 14 . 2 + / - 11 . 4 mU / L ( P < 0 . 01 ) and remained low throughout 4 weeks . Plasma glucose concentrations did not alter significantly . There was a fall in intranuclear NFkappaB , total cellular NFkappaB , and p47 ( phox ) subunit , with an increase in cellular IkappaBalpha at week 2 , which persisted until week 4 . There was a parallel fall in ROS generation by MNC at week 1 ; this progressed and persisted until week 4 ( P < 0 . 001 ) . Plasma TNF - alpha , sICAM - 1 , MCP - 1 , and PAI - 1 concentrations fell significantly at week 4 . Plasma IL - 10 concentration increased significantly , whereas plasma CRP concentrations decreased . We conclude that troglitazone has an antiinflammatory action that may contribute to its putative antiatherosclerotic effects . Tyrosine phosphorylation - dependent activation of NF - kappa B . Requirement for p56 LCK and ZAP - 70 protein tyrosine kinases . Phosphorylation of the N - terminal domain of I kappa B inhibitory subunits induces activation of the transcription factor NF - kappa B . Although serine phosphorylation has been shown to induce ubiquitination and subsequent proteasome - mediated degradation of I kappa B - alpha , little is known about the mechanisms that lead to release of active NF - kappa B in T cells as a consequence of tyrosine phosphorylation of I kappa B - alpha [ Imbert , V . , Rupec , R . A . , Livolsi , A . , Pahl , H . L . , Traenckner , B . M . , Mueller - Dieckmann , C . , Farahifar , D . , Rossi , B . , Auberger , P . , Baeuerle , P . & Peyron , J . F . ( 1996 ) Cell 86 , 787 - - 798 ] . The involvement of the tyrosine kinases p56 ( lck ) and ZAP - 70 in this reaction is demonstrated here using specific pharmacological inhibitors and Jurkat mutants unable to express these kinases . Although the inhibitors prevented both pervanadate - induced phosphorylation of I kappa B - alpha on Tyr42 and NF - kappa B activation , we observed that , in p56 ( lck ) - deficient Jurkat mutants , NF - kappa B could still associate with I kappa B - alpha despite phosphorylation on Tyr42 . Furthermore , the SH2 domain of p56 ( lck ) appeared to be required for pervanadate - induced NF - kappa B activation but not for Tyr42 phosphorylation . These results show that p56 ( lck ) and ZAP - 70 are key components of the signaling pathway that leads to phosphotyrosine - dependent NF - kappa B activation in T cells and confirm that tyrosine kinases must control at least two different steps to induce activation of NF - kappa B . Finally , we show that H ( 2 ) O ( 2 ) , which stimulates p56 ( lck ) and ZAP - 70 in T cells , is an activator of NF - kappa B through tyrosine phosphorylation of I kappa B - alpha . Specific missense mutations in NEMO result in hyper - IgM syndrome with hypohydrotic ectodermal dysplasia . The gene that encodes nuclear factor kappaB ( NF - kappaB ) essential modulator ( or NEMO , also known as IKKgamma ) is required for activation of the transcription factor NF - kappaB . We describe mutations in the putative zinc - finger domain of NEMO that result in an X - linked primary immunodeficiency characterized by hyper - IgM syndrome and hypohydrotic ectodermal dysplasia ( XHM - ED ) . These mutations prevent CD40 ligand ( CD40L ) - mediated degradation of inhibitor of NF - kappaB alpha ( IkappaB - alpha ) and account for the following observations : B cells from XHM - ED patients are unable to undergo immunoglobulin class - switch recombination and antigen - presenting cells ( APCs ) are unable to synthesize the NF - kappaB - regulated cytokines interleukin 12 ( IL - 12 ) or tumor necrosis factor alpha ( TNF - alpha ) when stimulated with CD40L . Nevertheless , innate immunity is preserved in XHM - ED patients because APCs retain the capacity to respond to stimulation by lipopolysaccharide or Staphylococcus aureus Cowan ' s antigen ( SAC ) . Overall , the phenotype observed in XHM - ED patients shows that the putative zinc - finger domain of NEMO has a regulatory function and demonstrates the definite requirement of CD40 - mediated NF - kappaB activation for B cell immunoglobulin class - switching . Granulocytic differentiation of human NB4 promyelocytic leukemia cells induced by all - trans retinoic acid metabolites . The metabolism of all - trans retinoic acid ( ATRA ) has been reported to be partly responsible for the in vivo resistance to ATRA seen in the treatment of human acute promyelocytic leukemia ( APL ) . However , ATRA metabolism appears to be involved in the growth inhibition of several cancer cell lines in vitro . The purpose of this study was to evaluate the in vitro activity of the principal metabolites of ATRA [ 4 - hydroxy - retinoic acid ( 4 - OH - RA ) , 18 - hydroxy - retinoic acid ( 18 - OH - RA ) , 4 - oxo - retinoic acid ( 4 - oxo - RA ) , and 5 , 6 - epoxy - retinoic acid ( 5 , 6 - epoxy - RA ) ] in NB4 , a human promyelocytic leukemia cell line that exhibits the APL diagnostic t ( 15 ; 17 ) chromosomal translocation and expresses the PML - RAR alpha fusion protein . We established that the four ATRA metabolites were indeed formed by the NB4 cells in vitro . NB4 cell growth was inhibited ( 69 - 78 % at 120 h ) and cell cycle progression in the G1 phase ( 82 - 85 % at 120 h ) was blocked by ATRA and all of the metabolites at 1 microM concentration . ATRA and its metabolites could induce NB4 cells differentiation with similar activity , as evaluated by cell morphology , by the nitroblue tetrazolium reduction test ( 82 - 88 % at 120 h ) or by the expression of the maturation specific cell surface marker CD11c . In addition , nuclear body reorganization to macropunctated structures , as well as the degradation of PML - RAR alpha , was found to be similar for ATRA and all of its metabolites . Comparison of the relative potency of the retinoids using the nitroblue tetrazolium reduction test showed effective concentrations required to differentiate 50 % of cells in 72 h as follows : ATRA , 15 . 8 + / - 1 . 7 nM ; 4 - oxo - RA , 38 . 3 + / - 1 . 3 nM ; 18 - OH - RA , 55 . 5 + / - 1 . 8 nM ; 4 - OH - RA , 79 . 8 + / - 1 . 8 nM ; and 5 , 6 - epoxy - RA , 99 . 5 + / - 1 . 5 nM . The ATRA metabolites were found to exert their differentiation effects via the RAR alpha nuclear receptors , because the RAR alpha - specific antagonist BMS614 blocked metabolite - induced CD11c expression in NB4 cells . These data demonstrate that the principal ATRA Phase 1 metabolites can elicit leukemia cell growth inhibition and differentiation in vitro through the RAR alpha signaling pathway , and they suggest that these metabolites may play a role in ATRA antileukemic activity in vivo . Expression of oestrogen and progesterone receptors by mast cells alone , but not lymphocytes , macrophages or other immune cells in human upper airways . BACKGROUND : Nasal polyposis often coexists with asthma in airway inflammatory conditions characterised by the infiltration of a range of immune cells . A potentially important role for ovarian hormones has been implicated in airway inflammation but the cellular target for such action is not known . METHODS : Expression of oestrogen receptors ( ER ) and progesterone receptors ( PR ) was examined using immunohistochemistry in formalin fixed nasal polyp tissues from 47 subjects . The cells positive for ER or PR were confirmed by spatial location , dual immunolabelling , and histochemical staining . RESULTS : Consistent with the known features of nasal polyps , CD4 + ( T helper / inducer ) , CD8 + ( cytotoxic / suppressor ) , CD68 + ( macrophages ) , mast cells , eosinophils and neutrophils were all clearly detected by their relevant monoclonal antibodies or appropriate histochemical staining , but only mast cells tested positive for ER / PR labelling with their polyclonal and monoclonal antibodies . The frequencies for expression were 61 . 7 % for ER positive and 59 . 6 % for PR positive cells . The expression of ER / PR was independent of patient sex and age but was highly correlated with the numbers of mast cells ( r = 0 . 973 , p < 0 . 001 for ER ; r = 0 . 955 , p < 0 . 001 for PR ) . Fewer than 5 % of mast cells were found to be negative for ER / PR expression . CONCLUSIONS : Mast cells alone , but not lymphocytes , macrophages , or other immune cells , express ER / PR in human upper airways . Numerous ER / PR positive mast cells exist in nasal polyps , indicating that this may be a major route for the involvement of sex hormones in airway inflammation when exposed to the higher and varying concentration of oestrogen and progesterone characteristic of females . NF kappa b signaling in posthypoxic endothelial cells : relevance to E - selectin expression and neutrophil adhesion . Our previous studies have implicated the nuclear transcription factor kappa B ( NF kappa B ) in the regulation of adhesion molecule expression in endothelial cells exposed to anoxia - reoxygenation ( A / R ) or a redox imbalance . The objectives of this study were ( 1 ) to define the kinetics of NF kappa B activation by examining I kappa B alpha degradation and the nuclear translocation of p65 in response to A / R or redox imbalance ( induced by treatment of cells with diamide and buthionine sulfoximine ) and ( 2 ) to determine whether the signal for I kappa B alpha degradation , nuclear translocation of p65 , and E - selectin - mediated neutrophil adhesion is related to the activity of protein tyrosine kinase ( PTK ) , protein tyrosine phosphatase ( PTPase ) and / or protein kinase C ( PKC ) . The results demonstrate that both A / R and redox imbalance led to I kappa B alpha degradation within 30 min and the concomitant appearance of p65 in the nucleus , consistent with rapid cytosolic activation of NF kappa B and subsequent nuclear translocation of the activated p65 subunit . Inhibition of PKC blocked I kappa B alpha degradation and p65 translocation in A / R - challenged , but not redox - altered , endothelial cells . However , both A / R - and redox - induced NF kappa B activation was blocked by inhibition of PTK . Similarly , A / R - induced E - selectin expression and neutrophil - endothelial cell adhesion were blocked by inhibition of PKC or PTK , while only PTK inhibited the redox - induced adhesion response . Pretreatment of cells with N - acetyl cysteine effectively blocked A / R - or redox - induced I kappa B degradation and significantly attenuated the respective neutrophil adhesion responses . Collectively , these findings indicate that A / R - induced E - selectin expression and neutrophil - endothelial cell adhesion are mediated by both PKC and PTK , which signal rapid activation of NF kappa B . This A / R - induced NF kappa B signaling response appears to be mediated , at least in part , by intracellular redox imbalance . Copyright 2001 S . Karger AG , Basel Induction of apoptosis in human lymphocytes by the herbicide 2 , 4 - dichlorophenoxyaceti acid . Dimethylammonium salt of 2 , 4 - dichlorophenoxyaceti acid ( DMA - 2 , 4 - D ) is a widely used herbicide that is considered moderately toxic . In the present study we found that DMA - 2 , 4 - D is able to cause apoptosis in peripheral blood lymphocytes of healthy individuals and Jurkat T cells . Apoptosis induced by DMA - 2 , 4 - D was dose and time dependent , independent of Fas , TNF receptor 1 or the aromatic hydrocarbon receptor , and involved disruption of the mitochondrial transmembrane potential and activation of caspase - 9 . ZVAD - FMK , a broad - spectrum inhibitor of caspases , blocked DMA - 2 , 4 - D - induced apoptosis completely . While an inhibitor of caspase - 9 , as well as caspase - 9 and caspase - 3 inhibitors in combination , strongly blocked DMA - 2 , 4 - D - induced apoptosis , an inhibitor of caspase - 3 had a moderate inhibitory effect . Unlike Fas - mediated apoptosis , the initiator caspase , caspase - 8 , was not involved in DMA - 2 , 4 - D - induced apoptosis . Transfection of Jurkat cells with Bcl - 2 prevented DMA - 2 , 4 - D - induced disruption of the mitochondrial transmembrane potential and led to a complete blockage of apoptosis . Our data indicate that DMA - 2 , 4 - D kills human lymphocytes by initiating apoptosis via a direct effect on mitochondria . The activation of caspases occurs downstream of mitochondrial damage , and the dysfunction of mitochondria appears to be sufficient for triggering all downstream events leading to apoptosis . Inhibition of Th1 differentiation by IL - 6 is mediated by SOCS1 . Interleukin 6 ( IL - 6 ) is a cytokine produced by immune and nonimmune cells and exhibits functional pleiotropy and redundancy . IL - 6 plays an important role in the differentiation of several cell types . Here , we describe a novel function of IL - 6 : the negative regulation of CD4 + Th1 cell differentiation . While IL - 6 - directed CD4 + Th2 differentiation is mediated by IL - 4 , inhibition of Th1 differentiation by IL - 6 is independent of IL - 4 . IL - 6 upregulates suppressor of cytokine signaling 1 ( SOCS1 ) expression in activated CD4 + T cells , thereby interfering with signal transducer and activator of transcription 1 ( STAT1 ) phosphorylation induced by interferon gamma ( IFNgamma ) . Inhibition of IFNgamma receptor - mediated signals by IL - 6 prevents autoregulation of IFNgamma gene expression by IFNgamma during CD4 + T cell activation , thereby preventing Th1 differentiation . Thus , IL - 6 promotes CD4 + Th2 differentiation and inhibits Th1 differentiation by two independent molecular mechanisms . Interaction between CCAAT / enhancer binding protein and cyclic AMP response element binding protein 1 regulates human immunodeficiency virus type 1 transcription in cells of the monocyte / macrophage lineage . Recent observations have shown two CCAAT / enhancer binding protein ( C / EBP ) binding sites to be critically important for efficient human immunodeficiency virus type 1 ( HIV - 1 ) replication within cells of the monocyte / macrophage lineage , a cell type likely involved in transport of the virus to the brain . Additionally , sequence variation at C / EBP site I , which lies immediately upstream of the distal nuclear factor kappa B site and immediately downstream of a binding site for activating transcription factor ( ATF ) / cyclic AMP response element binding protein ( CREB ) , has been shown to affect HIV - 1 long terminal repeat ( LTR ) activity . Given that C / EBP proteins have been shown to interact with many other transcription factors including members of the ATF / CREB family , we proceeded to determine whether an adjacent ATF / CREB binding site could affect C / EBP protein binding to C / EBP site I . Electrophoretic mobility shift analyses indicated that selected ATF / CREB site variants assisted in the recruitment of C / EBP proteins to an adjacent , naturally occurring , low - affinity C / EBP site . This biophysical interaction appears to occur via at least two mechanisms . First , low amounts of CREB - 1 and C / EBP appear to heterodimerize and bind to a site consisting of a half site from both the ATF / CREB and C / EBP binding sites . In addition , CREB - 1 homodimers bind to the ATF / CREB site and recruit C / EBP dimers to their cognate weak binding sites . This interaction is reciprocal , since C / EBP dimer binding to a strong C / EBP site leads to enhanced CREB - 1 recruitment to ATF / CREB sites that are weakly bound by CREB . Sequence variation at both C / EBP and ATF / CREB sites affects the molecular interactions involved in mediating both of these mechanisms . Most importantly , sequence variation at the ATF / CREB binding site affected basal LTR activity as well as LTR function following interleukin - 6 stimulation , a treatment that leads to increases in C / EBP activation . Thus , HIV - 1 LTR ATF / CREB binding site sequence variation may modulate cellular signaling at the viral promoter through the C / EBP pathway Selective inhibition of interleukin - 4 gene expression in human T cells by aspirin . Previous studies indicated that aspirin ( acetylsalicylic acid [ ASA ] ) can have profound immunomodulatory effects by regulating cytokine gene expression in several types of cells . This study is the first in which concentrations of ASA in the therapeutic range were found to significantly reduce interleukin ( IL ) - 4 secretion and RNA expression in freshly isolated and mitogen - primed human CD4 + T cells . In contrast , ASA did not affect IL - 13 , interferon - gamma , and IL - 2 expression . ASA inhibited IL - 4 , but not IL - 2 , promoter - driven chloramphenicol acetyltransferase expression in transiently transfected Jurkat T cells . The structurally unrelated nonsteroidal anti - inflammatory drugs indomethacin and flurbiprofen did not affect cytokine gene expression in T cells , whereas the weak cyclo - oxygenase inhibitor salicylic acid was at least as effective as ASA in inhibiting IL - 4 expression and promoter activity . The inhibitory effect of ASA on IL - 4 transcription was not mediated by decreased nuclear expression of the known salicylate target nuclear factor ( NF ) - kappaB and was accompanied by reduced binding of an inducible factor to an IL - 4 promoter region upstream of , but not overlapping , the NF of activated T cells - and NF - kappaB - binding P1 element . It is concluded that anti - inflammatory salicylates , by means of a previously unrecognized mechanism of action , can influence the nature of adaptive immune responses by selectively inhibiting the expression of IL - 4 , a critical effector of these responses , in CD4 + T cells . Molecular and cellular mediators of interleukin - 1 - dependent acute inflammatory arthritis . OBJECTIVE : To examine the molecular and cellular mechanisms in a model of acute inflammatory monarticular arthritis induced by methylated bovine serum albumin ( mBSA ) and interleukin - 1 ( IL - 1 ) . METHODS : Mice were injected intraarticularly with mBSA on day 0 and subcutaneously with recombinant human IL - 1beta on days 0 - 2 . At day 7 , knee joints were removed and assessed histologically . Flow cytometry and RNase protection were used to analyze IL - 1 - dependent events . RESULTS : C57BL / 6 ( B6 ) , 129 / Sv , and ( B6 x 129 / Sv ) F1 hybrid mice , all H - 2b strains , were susceptible to mBSA / IL - 1 - induced arthritis , whereas C3H / HeJ ( H - 2k ) mice were not . B6 mice lacking T and B cells ( RAG1 - / - ) or major histocompatibility complex ( MHC ) class II antigens ( MHCII - / - ) , and B6 mice treated with a CD4 + T cell - depleting monoclonal antibody , were resistant to disease . In contrast , B cell - deficient ( muMT / muMT ) mice developed arthritis at an incidence and severity similar to that of controls . RelB - deficient ( RelB - / - ) bone marrow chimeric mice had arthritis that was significantly reduced in incidence and severity . In B6 mice , flow cytometry demonstrated an IL - 1 - dependent leukocyte infiltration into the synovial compartment and RNase protection assays revealed induction of messenger RNA ( mRNA ) for the chemokines monocyte chemoattractant protein 1 , macrophage inhibitory protein 2 ( MIP - 2 ) , RANTES , MIP - 1alpha , and MIP - 1beta , in vivo and in vitro . CONCLUSION : Arthritis induced by mBSA / IL - 1 is strain specific and dependent on CD4 + T lymphocytes and at least partially on RelB , but not on B lymphocytes or antibody . IL - 1 contributes to leukocyte recruitment to the synovium and directly induces chemokine mRNA production by synovial cells . This model of acute monarticular arthritis is particularly suitable for further investigations into cell - mediated immunity in arthritis and the role of IL - 1 . Positive and negative regulation of granulopoiesis by endogenous RARalpha . Acute promyelocytic leukemia ( APL ) is always associated with chromosomal translocations that disrupt the retinoic acid receptor alpha ( RARalpha ) gene . Whether these translocations relate to a role for endogenous RARalpha in normal granulopoiesis remains uncertain because most studies addressing this question have used non - physiological overexpression systems . Granulocyte differentiation in cells derived from RARalpha - deficient ( RARalpha ( - / - ) ) mice was studied and evaluated in the context of agonist - bound and ligand - free RARalpha . Our results demonstrate that RARalpha is dispensable for granulopoiesis , as RARalpha ( - / - ) mice have a normal granulocyte population despite an impaired ability to respond to retinoids . However , although it is not absolutely required , RARalpha can bidirectionally modulate granulopoiesis . RARalpha stimulates differentiation in response to exogenous retinoic acid . Furthermore , endogenous retinoids control granulopoiesis in vivo , as either vitamin A - deficient mice or animals treated with an RAR antagonist accumulate more immature granulocytes in their bone marrow . Conversely , RARalpha acts to limit differentiation in the absence of ligand because granulocyte precursors from RARalpha ( - / - ) mice differentiate earlier in culture . Thus , the block in granulopoiesis exerted by RARalpha fusion proteins expressed in APL cells may correspond to an amplification of a normal function of unliganded RARalpha . Expression and function of a stem cell promoter for the murine CBFalpha2 gene : distinct roles and regulation in natural killer and T cell development . The Runt family transcription factor CBFalpha2 ( AML1 , PEBP2alphaB , or Runx1 ) is required by hematopoietic stem cells and expressed at high levels in T - lineage cells . In human T cells CBFalpha2 is usually transcribed from a different promoter ( distal promoter ) than in myeloid cells ( proximal promoter ) , but the developmental and functional significance of this promoter switch has not been known . Here , we report that both coding and noncoding sequences of the distal 5 ' end are highly conserved between the human and the murine genes , and the distal promoter is responsible for the overwhelming majority of CBFalpha2 expression in murine hematopoietic stem cells as well as in T cells . Distal promoter activity is maintained throughout T cell development and at lower levels in B cell development , but downregulated in natural killer cell development . The distal N - terminal isoform binds to functionally important regulatory sites from known target genes with two - to threefold higher affinity than the proximal N - terminal isoform . Neither full - length isoform alters growth of a myeloid cell line under nondifferentiating conditions , but the proximal isoform selectively delays mitotic arrest of the cell line under differentiating conditions , resulting in the generation of greater numbers of neutrophils . Constitutive PI3 - K activity is essential for proliferation , but not survival , of Theileria parva - transformed B cells . Theileria is an intracellular parasite that causes lymphoproliferative disorders in cattle , and infection of leucocytes induces a transformed phenotype similar to tumour cells , but the mechanisms by which the parasite induces this phenotype are not understood . Here , we show that infected B lymphocytes display constitutive phosphoinositide 3 - kinase ( PI3 - K ) activity , which appears to be necessary for proliferation , but not survival . Importantly , we demonstrate that one mechanism by which PI3 - K mediates the proliferation of infected B lymphocytes is through the induction of a granulocyte - monocyte colony - stimulating factor ( GM - CSF ) - dependent autocrine loop . PI3 - K induction of GM - CSF appears to be at the transcriptional level and , consistently , we demonstrate that PI3 - K is also involved in the constitutive induction of AP - 1 and NF - kappaB , which characterizes Theileria - infected leucocytes . Taken together , our results highlight a novel strategy exploited by the intracellular parasite Theileria to induce continued proliferation of its host leucocyte . Lymphokine dependence of STAT3 activation produced by surface immunoglobulin cross - linking and by phorbol ester plus calcium ionophore treatment in B cells . Stimulation of B cells by surface immunoglobulin ( sIg ) triggering , or through the mitogenic combination of phorbol ester and calcium ionophore , is accompanied by activation of STAT transcription factors . The mechanism responsible for the delayed nuclear accumulation of phosphorylated STAT3 was examined in detail , focusing on the role of B cell - derived lymphokines . sIg - induced activation of STAT3 was partially inhibited in B cells obtained from IL - 6 - or IL - 10 - deficient mice , and was partially blocked by neutralizing antibodies directed against either of these lymphokines . sIg - induced STAT3 activation was completely inhibited by combining IL - 6 - and IL - 10 - specific neutralizing antibodies , or by adding individual neutralizing antibodies to B cells obtained from lymphokine - deficient animals . In contrast , IL - 10 alone appeared to account for STAT3 activation resulting from B cell stimulation with phorbol ester and calcium ionophore . In keeping with these results , soluble IL - 6 and IL - 10 were found in supernatant fluid obtained from stimulated B cells . This work indicates that a lymphokine pathway is responsible for STAT3 activation that occurs late after B cell stimulation , and points out differences in B cell activation that result from stimulation through the antigen receptor and through pharmacological mimicry of signaling mediators . Transcription factor AP - 4 is a ligand for immunoglobulin - kappa promoter E - box elements . Immunoglobulin ( Ig ) - kappa promoters from humans and mice share conserved sequences . The octamer element is common to all Ig promoters and pivotal for their function . However , other conserved sequence motifs , that differ between Ig variable gene families , are required for normal promoter function . These conserved motifs do not stimulate transcription in the absence of an octamer . One example is an E - box of the E47 / E12 type ( 5 ' - CAGCTG - 3 ' ) , which is found in all promoters of the human and murine Ig - kappa gene subgroups / families , with the exception of subgroups II and VI and their related murine families . In the present study we show that the ubiquitously expressed transcription factor AP - 4 , and not E47 , interacts specifically with the kappa promoter E - boxes when tested in electrophoretic mobility - shift assays using nuclear extracts derived from human and murine B - cell lines . Furthermore , AP - 4 , unlike E47 , did not act as a transactivator , which is in agreement with previous studies on intact kappa promoters , showing that transcription is absent when the octamer element has been mutated . Based on these data , and the conservation of the 5 ' - CAGCTG - 3 ' motif among human and murine kappa promoters , we propose that AP - 4 is the major ligand for Ig - kappa promoter E - boxes . A 16 - mer peptide ( RQIKIWFQNRRMKWKK ) from antennapedia preferentially targets the Class I pathway . Translocation of antigenic peptides into the cytosol of antigen presenting cells facilitates proteosomal processing and loading into Class I molecules for MHC presentation on the cell surface . The DNA binding domain of the Drosophila transcription factor ( Antennapedia ) , a 60 amino acid protein , is rapidly taken up by cells and has been fused to selected antigens to enhance their immunogenicity . We now demonstrate that a 16 amino acid peptide from antennapedia can facilitate the cytoplasmic uptake of CTL epitope 9 - mer peptides . Synthetic peptides were made containing the 16 - mer antennapedia peptide linked in tandem to the ovalbumin SIINFEKL CTL peptide . The peptide complex was shown to rapidly internalise into APCs by confocal microscopy . This peptide induced CTL in C57BL / 6 mice and protected them against growth of an ovalbumin expressing tumour cell line ( E . G7 - OVA ) . The ability of the hybrid peptide to be processed and presented by APCs was similar , whether the SIINFEKL sequence was appended at the C - terminus or N - terminus of the Antennapedia peptide . The production of synthetic peptides containing other CTL peptide epitopes may be useful for priming CTLs in vitro and in vivo Bone marrow cells promote TH2 polarization and inhibit virus - specific CTL generation . This laboratory recently reported that human bone marrow cells ( BMC ) inhibit the generation of virus - specific CTL in culture . The culture supernatants contained increased levels of prostaglandin E ( 2 ) ( PGE ( 2 ) ) ( shown to favor TH2 cell development ) and also inhibited EBV - CTL effector cell development . In this study , we obtained PBL from Epstein - Barr virus ( EBV ) IgG antibody positive kidney transplant recipients ( R ) and their living - related donors ( LRD ) one year after renal transplantation . EBV - specific CTL were then generated in vitro by stimulating PBL with autologous EBV - transformed B cells ( EBV - B ) in the presence or absence of autologous BMC . The addition of BMC to the EBV - CTL generation cultures increased the intracellular expression in CD3 + cells of IL - 4 , - 5 , - 6 , - 10 , and - 13 . These CD3 + cells also expressed increased levels of the TH2 associated receptor CCR3 . Inhibition was even observed by preparing EBV - CTL generating cultures in trans - wells that separated the autologous BMC from the PBL + EBV - B . It was then observed that CD3 + cells obtained after 7 days of culture in the presence of autologous BMC could be used as inhibitors of EBV - CTL generation . Protein Kinase A ( PKA ) , a cAMP kinase that is involved in the upregulation of TH2 cytokine activity , was increased in EBV - CTL cultures by the presence of BMC . Additionally , IL - 4 - mediated signal transduction and activation of transcription ( STAT - 6 ) phosphorylation was slightly increased . These results show that the BMC inhibition is mediated by soluble factors ( cytokines ) and that cell - cell contact in this autologous system is not required , so that BMC ( at least partially , via cytokine production ) promote TH2 polarization in culture . Moreover , TH2 cells induced by culturing with autologous BMC directly inhibit EBV - CTL generation , and TH2 associated PKA , CCR3 , and STAT - 6 phosphorylation are enhanced by BMC . Reduction in DNA binding activity of the transcription factor Pax - 5a in B lymphocytes of aged mice . Aging has been associated with intrinsic changes of the humoral immune response , which may lead to an increased occurrence of autoimmune disorders and pathogenic susceptibility . The transcription factor Pax - 5 is a key regulator of B cell development . Pax - 5a / B cell - specific activator protein and an alternatively spliced isoform , Pax - 5d , may have opposing functions in transcriptional regulation due to the lack of a transactivation domain in Pax - 5d . To study B cell - specific changes that occur during the aging process , we investigated expression patterns of Pax - 5a and 5d in mature B cells of young and aged mice . RNase protection assays showed a similar transcriptional pattern for both age groups that indicates that aging has no affect on transcription initiation or alternative splicing for either isoform . In contrast , a significant reduction in the DNA binding activity of Pax - 5a but not Pax - 5d protein was observed in aged B cells in vitro , while Western blot analyses showed that similar levels of Pax - 5a and 5d proteins were present in both age groups . The observed decrease in Pax - 5a binding activity correlated with changes in expression of two Pax - 5 target genes in aged B cells . Expression of the Ig J chain and the secreted form of Ig mu , which are both known to be suppressed by Pax - 5a in mature B cells , were increased in B cells of aged mice . Together , our studies suggest that changes associated with the aging phenotype cause posttranslational modification ( s ) of Pax - 5a but not Pax - 5d , which may lead to an abnormal B cell phenotype in aged mice , associated with elevated levels of J chain , and secretion of IgM NF - kappa B / Rel participation in the lymphokine - dependent proliferation of T lymphoid cells . Proliferative responses of lymphoid cells to IL - 2 and IL - 4 depend on activation of the cells , but the mechanism ( s ) by which activation enhances cellular competence to respond to cytokines is not fully understood . The NF - kappaB / Rel family represents one signal transduction pathway induced during such activation . We show in this study that inhibition of NF - kappaB through the expression of an IkappaBalpha ( inhibitory protein that dissociates from NF - kappaB ) mutant refractory to signal - induced degradation ( IkappaBalpha ( DeltaN ) ) interfered with the acquisition of competence to proliferate in response to IL - 4 as well as IL - 2 . Thymocytes and T cells from IkappaBalpha ( DeltaN ) transgenic mice expressed normal levels of IL - 2R subunits . However , transgenic cells exhibited a dramatic defect in Stat5A activation treatment with IL - 2 , and a similar defect was observed for IL - 4 - induced Stat5 . In contrast , T lymphoid cells with inhibition of NF - kappaB showed normal insulin receptor substrate - 2 phosphorylation and only a modest decrease in Stat6 activation and insulin receptor substrate - 1 phosphorylation after IL - 4 stimulation . These results indicate that the NF - kappaB / Rel / IkappaBalpha system can regulate cytokine receptor capacitation through effects on the induction of downstream signaling by the Stat transcription factor family . BMS - 189453 , a novel retinoid receptor antagonist , is a potent testicular toxin . BMS - 189453 is a synthetic retinoid that acts as an antagonist at retinoic acid receptors alpha , beta , and gamma . In Sprague Dawley rats at daily oral doses of 15 , 60 , or 240 mg / kg for 1 month , BMS - 189453 produced increases in leukocyte counts , alkaline phosphatase and alanine aminotransferase levels , and marked testicular degeneration and atrophy at all doses . Significant overt signs of toxicity and deaths occurred at 240 mg / kg , whereas body - weight and food - consumption decreases occurred at 60 and 240 mg / kg . When BMS - 189453 was administered to male rats at daily doses ranging from 12 . 5 to 100 mg / kg for 1 week , only minimal testicular changes occurred at all doses , shortly after the dosing period . However , after a 1 - month drug - free observation period , marked testicular atrophy was evident at all doses . BMS - 189453 was then administered at doses of 2 , 10 , or 50 mg / kg to male rats for 1 , 3 , or 7 consecutive days . Dose - and duration - dependent testicular toxicity that occurred after a 1 - month observation period did not recover , and , in some cases , was more severe 4 months after the last dose . In rabbits administered BMS - 189453 at oral doses of 2 , 10 , or 50 mg / kg for 1 week , testicular degeneration and atrophy were evident in the high - dose group at 1 month following treatment . These studies indicate that retinoid antagonists can selectively produce progressive and prolonged testicular toxicity after single or repeated oral doses that are otherwise well tolerated . Sequential involvement of NFAT and Egr transcription factors in FasL regulation . The critical function of NFAT proteins in maintaining lymphoid homeostasis was revealed in mice lacking both NFATp and NFAT4 ( DKO ) . DKO mice exhibit increased lymphoproliferation , decreased activation - induced cell death , and impaired induction of FasL . The transcription factors Egr2 and Egr3 are potent activators of FasL expression . Here we find that Egr2 and Egr3 are NFAT target genes . Activation of FasL occurs via the NFAT - dependent induction of Egr3 , as demonstrated by the ability of exogenously provided NFATp to restore Egr - dependent FasL promoter activity in DKO lymph node cells . Further , Egr3 expression is enriched in Th1 cells , suggesting a molecular basis for the known preferential expression of FasL in the Th1 versus Th2 subset . Mechanisms and clinical relevance of nongenomic glucocorticoid actions . Glucocorticoids have profound anti - inflammatory and immunosuppressive actions when used therapeutically . The therapeutic dose is quite variable and depends on the disease , but ranges from very low to extremely high . The rationale for the use of various dosage regimens for specific clinical indications is the existence of three distinct , therapeutically relevant effects : genomic , specific nongenomic and unspecific nongenomic . Genomic effects are mediated by cytosolic receptors that alter expression of specific genes . Specific nongenomic effects occur within a few minutes and are mediated by steroid - selective membrane receptors . Unspecific nongenomic effects occur within seconds , but only at high glucocorticoid dosages , and seem to result from direct interactions with biological membranes . For unspecific nongenomic effects , methylprednisolone and other glucocorticoids have been shown to inhibit cation cycling across the plasma membrane , but to have little effect on protein synthesis . Thus , glucocorticoids could diminish or prevent the acute immune response by interfering with processes such as the rise in intracellular Ca2 + concentration . It is proposed that the additional therapeutic benefit of higher doses is obtained via these nongenomic effects . High glucose - induced intercellular adhesion molecule - 1 ( ICAM - 1 ) expression through an osmotic effect in rat mesangial cells is PKC - NF - kappa B - dependent . AIMS / HYPOTHESIS : Infiltration of mononuclear cells and glomerular enlargement accompanied by glomerular cell proliferation are very early characteristics of the pathophysiology of diabetes . To clarify the mechanism of early diabetic nephropathy , we measured [ 3H ] - thymidine incorporation and cell numbers to show the influence of a high ambient glucose concentration and the osmotic effect on rat mesangial cell proliferation . We also measured the effect of high glucose on the expression of intercellular adhesion molecule - 1 and vascular adhesion molecule - 1 by flow cytometry and semiquantitative RT - PCR in mesangial cells and the adhesion of leukocytes to mesangial cells . METHODS / RESULTS : Cells exposed to high D - glucose ( 30 mmol / l ) caused an increase in [ 3H ] - thymidine incorporation and cell numbers at 24 and 48 h and normalized at 72 h ( p < 0 . 05 ) , whereas these changes were not found in high mannitol ( 30 mmol / l ) , IL - 1 beta , or TNF alpha - stimulated mesangial cells . Cells exposed to high - glucose ( 15 , 30 , or 60 mmol / l ) or osmotic agents ( L - glucose , raffinose and mannitol ) showed that intercellular adhesion molecule - 1 expression began to increase after 24 h , reached its maximum at 24 and 48 h and gradually decreased afterwards . The stimulatory effects of high glucose and high mannitol on mRNA expression were observed as early as 6 h and reached its maximum at 12 h . Up - regulation of ICAM - 1 protein and mRNA was also found in IL - 1 - beta and TNF - alpha - stimulated mesangial cells . Neither vascular adhesion molecule - 1 protein nor mRNA expression was , however , affected by high glucose and high mannitol . Notably , the protein kinase C inhibitors calphostin C and staurosporine reduced high glucose - or high mannitol - induced intercellular adhesion molecule - 1 mRNA expression and high glucose - induced proliferation . Furthermore , the NF - kappa B inhibitor N - tosyl - L - phenylalanine chloromethyl ketone reduced high glucose - or high mannitol - induced intercellular adhesion molecule - 1 mRNA expression and high glucose - induced proliferation . Results showed that high glucose ( 15 , 30 mmol / l ) or high concentrations of osmotic agents remarkably increased the number of adherent leukocytes to mesangial cells ( p < 0 . 01 ) compared with control cells ( 5 mmol / l D - glucose ) . Functional blocking of intercellular adhesion molecule - 1 on mesangial cells with rat intercellular adhesion molecule - 1 monoclonal antibody , calphostin C , staurosporine , or N - tosyl - L - phenylalanine chloromethyl ketone significantly inhibited high glucose - or high mannitol - induced increase in leukocyte adhesion ( p < < 0 . 05 ) . CONCLUSION / INTERPRETATION : These results suggest that high glucose can upregulate intercellular adhesion molecule - 1 protein and mRNA expression but not vascular adhesion molecule - 1 expression in mesangial cells and promote leukocyte adhesion through up - regulation of intercellular adhesion molecule - 1 through osmotic effect , possibly depending on the protein kinase C nuclear factor - kappa B ( PKC - NF - kappa B ) pathway . High glucose itself can also promote mesangial cell proliferation through the PKC - NF - kappa B pathways . We conclude that hyperglycaemia in itself seems to be an important factor in the development of early diabetic nephropathy . Combined corticosteroid / granulocyte colony - stimulating factor ( G - CSF ) therapy in the treatment of severe congenital neutropenia unresponsive to G - CSF : Activated glucocorticoid receptors synergize with G - CSF signals . More than 90 % of patients with severe congenital neutropenia ( SCN ) respond to granulocyte colony - stimulating factor ( G - CSF ) therapy . The basis for the refractory state in the remaining patients is unknown . To address this issue , we studied a child with SCN who was totally unresponsive to G - CSF and had a novel point mutation in the extracellular domain of the G - CSF receptor ( GCSF - R ) . Marrow stromal support of granulopoiesis was evaluated by plating CD34 ( + ) cells on preformed stromal layers . Nonadherent cells were harvested and assayed in clonogenic assays for granulocytic colony production . The in vitro effect of G - CSF and corticosteroids on granulopoiesis was evaluated in clonogenic assays of marrow mononuclear cells , by proliferation studies of the murine myeloid cell line 32D expressing the patient ' s mutated G - CSFR , and by measuring STAT5 activation in nuclear extracts from stimulated cells . Patient ' s stroma supported granulopoiesis derived from control marrow CD34 ( + ) cells in a normal manner . Normal stroma , however , failed to induce granulopoiesis from patient ' s CD34 ( + ) cells . Clonogenic assays of the patient ' s marrow mononuclear cells incorporating either G - CSF or hydrocortisone produced little neutrophil growth . In contrast , inclusion of both G - CSF and hydrocortisone in the cytokine ` ` cocktail ' ' markedly increased the neutrophil numbers . Proliferation of 32D cells expressing the mutated receptor and STAT5 activation were improved by a combination of G - CSF and dexamethasone . When small daily doses of oral prednisone were then administered to the patient with conventional doses of subcutaneous G - CSF , the patient responded with increased neutrophil numbers and with a complete reversal of the infectious problems . These data provide insight into SCN unresponsive to standard G - CSF treatment and to the potential corrective action of combined treatment with G - CSF and corticosteroids through synergistic activation of STAT5 . Human renal mesangial cells are a target for the anti - inflammatory action of 9 - cis retinoic acid . Mesangial cells play an active role in the inflammatory response to glomerular injury . We have studied in cultured human mesangial cells ( CHMC ) several effects of 9 - cis retinoic acid ( 9 - cRA ) , an activator of both retinoic acid receptors ( RARs ) and retinoid X receptors ( RXRs ) . 9 - cRA inhibited foetal calf serum - induced CHMC proliferation . It also prevented CHMC death induced by the inflammatory mediator H ( 2 ) O ( 2 ) . This preventive effect was not due to any increase in H ( 2 ) O ( 2 ) catabolism and it persisted even when both catalase and glutathione synthesis were inhibited . Finally , 9 - cRA diminished monocyte adhesion to FCS - stimulated CHMC . Interestingly , the retinoid also inhibited in FCS - stimulated cells the protein expression of two mesangial adhesion molecules , fibronectin and osteopontin , but it did not modify the protein expression of intercellular adhesion molecule - 1 and vascular adhesion molecule - 1 . All major RARs and RXRs isotypes were expressed in CHMC regardless of the presence or absence of 9 - cRA . Transcripts to RAR - alpha , RAR - beta and RXR - alpha increased after incubation with 9 - cRA whereas RXR - gamma was inhibited , suggesting a major role for RARs and RXRs in 9 - cRA - anti - inflammatory effects . 9 - cRA was toxic only at 50 microM ( a concentration 50 - 5000 times higher than required for the effects above ) . Cell death occurred by apoptosis , whose onset was associated with a pronounced increase in catalase activity and reduced glutathione content , being more effectively induced by all - trans retinoic acid . Modulation of the oxidant / antioxidant balance failed to inhibit apoptosis . We conclude that mesangial cells might be a target for the treatment of inflammatory glomerulopathies with 9 - cRA . Expression of mammalian defensin genes . Antimicrobial peptides are a prevalent mechanism of host defense found throughout nature . In mammals , defensins are among the most abundant of these broad - spectrum antibiotics , and are expressed in epithelial and hematopoietic cells . The defensin peptides are especially abundant in neutrophils ; however , gene expression is limited to the promyelocyte stage . In epithelial cells , defensin genes are found as both constitutively expressed and inducible . Induction has been observed in vitro by stimulation with bacterial lipopolysaccharide as well as inflammatory mediators . In vivo , up - regulation of several defensin genes occurs in both infectious and inflammatory states . Gene regulation occurs via signal transduction pathways common to other innate immune responses , utilizing transcription factors such as nuclear factor ( NF ) - kappaB and NF interleukin - 6 . Together , the data suggest a broad - based innate host defense whereby potent antimicrobial peptides are present to prevent initial colonization by pathogenic microorganisms . In addition , the recognition of bacteria coupled with a nascent inflammatory response can bolster this defense by a coordinated up - regulation of the peptides . Multiple signals required for cyclic AMP - responsive element binding protein ( CREB ) binding protein interaction induced by CD3 / CD28 costimulation . The optimal activation of cAMP - responsive element binding protein ( CREB ) , similar to the full activation of T lymphocytes , requires the stimulation of both CD3 and CD28 . Using a reporter system to detect interaction of CREB and CREB - binding protein ( CBP ) , in this study we found that CREB binds to CBP only by engagement of both CD3 and CD28 . CD3 / CD28 - promoted CREB - CBP interaction was dependent on p38 mitogen - activated protein kinase ( MAPK ) and calcium / calmodulin - dependent protein kinase ( CaMK ) IV in addition to the previously identified extracellular signal - regulated kinase pathway . Extracellular signal - regulated kinase , CaMKIV , and p38 MAPK were also the kinases involved in CREB Ser ( 133 ) phosphorylation induced by CD3 / CD28 . A reconstitution experiment illustrated that optimum CREB - CBP interaction and CREB trans - activation were attained when these three kinase pathways were simultaneously activated in T cells . Our results demonstrate that coordinated activation of different kinases leads to full activation of CREB . Notably , CD28 ligation activated p38 MAPK and CaMKIV , the kinases stimulated by CD3 engagement , suggesting that CD28 acts by increasing the activation extent of p38 MAPK and CaMKIV . These results support the model of a minimum activation threshold for CREB - CBP interaction that can be reached only when both CD3 and CD28 are stimulated . The murine IL - 2 promoter contains distal regulatory elements responsive to the Ah receptor , a member of the evolutionarily conserved bHLH - PAS transcription factor family . Signaling through the TCR and costimulatory signals primarily control transcription of the IL - 2 gene in naive T cells . The minimal promoter necessary for this expression lies proximal , between - 300 and the transcription start site . We had previously shown that activation of the arylhydrocarbon receptor ( AHR ) , a member of the bHLH - PAS family of transcription factors , leads to increased mRNA expression of IL - 2 in murine fetal thymocytes . The AHR is abundant in the thymus and may play a role for the development of the immune system . Moreover , its overactivation by chemicals such as dioxins leads to immunosuppression and thymic involution . Binding motifs for the liganded AHR can be identified in the distal region - 1300 to - 800 of the mouse IL - 2 promoter . We show here that these DNA motifs , the so - called dioxin response elements , after binding to the liganded AHR are sufficient to transactivate luciferase expression in a reporter gene system . The IL - 2 gene can be induced by the AHR also in thymocytes in vivo after injection of 2 , 3 , 7 , 8 - tetrachlorodibenzo - p - dioxin , a potent ligand of the AHR . The AHR mediates the IL - 2 induction as shown with AHR - deficient mice . However , in spleen cells in vitro costimulation via the TCR is necessary for optimal IL - 2 gene induction . Thus , the IL - 2 promoter region contains novel distal regulatory elements that can be addressed by the AHR to induce IL - 2 and can cooperate with the proximal promoter Visualization of Syk - antigen receptor interactions using green fluorescent protein : differential roles for Syk and Lyn in the regulation of receptor capping and internalization . The cross - linking of the B cell Ag receptor ( BCR ) is coupled to the stimulation of multiple intracellular signal transduction cascades via receptor - associated , protein tyrosine kinases of both the Src and Syk families . To monitor changes in the subcellular distribution of Syk in B cells responding to BCR cross - linking , we expressed in Syk - deficient DT40 B cells a fusion protein consisting of Syk coupled to green fluorescent protein . Treatment of these cells with anti - IgM Abs leads to the recruitment of the kinase from cytoplasmic and nuclear compartments to the site of the cross - linked receptor at the plasma membrane . The Syk - receptor complexes aggregate into membrane patches that redistribute to form a cap at one pole of the cell . Syk is not demonstrably associated with the internalized receptor . Catalytically active Syk promotes and stabilizes the formation of tightly capped BCR complexes at the plasma membrane . Lyn is not required for the recruitment of Syk to the cross - linked receptor , but is required for the internalization of the clustered BCR complexes . In the absence of Lyn , receptor - Syk complexes at the plasma membrane are long lived , and the receptor - mediated activation of the NF - AT transcription factor is enhanced . Thus , Lyn appears to function to negatively regulate aspects of BCR - dependent signaling by stimulating receptor internalization and down - regulation . Renal interstitial fibrosis is reduced in angiotensin II type 1a receptor - deficient mice . Unilateral ureteral obstruction ( UUO ) results in tubulointerstitial fibrosis of the affected kidney by stimulating the renin - angiotensin system . This study established a UUO model in angiotensin type 1a receptor ( AT1a ) deficient ( mutant ) mice to elucidate the role of angiotensin II through AT1a on the fibrosis of the obstructed kidney ( OBK ) . The relative volume of the tubulointerstitium was measured by an image analyzer ; deposition of collagen types III and IV and monocyte / macrophage infiltration were histologically examined using specific antibodies . Also determined were the mRNA levels of transforming growth factor - beta by Northern blot analysis . Nuclear factor - kappaB activity was assessed by gel shift assay . UUO in wild mice resulted in a marked expansion of relative volume of the tubulointerstitium , together with increased deposition of collagen types III and IV and number of infiltrated monocytes / macrophages in the interstitium , relative to sham - operated mice . In comparison , these changes were significantly lower in mutant mice with UUO . The mRNA level of transforming growth factor - beta was significantly higher in the OBK of wild mice with UUO compared with sham - operated mice . In contrast , the increase in mRNA level in the OBK of mutant mice was significantly less than in wild mice . Finally , UUO resulted in activation of nuclear factor - kappaB in wild mice but was inhibited in the OBK of mutant mice . The results provide direct evidence that angiotensin II acting via the AT1a plays a pivotal role in the development of tubulointerstitial fibrosis in UUO . HLA - DQ tetramers identify epitope - specific T cells in peripheral blood of herpes simplex virus type 2 - infected individuals : direct detection of immunodominant antigen - responsive cells . Ag - specific CD4 + T cells are present in peripheral blood in low frequency , where they undergo recruitment and expansion during immune responses and in the pathogenesis of numerous autoimmune diseases . MHC tetramers , which constitute a labeled MHC - peptide ligand suitable for binding to the Ag - specific receptor on T cells , provide a novel approach for the detection and characterization of such rare cells . In this study , we utilized this technology to identify HLA DQ - restricted Ag - specific T cells in the peripheral blood of human subjects and to identify immunodominant epitopes associated with viral infection . Peptides representing potential epitope regions of the VP16 protein from HSV - 2 were loaded onto recombinant DQ0602 molecules to generate a panel of Ag - specific DQ0602 tetramers . VP16 Ag - specific DQ - restricted T cells were identified and expanded from the peripheral blood of HSV - 2 - infected individuals , representing two predominant epitope specificities . Although the VP16 369 - 380 peptide has a lower binding affinity for DQ0602 molecules than the VP16 33 - 52 peptide , T cells that recognized the VP16 369 - 380 peptide occurred at a much higher frequency than those that were specific for the VP16 33 - 52 peptide . Down - regulation of BOB . 1 / OBF . 1 and Oct2 in classical Hodgkin disease but not in lymphocyte predominant Hodgkin disease correlates with immunoglobulin transcription . In contrast to the tumor cells ( L & H cells ) of lymphocyte predominant Hodgkin disease ( LPHD ) , Hodgkin and Reed - Sternberg ( HRS ) cells of classical Hodgkin disease ( cHD ) are unable to transcribe immunoglobulin , despite the presence of rearranged immunoglobulin genes . Although initial studies have suggested crippling immunoglobulin gene mutations to be the cause of absent immunoglobulin expression in cHD , recent work of our group has demonstrated an impaired activation of the immunoglobulin promoter as a superior mechanism . As immunoglobulin transcription is mainly regulated by the B - cell transcription factors Oct2 and BOB . 1 / OBF . 1 , we analyzed 35 cases of LPHD , 32 cases of cHD , and 2 Hodgkin disease cell lines for the expression of these transcription factors and also in parallel for immunoglobulin expression . Our results demonstrate an absence of Oct2 and / or BOB . 1 / OBF . 1 in cHD and a striking overexpression of Oct2 in LPHD . Immunoglobulin expression was lacking in cHD but present in LPHD . Furthermore , the reintroduction of BOB . 1 / OBF . 1 and Oct2 into cultured HRS cells restored the activity of cotransduced immunoglobulin promoter constructs . Our findings dismiss the concept that the different immunoglobulin expression in cHD and LPHD is due to disrupting mutations of immunoglobulin V genes in cHD but is most likely due to a down - regulation of Oct2 and / or BOB . 1 / OBF . 1 . This study further revealed Oct2 as a new and valuable marker for the identification of L & H cells and their distinction from HRS cells . The impairment of immunoglobulin transcription with a down - regulated synthesis of Oct2 and BOB . 1 / OBF . 1 is the first established general recurrent defect found in HRS cells . Constitutive expression of NF - kappa B is a characteristic feature of mycosis fungoides : implications for apoptosis resistance and pathogenesis . The NF - kappa B family of transcription factors is an important regulator of genes expressed during inflammatory responses , immunoglobulin ( Ig ) class switching , cellular differentiation , and apoptosis . Recently , members of the NF - kappaB family , including p65 ( Rel A ) , have been implicated in promoting survival of various hematopoeitic neoplasms , including T cell malignancies such as adult T cell leukemia - lymphoma . We investigated the expression of active NF - kappa B p65 ( Rel A ) in cases of mycosis fungoides ( MF ) and the effect of chemical inhibitors of NF - kappa B on apoptosis in cutaneous T cell lymphoma ( CTCL ) cell lines . Paraffin - embedded tissues from 23 cutaneous lesions and a single lymph node biopsy from patients diagnosed with MF were evaluated for p65 ( Rel A ) expression by using a monoclonal mouse antibody that detects the activated form of p65 ( Rel A ) . Apoptosis after treatment with the NF - kappa B inhibitors gliotoxin , MG132 , BAY 11 - 7082 , and BAY 11 - 7085 was quantitatively measured in the CTCL cell lines HuT - 78 and HH by propidium iodide ( PI ) / cell cycle analysis for detection of a hypodiploid ( sub - G ( 0 ) ) population and by determination of increased Annexin V / 7 - amino - actinomycin D ( 7 - AAD ) expression . Nuclear extracts from CTCL cells before and after chemical inhibition were analyzed for NF - kappa B nuclear DNA - binding activity by electrophoretic mobility shift assay ( EMSA ) with quantitative densitometry . Nuclear expression of p65 ( Rel A ) before and after treatment with the various inhibitory compounds was measured by immunofluorescence staining in each CTCL cell line . Neoplastic T lymphocytes from 22 of 24 cases of MF showed strong nuclear and cytoplasmic expression of active p65 ( Rel A ) . Compared with untreated control cells , a marked increase in apoptosis , a significant decrease in NF - kappa B DNA - binding activity , and a marked decrease in nuclear p65 ( Rel A ) expression were seen in cells from both CTCL cell lines after chemical NF - kappa B inhibition . These data show that the active form of NF - kappa B p65 ( Rel A ) is commonly expressed in neoplastic T lymphocytes in patients with MF . In CTCL cell lines , the significant decrease in nuclear NF - kappa B expression and the marked increase in spontaneous apoptosis caused by chemical NF - kappa B inhibition suggest a critical role for NF - kappa B in the pathogenesis and tumor cell maintenance of CTCLs . HUM PATHOL 31 : 1482 - 1490 . Human T - cell leukemia virus type 1 tax protein activates transcription through AP - 1 site by inducing DNA binding activity in T cells . Human T - cell leukemia virus type 1 ( HTLV - 1 ) Tax protein induces the expression of various family members of the transcription factor AP - 1 , such as c - Jun , JunD , c - Fos , and Fra - 1 , at the level of RNA expression in T cells . We examined the activity of Tax in transcription through AP - 1 - binding sites ( AP - 1 site ) in T cells . Transient transfection studies showed that Tax activated the expression of a luciferase gene regulated by two copies of an AP - 1 site in the human Jurkat T - cell line . Tax activates the expression of viral and cellular genes through two different enhancers : a cAMP - responsive ( CRE ) - like element and a kappaB element . Two Tax mutants differentially activated expression of these two elements . Tax703 preferentially activated the kappaB element but not the CRE - like one , whereas TaxM22 showed the reverse . In addition , Tax703 and Tax , but not TaxM22 , converted cell growth of a mouse T - cell line from being interleukin ( IL ) - 2 - dependent to being IL - 2 - independent . Unlike the wild - type Tax , Tax703 and TaxM22 only weakly activated the AP - 1 site in the T - cell line . Thus , Tax seems to activate the AP - 1 site via mechanisms distinct from those of kappaB or CRE - like elements , and the activation of the AP - 1 site is dispensable for IL - 2 - independent growth of CTLL - 2 . Electrophoretic mobility shift assays showed that Tax induced strong binding activity to an AP - 1 site in CTLL - 2 , whereas Tax703 did not , indicating that the induction of binding activity to the AP - 1 site is essential for the transcriptional activation by Tax . The binding complex induced by Tax in CTLL - 2 contained JunD and Fra - 2 . Other AP - 1 proteins were undetectable . Activation of transcription through the AP - 1 site in Jurkat cells by JunD and / or Fra - 2 was weak . c - Jun , JunB , and c - Fos activation was greater , although the level was still less than that with Tax . Thus , the induction of AP - 1 mRNA by Tax may not be sufficient for a complete activation of AP - 1 site by Tax . Our results suggest that Tax activates the transcription of cellular genes with AP - 1 sites by inducing the DNA - binding activity of AP - 1 proteins in T cells , a mechanism distinct from those of CRE - like and kappaB elements . Copyright 2001 Academic Press . Strict control of human immunodeficiency virus type 1 replication by a genetic switch : Tet for Tat . Live - attenuated human immunodeficiency virus type 1 ( HIV - 1 ) variants have shown great promise as AIDS vaccines , but continued replication can lead to the selection of faster - replicating variants that are pathogenic . We therefore designed HIV - 1 genomes that replicate exclusively upon addition of the nontoxic effector doxycycline ( dox ) . This was achieved by replacement of the viral TAR - Tat system for transcriptional activation by the Escherichia coli - derived Tet system for inducible gene expression . These designer ` ` HIV - rtTA ' ' viruses replicate in a strictly dox - dependent manner both in a T - cell line and in primary blood cells , and the rate of replication can be fine - tuned by simple variation of the dox concentration . These HIV - rtTA viruses provide a tool to perform genetics , e . g . , selection and optimization experiments , with the E . coli - derived Tet reagents in a eukaryotic background . Furthermore , such viruses may represent improved vaccine candidates because their replication can be turned on and off at will . Synovial fluid induced nuclear factor - kappaB DNA binding in a monocytic cell line . OBJECTIVE : To determine the effects of synovial fluids ( SF ) on DNA binding activity of transcription factor nuclear factor - kappaB ( NF - kappaB ) in the Mono Mac 6 monocytic / macrophage cell line as a model for the interaction between SF and synovial tissue macrophages in arthritis . METHODS : Mono Mac 6 cells were incubated with SF from the knee joints of human subjects with rheumatoid arthritis ( RA ) , undifferentiated seronegative oligoarthritis , and osteoarthritis ( OA ) . Nuclear extracts prepared from the Mono Mac 6 cells and RA synovial tissue were analyzed by electrophoretic mobility shift analysis ( EMSA ) for NF - kappaB DNA binding proteins . RESULTS : Induction of NF - kappaB DNA binding by the p65 ( RelA ) / p50 heterodimer was observed in response to incubation of Mono Mac 6 cells with SF ( 20 % in culture medium ) from 5 of 8 subjects with RA , 4 of 5 with OA , and none of 3 with undifferentiated seronegative oligoarthritis . Incubation of SF with neutralizing antibodies against tumor necrosis factor - alpha ( TNF - alpha ) , but not antibodies against interleukin 6 ( IL - 6 ) , significantly reduced the induction of p65 / p50 binding activity in SF from subjects with RA and OA . Unexpectedly , a slowly migrating SF inducible NF - kappaB - binding complex was observed in EMSA of Mono Mac 6 cells after incubation with SF from 5 of 8 RA and 2 of 5 OA subjects . The induction of this complex by SF was not affected by neutralization of TNF - alpha or IL - 6 in SF , and the complex was not inducible by TNF - alpha , IL - 1beta , TNF - alpha / IL - 1beta , IL - 6 , platelet derived growth factor , lipopolysaccharide , or tetradecanoyl phorbol acetate . The slowly migrating complex could not be supershifted with antibodies against NF - kappaB , Jun , or the transcriptional coactivators p300 or CBP . A NF - kappaB - binding complex with similar slow mobility was observed in nuclear extracts prepared from fresh human RA synovial tissue . CONCLUSION : Biological activity of TNF - alpha in SF from RA and OA subjects is capable of inducing p65 / p50 NF - kappaB DNA binding activity in macrophages . A property of SF that is independent of TNF - alpha and other cytokines is responsible for the induction of a novel slowly migrating NF - kappaB - binding complex . Soluble mediators in SF of subjects with RA and OA can therefore modulate binding of nuclear proteins to the NF - kappaB binding site in macrophages and may play a role in inflammatory gene expression in arthritis . Peroxisome proliferator activator receptor - gamma agonists and 15 - deoxy - Delta ( 12 , 14 ) ( 12 , 14 ) - PGJ ( 2 ) induce apoptosis in normal and malignant B - lineage cells . The research described herein evaluates the expression and functional significance of peroxisome proliferator activator receptor - gamma ( PPAR - gamma ) on B - lineage cells . Normal mouse B cells and a variety of B lymphoma cells reflective of stages of B cell differentiation ( e . g . , 70Z / 3 , CH31 , WEHI - 231 , CH12 , and J558 ) express PPAR - gamma mRNA and , by Western blot analysis , the 67 - kDa PPAR - gamma protein . 15 - Deoxy - Delta ( 12 , 14 ) - PGJ ( 2 ) ( 15d - PGJ ( 2 ) ) , a PPAR - gamma agonist , has a dose - dependent antiproliferative and cytotoxic effect on normal and malignant B cells as shown by [ ( 3 ) H ] thymidine and 3 - [ 4 , 5 - dimethylthiazol - 2 - yl ] - 2 , 5 - diphenyltetrazolium bromide assays . Only PPAR - gamma agonists ( thiazolidinediones ) , and not PPAR - alpha agonists , mimicked the effect of 15d - PGJ ( 2 ) on B - lineage cells , indicating that the mechanism by which 15d - PGJ ( 2 ) negatively affects B - lineage cells involves in part PPAR - gamma . The mechanism by which PPAR - gamma agonists induce cytotoxicity is via apoptosis , as shown by annexin V staining and as confirmed by DNA fragmentation detected using the TUNEL assay . Interestingly , addition of PGF ( 2alpha ) , which was not known to affect lymphocytes , dramatically attenuated the deleterious effects of PPAR - gamma agonists on B lymphomas . Surprisingly , 15d - PGJ ( 2 ) induced a massive increase in nuclear mitogen - activated protein kinase activation , and pretreatment with PGF ( 2alpha ) blunted the mitogen - activated protein kinase activation . This is the first study evaluating PPAR - gamma expression and its significance on B lymphocytes . PPAR - gamma agonists may serve as a counterbalance to the stimulating effects of other PGs , namely PGE ( 2 ) , which promotes B cell differentiation . Finally , the use of PGs , such as 15d - PGJ ( 2 ) , and synthetic PPAR - gamma agonists to induce apoptosis in B - lineage cells may lead to the development of novel therapies for fatal B lymphomas Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl - 1 expression . Large granular lymphocyte ( LGL ) leukemia is characterized by the expansion of antigen - activated cytotoxic T lymphocytes . These leukemic cells are resistant to Fas - mediated apoptosis despite expressing high levels of Fas . We found that leukemic LGL from 19 patients displayed high levels of activated STAT3 . Treatment of leukemic LGL with the JAK - selective tyrosine kinase inhibitor AG - 490 induced apoptosis with a corresponding decrease in STAT - DNA binding activity . Moreover , using an antisense oligonucleotide approach to diminish STAT3 expression , we found that Fas sensitivity was restored in leukemic LGL . AG - 490 - induced apoptosis in leukemic LGL was independent of Bcl - xL or Bcl - 2 expression . However , we found that the Bcl - 2 - family protein Mcl - 1 was significantly reduced by AG - 490 treatment . Activated STAT3 was shown to bind an SIE - related element in the murine mcl - 1 promoter . Using a luciferase reporter assay , we demonstrated that v - src overexpression in NIH3T3 induced STAT3 - dependent transcriptional activity from the mcl - 1 promoter and increased endogenous Mcl - 1 protein levels . We conclude that STAT3 activation contributed to accumulation of the leukemic LGL clones . These findings suggest that investigation should focus on novel strategies targeting STAT3 in the treatment of LGL leukemia . Decreased immediate inflammatory gene induction in activating transcription factor - 2 mutant mice . Transcription factor activating transcription factor ( ATF ) - 2 is activated by inflammatory signals transduced by the JNK and p38 MAP kinase pathways . To better define the role of ATF - 2 in inflammation , adult mice expressing small amounts of a mutant ATF - 2 protein were challenged with lipopolysaccharide ( LPS ) , anti - CD3 antibody or virus . Within 3 h of challenge by LPS , ATF - 2 mutant mice had decreased induction of the adhesion molecules E - selectin , P - selectin and VCAM - 1 as well as the cytokines tumor necrosis factor - alpha , IL - 1beta and IL - 6 compared with control mice . Stimulation of T lymphocytes by anti - CD3 antibody also showed less induction of IL - 1 and IL - 6 in ATF - 2 mutant tissues . ATF - 2 mutant thymocytes treated with anti - CD3 antibody in vitro demonstrated reduced induction of c - Jun , JunB , JunD and Fra - 2 . However , similar to what was observed after p38 kinase inhibition in normal mice , relative ATF - 2 deficiency did not prevent the development of a mononuclear cell infiltrate in the week following an inflammatory stimulus . ATF - 2 mutant mice proved more susceptible to death than control mice from LPS plus D - galactosamine injection or Coxsackievirus B3 infection and had a higher incidence of mononuclear pulmonary infiltrates after exposure to Herpes simplex virus - 1 . ATF - 2 is essential for maximal immediate induction of adhesion molecules and cytokine genes , but at later time points may even protect against overactive immune responses . LIGHT , a TNF - like molecule , costimulates T cell proliferation and is required for dendritic cell - mediated allogeneic T cell response . LIGHT is a recently identified member of the TNF superfamily and its receptors , herpesvirus entry mediator and lymphotoxin beta receptor , are found in T cells and stromal cells . In this study , we demonstrate that LIGHT is selectively expressed on immature dendritic cells ( DCs ) generated from human PBMCs . In contrast , LIGHT is not detectable in DCs either freshly isolated from PBMCs or rendered mature in vitro by LPS treatment . Blockade of LIGHT by its soluble receptors , lymphotoxin beta receptor - Ig or HVEM - Ig , inhibits the induction of DC - mediated primary allogeneic T cell response . Furthermore , engagement of LIGHT costimulates human T cell proliferation , amplifies the NF - kappaB signaling pathway , and preferentially induces the production of IFN - gamma , but not IL - 4 , in the presence of an antigenic signal . Our results suggest that LIGHT is a costimulatory molecule involved in DC - mediated cellular immune responses . Suppression of HIV type 1 replication by a dominant - negative Ets - 1 mutant . Activity of the distal region of the human immunodeficiency virus ( HIV - 1 ) long terminal repeat ( LTR ) , which contains binding sites for the Ets - 1 and USF - 1 proteins , is integral for HIV - 1 replication . The Ets - 1 and USF - 1 proteins play a critical role in the activity of the HIV - 1 LTR distal enhancer region , as indicated by the potent dominant negative effect of a mutant Ets - 1 lacking trans - activation domains on the transcriptional activity of the LTR . To determine the biological relevance of the Ets - 1 and USF - 1 proteins in HIV - 1 replication , we examined the effect of expression of the dominant - negative mutant of Ets - 1 ( dnEts - 1 ) on HIV - 1 infection of T cells . We demonstrated that expression of dnEts markedly suppressed HIV - 1 infection of a T cell line . This finding indicates that formation of a transcriptionaly active USF - 1 / Ets - 1 complex is important in the productive infection of cells by HIV - 1 , and suggests that inhibition of the interaction between USF - 1 and Ets - 1 with the HIV - 1 LTR may provide a new target for anti - HIV - 1 gene therapy . Human eosinophils constitutively express nuclear factor of activated T cells p and c . BACKGROUND : Eosinophils are now known to produce a variety of proinflammatory cytokines , although the molecular factors that regulate their production are poorly understood . The expression of almost all of the cytokines produced by eosinophils , including the proallergic cytokine IL - 4 , is now known to be regulated at the level of transcription by members of the nuclear factor of activated T cells ( NFAT ) family of transcription factors . OBJECTIVE : We sought to characterize the expression of different NFAT proteins in resting and activated eosinophils . METHODS : Nuclear and whole cell extracts were obtained from both peripheral blood eosinophils and those obtained from bronchoalveolar lavage fluid of asthmatic subjects after endobronchial allergen challenge . NFAT expression was determined by using immunoprecipitation and Western blot analysis , DNA - binding assays , and RT - PCR analysis of eosinophil mRNA . RESULTS : Both peripheral blood and bronchoalveolar lavage fluid eosinophils expressed NFATp and NFATc protein . Unlike activated T cells , which express multiple NFATc isoforms , eosinophils preferentially express the approximately 85 - kd isoform . In addition , eosinophils were found to constitutively express NFATc mRNA . A brief incubation with the T ( H ) 2 cytokines IL - 4 and IL - 5 was sufficient to induce the nuclear translocation of NFATc . Eosinophil nuclear extracts contain multiple factors that can specifically recognize the IL - 4 promoter P1 NFAT site in DNA - binding assays , including NFATp . CONCLUSION : NFATp and NFATc can regulate the expression of cytokines and other genes in eosinophils but appear to be regulated by a novel signal transduction mechanism in these cells . BLyS BINDS TO B CELLS WITH HIGH AFFINITY AND INDUCES ACTIVATION OF THE TRANSCRIPTION FACTORS NF - kappaB AND ELF - 1 . B lymphocyte stimulator ( BLyS ) is a novel member of the TNF family of proteins expressed by myeloid cells as membrane - bound and soluble forms . BLyS was shown to act specifically on B cells , inducing proliferation and immunoglobulin production both in vitro and in vivo . The present study was undertaken to characterize binding of radiolabeled BLyS to its cognate receptor on human B lymphocytes and examine intracellular events initiated by BLyS binding . Similar to other TNF family members , BLyS is present in solution as a homotrimer as determined by gel filtration chromatography and light scattering analysis . BLyS binding to B cells is specific as other TNF family members tested did not compete for ( 125 ) I - BLyS binding . Analysis of equilibrium binding of ( 125 ) I - labeled BLyS to purified human tonsillar B cells demonstrated saturable binding . Scatchard analysis of the binding data revealed a single class of high - affinity binding on human B cells with approximately 2600 binding sites per cell and an apparent dissociation constant ( K ( D ) ) of about 0 . 1 nM . In addition we report that BLyS binding to B cells results in the activation of NF - kappaB and the Ets family transcription factor , ELF - 1 , and in the induction of mRNA for Polo - like kinase ( PLK ) . Copyright 2001 Academic Press . Design and use of an inducibly activated human immunodeficiency virus type 1 Nef to study immune modulation . The Nef protein of the human immunodeficiency virus type 1 ( HIV - 1 ) has been shown to enhance the infectivity of virus particles , downmodulate cell surface proteins , and associate with many intracellular proteins that are thought to facilitate HIV infection . One of the challenges in defining the molecular events regulated by Nef has been obtaining good expression of Nef protein in T cells . This has been attributed to effects of Nef on cell proliferation and apoptosis . We have designed a Nef protein that is readily expressed in T - cell lines and whose function is inducibly activated . It is composed of a fusion between full - length Nef and the estrogen receptor hormone - binding domain ( Nef - ER ) . The Nef - ER is kept in an inactive state due to steric hindrance , and addition of the membrane - permeable drug 4 - hydroxytamoxifen ( 4 - HT ) , which binds to the ER domain , leads to inducible activation of Nef - ER within cells . We demonstrate that Nef - ER inducibly associates with the 62 - kDa Ser / Thr kinase and is localized to specific membrane microdomains ( lipid rafts ) only after activation . Using this inducible Nef , we also compared the specific requirements for CD4 and HLA - A2 downmodulation in a SupT1 T - cell line . Half - maximal downmodulation of cell surface CD4 required very little active Nef - ER and occurred as early as 4 h after addition of 4 - HT . In contrast , 50 % downmodulation of HLA - A2 by Nef required 16 to 24 h and about 50 - to 100 - fold - greater concentrations of 4 - HT . These data suggest that HLA - A2 downmodulation may require certain threshold levels of active Nef . The differential timing of CD4 and HLA - A2 downmodulation may have implications for HIV pathogenesis and immune evasion . Regulation of chemokine mRNA expression in a rat model of vanadium - induced pulmonary inflammation . Environmental and occupational exposure to vanadium dusts results in toxic effects mainly confined to the respiratory system . Using a rat model of acute lung inflammation induced by intratracheal instillation of sodium metavanadate ( NaVO3 ) at the dose of 200 microg V / kg , we investigated the relationship between the cytologic characterization of pulmonary inflammation and the expression of chemokine mRNA . Significant polymorphonuclear leukocyte ( PMN ) influx ( P < 0 . 01 ) into the lung was noted 4 h after NaVO3 instillation , whereas alveolar macrophages ( AMs ) in bronchoalveolar lavage ( BAL ) cells appeared to decrease significantly . In contrast , neither PMNs nor AMs changed substantially 1 h after NaVO3 instillation . By Northern analysis , macrophage inflammatory protein ( MIP ) - 2 mRNA in BAL cells increased markedly 1 h after NaVO3 instillation and reduced a little bit at 4 h , whereas MIP - 1alpha mRNA in BAL cells was expressed relatively high 1 h after NaVO3 instillation , although a basal expression was detected in control group , and returned rapidly nearly to control level at 4 h . Since MIP - 2 is a potent PMN chemoattractant and MIP - 1alpha is a potent macrophage / monocyte chemoattractant has been well known . The facts that PMN influx was preceded by increased MIP - 2 mRNA expression , suggesting that MIP - 2 is involved in the development of NaVO3 - induced pulmonary inflammation , whereas increased MIP - 1alpha mRNA expression was followed by decreased AMs in BAL cells , suggesting AMs might be activated by MIP - 1alpha , adherent to the lining surface of the airways and then resistant to be washed out . To delineate the mechanisms of transcriptional activation , we recently cloned the 5 ' - flanking region of the MIP - 2 gene . The promotor region contains consensus binding sites for transcription factor nuclear factor kappaB ( NF - kappaB ) and activator protein - 1 ( AP - 1 ) . Using electrophoretic mobility shift assay , increased nuclear NF - kappaB , not AP - 1 , binding activity was detected 1 h after NaVO3 instillation , which correlated with the induction of MIP - 2 mRNA . p65 ( Rel A ) and p50 protein appears to be involved in MIP - 2 NF - kappaB binding . Taken together , our studies suggest that MIP - 2 is an important mediator of NaVO3 - induced pulmonary inflammation in the rat model . In addition , elevated MIP - 2 mRNA levels are accompanied by increased NF - kappaB binding activity in BAL cells , suggesting possible MIP - 2 transcriptional regulation through NF - kappaB . Activation of signal transduction and apoptosis in healthy lymphomonocytes exposed to bystander HIV - 1 - infected cells . Persistent activation of the immune system is one of the hallmarks of HIV - 1 infection . In this study we analysed the induction of factors involved in cytokine signal transduction , such as STAT 1 proteins and IRF - 1 mRNA , in normal peripheral blood mononuclear cells ( PBMC ) exposed to HIV - infected cells , and the induction of apoptosis . Western blot analyses and reverse transcriptase - polymerase chain reaction results indicate that both cells infected with a X4 strain and cells infected with a R5 strain are able to increase intracellular levels of STAT 1alpha and beta proteins as well as IRF - 1 mRNA . This effect was prevented by neutralizing antibodies against interferon - alpha ( IFN - alpha ) . HIV - 1 - infected cells dose - dependently induced apoptotic commitment in normal PBMC , as revealed by DNA fragmentation analysis , but this was not accompanied by an increase of caspase - 3 activity , even if a slight up - regulation of IL - 1beta - converting enzyme mRNA was detected . Apoptosis induction could be abrogated mainly by antibodies against tumour necrosis factor - alpha ( TNF - alpha ) and , to a lesser extent , by antibodies against IFN - gamma . All these findings suggest that uninfected PBMC can undergo activation of signal transduction and apoptosis after exposure to bystander HIV - infected cells , subsequent to the induction of cytokines such as IFNs and TNF - alpha . The physical association of protein kinase C theta with a lipid raft - associated inhibitor of kappa B factor kinase ( IKK ) complex plays a role in the activation of the NF - kappa B cascade by TCR and CD28 . We investigated the role of protein kinase C theta ( PKCtheta ) in the activation of the NF - kappaB cascade in primary human CD4 ( + ) lymphocytes . Among six or so PKC isoforms expressed in T cells , only PKCtheta participates in the assembly of the supramolecular activation clusters at the contact site of the TCR with Ag . Signaling via both the TCR and CD28 is required for optimal activation of the multisubunit IkappaB kinase ( IKK ) complex in primary human T lymphocytes ; this activation could be inhibited by a Ca ( 2 + ) - independent PKC isoform inhibitor , rottlerin . Moreover , endogenous PKCtheta physically associates with activated IKK complexes in CD3 / CD28 - costimulated primary CD4 ( + ) T cells . The same set of stimuli also induced relocation of endogenous PKCtheta and IKKs to a GM1 ganglioside - enriched , detergent - insoluble membrane compartment in primary T cells . IKKs recruited to these lipid rafts were capable of phosphorylating a recombinant IkappaBalpha sustrate . Confocal microscopy further demonstrated that exogenously expressed PKCtheta and IKKss colocalize in the membrane of CD3 / CD28 - costimulated Jurkat T cells . Constitutively active but not kinase - inactive PKCtheta activated IKKbeta in Jurkat T cells . Expression of dominant - active PKCtheta also had stimulatory effects on the CD28 response element of the IL - 2 promoter . Taken together , these data show that the activation of PKCtheta by the TCR and CD28 plays an important role in the assembly and activation of IKK complexes in the T cell membrane T - cell - mediated regulation of osteoclastogenesis by signalling cross - talk between RANKL and IFN - gamma . Bone resorption is regulated by the immune system , where T - cell expression of RANKL ( receptor activator of nuclear factor ( NF ) - kappaB ligand ) , a member of the tumour - necrosis factor family that is essential for osteoclastogenesis , may contribute to pathological conditions , such as autoimmune arthritis . However , whether activated T cells maintain bone homeostasis by counterbalancing the action of RANKL remains unknown . Here we show that T - cell production of interferon ( IFN ) - gamma strongly suppresses osteoclastogenesis by interfering with the RANKL - RANK signalling pathway . IFN - gamma induces rapid degradation of the RANK adapter protein , TRAF6 ( tumour necrosis factor receptor - associated factor 6 ) , which results in strong inhibition of the RANKL - induced activation of the transcription factor NF - kappaB and JNK . This inhibition of osteoclastogenesis is rescued by overexpressing TRAF6 in precursor cells , which indicates that TRAF6 is the target critical for the IFN - gamma action . Furthermore , we provide evidence that the accelerated degradation of TRAF6 requires both its ubiquitination , which is initiated by RANKL , and IFN - gamma - induced activation of the ubiquitin - proteasome system . Our study shows that there is cross - talk between the tumour necrosis factor and IFN families of cytokines , through which IFN - gamma provides a negative link between T - cell activation and bone resorption . Our results may offer a therapeutic approach to treat the inflammation - induced tissue breakdown . Stromal - derived factor 1 and thrombopoietin regulate distinct aspects of human megakaryopoiesis . The role of the chemokine binding stromal - derived factor 1 ( SDF - 1 ) in normal human megakaryopoiesis at the cellular and molecular levels and its comparison with that of thrombopoietin ( TPO ) have not been determined . In this study it was found that SDF - 1 , unlike TPO , does not stimulate alpha ( IIb ) beta ( 3 ) ( + ) cell proliferation or differentiation or have an antiapoptotic effect . However , it does induce chemotaxis , trans - Matrigel migration , and secretion of matrix metalloproteinase 9 ( MMP - 9 ) and vascular endothelial growth factor ( VEGF ) by these cells , and both SDF - 1 and TPO increase the adhesion of alpha ( IIb ) beta ( 3 ) ( + ) cells to fibrinogen and vitronectin . Investigating the intracellular signaling pathways induced by SDF - 1 and TPO revealed some overlapping patterns of protein phosphorylation / activation ( mitogen - activated protein kinase [ MAPK ] p42 / 44 , MAPK p38 , and AKT [ protein kinase B ] ) and some that were distinct for TPO ( eg , JAK - STAT ) and for SDF - 1 ( eg , NF - kappa B ) . It was also found that though inhibition of phosphatidyl - inositol 3 - kinase ( PI - 3K ) by LY294002 in alpha ( IIb ) beta ( 3 ) ( + ) cells induced apoptosis and inhibited chemotaxis adhesion and the secretion of MMP - 9 and VEGF , the inhibition of MAPK p42 / 44 ( by the MEK inhibitor U0126 ) had no effect on the survival , proliferation , and migration of these cells . Hence , it is suggested that the proliferative effect of TPO is more related to activation of the JAK - STAT pathway ( unique to TPO ) , and the PI - 3K - AKT axis is differentially involved in TPO - and SDF - 1 - dependent signaling . Accordingly , PI - 3K is involved in TPO - mediated inhibition of apoptosis , TPO - and SDF - 1 - regulated adhesion to fibrinogen and vitronectin , and SDF - 1 - mediated migration . This study expands the understanding of the role of SDF - 1 and TPO in normal human megakaryopoiesis and indicates the molecular basis of the observed differences in cellular responses . ( Blood . 2000 ; 96 : 4142 - 4151 ) Adhesion of immature and mature T cells induces in human thymic epithelial cells ( TEC ) activation of IL - 6 gene trascription factors ( NF - kappaB and NF - IL6 ) and IL - 6 gene expression : role of alpha3beta1 and alpha6beta4 integrins . T cell precursors homed to thymus develop in close contact with stromal cells . Among them , thymic epithelial cells ( TEC ) are known to exert dominant roles in their survival and functional shaping . Key molecules mediating TEC / thymocytes interactions include cytokines and growth factors secreted by the two cell types and adhesion receptors mediating cell contact . Signaling events triggered in thymocytes by adhesion to epithelial cells have been extensively investigated , whereas little is known on the opposite phenomenon . We have previously investigated this issue in a co - culture system composed of TEC cultures derived from human normal thymus and heterologous thymocytes . We demonstrated that thymocytes adhere to TEC involving beta1 and beta4 integrins and induce the clustering of alpha3beta1 and alpha6beta4 heterodimers at the TEC surface . In addition thymocyte adhesion was followed by activation of NF - kappaB and NF - IL6 gene transcription factors and enhanced IL - 6 production . The two latter phenomena were reproduced by the cross - linking of the alpha3 , alpha6 , beta1 and beta4 integrins , thus implying that the alpha3beta1 and alpha6beta4 heterodimers can signal during thymocyte adhesion . We have extended our previous work investigating in the same experimental setting the inducing activity of non stimulated or activated policlonal or clonal mature T cells as representative of the more mature thymocyte subset . We found that adhesion of unstimulated T cell i ) involved beta1 , but not beta4 integrin functions at the surface ii ) induced the clustering of alpha3beta1 , but not alpha2beta1 heterodimers at the TEC surface and iii ) up - regulated the nuclear binding activity of NF - kappaB transcription factor and the IL - 6 secretion . We propose that alpha3beta1 and alpha6beta4 heterodimers are induced to cluster at the TEC surface recognizing yet unknown cellular ligands differentially expressed during T cell development . Identification and characterization of SKAT - 2 , a novel Th2 - specific zinc finger gene . We have identified a novel Kruppel - type zinc finger ( ZF ) gene , SKAT - 2 , which is selectively expressed by murine Th2 cells . The protein encoded by this gene has 14 C2H2 - type ZF tandemly arrayed at its C terminus and N - terminal SCAN box and KRAB domains . SKAT - 2 is tissue restricted in expression at the RNA level , detectable only in brain and at low levels in kidney and spleen and few hematopoietic cell lines . By in situ hybridization , SKAT - 2 expression was found to peak in antigen - stimulated CD4 ( + ) T cells after 2 - 3 days of culture under Th2 but not Th1 biasing conditions . This pattern of expression closely mirrored that of GATA - 3 in the same cells . In transient transfection experiments in phorbol 12 - myristate 13 - acetate / ionomycin - stimulated EL4 cells , SKAT - 2 was found to up - regulate the activity of the IL - 4 but not the IL - 5 promoter , contrasting with the ability of GATA - 3 to activate both promoters . This result was confirmed using clones of EL4 cells stably expressing an inducible form of SKAT - 2 , thus SKAT - 2 is a novel Th2 - specific gene that may play a role in selective regulation of cytokine genes in T cells . hsp70 interacting protein Hip does not affect glucocorticoid receptor folding by the hsp90 - based chaperone machinery except to oppose the effect of BAG - 1 . Reticulocyte lysate contains a chaperone system that assembles glucocorticoid receptor ( GR ) . hsp90 heterocomplexes . Using purified proteins , we have prepared a five - protein heterocomplex assembly system consisting of two proteins essential for heterocomplex assembly - hsp90 and hsp70 - and three proteins that act as co - chaperones to enhance assembly - Hop , hsp40 , p23 [ Morishima , Y . , Kanelakis , K . C . , Silverstein , A . M . , Dittmar , K . D . , Estrada , L . , and Pratt , W . B . ( 2000 ) J . Biol . Chem . 275 , 6894 - 6900 ] . The hsp70 co - chaperone Hip has been recovered in receptor . hsp90 heterocomplexes at an intermediate stage of assembly in reticulocyte lysate , and Hip is also thought to be an intrinsic component of the assembly machinery . Here we show that immunodepletion of Hip from reticulocyte lysate or addition of high levels of Hip to the purified five - protein system does not affect GR . hsp90 heterocomplex assembly or the activation of steroid binding activity that occurs with assembly . Despite the fact that Hip does not affect assembly , it is recovered in GR . hsp90 heterocomplexes assembled by both systems . In the five - protein system , Hip prevents inhibition of assembly by the hsp70 co - chaperone BAG - 1 , and cotransfection of Hip with BAG - 1 opposes BAG - 1 reduction of steroid binding activity in COS cells . We conclude that Hip is not a component of the assembly machinery but that it could play a regulatory role in opposition to BAG - 1 . Cutting edge : STAT6 - deficient mice have enhanced tumor immunity to primary and metastatic mammary carcinoma . STAT4 and STAT6 are essential for the development of CD4 ( + ) Th1 and Th2 development , respectively . Tumor immunologists have hypothesized that Th1 cells are critical in tumor immunity because they facilitate differentiation of CD8 ( + ) T cells , which are potent anti - tumor effectors . We have used STAT4 ( - / - ) and STAT6 ( - / - ) mice to test this hypothesis . BALB / c and knockout mice were challenged in the mammary gland with the highly malignant and spontaneously metastatic BALB / c - derived 4T1 mammary carcinoma . Primary tumor growth and metastatic disease are reduced in STAT6 ( - / - ) mice relative to BALB / c and STAT4 ( - / - ) mice . Ab depletions demonstrate that the effect is mediated by CD8 ( + ) T cells , and immunized STAT6 ( - / - ) mice have higher levels of 4T1 - specific CTL than BALB / c or STAT4 ( - / - ) mice . Surprisingly , Th1 or Th2 cells are not involved , because CD4 depletion does not diminish the anti - tumor effect . Therefore , deletion of the STAT6 gene facilitates development of potent anti - tumor immunity via a CD4 ( + ) - independent pathway . Activation of oncogenic transcription factor AP - 1 in T cells infected with human T cell leukemia virus type 1 . Human T cell leukemia virus type 1 ( HTLV - 1 ) Tax protein transforms primary human T cells in vitro . We previously showed that Tax induces the expression of various family members of the transcription factor AP - 1 such as c - Jun , JunD , c - Fos , and Fra - 1 at the mRNA level in T cells . In this study , we have examined the ability of Tax to activate transcription through the AP - 1 - binding site ( AP - 1 site ) . A transient transfection study showed that Tax can activate transcription through the AP - 1 - binding site in a human T cell line , whereas any combination of AP - 1 proteins did so much less than Tax , indicating that the activation of the AP - 1 site by Tax may require a mechanism other than the induction of AP - 1 mRNA . Fresh peripheral blood leukemia cells of all surveyed ATL patients displayed constitutive AP - 1 DNA - binding activity , whereas no normal individuals did . However , the HTLV - 1 genes , including tax , are not significantly expressed in fresh leukemia cells from ATL patients . Our present results suggest that activation of AP - 1 occurs through Tax - dependent and - independent mechanisms in HTLV - 1 - infected T cells , which may play some roles in dysregulated phenotypes of HTLV - 1 - infected cells . 2 , 2 ' , 4 , 6 , 6 ' - pentachlorobiphenyl induces apoptosis in human monocytic cells . Polychlorinatedbiphe ( PCBs ) are a group of persistent and widely dispersed environmental pollutants , some of which may be immunotoxic . In the present study , we investigated the effect of PCBs on immune system by assessing apoptotic cell death in human monocytic U937 cells . Among the various congeners tested , 2 , 2 ' , 4 , 6 , 6 ' - pentachlorobiphenyl ( PeCB ) , a highly ortho - substituted congener , specifically induced DNA fragmentation , a hallmark of apoptosis , while the other examined di - , tri - , tetra - , and pentachlorobiphenyls did not . To further study the 2 , 2 ' , 4 , 6 , 6 ' - PeCB - induced cell death , various features of apoptosis were examined . 2 , 2 ' , 4 , 6 , 6 ' - PeCB caused a decrease in cell viability and induced cellular morphologic features characteristic of apoptosis such as chromatin aggregation and apoptotic bodies . In addition , caspase - 3 , an executioner of apoptosis , was activated and its substrate , poly ( ADP - ribose ) polymerase ( PARP ) , was cleaved during 2 , 2 ' , 4 , 6 , 6 ' - PeCB - induced apoptosis . In contrast , 3 , 3 ' , 4 , 4 ' , 5 - PeCB , a congener of coplanar structure , as well as 2 , 3 , 7 , 8 - TCDD did not induce apoptosis in these human monocytic cells , although they potently induced CYP 1A1 in human hepatoma Hep G2 cells . Taken together , the data indicate that 2 , 2 ' , 4 , 6 , 6 ' - PeCB induces apoptosis in human monocytic cells through a mechanism that is independent of the arylhydrocarbon receptor . This suggests a possibly separate mechanism by which PCBs cause immunosuppression . Effects of deregulated Raf activation on integrin , cytokine - receptor expression and the induction of apoptosis in hematopoietic cells . The effects of deregulated Raf activation on the growth and differentiation of hematopoietic cells were investigated . The cytokine - dependent murine myeloid FDC - P1 and human erythroleukemic TF - 1 cell lines were transformed to grow in response to deregulated Raf expression in the absence of exogenous cytokines . The conditionally active Raf proteins were regulated by beta - estradiol as cDNAs containing the Raf catalytic , but lacking negative - regulatory domains , were ligated to the hormone binding domain of the estrogen receptor ( deltaRaf : ER ) . Continuous deltaRaf expression prevented apoptosis in the absence of exogenous cytokines and altered the morphology of the FD / deltaRaf : ER cells as they grew in large aggregated masses ( > 100 cells ) whereas the parental cytokine - dependent FDC - P1 cells grew in smaller grape - like clusters ( < 10 cells ) . FD / deltaRaf - 1 : ER cells growing in response to Raf activation displayed decreased levels of the Mac - 2 and Mac - 3 molecules on their cell surface . In contrast , when these cells were cultured in IL - 3 , higher levels of these adhesion molecules were detected . Expression of activated Raf oncoproteins also abrogated cytokine dependency and prevented apoptosis of TF - 1 cells . Moreover , the differentiation status of these Raf - responsive cells was more immature upon Raf activation as culture with the differentiation - inducing agent phorbol 12 myristate 13 - acetate ( PMA ) and beta - estradiol resulted in decreased levels of the CD11b and CD18 integrin molecules on the cell surface . In contrast when the Raf - responsive cells were induced to differentiate with PMA and GM - CSF , in the absence of deltaRaf : ER activation , increased levels of the CD11b and CD18 molecules were detected . Retinoic acid ( RA ) inhibited 3H - thymidine incorporation in response to GM - CSF . Interestingly , Raf activation counterbalanced the inhibition of DNA synthesis caused by RA but not PMA . Thus deregulated Raf expression can alter cytokine dependency , integrin expression and the stage of differentiation . These Raf - responsive cell lines will be useful in elucidating the roles of the MAP kinase cascade on hematopoietic cell differentiation and malignant transformation Cyclic AMP activates p38 mitogen - activated protein kinase in Th2 cells : phosphorylation of GATA - 3 and stimulation of Th2 cytokine gene expression . cAMP is an important second messenger with immunomodulatory properties . Elevation of intracellular cAMP in T cells , induced by agents such as IL - 1alpha or PGs , inhibits T cell activation . In effector T cells , an increase in the level of intracellular cAMP inhibits cytokine production in Th1 cells but stimulates cytokine production in Th2 cells . Here we report that cAMP - induced effects in Th2 cells occur independently of the protein kinase A pathway , which is the major mediator of cAMP - induced signaling events in most cell types . Instead , cAMP stimulates activation of p38 mitogen - activated protein kinase in Th2 cells . This appears to be a Th2 - selective event because cAMP barely increased p38 phosphorylation in Th1 cells . We show that in Th2 cells , cAMP promotes the production of both IL - 5 and IL - 13 , which play distinct but critical roles in asthma pathogenesis . Our data also show that cAMP causes increased phosphorylation of the transcription factor GATA - 3 , which we have shown is a critical regulator of Th2 cytokine gene expression and , in turn , of airway inflammation in mice . Thus , Th2 - specific GATA - 3 expression and p38 mitogen - activated protein kinase activation together provide a molecular basis for the differential effects of cAMP in the two T helper cell subsets . Characterization of IL - 4 and IL - 13 signals dependent on the human IL - 13 receptor alpha chain 1 : redundancy of requirement of tyrosine residue for STAT3 activation . IL - 4 and IL - 13 are pleiotropic cytokines whose biological activities overlap with each other . IL - 13 receptor alpha chain 1 ( IL - 13R alpha 1 ) is necessary for binding to IL - 13 , and the heterodimer composed of IL - 13R alpha 1 and IL - 4R alpha chain transduces IL - 13 and IL - 4 signals ; however , the functional mapping of the intracellular domain of IL - 13R alpha 1 is not fully understood . In this study , we constructed wild and mutated types of human IL - 13R alpha 1 , and analyzed IL - 4 and IL - 13 signals using an IL - 13R alpha 1 - transfected human B cell line . Expression of IL - 13R alpha 1 evoked STAT3 activation by IL - 4 and IL - 13 , and in stimulated human B cells , on which IL - 13R alpha 1 was highly expressed , IL - 4 and IL - 13 induced STAT3 activation . Replacement of the two tyrosine residues completely abolished STAT3 activation , although replacing either tyrosine residue alone retained it . Furthermore , we found that the Box1 region and the C - terminal tail of IL - 13R alpha 1 were critical for binding to Tyk2 , and activation of Jak1 , Tyk2 , the insulin receptor substrate - 1 and STAT6 respectively . These results suggest that STAT3 activation is involved with IL - 4 and IL - 13 signals in human B cells along with the activation of STAT6 , and that there is a unique sequence in IL - 13R alpha 1 to activate STAT3 . Functional uncoupling of the Janus kinase 3 - Stat5 pathway in malignant growth of human T cell leukemia virus type 1 - transformed human T cells . Human T cell leukemia virus type 1 ( HTLV - 1 ) transforms cytokine - dependent T lymphocytes and causes adult T cell leukemia . Janus tyrosine kinase ( Jak ) 3 and transcription factors Stat5a and Stat5b are essential for the proliferation of normal T cells and are constitutively hyperactivated in both HTLV - 1 - transformed human T cell lines and lymphocytes isolated from HTLV - 1 - infected patients ; therefore , a critical role for the Jak3 - Stat5 pathway in the progression of this disease has been postulated . We recently reported that tyrphostin AG - 490 selectively blocked IL - 2 activation of Jak3 / Stat5 and growth of murine T cell lines . Here we demonstrate that disruption of Jak3 / Stat5a / b signaling with AG - 490 ( 50 & mgr ; M ) blocked the proliferation of primary human T lymphocytes , but paradoxically failed to inhibit the proliferation of HTLV - 1 - transformed human T cell lines , HuT - 102 and MT - 2 . Structural homologues of AG - 490 also inhibited the proliferation of primary human T cells , but not HTLV - 1 - infected cells . Disruption of constitutive Jak3 / Stat5 activation by AG - 490 was demonstrated by inhibition of 1 ) tyrosine phosphorylation of Jak3 , Stat5a ( Tyr ( 694 ) ) , and Stat5b ( Tyr ( 699 ) ) ; 2 ) serine phosphorylation of Stat5a ( Ser ( 726 ) ) as determined by a novel phosphospecific Ab ; and 3 ) Stat5a / b DNA binding to the Stat5 - responsive beta - casein promoter . In contrast , AG - 490 had no effect on DNA binding by p50 / p65 components of NF - kappaB , a transcription factor activated by the HTLV - 1 - encoded phosphoprotein , Tax . Collectively , these data suggest that the Jak3 - Stat5 pathway in HTLV - 1 - transformed T cells has become functionally redundant for proliferation . Reversal of this functional uncoupling may be required before Jak3 / Stat5 inhibitors will be useful in the treatment of this malignancy . The Epstein - Barr virus promoter initiating B - cell transformation is activated by RFX proteins and the B - cell - specific activator protein BSAP / Pax5 . Epstein - Barr virus ( EBV ) - induced B - cell growth transformation , a central feature of the virus ' strategy for colonizing the human B - cell system , requires full virus latent gene expression and is initiated by transcription from the viral promoter Wp . Interestingly , when EBV accesses other cell types , this growth - transforming program is not activated . The present work focuses on a region of Wp which in reporter assays confers B - cell - specific activity . Bandshift studies indicate that this region contains three factor binding sites , termed sites B , C , and D , in addition to a previously characterized CREB site . Here we show that site C binds members of the ubiquitously expressed RFX family of proteins , notably RFX1 , RFX3 , and the associated factor MIBP1 , whereas sites B and D both bind the B - cell - specific activator protein BSAP / Pax5 . In reporter assays with mutant Wp constructs , the loss of factor binding to any one of these sites severely impaired promoter activity in B cells , while the wild - type promoter could be activated in non - B cells by ectopic BSAP expression . We suggest that Wp regulation by BSAP helps to ensure the B - cell specificity of EBV ' s growth - transforming function . Activation of the Lck tyrosine protein kinase by the Herpesvirus saimiri tip protein involves two binding interactions . The Tip protein of Herpesvirus saimiri strain 484C binds to and activates the Lck tyrosine protein kinase . Two sequences in the Tip protein were previously shown to be involved in binding to Lck . A proline - rich region , residues 132 - 141 , binds to the SH3 domain of the Lck protein . We show here that the other Lck - binding domain , residues 104 - 113 , binds to the carboxyl - terminal half of Lck and that this binding does not require the Lck SH3 domain . Mutated Tip containing only one functional Lck - binding domain can bind stably to Lck , although not as strongly as wild - type Tip . Interaction of Tip with Lck through either Lck - binding domain increases the activity of Lck in vivo . Simultaneous binding of both domains is required for maximal activation of Lck . The transient expression of Tip in T cells was found to stimulate both Stat3 - dependent and NF - AT - dependent transcription . Mutant forms of Tip lacking one or the other of the two Lck - binding domains retained the ability to stimulate Stat3 - dependent transcription . Tip lacking the proline - rich Lck - binding domain exhibited almost wild - type activity in this assay . In contrast , ablation of either Lck - binding domain abolished the ability of Tip to stimulate NF - AT - dependent transcription . Full biological activity of Tip , therefore , appears to require both Lck - binding domains . Accumulation of RXR alpha during activation of cycling human T lymphocytes : modulation of RXRE transactivation function by mitogen - activated protein kinase pathways . We have previously reported that the activation of resting human immature peripheral blood T ( PBT ) lymphocytes is associated with the loss of retinoid X receptor alpha ( RXRalpha ) expression . In the present study , we have demonstrated that , unlike resting cells , activation of cycling human mature PBT lymphocytes , and T lymphocyte leukemia cell lines is accompanied by the accumulation of RXRalpha mRNA and protein . Interestingly , cyclosporin A further augmented RXRalpha expression , indicating the involvement of calcineurin pathways in the process . 9 - cis retinoic acid inhibited the accumulation , suggesting that retinoids can regulate the synthesis of their own receptors during T cell activation . Transfection analysis in Jurkat cells , using RXRE - dependent reporter assays , showed that RXRalpha accumulated during T cell activation was transcriptionally inactive . To investigate the mechanism of such inhibition , the role of two mitogen - activated protein kinase pathways , c - Jun N - terminal kinase ( JNK ) and extracellular signal - regulated kinase ( ERK ) , in modulating RXRE - dependent transcription , was explored . The expression of constitutively active MAP / ERK kinase kinase 1 ( MEKK1 ) inhibited RXRE - dependent transcription , whereas dominant negative MEKK1 increased the transcription , indicating the involvement of JNK signaling pathways in the process . In contrast , expression of constitutively active MEK1 , which activates ERK pathway , enhanced RXRE - dependent activation . When both were activated simultaneously , JNK pathway was dominant over ERK pathway and resulted in inhibition of RXRE - mediated transcription . These data demonstrate a dual regulatory control of RXRalpha expression during the activation of resting and cycling T lymphocytes and indicate a dynamic balance between JNK and ERK pathways in modulating RXRE - mediated transactivation . The proteasome regulates receptor - mediated endocytosis of interleukin - 2 . Recent studies have increasingly implicated the proteasome in the regulation of cell surface receptors . In the present study , we investigated the role of the proteasome for ligand - dependent endocytosis and degradation of the interleukin - 2 ( IL - 2 ) - interleukin - 2 receptor ( IL - 2R ) complex . Proteasome inhibitors impaired internalization of IL - 2 . IL - 2R and prevented the lysosomal degradation of this cytokine . Based on time - course studies , proteasome activity is primarily required after initial endocytosis of the IL - 2 . IL - 2R . Proteasome function was also necessary for the lysosomal degradation of IL - 2 internalized by IL - 2R that were comprised of cytoplasmic tailless beta - or gamma c - subunits , suggesting that the target protein for the proteasome is independent of either the cytoplasmic tail of the IL - 2R beta - or gamma c - subunits and their associated signaling components . Therefore , a functional proteasome is required for optimal endocytosis of the IL - 2R / ligand complex and is essential for the subsequent lysosomal degradation of IL - 2 , possibly by regulating trafficking to the lysosome . Functional characterization of the two alternative promoters of human p45 NF - E2 gene . OBJECTIVE : The transcription factor NF - E2 , a heterodimeric protein complex composed of p45 and small Maf family proteins , is considered crucial for the proper differentiation of erythrocytes and megakaryocytes in vivo . We report the results of studies aimed at understanding the regulatory mechanisms controlling p45 gene expression in erythroid cells . MATERIALS AND METHODS : Human p45 mRNAs have two alternative isoforms , aNF - E2 and fNF - E2 , and these isoforms are transcribed from the alternative promoters . We investigated lineage - specific expression of both isomers in human erythroid and megakaryocytic cells by reverse transcriptase polymerase chain reaction or Northern blot analysis . For functional characterization of both promoters , plasmids in which reporter genes were placed under the control of a series of truncated or mutated promoter fragments were transfected to human hematopoietic cell lines . RESULTS : When CD34 ( + ) cells isolated from human cord blood were induced to unilineage erythroid or megakaryocytic differentiation in liquid suspension culture , both transcripts , although barely detected at day 0 , were induced in both erythroid and megakaryocytic cultures . fNF - E2 mRNA was found to be more abundant in erythroid cells than megakaryocytic cells at day 7 of culture . Although both isomers were expressed in human erythroid - megakaryocytic cell lines , megakaryocytic maturation with loss of erythroid phenotype induced by phorbol 12 - myristate 13 - acetate ( PMA ) resulted in exclusive downregulation of fNF - E2 , suggesting that fNF - E2 promoter is more erythroid specific . Functional analysis of fNF - E2 promoter showed that the promoter is active only in erythroid - megakaryocytic cells and that the double GATA sit e in the proximal region is necessary for its efficient activity . CONCLUSION : These results suggest that GATA proteins , which govern the differentiation of erythroid lineage cells , are required for full promoter activity of the p45 gene . Transcriptional activation of heme oxygenase - 1 and its functional significance in acetaminophen - induced hepatitis and hepatocellular injury in the rat . BACKGROUND / AIM : Glutathione depletion contributes to acetaminophen hepatotoxicity and is known to induce the oxidative stress reactant heme oxygenase - 1 . The metabolites of the heme oxygenase pathway , biliverdin , carbon monoxide , and iron may modulate acetaminophen toxicity . The aim of this study was to assess cell - type specific expression of heme oxygenase - 1 and its impact on liver injury and microcirculatory disturbances in a model of acetaminophen - induced hepatitis . METHODS : Gene expression of heme oxygenase - 1 was studied by Northern - and Western analysis as well as immunohistochemistry . The time course of heme oxygenase - 1 and - 2 , cytokine - induced neutrophil chemoattractant - 1 , and intercellular adhesion molecule - 1 was studied by Northern analysis . DNA - binding activity of nuclear factor - kappaB was determined by electrophoretic mobility shift assay . Sinusoidal perfusion and leukocyte - endothelial interactions were assessed by intravital microscopy . RESULTS : Acetaminophen caused a moderate sinusoidal perfusion failure ( - 15 % ) and infiltration of neutrophils along with activation of nuclear factor - kappaB and intercellular adhesion molecule - 1 and cytokine - induced neutrophil chemoattractant - 1 mRNAs . Induction of heme oxygenase - 1 mRNA and protein ( approximately 30 - fold ) in hepatocytes and non - parenchymal cells paralleled the inflammatory response . Blockade of heme oxygenase activity with tin - protoporphyrin - IX abrogated acetaminophen - induced hepatic neutrophil accumulation and nuclear factor - kappaB activation , but failed to affect sinusoidal perfusion and liver injury . CONCLUSIONS : The inflammatory response associated with acetaminophen hepatotoxicity is modulated by the parallel induction of the heme oxygenase - 1 gene . However , heme oxygenase - 1 has no permissive effect on sinusoidal perfusion and does not affect liver injury in this model . These data argue against a central role of nuclear factor - kappaB activation and neutrophil infiltration as perpetuating factors of liver injury in acetaminophen toxicity . Tumor necrosis factor - alpha - induced proliferation requires synthesis of granulocyte - macrophage colony - stimulating factor . OBJECTIVE : Tumor necrosis factor - alpha ( TNF - alpha ) induces a variety of cellular responses , some of them being at least seemingly contradictory . Thus , we set out to find differences in the modes of proliferative and apoptotic responses to TNF - alpha . MATERIALS AND METHODS : We screened a panel of acute myeloid leukemia - derived cell lines for TNF - alpha - responsiveness . In two lines ( OCI - AML - 1 , OCI - AML - 11 ) , TNF - alpha acted as an apoptotic agent ; in others ( HU - 3 , M - 07e , TF - 1 ) , it had the opposite effect , preventing apoptosis and inducing proliferation . Direct and indirect signaling mechanisms , including NF - kappaB activation and cytokine synthesis , were analyzed . RESULTS : All cell lines tested expressed TNF - alpha receptors I and II and responded to TNF - alpha by upregulation of intercellular adhesion molecule - 1 . In contrast to granulocyte - macrophage colony - stimulating factor ( GM - CSF ) , TNF - alpha did not activate the MAP kinase and p70S6 kinase pathways . Nevertheless , inhibitors of these pathways clearly reduced the TNF - alpha - induced cell growth , indicating that TNF - alpha - proliferative cells produced a growth factor that induced proliferation upon stimulation of the above pathways . Anti - GM - CSF antibodies inhibited the TNF - alpha - induced growth , suggesting the presence of an autocrine loop for cell proliferation mediated by GM - CSF . Supporting this notion , TNF - alpha - induced upregulation of GM - CSF mRNA levels and protein secretion in the TNF - alpha - proliferative , but not in the TNF - alpha - apoptotic cell lines . CONCLUSION : These data identify GM - CSF synthesis as an early and essential step in TNF - alpha - induced proliferation . We show for the first time that TNF - alpha - treated cell lines producing no or only minimal amounts of GM - CSF demonstrate an apoptotic phenotype , while cell lines with high GM - CSF expression rates can escape from growth arrest or even apoptosis . In this context , we discuss arguments pointing at NF - kappaB as regulator of GM - CSF synthesis and thus indirectly as regulator for the escape of TNF - alpha - induced apoptosis Glucocorticoid receptor content of T lymphocytes : evidence for heterogeneity . Glucocorticoid receptors were measured in T lymphocytes that were isolated from peripheral blood by either nylon wool filtration or E - rosette sedimentation . T cells isolated by nylon wool filtration specifically bind 6 . 7 + / - 0 . 2 fmol of dexamethasone per million cells ( equivalent to 4000 + / - 200 receptors per cell ) , whereas T cells isolated by E - rosette sedimentation bind 12 . 0 + / - 0 . 7 fmol of dexamethasone per million cells ( equivalent to 7200 + / - 400 receptors per cell ) . This difference in the amount of dexamethasone bound by the two T cell preparations was significant ( p less than . 001 ) and was present immediately after cell isolation . The binding affinities of the different T cell preparations for dexamethasone were similar . T cells that are isolated by a combination of nylon wool filtration followed by E - rosette sedimentation bind the same amount of dexamethasone as T cells isolated by nylon wool filtration alone . T cells isolated by a combination of E - rosette sedimentation following by nylon wool filtration bind less dexamethasone than do T cells isolated by E - rosette sedimentation alone . These findings suggest that T cells are heterogeneous with respect to their quantity of glucocorticoid receptors . Isolation of T cells by E - rosette sedimentation enriches for T cells that have a greater number of glucocorticoid receptors , and isolation of T cells by nylon wool filtration enriches for T cells that have a lesser number of glucocorticoid receptors . Glucocorticoid receptors and glucocorticoid sensitivity of human leukemic cells . We have established optimal conditions for the measurement of glucocorticoid receptors ( GR ) in human white cells using a whole - cell binding assay with [ 3H ] dexamethasone as the ligand , and the subsequent determination of the GR content in normal human lymphocytes and in leukemic cells of patients with various forms of acute and chronic leukemia . A number of leukemia cell lines in continuous culture were also subjected to the GR assay , and the results were correlated with the sensitivity of these cell lines to glucocorticoid steroids in vitro . The GR content of normal human lymphocytes amounted to 4 , 850 + / - 1 , 340 ( mean + / - SD ) receptors / cell . The mean equilibrium dissociation constant ( KD ) of the interaction of [ 3H ] dexamethasone with the GR was 1 . 2 x 10 ( - 8 ) M . Steroidal compounds with a known glucocorticoid potency effectively competed for the binding , whereas steroids devoid of glucocorticoid activity ( e . g . estradiol - 17 beta and testosterone ) were ineffective . The GR content of the blast cells obtained from eight patients suffering from acute leukemia and four patients with a blast crisis of chronic myelocytic leukemia was found to be highly variable ( 3 , 230 - 29 , 900 receptors / cell ) , while the lymphocytes of six patients with chronic lymphatic leukemia contained a rather stable GR content ( 2 , 930 - 5 , 120 receptors / cell ) , which was comparable with that of normal lymphocytes . GR was identified in all the 12 malignant continuous white cell lines studied . Large cells contained more GR than the smaller ones . There was no apparent correlation between the GR concentration and the sensitivity of the cells in vitro to glucocorticoids as judged by [ 3H ] thymidine incorporation studies . Distribution of the surface markers in the leukemic cell lines did not relate to the GR concentration . We conclude that the presence of GR is probably a universal feature of the leukemic cells , and , from a clinical standpoint , probably does not alone imply steroid responsiveness . Evidence for a steroid receptor in rheumatoid synovial tissue cells . One mechanism by which glucocorticoids could exert their anti - inflammatory action is via rapidly saturable , stereo - specific cytoplasmic protein receptors . This report is of an investigation into such a possibility in synovial cells . Synovium , obtained from knee joints of rheumatoid patients undergoing surgery , was incubated with clostridiopeptidase A and trypsin - EDTA to obtain cell suspensions . These , together with cells obtained from synovial fluid aspirated from patients with rheumatoid arthritis , were identified by electron microscopy . Duplicate samples of these cell suspensions were incubated with increasing concentrations of H3Dexamethasone ( 1 x 10 ( - 10 ) M - 1 x 10 ( - 9 ) M ) for 30 minutes at 37 degrees C . Analysis of the proportion of steroid bound to whole cells showed evidence for specific , rapidly saturable , receptors in the cells obtained from synovial tissue , but this was not found in synovial fluid cells . Electron micrographs showed that cells obtained from synovial tissue consisted of synovial fibroblast - and macrophage - types , lymphocytes , monocytes and macrophages . Polymorphonuclear leucocytes appeared to be absent . However , in synovial fluid cell type polymorphonuclear leucocytes were the predominant cell type . We concluded from this , that one or more of the cell types present in synovial tissue contain a specific steroid receptor , but that this is lacking in synovial fluid polymorphonuclear leucocytes . Clinical implications of glucocorticoid receptors in human leukemia . Glucorticoid receptors were studied in various populations of normal human peripheral blood lymphocytes and leukemic lymphoblasts . Normal lymphocytes contain low levels of glucocorticoid receptor ( approximately 2 , 500 sites / cell ) which are identical in T - and non - T - fractions . Phytohemagglutinin treatment increases levels about 3 - fold . Leukemic lymphoblasts contain larger numbers of receptor sites . Presence of receptor is correlated with in vitro sensitivitiy to glucocorticoids and in vivo response to therapy . Quantity of receptor is also correlated with complete remission duration independently of leukemic cell type ( T or null ) , initial WBC , or age of patient . Quantitative determination of glucocorticoid receptor levels in acute lymphoblastic leukemia may be of value both as an independent prognostic variable and in suggesting which patients should receive glucocorticoid therapy . Functional and physical interaction of protein - tyrosine kinases Fyn and Csk in the T - cell signaling system . The Src - like protein - tyrosine kinase Fyn is associated with T - cell antigen receptor . Transient expression of actively mutated Fyn , having Phe - 528 instead of Tyr - 528 or Thr - 338 instead of Ile - 338 , in Jurkat T - cells stimulated the serum response element ( SRE ) , 12 - O - tetradecanoyl - phorbol - 13 - acetate response element , cyclic AMP response element , and c - fos promoter . The stimulation of SRE was particularly prominent not only with active Fyn but also with normal ( wild - type ) Fyn . SRE was also stimulated by both normal and active Lck . Furthermore , normal and active Fyn stimulated transcription from the IL - 2 gene promoter when transfected cells were stimulated by concanavalin A plus 12 - O - tetradecanoylphorbol - 13 - acetate . Under the same conditions , Lck did not stimulate IL - 2 promoter unless it was activated by mutation . Interestingly , a mutant Fyn , which has deletions within the SH2 region and so is able to transform chicken embryo fibroblasts , did not stimulate either the c - fos or IL - 2 promoter , suggesting the importance of this region in T - cell signaling . Csk , which phosphorylates tyrosine residues in the negative regulatory sites of Src family kinases , down - regulated Fyn - and Lck - mediated stimulation of the serum response element and Fyn - mediated enhancement of IL - 2 promoter activity . These data suggest that Fyn and Lck , whose activities are regulated by Csk , are involved in different phases of T - cell activation . A novel NF - kappa B complex containing p65 homodimers : implications for transcriptional control at the level of subunit dimerization . The predominant inducible form of the NF - kappa B transcription factor is a heteromeric complex containing two Rel - related DNA - binding subunits , termed p65 and p50 . Prior transfection studies have shown that when these p65 and p50 subunits are expressed independently as stable homodimers , p65 stimulates kappa B - directed transcription , whereas p50 functions as a kappa B - specific repressor . While authentic p50 homodimers ( previously termed KBF1 ) have been detected in nuclear extracts from nontransfected cells , experimental evidence supporting the existence of p65 homodimers in vivo was lacking . We now provide direct biochemical evidence for the presence of an endogenous pool of inducible p65 homodimers in intact human T cells . As with the prototypical NF - kappa B p50 - p65 heterodimer , this novel p65 homodimeric form of NF - kappa B is functionally sequestered in the cytoplasm but rapidly appears in the nuclear compartment following cellular stimulation . Site - directed mutagenesis studies indicate that the homodimerization function of p65 is dependent upon the presence of cysteine 216 and a conserved recognition motif for protein kinase A ( RRPS ; amino acids 273 to 276 ) , both of which reside within a 91 - amino - acid segment of the Rel homology domain that mediates self - association . In contrast , mutations at these two sites do not affect heterodimerization of p65 with p50 or its functional interaction with I kappa B alpha . These later findings indicate that neither homo - nor heterodimer formation is an absolute prerequisite for I kappa B alpha recognition of p65 . Taken together with prior in vivo transcription studies , these results suggest that the biological activities of p65 and p50 homodimers are independently regulated , thereby providing an integrated and flexible control mechanism for the rapid activation and repression of NF - kappa B / Rel - directed gene expression . Carrier determination for X - linked agammaglobulinemia using X inactivation analysis of purified B cells . We report the development of a relatively quick and simple method for the assessment of X inactivation status for carrier determination in families affected by X - linked agammaglobulinemia ( XLA ) . This method utilises an immunomagnetic separation technique for B cell purification and a polymerase chain reaction ( PCR ) based assay for the determination of methylation status at the androgen receptor ( AR ) gene locus to assess whether X inactivation is random or non - random at this locus . We report the results we have obtained using this assay to investigate females known to be carriers of various X - linked immunodeficiency disorders . In addition , we investigated four females from different families affected by XLA , two of whom were of unknown carrier status , and we discuss the results obtained with this and other X - inactivation assays . A similar assay has recently been described by Allen et al . ( 1992 ) and applied to members of one family affected by XLA . Effects of IL - 4 and Fc gamma receptor II engagement on Egr - 1 expression during stimulation of B lymphocytes by membrane immunoglobulin crosslinking . Egr - 1 is an immediate early gene that is rapidly upregulated in response to mitogenic signals induced by antigen receptor crosslinking on murine B lymphocytes . It has been shown that levels of Egr - 1 expression are closely correlated with B cell proliferation in several models of B cell activation and tolerance . We compared the expression of Egr - 1 during B cell stimulation with Fab ' 2 and IgG anti - immunoglobulin ( anti - Ig ) , since it is known that Fab ' 2 anti - Ig is mitogenic while IgG anti - Ig is not , owing to a dominant inhibitory effect of crosslinking the B cell Fc gamma RII to membrane Ig . While mitogenic doses of Fab ' 2 anti - Ig induce large and rapid increases in Egr - 1 expression , IgG anti - Ig results in smaller increases in Egr - 1 mRNA , comparable to that seen with submitogenic concentrations of Fab ' 2 anti - Ig . However , the correlation between Egr - 1 expression and B cell proliferation breaks down when IL - 4 is added as a co - mitogen to induce B cell proliferation with IgG anti - Ig or submitogenic concentrations of Fab ' 2 anti - Ig . No corresponding increases in Egr - 1 mRNA levels are observed when IL - 4 is added . Therefore , IL - 4 overcomes Fc receptor - mediated inhibition of B cell proliferation without affecting inhibition of Egr - 1 mRNA induction , as demonstrated earlier for c - myc mRNA in this system . Identification of a novel cyclosporin - sensitive element in the human tumor necrosis factor alpha gene promoter . Tumor necrosis factor alpha ( TNF - alpha ) , a cytokine with pleiotropic biological effects , is produced by a variety of cell types in response to induction by diverse stimuli . In this paper , TNF - alpha mRNA is shown to be highly induced in a murine T cell clone by stimulation with T cell receptor ( TCR ) ligands or by calcium ionophores alone . Induction is rapid , does not require de novo protein synthesis , and is completely blocked by the immunosuppressant cyclosporin A ( CsA ) . We have identified a human TNF - alpha promoter element , kappa 3 , which plays a key role in the calcium - mediated inducibility and CsA sensitivity of the gene . In electrophoretic mobility shift assays , an oligonucleotide containing kappa 3 forms two DNA protein complexes with proteins that are present in extracts from unstimulated T cells . These complexes appear in nuclear extracts only after T cell stimulation . Induction of the inducible nuclear complexes is rapid , independent of protein synthesis , and blocked by CsA , and thus , exactly parallels the induction of TNF - alpha mRNA by TCR ligands or by calcium ionophore . Our studies indicate that the kappa 3 binding factor resembles the preexisting component of nuclear factor of activated T cells . Thus , the TNF - alpha gene is an immediate early gene in activated T cells and provides a new model system in which to study CsA - sensitive gene induction in activated T cells . Differences in expression of transcription factor AP - 1 in human promyelocytic HL - 60 cells during differentiation towards macrophages versus granulocytes . Commitment of HL - 60 cells to macrophage or granulocytic differentiation was achieved by incubation with 4 beta - phorbol 12 - myristate 13 - acetate ( PMA ) for 30 - 60 min or with dimethyl sulphoxide ( DMSO ) for 24 h respectively . The commitment stage towards PMA - induced macrophage differentiation was associated with increases in jun B and c - fos mRNA levels , as well as with an increase in the binding activity of transcription factor AP - 1 . Nevertheless , gel retardation analysis indicated that the AP - 1 activity detected in untreated cells was drastically reduced during the commitment stage of DMSO - induced HL - 60 differentiation towards granulocytes . When HL - 60 cells were treated with sodium butyrate , which induced monocytic differentiation , a remarkable increase in AP - 1 binding activity was detected . Treatment of HL - 60 cells with 1 alpha , 25 - dihydroxyvitamin D3 , another monocytic differentiation agent , induced a weak , but appreciable , increase in AP - 1 activity . Furthermore , addition of sodium butyrate or 1 alpha , 25 - dihydroxyvitamin D3 to HL - 60 cells induced the expression of c - fos , c - jun , jun B and jun D proto - oncogenes . In contrast , when HL - 60 cells were treated with retinoic acid , a granulocytic differentiation inducer , no enhanced AP - 1 binding activity was observed , and only a weak increase in jun D mRNA level was detected . These data indicate that formation of AP - 1 is not required for the induction of HL - 60 differentiation towards granulocytes , whereas induction of monocytic differentiation is correlated with an increase in AP - 1 activity . The differential expression of AP - 1 activity may be critical in the differentiation of HL - 60 cells towards monocytic or granulocytic lineages Glucocorticoid receptors and sensitivity in leukemias . In an attempt to investigate the utility of glucocorticoid receptor determination to predict clinical responsiveness in human leukemias we have studied glucocorticoid receptors in the leukemic cells from 46 patients and in the lymphocytes from 18 normal donors . In the normal lymphocytes there were 3 , 875 ( Median ) specific binding sites per cell . The blasts from 17 patients with ANLL had on average higher levels of binding sites per cell ( Median = 7 , 250 , range : 0 to 15 , 295 ) than the other leukemias . Of the 15 patients with CLL , six had received glucocorticoid treatment for 3 to 5 years . Their lymphocytes had lower number of receptors ( Median = 2 , 000 ) than the other cases which were newly diagnosed ( Median = 4 , 500 ) . Four patients had ALL / AUL , three patients had blast crisis as terminal phase of CML , and seven had leukemic Non - Hodgkin lymphomas ( Median = 3 , 500 sites / cell ) . In 24 patients we have also studied the in vitro sensitivity of the leukemic cells to dexamethasone . There was no marked correlation between glucocorticoid receptor levels and in vitro sensitivity . An attempt to correlate receptor levels with clinical responsiveness demonstrated that glucocorticoid receptor determination might be of value in patients with lymphoid malignancies but probably not in patients with other leukemias . ' Activation - labile ' glucocorticoid - receptor complexes of a steroid - resistant variant of CEM - C7 human lymphoid cells . For cytoplasmic glucocorticoid - receptor complexes to enter and accumulate in the nucleus a temperature - dependent event , ' activation ' is required . Activation can be achieved in vitro by increased ionic strength , dilution or gel filtration and is manifested by an increased affinity of steroid - receptor complex for DNA and an altered elution profile from ion - exchange resins . Munck and Foley have shown that activated complexes isolated from thymocytes elute from DEAE - cellulose in a manner identical to complexes activated in vitro . We report here that DEAE - cellulose chromatography of steroid - receptor complexes from CEM - C7 , a cloned human leukaemic T - cell line sensitive to the cytolytic action of glucocorticoids , and its steroid - resistant subclone 4R4 demonstrated that steroid receptors of clone 4R4 can not form stable activated complexes . This defines a new defect in receptor action , activation lability ( r + act1 ) , which is unlike either the r - , r + nt - , or r + nti phenotypes previously described for mouse lymphoid variants . Granulocytes in the endometrium of post - partum women . Endometrial samples of women at various stages of gonadal activity after parturition were examined for the presence and numbers of endometrial granulocytes . Although samples at all the stages contained significant numbers of the granulocytes ( i . e . greater than 7 / high - power field ) , the 100 % values for late - proliferative and adaptation hyperplasia were significantly higher than the values for the resting ( 81 . 8 % ) , early ( 82 . 4 % ) and mid - ( 87 . 9 % ) proliferative and secretory ( 83 . 3 % ) phases . We suggest that this correlates with the suggestion that the granulocytes constitute a receptor system for oestrogens . Interaction of glucocorticoids with macrophages . Identification of glucocorticoid receptors in monocytes and macrophages . Glucocorticoid binding was measured in resident and thioglycollate - elicited mouse peritoneal macrophages , rabbit alveolar macrophages , and human monocytes . Two assays of binding were used - - an assay with intact cells in suspension or monolayers , and an assay of cytosol and nuclear forms of glucocorticoid receptors . The mononuclear phagocytes contained approximately equal to 4 - - 10 X 10 ( 3 ) high affinity receptor sites per cell , with dissociation constants of approximately equal to 2 - - 8 nM dexamethasone . The binding to the saturable sites was specific for steroids with glucocorticoid or antiglucocorticoid activity . Cortisol , corticosterone , and progesterone competed with dexamethasone for binding , whereas estradiol , dihydrotestosterone , and 11 - epicortisol competed very little . Binding of dexamethasone to cytosol and nuclear forms of the receptor complex and temperature - sensitive translocation of cytosol forms to nuclear forms were shown . At 37 degrees C the predominant form of the hormone - receptor complex was nuclear . These results demonstrate that corticosteroids interact with macrophages at physiological concentrations . Nitric oxide signaling : a possible role for G proteins . We have previously reported various inductive effects of nitric oxide on human PBMC . We describe a novel and potentially important mechanism of nitric oxide signaling - through direct activation of guanine nucleotide - binding proteins ( G proteins ) . We have found that nitric oxide treatment of membranes isolated from fresh human PBMC enhances the ability of these membranes to hydrolyze [ gamma - 32P ] GTP and bind [ gamma - 35S ] GTP . In addition , treatment of whole cells with nitric oxide yielded membranes with enhanced GTPase activity . Furthermore , the GTPase activity of pure , recombinant Gs alpha , Gi alpha 1 , and p21ras was greatly enhanced by nitric oxide . In support of the existence of this pathway in whole cells , we found that the G protein inhibitor , GDP - beta - S , blocked NF - kappa B translocation induced by nitric oxide or LPS in permeabilized cells . In addition , nitric oxide greatly reduced the pertussis toxin - mediated ADP - ribosylation of 45 - and 41 - kDa proteins in membranes of these cells . Because G proteins play a central role in many diverse signaling systems , activation by an endogenous and inducible oxidant may represent a novel signaling pathway . The granulocyte - macrophage colony - stimulating factor promoter cis - acting element CLE0 mediates induction signals in T cells and is recognized by factors related to AP1 and NFAT . Expression of the granulocyte - macrophage colony - stimulating factor ( GM - CSF ) gene in T cells is activated by the combination of phorbol ester ( phorbol myristate acetate ) and calcium ionophore ( A23187 ) , which mimic antigen stimulation through the T - cell receptor . We have previously shown that a fragment containing bp - 95 to + 27 of the mouse GM - CSF promoter can confer inducibility to reporter genes in the human Jurkat T - cell line . Here we use an in vitro transcription system to demonstrate that a cis - acting element ( positions - 54 to - 40 ) , referred to as CLE0 , is a target for the induction signals . We observed induction with templates containing intact CLE0 but not with templates with deleted or mutated CLE0 . We also observed that two distinct signals were required for the stimulation through CLE0 , since only extracts from cells treated with both phorbol myristate acetate and A23187 supported optimal induction . Stimulation probably was mediated by CLE0 - binding proteins because depletion of these proteins specifically reduced GM - CSF transcription . One of the binding factors possessed biochemical and immunological features identical to those of the transcription factor AP1 . Another factor resembled the T - cell - specific factor NFAT . The characteristics of these two factors are consistent with their involvement in GM - CSF induction . The presence of CLE0 - like elements in the promoters of interleukin - 3 ( IL - 3 ) , IL - 4 , IL - 5 , GM - CSF , and NFAT sites in the IL - 2 promoter suggests that the factors we detected , or related factors that recognize these sites , may account for the coordinate induction of these genes during T - cell activation . Identification and characterization of an Alu - containing , T - cell - specific enhancer located in the last intron of the human CD8 alpha gene . Expression of the human CD8 alpha gene is restricted to cells of the lymphoid lineage and developmentally regulated during thymopoiesis . As an initial step towards understanding the molecular basis for tissue - specific expression of this gene , we surveyed the surrounding chromatin structure for potential cis - acting regulatory regions by DNase I hypersensitivity mapping and found four hypersensitive sites , three of which were T cell restricted . By using a reporter - based expression approach , a T - cell - specific enhancer was identified by its close association with a prominent T - cell - restricted hypersensitive sites in the last intron of the CD8 alpha gene . Deletion studies demonstrated that the minimal enhancer is adjacent to a negative regulatory element . DNA sequence analysis of the minimal enhancer revealed a striking cluster of consensus binding sites for Ets - 1 , TCF - 1 , CRE , GATA - 3 , LyF - 1 , and bHLH proteins which were verified by electrophoretic mobility shift assays . In addition , the 5 ' end of the enhancer was composed of an Alu repeat which contained the GATA - 3 , bHLH , and LyF - 1 binding sites . Site - directed mutation of the Ets - 1 and GATA - 3 sites dramatically reduced enhancer activity . The functional importance of the other binding sites only became apparent when combinations of mutations were analyzed . Taken together , these results suggest that the human CD8 alpha gene is regulated by the interaction of multiple T - cell nuclear proteins with a transcriptional enhancer located in the last intron of the gene . Comparison of the CD8 alpha enhancer with other recently identified T - cell - specific regulatory elements suggests that a common set of transcription factors regulates several T - cell genes . Molecular regulation of the human IL - 3 gene : inducible T cell - restricted expression requires intact AP - 1 and Elf - 1 nuclear protein binding sites . Interleukin 3 ( IL - 3 ) is a hematopoietic stem - cell growth and differentiation factor that is expressed solely in activated T and NK cells . Studies to date have identified elements 5 ' to the IL - 3 coding sequences that regulate its transcription , but the sequences that confer T cell - specific expression remain to be clearly defined . We have now identified DNA sequences that are required for T cell - restricted IL - 3 gene transcription . A series of transient transfections performed with human IL - 3 - chloramphenicol acetyltransferase ( CAT ) reporter plasmids in T and non - T cells revealed that a plasmid containing 319 bp of 5 ' flanking sequences was active exclusively in T cells . Deletion analysis revealed that T cell specificity was conferred by a 49 - bp fragment ( bp - 319 to - 270 ) that included a potential binding site for AP - 1 transcription factors 6 bp upstream of a binding site for Elf - 1 , a member of the Ets family of transcription factors . DNaseI footprint and electrophoretic mobility shift assay analyses performed with MLA - 144 T cell nuclear extracts demonstrated that this 49 - bp region contains a nuclear protein binding region that includes consensus AP - 1 and Elf - 1 binding sites . In addition , extracts prepared from purified human T cells contained proteins that bound to synthetic oligonucleotides corresponding to the AP - 1 and Elf - 1 binding sites . In vitro - transcribed and - translated Elf - 1 protein bound specifically to the Elf - 1 site , and Elf - 1 antisera competed and super shifted nuclear protein complexes present in MLA - 144 nuclear extracts . Moreover , addition of anti - Jun family antiserum in electrophoretic mobility shift assay reactions completely blocked formation of the AP - 1 - related complexes . Transient transfection studies in MLA - 144 T cells revealed that constructs containing mutations in the AP - 1 site almost completely abolished CAT activity while mutation of the Elf - 1 site or the NF - IL - 3 site , a previously described nuclear protein binding site ( bp . - 155 to - 148 ) in the IL - 3 promoter , reduced CAT activity to < 25 % of the activity given by wild - type constructs . We conclude that expression of the human IL - 3 gene requires the AP - 1 and Elf - 1 binding sites ; however , unlike other previously characterized cytokine genes such as IL - 2 , the AP - 1 and Elf - 1 factors can bind independently in the IL - 3 gene . ( ABSTRACT TRUNCATED AT 400 WORDS ) Combination IL - 2 and IL - 4 reduces glucocorticoid receptor - binding affinity and T cell response to glucocorticoids . The mechanisms contributing to persistent T cell activation and poor response to glucocorticoids in chronic inflammatory illnesses such as steroid resistant ( SR ) asthma are poorly defined . We examined the possibility that certain cytokines , specifically IL - 2 and IL - 4 , could affect T cell response to glucocorticoids . A [ 3H ] dexamethasone radioligand - binding assay was used to measure the number of glucocorticoid receptors ( GR ) and dissociation constant ( Kd ) in PBMC from normal donors and patients with SR asthma , cultured in the absence and presence of these cytokines . PBMC from normal donors incubated for 48 h in the presence of combination IL - 2 + IL - 4 had nuclear GR with significantly reduced binding affinity ( GR Kd = 36 . 1 + / - 1 . 63 nM , mean + / - SEM ; p = 0 . 0001 ) as compared with PBMC incubated with medium alone ( GR Kd = 6 . 74 + / - 0 . 46 nM ) . The cytosolic GR Kd remained unchanged . However , when PBMC were incubated with IL - 2 alone or IL - 4 alone , no change in GR - binding affinity was observed . Furthermore , when T cells and non - T cells were individually stimulated with combination IL - 2 + IL - 4 , a significant reduction in GR - binding affinity was observed only in the T cell population ( p = 0 . 0001 ) . The IL - 2 + IL - 4 - induced alteration in PBMC GR Kd was associated with an increase in GR number ( 8348 + / - 964 vs 1710 + / - 228 sites / cell ; p = 0 . 0003 ) . More importantly , the alteration in PBMC GR - binding affinity with IL - 2 + IL - 4 was associated with a functional change in T cell response to methylprednisolone MPN , i . e . , a reduced inhibitory effect of MPN on PMA / ionomycin - induced T cell proliferation . These effects of IL - 2 + IL - 4 on PBMC GR affinity and response to MPN were blocked by co - incubation with IFN - gamma . Freshly isolated PBMC from four patients with SR asthma had a significantly reduced GR - binding affinity ( Kd = 40 . 0 + / - 2 . 68 nM ; p = 0 . 0001 ) when compared with seven normal subjects ( 7 . 15 + / - 0 . 41 nM ) . The altered PBMC GR binding from patients with SR asthma reversed to normal when incubated with medium alone , but was sustained with IL - 2 + IL - 4 . These observations suggest that with persistent inflammation certain cytokines may contribute to an impaired response to glucocorticoids . Furthermore , the effects of IL - 2 and IL - 4 were blocked by IFN - gamma . Characterization of the human CD4 gene promoter : transcription from the CD4 gene core promoter is tissue - specific and is activated by Ets proteins . We analyzed the 5 ' transcription control sequences of the human CD4 gene . We located the transcription initiation site and showed that the CD4 core promoter ( positions - 40 to + 16 ) lacks a classical ` ` TATA ' ' or initiator positioning consensus sequence but directs precise and efficient transcription when coupled to the ubiquitously active simian virus 40 enhancer . The transcriptional activity of the CD4 gene promoter correlated with CD4 expression in various cell types . Interestingly , the CD4 core promoter also displayed a tissue - specific transcriptional activity . Within this fragment , three nucleic acid sequences are completely conserved in the murine CD4 gene . One of these sequences contains a perfect ETS consensus sequence . Another ETS consensus sequence is located 1060 nt upstream . Electrophoretic - mobility - shift assays showed that the core promoter ETS motif binds an Ets - related protein specifically expressed at high levels in CD4 + cells . Moreover , in CD4 - cells , overexpression of Ets - 1 or Ets - 2 efficiently and specifically activated transcription from the CD4 promoter and core promoter . These data indicate that Ets transcription factors play a central role in controlling CD4 gene expression , by binding to both a classical remote site and an unusual proximal activator sequence Glucocorticoid receptor activation and inactivation in c ultured human lymphocytes . Although glucocorticoids are not cytolytic for and do not inhibit the growth of the IM - 9 line of cultured human lymphoblasts , these cells have a high steroid - binding capacity . We have used IM - 9 cells in order to examine whether unoccupied glucocorticoid receptors are inactivated and activated in intact cells . when IM - 9 cells are incubated in glucose - free medium in a nitrogen atmosphere , both their ability to bind triamcinolone acetonide and their ATP levels decline and , when glucose and oxygen are reintroduced , ATP levels and receptor activity return . The specific glucocorticoid - binding activity of cytosol prepared from cells exposed to various degrees of energy limitation is directly correlated with the ATP content . Receptor activation in intact cells is rapid and independent of protein synthesis . Cytosol prepared from inactivated cells can not be activated by addition of ATP . The inactivation of glucocorticoid receptors that occurs when cytosol from normal IM - 9 cells is incubated at 25 degrees C is inhibited by molybdate , vanadate , fluoride , ATP , and several other nucleotides . The experiments with intact human lymphoblasts suggest that assays of specific glucocorticoid - binding capacity do not necessarily reflect the cellular content of receptor protein . Glucocorticoids and lymphocytes . II . Cell cycle - dependent changes in glucocorticoid receptor content . To study variations in glucocorticoid receptor levels during the cell cycle , we have separated mitogen - stimulated human peripheral lymphocytes and rat lymph node cells by unit gravity sedimentation and measured glucocorticoid binding in the resultant fractions . By morphologic criteria and thymidine incorporation , the fractions were separated into populations of G0 and G1 phase and S and post - S phase cells . A 2 - to 3 - fold increase in glucocorticoid receptor sites per cell , for cells in the S and post - S phase over those in G0 and G1 , was observed with both nonstimulated rat lymph node cell suspensions and concanavalin A - stimulated human peripheral lymphocytes . These observations together with those from other studies indicate that formation of new glucocorticoid receptors near the S phase may be a general phenomenon in proliferating cells . We propose that this increase in glucocorticoid receptors during the cell cycle may explain the increase in glucocorticoid receptors in mitogen - stimulated lymphocytes . The leukocyte migration inhibition response to certain breast cancer - related antigens ( MCF - 7 and MuMTV ) : their potential as discriminants . Certain oncogenic viruses have been implicated in human breast cancer , including the murine mammary tumor virus ( MuMTV ) and the Mason - Pfizer monkey virus ( MPMV ) . We have used the leukocyte migration inhibition ( LMI ) response to assay the response to several potential breast cancer - related antigens , including MuMTV , MPMV , and a breast cancer cultured cell line , MCF - 7 , in 96 breast cancer patients , in 32 women with benign breast disease , and in 67 normal women . The lowest tenth percentile of control ( LMI ) responses was used as the cutoff point to designate responders . Breast cancer patients showed significant responses to MuMTV ( 49 % and to MCF - 7 ( 50 % ) , but not to MPMV ( 29 % ) . In a paired - antigen study using MuMTV and MCF - 7 , 75 % of the breast cancer patients responded , versus 18 % of the normal women ( P less than 0 . 0050 ) . The potential for this assay to distinguish ` ` normal ' ' from ` ` breast cancer ' ' was analyzed using a migration index derived from discriminant analysis . The ability of the assay to discriminate ` ` normal ' ' from ` ` cancer ' ' was significant ( P less than 0 . 001 ) and showed a sensitivity of detecting ` ` cancer ' ' of 75 % . The overall responses to MuMTV and MCF - 7 were analyzed with reference to certain prognostic factors , but showed no relation to age , menstrual status , estrogen receptor status , or stage of disease . The above reactions suggest that a large proportion of breast cancer patients exhibit presensitization to antigenfs found in MuMTV and MCF - 7 , which may be cross - reactive with antigens in the primary cancer . These responses appear to be independent of major prognostic variables . Further refinement of this assay may yield one which is more highly discriminating for breast cancer . Chronic lymphatic leukaemia : cellular effects of glucocorticoids in vitro . Glucocorticoid receptor levels and steroid induced inhibition of nucleic acid precursors have been examined in lymphocytes from 27 patients at different stages of chronic lymphatic leukaemia . No correlation can be found between the level of glucocorticoid receptors and the stage of the disease . On the other hand , a significant difference ( P less than 0 . 02 ) was found between stage O and stage III / IV patients , in terms of the in vitro effect of dexamethasone on [ 3H ] uridine incorporation . Pyrrolidine dithiocarbamate inhibits NF - kappa B mobilization and TNF production in human monocytes . The human TNF promoter contains four potential nuclear factor - kappa B ( NF - kappa B ) - binding sites , with the strongest binding seen for the - 605 motif . Nuclear extracts from unstimulated cells of the human monocytic cell line , Mono Mac 6 , contain one specific binding protein ( complex II ) , consistent with a constitutive p50 homodimer . Stimulation of Mono Mac 6 cells with LPS will increase complex II and will strongly induce a second specific complex ( complex I ) , which represents the p50 / 65 heterodimer . Treatment of Mono Mac 6 cells with pyrrolidine - dithiocarbamate ( PDTC ) at 300 microM will block the LPS - induced complex I almost completely and will reduce complex II to the constitutive level . Binding activity of other nuclear factors that recognize the SP - 1 and c / EBP motifs of the human TNF promoter is not affected by such treatment . Northern blot analysis demonstrates that PDTC treatment will strongly reduce LPS - induced TNF transcripts . Secreted TNF protein as detected in the Wehi 164S / ActD bioassay and in a sandwich immunoassay was similarly reduced by PDTC . Kinetic analyses show that after LPS stimulation , NF - kappa B will peak at 1 h , TNF transcript prevalence at 2 h , and TNF protein at 4 h . PDTC did not shift this response to LPS to a later time , but suppressed NF - kappa B mobilization , TNF transcripts , and TNF protein over the entire 8 - h observation period . Analysis of freshly isolated , LPS - stimulated blood monocytes showed a similar blockade of NF - kappa B . Furthermore , in these primary cells , induction of TNF transcripts , as determined by Northern blot analysis and by quantitative polymerase chain reaction , was prevented by PDTC as was TNF protein production . These data show that dithiocarbamates can profoundly affect cytokine expression and suggest that NF - kappa B is involved in LPS - induced TNF gene expression in human monocytes . Comparing regions of the Epstein - Barr virus ZEBRA protein which function as transcriptional activating sequences in Saccharomyces cerevisiae and in B cells . The ZEBRA protein activates expression of Epstein - Barr virus early - lytic - cycle genes in human B lymphocytes . Here it is shown that ZEBRA also behaves as a sequence - specific transcriptional activator in Saccharomyces cerevisiae . Deletional mutagenesis defined three regions of ZEBRA that participate in activation in S . cerevisiae . These regions are designated YI ( amino acids [ aa ] 1 to 25 ) , YII ( aa 51 to 102 ) , and YIII ( aa 228 to 245 ) . Two of the three regions of the native ZEBRA protein act together to mediate activation when assayed on ZEBRA binding sites . However , when fused to the DNA binding domain of GAL 4 and assayed on GAL4 binding sites , regions YII and YIII were each sufficient to confer activation in S . cerevisiae . Regions of ZEBRA which affected activation in S . cerevisiae were also required in human B lymphocytes . The amino - terminal region of ZEBRA ( aa 1 to 98 ) was required for activation both in S . cerevisiae and in human B cells ; deletion of the carboxy - terminal 18 aa also significantly reduced activation in both cell types . Thus , the behavior of ZEBRA in human B cells and S . cerevisiae suggests that the protein contains universal activation motifs that interact with conserved components of the transcription machinery . However , certain deletion mutants of ZEBRA containing mutations in the N - terminal region exhibited discordant behaviors in S . cerevisiae and in B cells . For example , deletion of ZEBRA aa 26 to 51 impaired activation to a great extent in B cells but had little or no effect in S . cerevisiae . The discordant mutants may reflect interactions with a variable domain of a conserved component or unique interactions with specialized components of the basal transcription apparatus in different cells . Functional interaction of the v - Rel and c - Rel oncoproteins with the TATA - binding protein and association with transcription factor IIB . Rel family proteins regulate the expression of genes linked to kappa B - binding motifs . Little is known , however , of the mechanism by which they enhance transcription . We have investigated the ability of the v - Rel and c - Rel oncoproteins to interact with components of the basal transcription machinery . Here we report that both the acidic transcription activation domain mapping to the unique C terminus of chicken c - Rel and the F9 cell - specific activation region common to both v - Rel and c - Rel interact with the TATA - binding protein ( TBP ) and transcription factor IIB ( TFIIB ) in vitro and in vivo . We also demonstrate that TPB interaction with Rel activation regions leads to synergistic activation of transcription of a kappa B - linked reporter gene . Combined with the observation that the mouse c - Rel and human RelA proteins also interact with TBP and TFIIB in vitro , these results suggest that association with basal transcription factors is important for the transcriptional activities of Rel family proteins . p21ras and calcineurin synergize to regulate the nuclear factor of activated T cells . In T lymphocytes , triggering of the T cell receptor ( TCR ) induces several signaling cascades which ultimately synergize to induce the activity of the nuclear factor of activated T cells ( NFAT ) , a DNA binding complex critical to the inducibility and T cell specificity of the T cell growth factor interleukin 2 . One immediate consequence of T cell activation via the TCR is an increase in cytosolic calcium . Calcium signals are important for NFAT induction , and recent studies have identified calcineurin , a calcium - calmodulin dependent serine - threonine phosphatase , as a prominent component of the calcium signaling pathway in T cells . A second important molecule in TCR signal transduction is the guanine nucleotide binding protein , p21ras , which is coupled to the TCR by a protein tyrosine kinase dependent mechanism . The experiments presented here show that expression by transfection of mutationally activated calcineurin or activated p21ras alone is insufficient for NFAT transactivation . However , coexpression of the activated calcineurin with activated p21ras could mimic TCR signals in NFAT induction . These data identify calcineurin and p21ras as cooperative partners in T cell activation . Expression of the chicken GATA factor family during early erythroid development and differentiation . The DNA motif WGATAR has been identified within transcriptional regulatory domains of globin and other erythroid - specific genes and the activator proteins that bind to this regulatory element , the GATA factors , belong to a multi - gene family that is expressed in chicken erythroid cells . Here we show that , as in chickens , multiple members of the GATA factor family are expressed in human and murine erythroid cells . During the early stages of chicken embryogenesis ( well before blood island formation ) , each of the GATA family members is transcribed with a unique temporal and spatial pattern . In the primitive erythroid lineage , transcription of the embryonic epsilon - globin gene parallels GATA - 1 expression while the switch to beta - globin transcription in definitive erythroid cells is directly preceded by a pronounced increase in GATA - 3 accumulation . The timing and pattern of expression of these different mRNAs during avian erythroid development and differentiation suggests that temporally regulated changes in GATA factor expression are required for vertebrate hematopoiesis . Molecular regulation of human interleukin 2 and T - cell function by interleukin 4 . Distinct functional T - cell subsets , differing in the patterns of lymphokines produced , regulate cell - mediated and humoral immune responses . The two major types and their principal products , interleukin 4 and interferon gamma ( IL - 4 and IFN - gamma ) , are reciprocally negatively interactive . To analyze the molecular mechanism of IL - 4 - mediated suppression of cell - mediated immunity we studied its effects on expression of interleukin 2 ( IL - 2 ) and IFN - gamma . IL - 4 pretreatment of Jurkat cells prior to stimulation resulted in a decrease in transcription of the IL2 gene . IL - 4 suppressed IL - 2 and IFN - gamma mRNA levels in primary human T cells , and addition of anti - CD28 antibodies relieved this suppression . Using enhancer - reporter constructs , IL - 4 specifically down - regulated the NFIL - 2B element . Electrophoretic mobility shift assays using a DNA oligomer containing the NFIL - 2B binding site indicated that IL - 4 inhibited the NFIL - 2B complex and that the NFIL - 2B DNA binding factor is distinct from AP - 1 . These results suggest that IL - 4 may regulate development and function of T - cell subsets involved in cell - mediated immunity in part by inhibiting factors required for transcription of the IL2 gene Immunochemical differences between glucocorticoid receptors from corticoid - sensitive and - resistant malignant lymphocytes . We have explored the possibility of using antibodies against purified rat liver glucocorticoid receptors to study the immunochemical properties of glucocorticoid receptors from murine and human malignant lymphocytes . For this purpose , purified immune immunoglobulin G was covalently linked to Sepharose CL - 4B . We then examined the ability of the affinity gel to recognize cytosolic [ 3H ] triamcinolone acetonide - receptor complexes from the corticoid - sensitive ( CS ) and - resistant strains of mouse lymphoma P1798 , from CS lymphocytes of patients with chronic lymphatic leukemia , and from a CS clone of human leukemic lymphoblasts in tissue culture ( CH6 ) . Mouse thymus was used as a source of glucocorticoid receptor from normal CS lymphocytes . Whereas the immunoaffinity column retained 70 to 84 % of the 58 - to 62 - A ( Stokes radius ) [ 3H ] triamcinolone acetonide - receptor complexes characteristic of the CS mouse and human lymphocytes , it failed to recognize the 27 - to 28 - A ( Stokes radius ) glucocorticoid receptor present in corticoid - resistant mouse lymphoma P1798 cells . Therefore , under appropriate experimental conditions , it was possible to demonstrate cross - reactivity between the antiserum against rat liver glucocorticoid receptor and the 58 - to 62 - A ( Stokes radius ) glucocorticoid receptor from species as diverse as mouse and humans . Heterogeneity of the in vitro responses to glucocorticoids in acute leukemia . In leukocyte population freshly isolated from the blood of 26 patients with acute leukemia , we have measured several parameters including glucocorticoid receptors , nucleoside incorporation , percentage of cells in S phase , and steroid - induced cell lysis . In addition , in some cases , the short - term response to steroid therapy was determined . Although , in all the patients studied , leukocytes were found to contain glucocorticoid receptors , we failed to demonstrate any correlation between the level of binding sites and the in vitro or in vivo response to glucocorticoids . This absence of correlation could be in part explained by the marked heterogeneity of the steroid response demonstrated in leukocyte subpopulations . It appears , however , that the degree of steroid action in vitro as well as the extent of spontaneous and dexamethasone - induced cell death may be related to the number of cells in the S phase of the cell cycle . Glucocorticoid receptors in cytosol and nuclear extract of human leukocytes . Cortisol binding by cytosol and 0 . 4 M KCl extract of the nuclear fraction of human leukocytes were studied by gel chromatography and ion exchange filtration on DEAE cellulose . The cytoplasmic cortisol binding protein has a molecular weight 95 000 and the soluble nuclear binding protein 50 000 . The absence of the uptake of radioactive cortisol by isolated nuclei and the apparent requirement of the cytosol for glucocorticoid specific binding in nuclear receptor sites was observed . The association constant characterising the binding of cortisol to cytosol was KA = 3 . 5 . 10 ( 9 ) l / mol . Corticosteroid - induced lymphopenia , immunosuppression , and body defense . The apparent paradox of heightened adrenal corticosteroid levels associated with reduction in the competence of the body ' s defensive apparatus to cope with exposure to new microbial antigens is considered . The question is asked how this lowered defensive capability , which occurs in the face of a threat to body integrity , is consistent with Cannon ' s principals of the ` ` wisdom of the body . ' ' The suggestion is offered that the immunologic response to self - antigens exposed by disease or trauma may be suppressed by corticosteroid to offset the likelihood of autoimmune attack . Protein tyrosine kinase activation is required for lipopolysaccharide induction of cytokines in human blood monocytes . Bacterial LPS induce production of cytokines such as IL - 1 , IL - 6 , and TNF in mononuclear phagocytes , and this represents a central component in the pathogenesis of septic shock syndrome . However , the mechanisms by which LPS activates these cells to express cytokines are not completely characterized . The present study addressed the role of different protein kinases in the LPS induction of cytokines . It is shown that LPS induced a 12 - to 16 - fold increase in IL - 1 beta , IL - 6 , and TNF - alpha mRNA levels , and this was completely or more than 80 % blocked by the protein tyrosine kinase specific inhibitors herbimycin A and genistein at the concentrations of 1 . 7 and 37 microM , respectively . Protein kinase C inhibition by staurosporine reduced LPS induction of TNF - alpha , whereas it had no effects on IL - 6 and IL - 1 beta . Inhibition of protein kinase A by H89 reduced IL - 6 mRNA levels but did not detectably change IL - 1 beta or TNF - alpha mRNA levels . In contrast , LPS did not increase leukemia inhibitory factor mRNA , which was constitutively expressed and not significantly reduced by these inhibitors . In addition to cytokine mRNA levels , LPS - induced IL - 6 protein synthesis and IL - 6 bioactivity were also reduced to baseline levels by the PTK inhibitors herbimycin A and genistein . Both PTK inhibitors also reduced the LPS activation of nuclear factor - kappa B ( NF - kappa B ) , which is a transcription factor involved in the expression of cytokine genes such as IL - 6 and TNF - alpha . The activation of NF - kappa B was also reduced by H89 , whereas staurosporine had no effect on this response . In summary , these findings suggest that protein kinase C and protein kinase A appear to have selective effects in the LPS induction of cytokines , whereas PTK is required for LPS induction of a broad spectrum of cytokines and NF - kappa B activation in monocytes . In vivo control of NF - kappa B activation by I kappa B alpha . The transcription factor NF - kappa B is stored in the cytoplasm in complexes with the inhibitor protein I kappa B alpha . It has been shown in vitro that dissociation of I kappa B alpha from these complexes results in active NF - kappa B . In this report we show that lipopolysaccharide ( LPS ) - induced activation of B or pre - B cells results in loss of I kappa B alpha from NF - kappa B complexes in vivo . Many liberated NF - kappa B dimers reached the nucleus , where increased c - rel , p65 and p50 were detected by immunoblotting and by DNA binding assays . Some liberated dimers were retained in the cytoplasm , however , through binding to newly synthesized I kappa B alpha , a finding which strongly suggests ( i ) that the LPS - induced signal causes dissociation of complexes rather than preventing their association and ( ii ) that dissociation results from modification of I kappa B alpha and not of c - rel or p65 . No effect of LPS treatment was detected on p105 or p100 , which also retain rel family members in the cytoplasm . Quite unexpectedly , we also found that in unstimulated cells there is a constant ongoing process of degradation and replacement of complexed I kappa B alpha . We propose that this turnover results in the low level of active NF - kappa B presumably necessary even in the unstimulated cell , and that the high rate of synthesis of I kappa B alpha provides the ability to turn off NF - kappa B activity rapidly as soon as the activating signal ceases . Identification of a killer cell - specific regulatory element of the mouse perforin gene : an Ets - binding site - homologous motif that interacts with Ets - related proteins . The gene encoding the cytolytic protein perforin is selectively expressed by activated killer lymphocytes . To understand the mechanisms underlying the cell - type - specific expression of this gene , we have characterized the regulatory functions and the DNA - protein interactions of the 5 ' - flanking region of the mouse perforin gene ( Pfp ) . A region extending from residues + 62 through - 141 , which possesses the essential promoter activity , and regions further upstream , which are able to either enhance or suppress gene expression , were identified . The region between residues - 411 and - 566 was chosen for further characterization , since it contains an enhancer - like activity . We have identified a 32 - mer sequence ( residues - 491 to - 522 ) which appeared to be capable of enhancing gene expression in a killer cell - specific manner . Within this segment , a 9 - mer motif ( 5 ' - ACAGGAAGT - 3 ' , residues - 505 to - 497 ; designated NF - P motif ) , which is highly homologous to the Ets proto - oncoprotein - binding site , was found to interact with two proteins , NF - P1 and NF - P2 . NF - P2 appears to be induced by reagents known to up - regulate the perforin message level and is present exclusively in killer cells . Electrophoretic mobility shift assay and UV cross - linking experiments revealed that NF - P1 and NF - P2 may possess common DNA - binding subunits . However , the larger native molecular mass of NF - P1 suggests that NF - P1 contains an additional non - DNA - binding subunit ( s ) . In view of the homology between the NF - P motif and other Ets proto - oncoprotein - binding sites , it is postulated that NF - P1 and NF - P2 belong to the Ets protein family . Results obtained from the binding competition assay , nevertheless , suggest that NF - P1 and NF - P2 are related to but distinct from Ets proteins , e . g . , Ets - 1 , Ets - 2 , and NF - AT / Elf - 1 , known to be expressed in T cells . The role of NF - kappa B1 ( p50 / p105 ) gene expression in activation of human blood T - lymphocytes via CD2 and CD28 adhesion molecules . Stimulation of primary human T - lymphocytes via CD2 and CD28 adhesion molecules induces a long - lasting proliferation ( > 3 weeks ) . This potent activation does not require accessory cells , such as monocytes , but depends on persistent interleukin 2 ( IL - 2 ) secretion and receptivity , which is associated with high and prolonged expression of the inducible CD25 / IL - 2 receptor alpha ( IL - 2R alpha ) chain gene . The transcription factor NF - kappa B participates in the regulation of both IL - 2 and IL - 2R alpha genes , as well as multiple cellular genes involved in T - cell proliferation . To evaluate the role of NF - kappa B in human peripheral blood T - lymphocytes , we previously analyzed the activation of NF - kappa B - related complexes in response to CD2 + CD28 costimulation . We demonstrated a long - term induction of p50 / p65 heterodimer , a putative p65 / c - Rel heterodimer , and a constitutive nuclear expression of KBF1 / p50 homodimers . As the role of p50 remains unclear , we focused our present study on NF - kappa B1 ( p50 / p105 ) gene regulation . Using electrophoretic mobility shift assays and Western and Northern blot analyses , we studied NF - kappa B1 gene expression during T - cell stimulation via CD2 + CD28 . We observed a transient 4 - to 5 - fold increase of NF - kappa B1 gene expression at both the mRNA and protein levels , lasting for at least 24 h . p50 DNA - binding activity apparently stays highly controlled when p105 expression is enhanced by a physiological stimulus of peripheral blood T - cells . Partial inhibition of p50 and p105 expression by NF - kappa B1 antisense oligonucleotides significantly reduced T - cell proliferation and CD25 / IL - 2R alpha cell surface expression . ( ABSTRACT TRUNCATED AT 250 WORDS ) Vitamin D receptor quantitation in human blood mononuclear cells in health and disease . Vitamin D receptor ( VDR ) concentration was quantitated in human peripheral blood mononuclear cells ( PBMC ) from patients with absorptive hypercalciuria ( AH ) and patients with high 1 , 25 ( OH ) 2D3 due to acquired or transient disease states and the results compared to those in normal subjects . VDR concentration in resting cells was not different between the three groups and represented constitutive receptor expression of monocytes . Following activation with phytohemagglutinin , patients with hypercalcitriolemia demonstrated significantly greater VDR concentrations . Patients with AH demonstrated a normal value for the group , but 6 patients had significantly greater concentrations of VDR despite normal plasma 1 , 25 ( OH ) 2D3 in four of the patients . Proliferation , as assessed from [ 3H ] thymidine incorporation was inversely correlated with serum 1 , 25 ( OH ) 2D3 and was significant ( R = - 0 . 299 , p = 0 . 048 ) . Taken together , the results suggest that PBMC provide a useful system for studying VDR status in transient or acquired states of hypercalcitriolemia . Furthermore , the studies in patients with absorptive hypercalciuria disclosed it to be a heterogeneous disorder , characterized by both vitamin D - dependent and D - independent forms of receptor up - regulation . Reactive oxygen intermediates activate NF - kappa B in a tyrosine kinase - dependent mechanism and in combination with vanadate activate the p56lck and p59fyn tyrosine kinases in human lymphocytes . We have previously observed that ionizing radiation induces tyrosine phosphorylation in human B - lymphocyte precursors by stimulation of unidentified tyrosine kinases and this phosphorylation is substantially augmented by vanadate . Ionizing radiation generates reactive oxygen intermediates ( ROI ) . Because H2O2 is a potent ROI generator that readily crosses the plasma membrane , we used H2O2 to examine the effects of ROI on signal transduction . We now provide evidence that the tyrosine kinase inhibitor herbimycin A and the free radical scavenger N - acetyl - cysteine inhibit both radiation - induced and H2O2 - induced activation of NF - kappa B , indicating that activation triggered by ROI is dependent on tyrosine kinase activity . H2O2 was found to stimulate Ins - 1 , 4 , 5 - P3 production in a tyrosine kinase - dependent manner and to induce calcium signals that were greatly augmented by vanadate . The synergistic induction of tyrosine phosphorylation by H2O2 plus vanadate included physiologically relevant proteins such as PLC gamma 1 . Although treatment of cells with H2O2 alone did not affect the activity of src family kinases , treatment with H2O2 plus vanadate led to activation of the p56lck and p59fyn tyrosine kinases . The combined inhibition of phosphatases and activation of kinases provides a potent mechanism for the synergistic effects of H2O2 plus vanadate . Induction of tyrosine phosphorylation by ROI may thus lead to many of the pleiotropic effects of ROI in lymphoid cells , including downstream activation of PLC gamma 1 and NF - kappa B Influence of sex hormone binding globulin and serum albumin on the conversion of androstenedione to testosterone by human erythrocytes . The influence of human serum albumin and sex hormone binding globulin ( SHBG ) on the enzymic conversion of androstenedione to testosterone in human erythrocytes was investigated in vitro . Total plasma and albumin delayed the conversion rate of androstenedione , while SHBG increased it markedly . The effect of SHBG was largely abolished by heating to 60 degrees C for 1 h and by saturating its binding sites by DHT . The effect of both proteins was found to be related to their concentration . It appears that the binding sites of albumin provide a mechanism for retarding androstenedione uptake by the erythrocytes and that the high binding affinity of SHBG for testosterone facilitates the diffusion of this steroid out of the cell and thus , displaces the chemical equilibrium within the cell . Glucocorticoids and lymphocytes . I . Increased glucocorticoid receptor levels in antigen - stimulated lymphocytes . Recently a 2 - to 3 - fold increase in the number of glucocorticoid receptors in human peripheral lymphocytes has been noted after in vitro mitogen stimulation . Here , we extend these observations to in vivo immunization . After unilateral immunization of adrenalectomized male rats , a 50 % increase in glucocorticoid receptor sites per cell , determined by binding of dexamethasone , was observed in cell suspensions of homolateral lymph nodes over those from the contralateral nonimmunized side of the same animal . The association constant for dexamethasone was similar in both groups , as was the stereospecificity for various steroids , the time course of cytoplasmic and nuclear association , and cytoplasmic - to - nuclear translocation . Despite a 50 % increase in the number of glucocorticoid receptor sites per cell , the cells from the homolateral and controlateral lymph nodes were equally sensitive to the inhibitory effects of dexamethasone , as determined by measurements of the incorporation of radiolabeled precursors of protein , RNA , and DNA , or measurements of in vitro cell survival . Glucocorticoid receptors and actions in rat thymocytes and immunologically stimulated human peripheral lymphocytes . After reviewing briefly our earlier studies on glucocorticoid receptors and mechanisms in thymus cells , we have outlined results from the following two areas of current interest in our laboratories : the ` ` life - cycle ' ' of glucocorticoid receptors and complexes in thymus cells , and the levels of glucocorticoid receptors and sensitivity in immunologically stimulated human peripheral lymphocytes . Several of our results on energetics and kinetics of hormone binding to glucocorticoid receptors in rat thymus cells seem to require extension of the simplest model of hormone - receptor transformations in intact cells . ATP - depletion experiments suggest the existence of a nonbinding form of the receptor ; ` ` chase ' ' experiments suggest reaction of hormone directly with nuclear - bound receptor ; experiments on depletion and replenishment of cytoplasmic receptor using cortisol and dexamethasone suggest the existence of at least two subpopulations of nuclear - bound hormone - receptor complex . We have found that mitogen or immunologic stimulation of human peripheral lymphocytes in culture leads within 24 h or so to a striking increase in the number of glucocorticoid receptor sites per cell . We believe this increase may be due to partial synchronization of the cell population in a phase of the cell cycle in which receptor content is high . Contrary to the widely held view that mitogen - stimulated cells become insensitive to glucocorticoids , our experiments show that with respect to inhibition of thymidine and uridine incorporation and glucose uptake , the cells are highly sensitive to dexamethasone at 24 , 48 , and 72 h after stimulation with concanavalin A . Nuclear glucocorticoid binding in chronic lymphatic leukemia lymphocytes . A reliable procedure is described for isolating 3H - triamcinolone acetonide ( 3H - TA ) receptor complexes from purified chronic lymphatic leukemia ( CLL ) lymphocyte nuclei , based on the use of carbobenzoxy - L - phenylalanine ( CBZ - L - phe ) to prevent breakdown of hormone - receptor complexes during extraction of nuclei with 0 . 6M KCl . Using this method , specific nuclear glucocorticoid binding was demonstrated in 14 / 14 patients with untreated CLL . No correlation was found between levels of nuclear - associated 3H - TA and peripheral white blood cell count or rosetting ability of circulating lymphocytes . Multiple closely - linked NFAT / octamer and HMG I ( Y ) binding sites are part of the interleukin - 4 promoter . We show here that the immediate upstream region ( from position - 12 to - 270 ) of the murine interleukin 4 ( Il - 4 ) gene harbors a strong cell - type specific transcriptional enhancer . In T lymphoma cells , the activity of the Il - 4 promoter / enhancer is stimulated by phorbol esters , Ca + + ionophores and agonists of protein kinase A and inhibited by low doses of the immunosuppressant cyclosporin A . The Il - 4 promoter / enhancer is transcriptionally inactive in B lymphoma cells and HeLa cells . DNase I footprint protection experiments revealed six sites of the Il - 4 promoter / enhancer to be bound by nuclear proteins from lymphoid and myeloid cells . Among them are four purine boxes which have been described to be important sequence motifs of the Il - 2 promoter . They contain the motif GGAAA and are recognized by the inducible and cyclosporin A - sensitive transcription factor NFAT - 1 . Three of the Il - 4 NFAT - 1 sites are closely linked to weak binding sites of Octamer factors . Several purine boxes and an AT - rich protein - binding site of the Il - 4 promoter are also recognized by the high mobility group protein HMG I ( Y ) . Whereas the binding of NFAT - 1 and Octamer factors enhance the activity of the Il - 4 promoter , the binding of HMG I ( Y ) suppresses its activity and , therefore , appears to be involved in the suppression of Il - 4 transcription in resting T lymphocytes . Reversibility of the differentiated state in somatic cells . Analysis of de novo gene activation in multinucleated heterokaryons has shown that the differentiated state , although stable , is not irreversible , and can be reprogrammed in the presence of appropriate combinations of trans - acting regulatory molecules . These properties have been exploited to design strategies for identifying novel regulators of cellular differentiation . Phosphatidylcholine hydrolysis activates NF - kappa B and increases human immunodeficiency virus replication in human monocytes and T lymphocytes . We have tested whether breakdown of phosphatidylcholine ( PC ) initiated by exogenous addition of a PC - specific phospholipase C ( PC - PLC ) from Bacillus cereus or by endogenous overexpression of PC - PLC induces functional activation of NF - kappa B and increases human immunodeficiency virus ( HIV ) enhancer activity . PC - PLC - activated hydrolysis of PC was found to induce bona fide p50 / p65 NF - kappa B binding activity in three different cell lines of human or murine origin . No significant changes in the turnover of other cellular phospholipids were detected in PC - PLC - treated cells . Induction of NF - kappa B by PC - PLC did not depend on de novo synthesis of proteins or autocrine secretion of either tumor necrosis factor or interleukin 1 . In human monocytic and lymphoblastoid T - cell lines , induction of NF - kappa B by PC - PLC resulted in clear induction of luciferase expression vectors placed under the control of synthetic kappa B enhancers or wild type , but not kappa B - mutated , HIV long terminal repeat constructs . HIV replication was increased by PC - PLC in chronically infected monocytes and T lymphocytes . NF - kappa B activation promoted by addition of exogenous PC - PLC correlated with an intense production of diacylglycerol . However , addition of a phosphatidylinositol - specific PLC from B . cereus also induced diacylglycerol but did not activate kappa B enhancer - directed vectors . PC - PLC - induced NF - kappa B activation could not be blocked by a specific inhibitor of phorbol ester - inducible protein kinases C . These results indicate that a cellular transduction pathway , dependent on specific PC breakdown , is functional in T lymphocytes and monocytes and may be used by various transmembrane receptors to activate HIV transcription through NF - kappa B - dependent induction of the HIV enhancer . Novel mechanism for inhibition of human T cells by glucocorticoids . Glucocorticoids inhibit signal transduction through IL - 2 receptor . Interaction of IL - 2 with its high affinity membrane receptor complex ( IL - 2R ) present on activated T lymphocytes induces cell proliferation and mediates effector functions . Glucocorticoids inhibit IL - 2 production by inhibiting TCR - mediated signal transduction . We asked whether they also inhibit the action of IL - 2 by inhibiting signal transduction through IL - 2R . Human peripheral blood T cells , stimulated with PMA for 48 h ( PMA blasts ) , were incubated with IL - 2 in the presence of incremental dosages of dexamethasone ( Dex ; 10 ( - 5 ) - 10 ( - 9 ) M ) . Dex inhibited the IL - 2 - dependent proliferation of PMA blasts in a dose - dependent fashion ( IC50 , 5 x 10 ( - 8 ) M ) . Cell surface expression of IL - 2R alpha - and beta - chains as determined by immunofluorescence analysis was not affected by Dex . In addition , Scatchard plot analysis of 125I - labeled IL - 2 showed that Dex did not affect the binding of IL - 2 , thus suggesting that inhibition is due to a postreceptor effect . Inhibition of T cell proliferation by Dex was associated with decreased IL - 2 - dependent tyrosine phosphorylation of several intracellular proteins and decreased phosphorylation of the retinoblastoma gene product Rb , a protein essential for controlling the progression of cells through the cell cycle . IL - 2 - dependent IL - 2R alpha expression in PMA blasts and NF - kB induction in resting human T cells were also inhibited by Dex . These results demonstrate that glucocorticoids inhibit preactivated T cells by down - regulating signal transduction through IL - 2R . Chronic human immunodeficiency virus type 1 infection stimulates distinct NF - kappa B / rel DNA binding activities in myelomonoblastic cells . The relationship between human immunodeficiency virus type 1 ( HIV - 1 ) infection and the induction of NF - kappa B binding activity was examined in a myeloid cell model of HIV - 1 infection derived from the PLB - 985 cell line . Chronic infection of PLB - 985 cells led to increased monocyte - specific surface marker expression , increased c - fms gene transcription , and morphological alterations consistent with differentiation along the monocytic pathway . PLB - IIIB cells displayed a constitutive NF - kappa B - like binding activity that was distinct from that induced by tumor necrosis factor alpha or phorbol 12 - myristate 13 - acetate treatment of the parental PLB - 985 cell line . This unique DNA binding activity consisted of proteins of 70 , 90 , and 100 kDa with a high degree of binding specificity for the NF - kappa B site within the PRDII domain of beta interferon . In this report , we characterize the nature of these proteins and demonstrate that binding of these proteins is also induced following Sendai paramyxovirus infection . The 70 - kDa protein corresponds to the NF - kappa B RelA ( p65 ) subunit , which is activated in response to an acute paramyxovirus infection or a chronic HIV - 1 infection . Virus infection does not appear to alter the amount of RelA ( p65 ) or NFKB1 ( p50 ) but rather affects the capacity of I kappa B alpha to sequester RelA ( p65 ) , therefore leading to constitutive levels of RelA DNA binding activity and to increased levels of NF - kappa B - dependent gene activity . The virally induced 90 - to 100 - kDa proteins have a distinct binding specificity for the PRDII domain and an AT - rich sequence but do not cross - react with NF - kappa B subunit - specific antisera directed against NFKB1 ( p105 or p50 ) , NFKB2 ( p100 or p52 ) , RelA ( p65 ) , or c - rel . DNA binding of the 90 - to 100 - kDa proteins was not inhibited by recombinant I kappa B alpha / MAD - 3 and was resistant to tryptic digestion , suggesting that these proteins may not be NF - kappa B related . Transient cotransfection experiments demonstrated that RelA and NFKB1 expression maximally stimulated HIV - 1 LTR - and NF - kappa B - dependent reporter genes ; differences in NF - kappa B - like binding activity were also reflected in higher constitutive levels of NF - kappa B - regulated gene expression in HIV - 1 - infected myeloid cells . Presence of estrogen - binding sites on macrophage - like synoviocytes and CD8 + , CD29 + , CD45RO + T lymphocytes in normal and rheumatoid synovium . OBJECTIVE . To study the presence of estrogen - binding sites ( EBS ) in the synovial tissues of male and female patients with rheumatoid arthritis ( RA ) and in age - and sex - matched healthy controls . METHODS . Both type 1 ( high affinity , low binding capacity ) and type 2 ( reduced affinity , higher binding capacity ) EBS were investigated in both soluble and nuclear fractions of homogenized synovial tissue samples by a dextran - coated charcoal method . To determine what type of synovial cell was positive for EBS , cryosections of synovial tissues were immunostained with a specific monoclonal anti - estrogen receptor antibody ( anti - ER MAb ) using both immunofluorescence and immunoperoxidase techniques . Double immunostaining with the anti - ER MAb and with specific MAb to detect different macrophage antigens ( Ber - MAC3 , MAC387 , CD68 ) and CD8 + T cell subsets ( CD29 + , CD45RO + and CD29 - , CD45RO - ) was performed . RESULTS . Higher affinity EBS were found mostly in nuclear cell fractions of either RA or control synovial tissues ( 28 of the 33 ) . These EBS were present to a lesser extent in soluble cell fractions ( 11 of the 33 ) . Immunostaining showed the estrogen receptor - positive cells to be the macrophage - like synoviocytes and the CD8 + , CD29 + T cells both in RA and in control synovial tissues . Higher nuclear content of EBS was consistent with more intense nuclear staining of synoviocytes and T cells . CONCLUSION . It is conceivable that the immunomodulatory activity exerted by estrogens is at least partly mediated through their interaction with EBS that are present on macrophage - like synoviocytes , functioning as antigen - processing and antigen - presenting cells , and on antigen - experienced ( memory ) CD8 + T lymphocytes ( CD29 + , CD45RO +
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diff --git a/evaluation/benchmark/NCBI_disease_test_entities_mapping.jsonl b/evaluation/benchmark/NCBI_disease_test_entities_mapping.jsonl
new file mode 100644
index 0000000..bcffef4
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+++ b/evaluation/benchmark/NCBI_disease_test_entities_mapping.jsonl
@@ -0,0 +1,940 @@
+{"sentence_id": 0, "sentence_text": "Clustering of missense mutations in the ataxia - telangiectasia gene in a sporadic T - cell leukaemia .", "sentence_char_start_global": 0, "sentence_char_end_global": 103, "entities": [{"text": "ataxia - telangiectasia", "type": "ENTITY", "char_start": 40, "char_end": 63, "token_start": 6, "token_end": 8}, {"text": "sporadic T - cell leukaemia", "type": "ENTITY", "char_start": 74, "char_end": 101, "token_start": 12, "token_end": 16}], "entities_global": [{"text": "ataxia - telangiectasia", "type": "ENTITY", "char_start": 40, "char_end": 63, "token_start": 6, "token_end": 8, "note": null}, {"text": "sporadic T - cell leukaemia", "type": "ENTITY", "char_start": 74, "char_end": 101, "token_start": 12, "token_end": 16, "note": null}]}
+{"sentence_id": 1, "sentence_text": "Ataxia - telangiectasia ( A - T ) is a recessive multi - system disorder caused by mutations in the ATM gene at 11q22 - q23 ( ref . 3 ) .", "sentence_char_start_global": 104, "sentence_char_end_global": 241, "entities": [{"text": "Ataxia - telangiectasia", "type": "ENTITY", "char_start": 0, "char_end": 23, "token_start": 0, "token_end": 2}, {"text": "A - T", "type": "ENTITY", "char_start": 26, "char_end": 31, "token_start": 4, "token_end": 6}, {"text": "recessive multi - system disorder", "type": "ENTITY", "char_start": 39, "char_end": 72, "token_start": 10, "token_end": 14}], "entities_global": [{"text": "Ataxia - telangiectasia", "type": "ENTITY", "char_start": 104, "char_end": 127, "token_start": 0, "token_end": 2, "note": null}, {"text": "A - T", "type": "ENTITY", "char_start": 130, "char_end": 135, "token_start": 4, "token_end": 6, "note": null}, {"text": "recessive multi - system disorder", "type": "ENTITY", "char_start": 143, "char_end": 176, "token_start": 10, "token_end": 14, "note": null}]}
+{"sentence_id": 2, "sentence_text": "The risk of cancer , especially lymphoid neoplasias , is substantially elevated in A - T patients and has long been associated with chromosomal instability .", "sentence_char_start_global": 242, "sentence_char_end_global": 399, "entities": [{"text": "cancer", "type": "ENTITY", "char_start": 12, "char_end": 18, "token_start": 3, "token_end": 3}, {"text": "lymphoid neoplasias", "type": "ENTITY", "char_start": 32, "char_end": 51, "token_start": 6, "token_end": 7}, {"text": "A - T", "type": "ENTITY", "char_start": 83, "char_end": 88, "token_start": 13, "token_end": 15}], "entities_global": [{"text": "cancer", "type": "ENTITY", "char_start": 254, "char_end": 260, "token_start": 3, "token_end": 3, "note": null}, {"text": "lymphoid neoplasias", "type": "ENTITY", "char_start": 274, "char_end": 293, "token_start": 6, "token_end": 7, "note": null}, {"text": "A - T", "type": "ENTITY", "char_start": 325, "char_end": 330, "token_start": 13, "token_end": 15, "note": null}]}
+{"sentence_id": 3, "sentence_text": "By analysing tumour DNA from patients with sporadic T - cell prolymphocytic leukaemia ( T - PLL ) , a rare clonal malignancy with similarities to a mature T - cell leukaemia seen in A - T , we demonstrate a high frequency of ATM mutations in T - PLL .", "sentence_char_start_global": 400, "sentence_char_end_global": 651, "entities": [{"text": "tumour", "type": "ENTITY", "char_start": 13, "char_end": 19, "token_start": 2, "token_end": 2}, {"text": "sporadic T - cell prolymphocytic leukaemia", "type": "ENTITY", "char_start": 43, "char_end": 85, "token_start": 7, "token_end": 12}, {"text": "T - PLL", "type": "ENTITY", "char_start": 88, "char_end": 95, "token_start": 14, "token_end": 16}, {"text": "clonal malignancy", "type": "ENTITY", "char_start": 107, "char_end": 124, "token_start": 21, "token_end": 22}, {"text": "mature T - cell leukaemia", "type": "ENTITY", "char_start": 148, "char_end": 173, "token_start": 27, "token_end": 31}, {"text": "A - T", "type": "ENTITY", "char_start": 182, "char_end": 187, "token_start": 34, "token_end": 36}, {"text": "T - PLL", "type": "ENTITY", "char_start": 242, "char_end": 249, "token_start": 47, "token_end": 49}], "entities_global": [{"text": "tumour", "type": "ENTITY", "char_start": 413, "char_end": 419, "token_start": 2, "token_end": 2, "note": null}, {"text": "sporadic T - cell prolymphocytic leukaemia", "type": "ENTITY", "char_start": 443, "char_end": 485, "token_start": 7, "token_end": 12, "note": null}, {"text": "T - PLL", "type": "ENTITY", "char_start": 488, "char_end": 495, "token_start": 14, "token_end": 16, "note": null}, {"text": "clonal malignancy", "type": "ENTITY", "char_start": 507, "char_end": 524, "token_start": 21, "token_end": 22, "note": null}, {"text": "mature T - cell leukaemia", "type": "ENTITY", "char_start": 548, "char_end": 573, "token_start": 27, "token_end": 31, "note": null}, {"text": "A - T", "type": "ENTITY", "char_start": 582, "char_end": 587, "token_start": 34, "token_end": 36, "note": null}, {"text": "T - PLL", "type": "ENTITY", "char_start": 642, "char_end": 649, "token_start": 47, "token_end": 49, "note": null}]}
+{"sentence_id": 4, "sentence_text": "In marked contrast to the ATM mutation pattern in A - T , the most frequent nucleotide changes in this leukaemia were missense mutations .", "sentence_char_start_global": 652, "sentence_char_end_global": 790, "entities": [{"text": "A - T", "type": "ENTITY", "char_start": 50, "char_end": 55, "token_start": 9, "token_end": 11}, {"text": "leukaemia", "type": "ENTITY", "char_start": 103, "char_end": 112, "token_start": 20, "token_end": 20}], "entities_global": [{"text": "A - T", "type": "ENTITY", "char_start": 702, "char_end": 707, "token_start": 9, "token_end": 11, "note": null}, {"text": "leukaemia", "type": "ENTITY", "char_start": 755, "char_end": 764, "token_start": 20, "token_end": 20, "note": null}]}
+{"sentence_id": 5, "sentence_text": "These clustered in the region corresponding to the kinase domain , which is highly conserved in ATM - related proteins in mouse , yeast and Drosophila .", "sentence_char_start_global": 791, "sentence_char_end_global": 943, "entities": [], "entities_global": []}
+{"sentence_id": 6, "sentence_text": "The resulting amino - acid substitutions are predicted to interfere with ATP binding or substrate recognition .", "sentence_char_start_global": 944, "sentence_char_end_global": 1055, "entities": [], "entities_global": []}
+{"sentence_id": 7, "sentence_text": "Two of seventeen mutated T - PLL samples had a previously reported A - T allele .", "sentence_char_start_global": 1056, "sentence_char_end_global": 1137, "entities": [{"text": "T - PLL", "type": "ENTITY", "char_start": 25, "char_end": 32, "token_start": 4, "token_end": 6}, {"text": "A - T", "type": "ENTITY", "char_start": 67, "char_end": 72, "token_start": 12, "token_end": 14}], "entities_global": [{"text": "T - PLL", "type": "ENTITY", "char_start": 1081, "char_end": 1088, "token_start": 4, "token_end": 6, "note": null}, {"text": "A - T", "type": "ENTITY", "char_start": 1123, "char_end": 1128, "token_start": 12, "token_end": 14, "note": null}]}
+{"sentence_id": 8, "sentence_text": "In contrast , no mutations were detected in the p53 gene , suggesting that this tumour suppressor is not frequently altered in this leukaemia .", "sentence_char_start_global": 1138, "sentence_char_end_global": 1281, "entities": [{"text": "tumour", "type": "ENTITY", "char_start": 80, "char_end": 86, "token_start": 15, "token_end": 15}, {"text": "leukaemia", "type": "ENTITY", "char_start": 132, "char_end": 141, "token_start": 23, "token_end": 23}], "entities_global": [{"text": "tumour", "type": "ENTITY", "char_start": 1218, "char_end": 1224, "token_start": 15, "token_end": 15, "note": null}, {"text": "leukaemia", "type": "ENTITY", "char_start": 1270, "char_end": 1279, "token_start": 23, "token_end": 23, "note": null}]}
+{"sentence_id": 9, "sentence_text": "Occasional missense mutations in ATM were also found in tumour DNA from patients with B - cell non - Hodgkins lymphomas ( B - NHL ) and a B - NHL cell line .", "sentence_char_start_global": 1282, "sentence_char_end_global": 1439, "entities": [{"text": "tumour", "type": "ENTITY", "char_start": 56, "char_end": 62, "token_start": 9, "token_end": 9}, {"text": "B - cell non - Hodgkins lymphomas", "type": "ENTITY", "char_start": 86, "char_end": 119, "token_start": 14, "token_end": 20}, {"text": "B - NHL", "type": "ENTITY", "char_start": 122, "char_end": 129, "token_start": 22, "token_end": 24}, {"text": "B - NHL", "type": "ENTITY", "char_start": 138, "char_end": 145, "token_start": 28, "token_end": 30}], "entities_global": [{"text": "tumour", "type": "ENTITY", "char_start": 1338, "char_end": 1344, "token_start": 9, "token_end": 9, "note": null}, {"text": "B - cell non - Hodgkins lymphomas", "type": "ENTITY", "char_start": 1368, "char_end": 1401, "token_start": 14, "token_end": 20, "note": null}, {"text": "B - NHL", "type": "ENTITY", "char_start": 1404, "char_end": 1411, "token_start": 22, "token_end": 24, "note": null}, {"text": "B - NHL", "type": "ENTITY", "char_start": 1420, "char_end": 1427, "token_start": 28, "token_end": 30, "note": null}]}
+{"sentence_id": 10, "sentence_text": "The evidence of a significant proportion of loss - of - function mutations and a complete absence of the normal copy of ATM in the majority of mutated tumours establishes somatic inactivation of this gene in the pathogenesis of sporadic T - PLL and suggests that ATM acts as a tumour suppressor .", "sentence_char_start_global": 1440, "sentence_char_end_global": 1736, "entities": [{"text": "tumours", "type": "ENTITY", "char_start": 151, "char_end": 158, "token_start": 28, "token_end": 28}, {"text": "sporadic T - PLL", "type": "ENTITY", "char_start": 228, "char_end": 244, "token_start": 39, "token_end": 42}, {"text": "tumour", "type": "ENTITY", "char_start": 277, "char_end": 283, "token_start": 50, "token_end": 50}], "entities_global": [{"text": "tumours", "type": "ENTITY", "char_start": 1591, "char_end": 1598, "token_start": 28, "token_end": 28, "note": null}, {"text": "sporadic T - PLL", "type": "ENTITY", "char_start": 1668, "char_end": 1684, "token_start": 39, "token_end": 42, "note": null}, {"text": "tumour", "type": "ENTITY", "char_start": 1717, "char_end": 1723, "token_start": 50, "token_end": 50, "note": null}]}
+{"sentence_id": 11, "sentence_text": "As constitutional DNA was not available , a putative hereditary predisposition to T - PLL will require further investigation . .", "sentence_char_start_global": 1737, "sentence_char_end_global": 1865, "entities": [{"text": "T - PLL", "type": "ENTITY", "char_start": 82, "char_end": 89, "token_start": 12, "token_end": 14}], "entities_global": [{"text": "T - PLL", "type": "ENTITY", "char_start": 1819, "char_end": 1826, "token_start": 12, "token_end": 14, "note": null}]}
+{"sentence_id": 12, "sentence_text": "Myotonic dystrophy protein kinase is involved in the modulation of the Ca2 + homeostasis in skeletal muscle cells .", "sentence_char_start_global": 1866, "sentence_char_end_global": 1981, "entities": [{"text": "Myotonic dystrophy", "type": "ENTITY", "char_start": 0, "char_end": 18, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "Myotonic dystrophy", "type": "ENTITY", "char_start": 1866, "char_end": 1884, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 13, "sentence_text": "Myotonic dystrophy ( DM ) , the most prevalent muscular disorder in adults , is caused by ( CTG ) n - repeat expansion in a gene encoding a protein kinase ( DM protein kinase ; DMPK ) and involves changes in cytoarchitecture and ion homeostasis .", "sentence_char_start_global": 1982, "sentence_char_end_global": 2228, "entities": [{"text": "Myotonic dystrophy", "type": "ENTITY", "char_start": 0, "char_end": 18, "token_start": 0, "token_end": 1}, {"text": "DM", "type": "ENTITY", "char_start": 21, "char_end": 23, "token_start": 3, "token_end": 3}, {"text": "muscular disorder", "type": "ENTITY", "char_start": 47, "char_end": 64, "token_start": 9, "token_end": 10}, {"text": "DM", "type": "ENTITY", "char_start": 157, "char_end": 159, "token_start": 32, "token_end": 32}], "entities_global": [{"text": "Myotonic dystrophy", "type": "ENTITY", "char_start": 1982, "char_end": 2000, "token_start": 0, "token_end": 1, "note": null}, {"text": "DM", "type": "ENTITY", "char_start": 2003, "char_end": 2005, "token_start": 3, "token_end": 3, "note": null}, {"text": "muscular disorder", "type": "ENTITY", "char_start": 2029, "char_end": 2046, "token_start": 9, "token_end": 10, "note": null}, {"text": "DM", "type": "ENTITY", "char_start": 2139, "char_end": 2141, "token_start": 32, "token_end": 32, "note": null}]}
+{"sentence_id": 14, "sentence_text": "To obtain clues to the normal biological role of DMPK in cellular ion homeostasis , we have compared the resting [ Ca2 + ] i , the amplitude and shape of depolarization - induced Ca2 + transients , and the content of ATP - driven ion pumps in cultured skeletal muscle cells of wild - type and DMPK [ - / - ] knockout mice .", "sentence_char_start_global": 2229, "sentence_char_end_global": 2552, "entities": [], "entities_global": []}
+{"sentence_id": 15, "sentence_text": "In vitro - differentiated DMPK [ - / - ] myotubes exhibit a higher resting [ Ca2 + ] i than do wild - type myotubes because of an altered open probability of voltage - dependent l - type Ca2 + and Na + channels .", "sentence_char_start_global": 2553, "sentence_char_end_global": 2765, "entities": [], "entities_global": []}
+{"sentence_id": 16, "sentence_text": "The mutant myotubes exhibit smaller and slower Ca2 + responses upon triggering by acetylcholine or high external K + .", "sentence_char_start_global": 2766, "sentence_char_end_global": 2884, "entities": [], "entities_global": []}
+{"sentence_id": 17, "sentence_text": "In addition , we observed that these Ca2 + transients partially result from an influx of extracellular Ca2 + through the l - type Ca2 + channel .", "sentence_char_start_global": 2885, "sentence_char_end_global": 3030, "entities": [], "entities_global": []}
+{"sentence_id": 18, "sentence_text": "Neither the content nor the activity of Na + / K + ATPase and sarcoplasmic reticulum Ca2 + - ATPase are affected by DMPK absence .", "sentence_char_start_global": 3031, "sentence_char_end_global": 3161, "entities": [], "entities_global": []}
+{"sentence_id": 19, "sentence_text": "In conclusion , our data suggest that DMPK is involved in modulating the initial events of excitation - contraction coupling in skeletal muscle . .", "sentence_char_start_global": 3162, "sentence_char_end_global": 3309, "entities": [], "entities_global": []}
+{"sentence_id": 20, "sentence_text": "Constitutional RB1 - gene mutations in patients with isolated unilateral retinoblastoma .", "sentence_char_start_global": 3310, "sentence_char_end_global": 3399, "entities": [{"text": "unilateral retinoblastoma", "type": "ENTITY", "char_start": 62, "char_end": 87, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "unilateral retinoblastoma", "type": "ENTITY", "char_start": 3372, "char_end": 3397, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 21, "sentence_text": "In most patients with isolated unilateral retinoblastoma , tumor development is initiated by somatic inactivation of both alleles of the RB1 gene .", "sentence_char_start_global": 3400, "sentence_char_end_global": 3547, "entities": [{"text": "unilateral retinoblastoma", "type": "ENTITY", "char_start": 31, "char_end": 56, "token_start": 5, "token_end": 6}, {"text": "tumor", "type": "ENTITY", "char_start": 59, "char_end": 64, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "unilateral retinoblastoma", "type": "ENTITY", "char_start": 3431, "char_end": 3456, "token_start": 5, "token_end": 6, "note": null}, {"text": "tumor", "type": "ENTITY", "char_start": 3459, "char_end": 3464, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 22, "sentence_text": "However , some of these patients can transmit retinoblastoma predisposition to their offspring .", "sentence_char_start_global": 3548, "sentence_char_end_global": 3644, "entities": [{"text": "retinoblastoma", "type": "ENTITY", "char_start": 46, "char_end": 60, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "retinoblastoma", "type": "ENTITY", "char_start": 3594, "char_end": 3608, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 23, "sentence_text": "To determine the frequency and nature of constitutional RB1 - gene mutations in patients with isolated unilateral retinoblastoma , we analyzed DNA from peripheral blood and from tumor tissue .", "sentence_char_start_global": 3645, "sentence_char_end_global": 3837, "entities": [{"text": "unilateral retinoblastoma", "type": "ENTITY", "char_start": 103, "char_end": 128, "token_start": 16, "token_end": 17}, {"text": "tumor", "type": "ENTITY", "char_start": 178, "char_end": 183, "token_start": 27, "token_end": 27}], "entities_global": [{"text": "unilateral retinoblastoma", "type": "ENTITY", "char_start": 3748, "char_end": 3773, "token_start": 16, "token_end": 17, "note": null}, {"text": "tumor", "type": "ENTITY", "char_start": 3823, "char_end": 3828, "token_start": 27, "token_end": 27, "note": null}]}
+{"sentence_id": 24, "sentence_text": "The analysis of tumors from 54 ( 71 % ) of 76 informative patients showed loss of constitutional heterozygosity ( LOH ) at intragenic loci .", "sentence_char_start_global": 3838, "sentence_char_end_global": 3978, "entities": [{"text": "tumors", "type": "ENTITY", "char_start": 16, "char_end": 22, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "tumors", "type": "ENTITY", "char_start": 3854, "char_end": 3860, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 25, "sentence_text": "Three of 13 uninformative patients had constitutional deletions .", "sentence_char_start_global": 3979, "sentence_char_end_global": 4044, "entities": [], "entities_global": []}
+{"sentence_id": 26, "sentence_text": "For 39 randomly selected tumors , SSCP , hetero - duplex analysis , sequencing , and Southern blot analysis were used to identify mutations .", "sentence_char_start_global": 4045, "sentence_char_end_global": 4186, "entities": [{"text": "tumors", "type": "ENTITY", "char_start": 25, "char_end": 31, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "tumors", "type": "ENTITY", "char_start": 4070, "char_end": 4076, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 27, "sentence_text": "Mutations were detected in 21 ( 91 % ) of 23 tumors with LOH .", "sentence_char_start_global": 4187, "sentence_char_end_global": 4249, "entities": [{"text": "tumors", "type": "ENTITY", "char_start": 45, "char_end": 51, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "tumors", "type": "ENTITY", "char_start": 4232, "char_end": 4238, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 28, "sentence_text": "In 6 ( 38 % ) of 16 tumors without LOH , one mutation was detected , and in 9 ( 56 % ) of the tumors without LOH , both mutations were found .", "sentence_char_start_global": 4250, "sentence_char_end_global": 4392, "entities": [{"text": "tumors", "type": "ENTITY", "char_start": 20, "char_end": 26, "token_start": 8, "token_end": 8}, {"text": "tumors", "type": "ENTITY", "char_start": 94, "char_end": 100, "token_start": 26, "token_end": 26}], "entities_global": [{"text": "tumors", "type": "ENTITY", "char_start": 4270, "char_end": 4276, "token_start": 8, "token_end": 8, "note": null}, {"text": "tumors", "type": "ENTITY", "char_start": 4344, "char_end": 4350, "token_start": 26, "token_end": 26, "note": null}]}
+{"sentence_id": 29, "sentence_text": "Thus , a total of 45 mutations were identified in tumors of 36 patients .", "sentence_char_start_global": 4393, "sentence_char_end_global": 4466, "entities": [{"text": "tumors", "type": "ENTITY", "char_start": 50, "char_end": 56, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "tumors", "type": "ENTITY", "char_start": 4443, "char_end": 4449, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 30, "sentence_text": "Thirty - nine of the mutations - including 34 small mutations , 2 large structural alterations , and hypermethylation in 3 tumors - were not detected in the corresponding peripheral blood DNA .", "sentence_char_start_global": 4467, "sentence_char_end_global": 4660, "entities": [], "entities_global": []}
+{"sentence_id": 31, "sentence_text": "In 6 ( 17 % ) of the 36 patients , a mutation was detected in constitutional DNA , and 1 of these mutations is known to be associated with reduced expressivity .", "sentence_char_start_global": 4661, "sentence_char_end_global": 4822, "entities": [], "entities_global": []}
+{"sentence_id": 32, "sentence_text": "The presence of a constitutional mutation was not associated with an early age at treatment .", "sentence_char_start_global": 4823, "sentence_char_end_global": 4916, "entities": [], "entities_global": []}
+{"sentence_id": 33, "sentence_text": "In 1 patient , somatic mosaicism was demonstrated by molecular analysis of DNA and RNA from peripheral blood .", "sentence_char_start_global": 4917, "sentence_char_end_global": 5027, "entities": [], "entities_global": []}
+{"sentence_id": 34, "sentence_text": "In 2 patients without a detectable mutation in peripheral blood , mosaicism was suggested because 1 of the patients showed multifocal tumors and the other later developed bilateral retinoblastoma .", "sentence_char_start_global": 5028, "sentence_char_end_global": 5225, "entities": [{"text": "tumors", "type": "ENTITY", "char_start": 134, "char_end": 140, "token_start": 21, "token_end": 21}, {"text": "bilateral retinoblastoma", "type": "ENTITY", "char_start": 171, "char_end": 195, "token_start": 27, "token_end": 28}], "entities_global": [{"text": "tumors", "type": "ENTITY", "char_start": 5162, "char_end": 5168, "token_start": 21, "token_end": 21, "note": null}, {"text": "bilateral retinoblastoma", "type": "ENTITY", "char_start": 5199, "char_end": 5223, "token_start": 27, "token_end": 28, "note": null}]}
+{"sentence_id": 35, "sentence_text": "In conclusion , our results emphasize that the manifestation and transmissibility of retinoblastoma depend on the nature of the first mutation , its time in development , and the number and types of cells that are affected . .", "sentence_char_start_global": 5226, "sentence_char_end_global": 5452, "entities": [{"text": "retinoblastoma", "type": "ENTITY", "char_start": 85, "char_end": 99, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "retinoblastoma", "type": "ENTITY", "char_start": 5311, "char_end": 5325, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 36, "sentence_text": "Hereditary deficiency of the fifth component of complement in man .", "sentence_char_start_global": 5453, "sentence_char_end_global": 5520, "entities": [{"text": "Hereditary deficiency of the fifth component of complement", "type": "ENTITY", "char_start": 0, "char_end": 58, "token_start": 0, "token_end": 7}], "entities_global": [{"text": "Hereditary deficiency of the fifth component of complement", "type": "ENTITY", "char_start": 5453, "char_end": 5511, "token_start": 0, "token_end": 7, "note": null}]}
+{"sentence_id": 37, "sentence_text": "I .", "sentence_char_start_global": 5521, "sentence_char_end_global": 5524, "entities": [], "entities_global": []}
+{"sentence_id": 38, "sentence_text": "Clinical , immunochemical , and family studies .", "sentence_char_start_global": 5525, "sentence_char_end_global": 5573, "entities": [], "entities_global": []}
+{"sentence_id": 39, "sentence_text": "The first recognized human kindred with hereditary deficiency of the fifth component of complement ( C5 ) is described .", "sentence_char_start_global": 5574, "sentence_char_end_global": 5694, "entities": [{"text": "hereditary deficiency of the fifth component of complement", "type": "ENTITY", "char_start": 40, "char_end": 98, "token_start": 6, "token_end": 13}], "entities_global": [{"text": "hereditary deficiency of the fifth component of complement", "type": "ENTITY", "char_start": 5614, "char_end": 5672, "token_start": 6, "token_end": 13, "note": null}]}
+{"sentence_id": 40, "sentence_text": "The proband , a 20 - year - old black female with systemic lupus erythematosus since age 11 , lacked serum hemolytic complement activity , even during remission .", "sentence_char_start_global": 5695, "sentence_char_end_global": 5857, "entities": [{"text": "systemic lupus erythematosus", "type": "ENTITY", "char_start": 50, "char_end": 78, "token_start": 12, "token_end": 14}], "entities_global": [{"text": "systemic lupus erythematosus", "type": "ENTITY", "char_start": 5745, "char_end": 5773, "token_start": 12, "token_end": 14, "note": null}]}
+{"sentence_id": 41, "sentence_text": "C5 was undetectable in her serum by both immunodiffusion and hemolytic assays .", "sentence_char_start_global": 5858, "sentence_char_end_global": 5937, "entities": [], "entities_global": []}
+{"sentence_id": 42, "sentence_text": "Other complement components were normal during remission of lupus , but C1 , C4 , C2 , and C3 levels fell during exacerbations .", "sentence_char_start_global": 5938, "sentence_char_end_global": 6066, "entities": [], "entities_global": []}
+{"sentence_id": 43, "sentence_text": "A younger half - sister , who had no underlying disease , was also found to lack immunochemically detectable C5 .", "sentence_char_start_global": 6067, "sentence_char_end_global": 6180, "entities": [], "entities_global": []}
+{"sentence_id": 44, "sentence_text": "By hemolytic assay , she exhibited 1 - 2 % of the normal serum C5 level and normal concentrations of other complement components .", "sentence_char_start_global": 6181, "sentence_char_end_global": 6311, "entities": [], "entities_global": []}
+{"sentence_id": 45, "sentence_text": "C5 levels of other family members were either normal or approximately half - normal , consistent with autosomal codominant inheritance of the gene determining C5 deficiency .", "sentence_char_start_global": 6312, "sentence_char_end_global": 6486, "entities": [{"text": "C5 deficiency", "type": "ENTITY", "char_start": 159, "char_end": 172, "token_start": 24, "token_end": 25}], "entities_global": [{"text": "C5 deficiency", "type": "ENTITY", "char_start": 6471, "char_end": 6484, "token_start": 24, "token_end": 25, "note": null}]}
+{"sentence_id": 46, "sentence_text": "Normal hemolytic titers were restored to both homozygous C5 - deficient ( C5D ) sera by addition of highly purified human C5 .", "sentence_char_start_global": 6487, "sentence_char_end_global": 6613, "entities": [{"text": "C5 - deficient", "type": "ENTITY", "char_start": 57, "char_end": 71, "token_start": 8, "token_end": 10}, {"text": "C5D", "type": "ENTITY", "char_start": 74, "char_end": 77, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "C5 - deficient", "type": "ENTITY", "char_start": 6544, "char_end": 6558, "token_start": 8, "token_end": 10, "note": null}, {"text": "C5D", "type": "ENTITY", "char_start": 6561, "char_end": 6564, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 47, "sentence_text": "In specific C5 titrations , however , it was noted that when limited amounts of C5 were assayed in the presence of low dilutions of either C5D serum , curving rather than linear dose - response plots were consistently obtained , suggesting some inhibitory effect .", "sentence_char_start_global": 6614, "sentence_char_end_global": 6878, "entities": [{"text": "C5D", "type": "ENTITY", "char_start": 139, "char_end": 142, "token_start": 26, "token_end": 26}], "entities_global": [{"text": "C5D", "type": "ENTITY", "char_start": 6753, "char_end": 6756, "token_start": 26, "token_end": 26, "note": null}]}
+{"sentence_id": 48, "sentence_text": "Further studies suggested that low dilutions of C5D serum contain a factor ( or factors ) interfering at some step in the hemolytic assay of C5 , rather than a true C5 inhibitor or inactivator .", "sentence_char_start_global": 6879, "sentence_char_end_global": 7073, "entities": [{"text": "C5D", "type": "ENTITY", "char_start": 48, "char_end": 51, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "C5D", "type": "ENTITY", "char_start": 6927, "char_end": 6930, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 49, "sentence_text": "Of clinical interest are ( a ) the documentation of membranous glomerulonephritis , vasculitis , and arthritis in an individual lacking C5 ( and its biologic functions ) , and ( b ) a remarkable propensity to bacterial infections in the proband , even during periods of low - dose or alternate - day corticosteroid therapy .", "sentence_char_start_global": 7074, "sentence_char_end_global": 7398, "entities": [{"text": "glomerulonephritis", "type": "ENTITY", "char_start": 63, "char_end": 81, "token_start": 11, "token_end": 11}, {"text": "vasculitis", "type": "ENTITY", "char_start": 84, "char_end": 94, "token_start": 13, "token_end": 13}, {"text": "arthritis", "type": "ENTITY", "char_start": 101, "char_end": 110, "token_start": 16, "token_end": 16}, {"text": "bacterial infections", "type": "ENTITY", "char_start": 209, "char_end": 229, "token_start": 37, "token_end": 38}], "entities_global": [{"text": "glomerulonephritis", "type": "ENTITY", "char_start": 7137, "char_end": 7155, "token_start": 11, "token_end": 11, "note": null}, {"text": "vasculitis", "type": "ENTITY", "char_start": 7158, "char_end": 7168, "token_start": 13, "token_end": 13, "note": null}, {"text": "arthritis", "type": "ENTITY", "char_start": 7175, "char_end": 7184, "token_start": 16, "token_end": 16, "note": null}, {"text": "bacterial infections", "type": "ENTITY", "char_start": 7283, "char_end": 7303, "token_start": 37, "token_end": 38, "note": null}]}
+{"sentence_id": 50, "sentence_text": "Other observations indicate that the C5D state is compatible with normal coagulation function and the capacity to mount a neutrophilic leukocytosis during pyogenic infection . .", "sentence_char_start_global": 7399, "sentence_char_end_global": 7576, "entities": [{"text": "C5D", "type": "ENTITY", "char_start": 37, "char_end": 40, "token_start": 5, "token_end": 5}, {"text": "pyogenic infection", "type": "ENTITY", "char_start": 155, "char_end": 173, "token_start": 22, "token_end": 23}], "entities_global": [{"text": "C5D", "type": "ENTITY", "char_start": 7436, "char_end": 7439, "token_start": 5, "token_end": 5, "note": null}, {"text": "pyogenic infection", "type": "ENTITY", "char_start": 7554, "char_end": 7572, "token_start": 22, "token_end": 23, "note": null}]}
+{"sentence_id": 51, "sentence_text": "Susceptibility to ankylosing spondylitis in twins : the role of genes , HLA , and the environment .", "sentence_char_start_global": 7577, "sentence_char_end_global": 7676, "entities": [{"text": "ankylosing spondylitis", "type": "ENTITY", "char_start": 18, "char_end": 40, "token_start": 2, "token_end": 3}], "entities_global": [{"text": "ankylosing spondylitis", "type": "ENTITY", "char_start": 7595, "char_end": 7617, "token_start": 2, "token_end": 3, "note": null}]}
+{"sentence_id": 52, "sentence_text": "OBJECTIVE To determine the relative effects of genetic and environmental factors in susceptibility to ankylosing spondylitis ( AS ) .", "sentence_char_start_global": 7677, "sentence_char_end_global": 7810, "entities": [{"text": "ankylosing spondylitis", "type": "ENTITY", "char_start": 102, "char_end": 124, "token_start": 14, "token_end": 15}, {"text": "AS", "type": "ENTITY", "char_start": 127, "char_end": 129, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "ankylosing spondylitis", "type": "ENTITY", "char_start": 7779, "char_end": 7801, "token_start": 14, "token_end": 15, "note": null}, {"text": "AS", "type": "ENTITY", "char_start": 7804, "char_end": 7806, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 53, "sentence_text": "METHODS Twins with AS were identified from the Royal National Hospital for Rheumatic Diseases database .", "sentence_char_start_global": 7811, "sentence_char_end_global": 7915, "entities": [{"text": "AS", "type": "ENTITY", "char_start": 19, "char_end": 21, "token_start": 3, "token_end": 3}, {"text": "Rheumatic Diseases", "type": "ENTITY", "char_start": 75, "char_end": 93, "token_start": 12, "token_end": 13}], "entities_global": [{"text": "AS", "type": "ENTITY", "char_start": 7830, "char_end": 7832, "token_start": 3, "token_end": 3, "note": null}, {"text": "Rheumatic Diseases", "type": "ENTITY", "char_start": 7886, "char_end": 7904, "token_start": 12, "token_end": 13, "note": null}]}
+{"sentence_id": 54, "sentence_text": "Clinical and radiographic examinations were performed to establish diagnoses , and disease severity was assessed using a combination of validated scoring systems .", "sentence_char_start_global": 7916, "sentence_char_end_global": 8079, "entities": [], "entities_global": []}
+{"sentence_id": 55, "sentence_text": "HLA typing for HLA - B27 , HLA - B60 , and HLA - DR1 was performed by polymerase chain reaction with sequence - specific primers , and zygosity was assessed using microsatellite markers .", "sentence_char_start_global": 8080, "sentence_char_end_global": 8267, "entities": [], "entities_global": []}
+{"sentence_id": 56, "sentence_text": "Genetic and environmental variance components were assessed with the program Mx , using data from this and previous studies of twins with AS .", "sentence_char_start_global": 8268, "sentence_char_end_global": 8410, "entities": [{"text": "AS", "type": "ENTITY", "char_start": 138, "char_end": 140, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "AS", "type": "ENTITY", "char_start": 8406, "char_end": 8408, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 57, "sentence_text": "RESULTS Six of 8 monozygotic ( MZ ) twin pairs were disease concordant , compared with 4 of 15 B27 - positive dizygotic ( DZ ) twin pairs ( 27 % ) and 4 of 32 DZ twin pairs overall ( 12 . 5 % ) .", "sentence_char_start_global": 8411, "sentence_char_end_global": 8606, "entities": [], "entities_global": []}
+{"sentence_id": 58, "sentence_text": "Nonsignificant increases in similarity with regard to age at disease onset and all of the disease severity scores assessed were noted in disease - concordant MZ twins compared with concordant DZ twins .", "sentence_char_start_global": 8607, "sentence_char_end_global": 8809, "entities": [], "entities_global": []}
+{"sentence_id": 59, "sentence_text": "HLA - B27 and B60 were associated with the disease in probands , and the rate of disease concordance was significantly increased among DZ twin pairs in which the co - twin was positive for both B27 and DR1 .", "sentence_char_start_global": 8810, "sentence_char_end_global": 9017, "entities": [], "entities_global": []}
+{"sentence_id": 60, "sentence_text": "Additive genetic effects were estimated to contribute 97 % of the population variance .", "sentence_char_start_global": 9018, "sentence_char_end_global": 9105, "entities": [], "entities_global": []}
+{"sentence_id": 61, "sentence_text": "CONCLUSION Susceptibility to AS is largely genetically determined , and the environmental trigger for the disease is probably ubiquitous .", "sentence_char_start_global": 9106, "sentence_char_end_global": 9244, "entities": [{"text": "AS", "type": "ENTITY", "char_start": 29, "char_end": 31, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "AS", "type": "ENTITY", "char_start": 9135, "char_end": 9137, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 62, "sentence_text": "HLA - B27 accounts for a minority of the overall genetic susceptibility to AS .", "sentence_char_start_global": 9245, "sentence_char_end_global": 9324, "entities": [{"text": "AS", "type": "ENTITY", "char_start": 75, "char_end": 77, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "AS", "type": "ENTITY", "char_start": 9320, "char_end": 9322, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 63, "sentence_text": "Cell cycle - dependent colocalization of BARD1 and BRCA1 proteins in discrete nuclear domains .", "sentence_char_start_global": 9325, "sentence_char_end_global": 9420, "entities": [], "entities_global": []}
+{"sentence_id": 64, "sentence_text": "Germ - line mutations of the BRCA1 gene predispose women to early - onset breast and ovarian cancer by compromising the genes presumptive function as a tumor suppressor .", "sentence_char_start_global": 9421, "sentence_char_end_global": 9591, "entities": [{"text": "breast and ovarian cancer", "type": "ENTITY", "char_start": 74, "char_end": 99, "token_start": 14, "token_end": 17}, {"text": "tumor", "type": "ENTITY", "char_start": 152, "char_end": 157, "token_start": 26, "token_end": 26}], "entities_global": [{"text": "breast and ovarian cancer", "type": "ENTITY", "char_start": 9495, "char_end": 9520, "token_start": 14, "token_end": 17, "note": null}, {"text": "tumor", "type": "ENTITY", "char_start": 9573, "char_end": 9578, "token_start": 26, "token_end": 26, "note": null}]}
+{"sentence_id": 65, "sentence_text": "Although the biochemical properties of BRCA1 polypeptides are not understood , their expression pattern and subcellular localization suggest a role in cell - cycle regulation .", "sentence_char_start_global": 9592, "sentence_char_end_global": 9768, "entities": [], "entities_global": []}
+{"sentence_id": 66, "sentence_text": "When resting cells are induced to proliferate , the steady - state levels of BRCA1 increase in late G1 and reach a maximum during S phase .", "sentence_char_start_global": 9769, "sentence_char_end_global": 9908, "entities": [], "entities_global": []}
+{"sentence_id": 67, "sentence_text": "Moreover , in S phase cells , BRCA1 polypeptides are hyperphosphorylated and accumulate into discrete subnuclear foci termed \" BRCA1 nuclear dots .", "sentence_char_start_global": 9909, "sentence_char_end_global": 10056, "entities": [], "entities_global": []}
+{"sentence_id": 68, "sentence_text": "\" BRCA1 associates in vivo with a structurally related protein termed BARD1 .", "sentence_char_start_global": 10057, "sentence_char_end_global": 10134, "entities": [], "entities_global": []}
+{"sentence_id": 69, "sentence_text": "Here we show that the steady - state levels of BARD1 , unlike those of BRCA1 , remain relatively constant during cell cycle progression .", "sentence_char_start_global": 10135, "sentence_char_end_global": 10272, "entities": [], "entities_global": []}
+{"sentence_id": 70, "sentence_text": "However , immunostaining revealed that BARD1 resides within BRCA1 nuclear dots during S phase of the cell cycle , but not during the G1 phase .", "sentence_char_start_global": 10273, "sentence_char_end_global": 10416, "entities": [], "entities_global": []}
+{"sentence_id": 71, "sentence_text": "Nevertheless , BARD1 polypeptides are found exclusively in the nuclear fractions of both G1 - and S - phase cells .", "sentence_char_start_global": 10417, "sentence_char_end_global": 10532, "entities": [], "entities_global": []}
+{"sentence_id": 72, "sentence_text": "Therefore , progression to S phase is accompanied by the aggregation of nuclear BARD1 polypeptides into BRCA1 nuclear dots .", "sentence_char_start_global": 10533, "sentence_char_end_global": 10657, "entities": [], "entities_global": []}
+{"sentence_id": 73, "sentence_text": "This cell cycle - dependent colocalization of BARD1 and BRCA1 indicates a role for BARD1 in BRCA1 - mediated tumor suppression .", "sentence_char_start_global": 10658, "sentence_char_end_global": 10786, "entities": [{"text": "tumor", "type": "ENTITY", "char_start": 109, "char_end": 114, "token_start": 19, "token_end": 19}], "entities_global": [{"text": "tumor", "type": "ENTITY", "char_start": 10767, "char_end": 10772, "token_start": 19, "token_end": 19, "note": null}]}
+{"sentence_id": 74, "sentence_text": "Ethnic differences in the HFE codon 282 ( Cys / Tyr ) polymorphism .", "sentence_char_start_global": 10787, "sentence_char_end_global": 10855, "entities": [], "entities_global": []}
+{"sentence_id": 75, "sentence_text": "Recent studies have shown that hereditary hemochromatosis ( HH ) is likely to be caused by homozygosity for a Cys282Tyr mutation in the HFE gene located 4 .", "sentence_char_start_global": 10856, "sentence_char_end_global": 11012, "entities": [{"text": "hereditary hemochromatosis", "type": "ENTITY", "char_start": 31, "char_end": 57, "token_start": 5, "token_end": 6}, {"text": "HH", "type": "ENTITY", "char_start": 60, "char_end": 62, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "hereditary hemochromatosis", "type": "ENTITY", "char_start": 10887, "char_end": 10913, "token_start": 5, "token_end": 6, "note": null}, {"text": "HH", "type": "ENTITY", "char_start": 10916, "char_end": 10918, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 76, "sentence_text": "5 Mb telomeric to HLA - A .", "sentence_char_start_global": 11013, "sentence_char_end_global": 11040, "entities": [], "entities_global": []}
+{"sentence_id": 77, "sentence_text": "Population studies of this polymorphism are facilitated by the fact that the Cys282Tyr mutation creates a Rsal restriction site .", "sentence_char_start_global": 11041, "sentence_char_end_global": 11170, "entities": [], "entities_global": []}
+{"sentence_id": 78, "sentence_text": "We have studied the codon 282 ( Cys / Tyr ) polymorphism in different ethnic groups .", "sentence_char_start_global": 11171, "sentence_char_end_global": 11256, "entities": [], "entities_global": []}
+{"sentence_id": 79, "sentence_text": "In agreement with previous observations the Tyr allele appeared to be rare or absent in Asiatic ( Indian , Chinese ) populations .", "sentence_char_start_global": 11257, "sentence_char_end_global": 11387, "entities": [], "entities_global": []}
+{"sentence_id": 80, "sentence_text": "The highest allele frequency ( 7 . 5 % ) was found in Swedes .", "sentence_char_start_global": 11388, "sentence_char_end_global": 11450, "entities": [], "entities_global": []}
+{"sentence_id": 81, "sentence_text": "Saamis ( 2 % ) and Mordvinians ( 1 . 8 % ) had significantly lower frequencies of the Tyr allele .", "sentence_char_start_global": 11451, "sentence_char_end_global": 11549, "entities": [], "entities_global": []}
+{"sentence_id": 82, "sentence_text": "Comparisons with allele frequencies based on prevalence estimates of HH showed some disagreements with the RFLP data , particularly in Finns .", "sentence_char_start_global": 11550, "sentence_char_end_global": 11692, "entities": [{"text": "HH", "type": "ENTITY", "char_start": 69, "char_end": 71, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "HH", "type": "ENTITY", "char_start": 11619, "char_end": 11621, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 83, "sentence_text": "The newly described HFE marker provides a new approach to the screening of HH as well as studies of the relationship between the HFE Tyr allele and different disorders including cancer", "sentence_char_start_global": 11693, "sentence_char_end_global": 11877, "entities": [{"text": "HH", "type": "ENTITY", "char_start": 75, "char_end": 77, "token_start": 13, "token_end": 13}, {"text": "cancer", "type": "ENTITY", "char_start": 178, "char_end": 184, "token_start": 30, "token_end": 30}], "entities_global": [{"text": "HH", "type": "ENTITY", "char_start": 11768, "char_end": 11770, "token_start": 13, "token_end": 13, "note": null}, {"text": "cancer", "type": "ENTITY", "char_start": 11871, "char_end": 11877, "token_start": 30, "token_end": 30, "note": null}]}
+{"sentence_id": 84, "sentence_text": "Autosomal dominant neurohypophyseal diabetes insipidus associated with a missense mutation encoding Gly23 - - > Val in neurophysin II .", "sentence_char_start_global": 11878, "sentence_char_end_global": 12013, "entities": [{"text": "Autosomal dominant neurohypophyseal diabetes insipidus", "type": "ENTITY", "char_start": 0, "char_end": 54, "token_start": 0, "token_end": 4}], "entities_global": [{"text": "Autosomal dominant neurohypophyseal diabetes insipidus", "type": "ENTITY", "char_start": 11878, "char_end": 11932, "token_start": 0, "token_end": 4, "note": null}]}
+{"sentence_id": 85, "sentence_text": "Autosomal dominant neurohypophyseal diabetes insipidus ( ADNDI ) is an inherited disease caused by progressive degeneration of the magnocellular neurons of the hypothalamus leading to decreased ability to produce the hormone arginine vasopressin ( AVP ) .", "sentence_char_start_global": 12014, "sentence_char_end_global": 12269, "entities": [{"text": "Autosomal dominant neurohypophyseal diabetes insipidus", "type": "ENTITY", "char_start": 0, "char_end": 54, "token_start": 0, "token_end": 4}, {"text": "ADNDI", "type": "ENTITY", "char_start": 57, "char_end": 62, "token_start": 6, "token_end": 6}, {"text": "inherited disease", "type": "ENTITY", "char_start": 71, "char_end": 88, "token_start": 10, "token_end": 11}], "entities_global": [{"text": "Autosomal dominant neurohypophyseal diabetes insipidus", "type": "ENTITY", "char_start": 12014, "char_end": 12068, "token_start": 0, "token_end": 4, "note": null}, {"text": "ADNDI", "type": "ENTITY", "char_start": 12071, "char_end": 12076, "token_start": 6, "token_end": 6, "note": null}, {"text": "inherited disease", "type": "ENTITY", "char_start": 12085, "char_end": 12102, "token_start": 10, "token_end": 11, "note": null}]}
+{"sentence_id": 86, "sentence_text": "Affected individuals are not symptomatic at birth , but usually develop diabetes insipidus at 1 - 6 yr of age .", "sentence_char_start_global": 12270, "sentence_char_end_global": 12381, "entities": [{"text": "diabetes insipidus", "type": "ENTITY", "char_start": 72, "char_end": 90, "token_start": 11, "token_end": 12}], "entities_global": [{"text": "diabetes insipidus", "type": "ENTITY", "char_start": 12342, "char_end": 12360, "token_start": 11, "token_end": 12, "note": null}]}
+{"sentence_id": 87, "sentence_text": "The genetic locus of the disease is the AVP - neurophysin II ( NPII ) gene , and mutations that cause ADNDI have been found in both the signal peptide of the prepro - AVP - NPII precursor and within NPII itself .", "sentence_char_start_global": 12382, "sentence_char_end_global": 12594, "entities": [{"text": "ADNDI", "type": "ENTITY", "char_start": 102, "char_end": 107, "token_start": 21, "token_end": 21}], "entities_global": [{"text": "ADNDI", "type": "ENTITY", "char_start": 12484, "char_end": 12489, "token_start": 21, "token_end": 21, "note": null}]}
+{"sentence_id": 88, "sentence_text": "An affected girl who presented at 9 months of age and her similarly affected younger brother and father were all found to have a novel missense mutation ( G1758 - - > T ) encoding the amino acid substitution Gly23 - - > Val within NPII .", "sentence_char_start_global": 12595, "sentence_char_end_global": 12832, "entities": [], "entities_global": []}
+{"sentence_id": 89, "sentence_text": "The mutation was confirmed by restriction endonuclease analysis .", "sentence_char_start_global": 12833, "sentence_char_end_global": 12898, "entities": [], "entities_global": []}
+{"sentence_id": 90, "sentence_text": "A T1 - weighted magnetic resonance imaging of the fathers pituitary gland demonstrates an attenuated posterior pituitary bright spot .", "sentence_char_start_global": 12899, "sentence_char_end_global": 13033, "entities": [], "entities_global": []}
+{"sentence_id": 91, "sentence_text": "This mutation may be valuable for developing models of dominantly inherited neurodegeneration , as the early age of onset of symptoms suggests that this mutation may be particularly deleterious to the magnocellular neuron . .", "sentence_char_start_global": 13034, "sentence_char_end_global": 13259, "entities": [{"text": "dominantly inherited neurodegeneration", "type": "ENTITY", "char_start": 55, "char_end": 93, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "dominantly inherited neurodegeneration", "type": "ENTITY", "char_start": 13089, "char_end": 13127, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 92, "sentence_text": "Frequent inactivation of PTEN / MMAC1 in primary prostate cancer .", "sentence_char_start_global": 13260, "sentence_char_end_global": 13326, "entities": [{"text": "prostate cancer", "type": "ENTITY", "char_start": 49, "char_end": 64, "token_start": 8, "token_end": 9}], "entities_global": [{"text": "prostate cancer", "type": "ENTITY", "char_start": 13309, "char_end": 13324, "token_start": 8, "token_end": 9, "note": null}]}
+{"sentence_id": 93, "sentence_text": "Sporadic prostate carcinoma is the most common male cancer in the Western world , yet many of the major genetic events involved in the progression of this often fatal cancer remain to be elucidated .", "sentence_char_start_global": 13327, "sentence_char_end_global": 13526, "entities": [{"text": "Sporadic prostate carcinoma", "type": "ENTITY", "char_start": 0, "char_end": 27, "token_start": 0, "token_end": 2}, {"text": "male cancer", "type": "ENTITY", "char_start": 47, "char_end": 58, "token_start": 7, "token_end": 8}, {"text": "cancer", "type": "ENTITY", "char_start": 167, "char_end": 173, "token_start": 29, "token_end": 29}], "entities_global": [{"text": "Sporadic prostate carcinoma", "type": "ENTITY", "char_start": 13327, "char_end": 13354, "token_start": 0, "token_end": 2, "note": null}, {"text": "male cancer", "type": "ENTITY", "char_start": 13374, "char_end": 13385, "token_start": 7, "token_end": 8, "note": null}, {"text": "cancer", "type": "ENTITY", "char_start": 13494, "char_end": 13500, "token_start": 29, "token_end": 29, "note": null}]}
+{"sentence_id": 94, "sentence_text": "Numerous cytogenetic and allelotype studies have reported frequent loss of heterozygosity on chromosomal arm 10q in sporadic prostate cancer .", "sentence_char_start_global": 13527, "sentence_char_end_global": 13669, "entities": [{"text": "sporadic prostate cancer", "type": "ENTITY", "char_start": 116, "char_end": 140, "token_start": 16, "token_end": 18}], "entities_global": [{"text": "sporadic prostate cancer", "type": "ENTITY", "char_start": 13643, "char_end": 13667, "token_start": 16, "token_end": 18, "note": null}]}
+{"sentence_id": 95, "sentence_text": "Deletion mapping studies have unambiguously identified a region of chromosome 10q23 to be the minimal area of loss .", "sentence_char_start_global": 13670, "sentence_char_end_global": 13786, "entities": [], "entities_global": []}
+{"sentence_id": 96, "sentence_text": "A new tumor suppressor gene , PTEN / MMAC1 , was isolated recently at this region of chromosome 10q23 and found to be inactivated by mutation in three prostate cancer cell lines .", "sentence_char_start_global": 13787, "sentence_char_end_global": 13966, "entities": [{"text": "tumor", "type": "ENTITY", "char_start": 6, "char_end": 11, "token_start": 2, "token_end": 2}, {"text": "prostate cancer", "type": "ENTITY", "char_start": 151, "char_end": 166, "token_start": 28, "token_end": 29}], "entities_global": [{"text": "tumor", "type": "ENTITY", "char_start": 13793, "char_end": 13798, "token_start": 2, "token_end": 2, "note": null}, {"text": "prostate cancer", "type": "ENTITY", "char_start": 13938, "char_end": 13953, "token_start": 28, "token_end": 29, "note": null}]}
+{"sentence_id": 97, "sentence_text": "We screened 80 prostate tumors by microsatellite analysis and found chromosome 10q23 to be deleted in 23 cases .", "sentence_char_start_global": 13967, "sentence_char_end_global": 14079, "entities": [{"text": "prostate tumors", "type": "ENTITY", "char_start": 15, "char_end": 30, "token_start": 3, "token_end": 4}], "entities_global": [{"text": "prostate tumors", "type": "ENTITY", "char_start": 13982, "char_end": 13997, "token_start": 3, "token_end": 4, "note": null}]}
+{"sentence_id": 98, "sentence_text": "We then proceeded with sequence analysis of the entire PTEN / MMAC1 coding region and tested for homozygous deletion with new intragenic markers in these 23 cases with 10q23 loss of heterozygosity .", "sentence_char_start_global": 14080, "sentence_char_end_global": 14278, "entities": [], "entities_global": []}
+{"sentence_id": 99, "sentence_text": "The identification of the second mutational event in 10 ( 43 % ) tumors establishes PTEN / MMAC1 as a main inactivation target of 10q loss in sporadic prostate cancer . .", "sentence_char_start_global": 14279, "sentence_char_end_global": 14449, "entities": [{"text": "tumors", "type": "ENTITY", "char_start": 65, "char_end": 71, "token_start": 13, "token_end": 13}, {"text": "sporadic prostate cancer", "type": "ENTITY", "char_start": 142, "char_end": 166, "token_start": 27, "token_end": 29}], "entities_global": [{"text": "tumors", "type": "ENTITY", "char_start": 14344, "char_end": 14350, "token_start": 13, "token_end": 13, "note": null}, {"text": "sporadic prostate cancer", "type": "ENTITY", "char_start": 14421, "char_end": 14445, "token_start": 27, "token_end": 29, "note": null}]}
+{"sentence_id": 100, "sentence_text": "Risk reversals in predictive testing for Huntington disease .", "sentence_char_start_global": 14450, "sentence_char_end_global": 14511, "entities": [{"text": "Huntington disease", "type": "ENTITY", "char_start": 41, "char_end": 59, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "Huntington disease", "type": "ENTITY", "char_start": 14491, "char_end": 14509, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 101, "sentence_text": "The first predictive testing for Huntington disease ( HD ) was based on analysis of linked polymorphic DNA markers to estimate the likelihood of inheriting the mutation for HD .", "sentence_char_start_global": 14512, "sentence_char_end_global": 14689, "entities": [{"text": "Huntington disease", "type": "ENTITY", "char_start": 33, "char_end": 51, "token_start": 5, "token_end": 6}, {"text": "HD", "type": "ENTITY", "char_start": 54, "char_end": 56, "token_start": 8, "token_end": 8}, {"text": "HD", "type": "ENTITY", "char_start": 173, "char_end": 175, "token_start": 28, "token_end": 28}], "entities_global": [{"text": "Huntington disease", "type": "ENTITY", "char_start": 14545, "char_end": 14563, "token_start": 5, "token_end": 6, "note": null}, {"text": "HD", "type": "ENTITY", "char_start": 14566, "char_end": 14568, "token_start": 8, "token_end": 8, "note": null}, {"text": "HD", "type": "ENTITY", "char_start": 14685, "char_end": 14687, "token_start": 28, "token_end": 28, "note": null}]}
+{"sentence_id": 102, "sentence_text": "Limits to accuracy included recombination between the DNA markers and the mutation , pedigree structure , and whether DNA samples were available from family members .", "sentence_char_start_global": 14690, "sentence_char_end_global": 14856, "entities": [], "entities_global": []}
+{"sentence_id": 103, "sentence_text": "With direct tests for the HD mutation , we have assessed the accuracy of results obtained by linkage approaches when requested to do so by the test individuals .", "sentence_char_start_global": 14857, "sentence_char_end_global": 15018, "entities": [{"text": "HD", "type": "ENTITY", "char_start": 26, "char_end": 28, "token_start": 5, "token_end": 5}], "entities_global": [{"text": "HD", "type": "ENTITY", "char_start": 14883, "char_end": 14885, "token_start": 5, "token_end": 5, "note": null}]}
+{"sentence_id": 104, "sentence_text": "For six such individuals , there was significant disparity between the tests .", "sentence_char_start_global": 15019, "sentence_char_end_global": 15097, "entities": [], "entities_global": []}
+{"sentence_id": 105, "sentence_text": "Three went from a decreased risk to an increased risk , while in another three the risk was decreased .", "sentence_char_start_global": 15098, "sentence_char_end_global": 15201, "entities": [], "entities_global": []}
+{"sentence_id": 106, "sentence_text": "Knowledge of the potential reasons for these changes in results and impact of these risk reversals on both patients and the counseling team can assist in the development of strategies for the prevention and , where necessary , management of a risk reversal in any predictive testing program . .", "sentence_char_start_global": 15202, "sentence_char_end_global": 15496, "entities": [], "entities_global": []}
+{"sentence_id": 107, "sentence_text": "A novel common missense mutation G301C in the N - acetylgalactosamine - 6 - sulfate sulfatase gene in mucopolysaccharidosis IVA .", "sentence_char_start_global": 15497, "sentence_char_end_global": 15626, "entities": [{"text": "mucopolysaccharidosis IVA", "type": "ENTITY", "char_start": 102, "char_end": 127, "token_start": 18, "token_end": 19}], "entities_global": [{"text": "mucopolysaccharidosis IVA", "type": "ENTITY", "char_start": 15599, "char_end": 15624, "token_start": 18, "token_end": 19, "note": null}]}
+{"sentence_id": 108, "sentence_text": "Mucopolysaccharidosis IVA ( MPS IVA ) is an autosomal recessive lysosomal storage disorder caused by a genetic defect in N - acetylgalactosamine - 6 - sulfate sulfatase ( GALNS ) .", "sentence_char_start_global": 15627, "sentence_char_end_global": 15807, "entities": [{"text": "Mucopolysaccharidosis IVA", "type": "ENTITY", "char_start": 0, "char_end": 25, "token_start": 0, "token_end": 1}, {"text": "MPS IVA", "type": "ENTITY", "char_start": 28, "char_end": 35, "token_start": 3, "token_end": 4}, {"text": "autosomal recessive lysosomal storage disorder", "type": "ENTITY", "char_start": 44, "char_end": 90, "token_start": 8, "token_end": 12}, {"text": "genetic defect", "type": "ENTITY", "char_start": 103, "char_end": 117, "token_start": 16, "token_end": 17}], "entities_global": [{"text": "Mucopolysaccharidosis IVA", "type": "ENTITY", "char_start": 15627, "char_end": 15652, "token_start": 0, "token_end": 1, "note": null}, {"text": "MPS IVA", "type": "ENTITY", "char_start": 15655, "char_end": 15662, "token_start": 3, "token_end": 4, "note": null}, {"text": "autosomal recessive lysosomal storage disorder", "type": "ENTITY", "char_start": 15671, "char_end": 15717, "token_start": 8, "token_end": 12, "note": null}, {"text": "genetic defect", "type": "ENTITY", "char_start": 15730, "char_end": 15744, "token_start": 16, "token_end": 17, "note": null}]}
+{"sentence_id": 109, "sentence_text": "In previous studies , we have found two common mutations in Caucasians and Japanese , respectively .", "sentence_char_start_global": 15808, "sentence_char_end_global": 15908, "entities": [], "entities_global": []}
+{"sentence_id": 110, "sentence_text": "To characterize the mutational spectrum in various ethnic groups , mutations in the GALNS gene in Colombian MPS IVA patients were investigated , and genetic backgrounds were extensively analyzed to identify racial origin , based on mitochondrial DNA ( mtDNA ) lineages .", "sentence_char_start_global": 15909, "sentence_char_end_global": 16179, "entities": [{"text": "MPS IVA", "type": "ENTITY", "char_start": 108, "char_end": 115, "token_start": 17, "token_end": 18}], "entities_global": [{"text": "MPS IVA", "type": "ENTITY", "char_start": 16017, "char_end": 16024, "token_start": 17, "token_end": 18, "note": null}]}
+{"sentence_id": 111, "sentence_text": "Three novel missense mutations never identified previously in other populations and found in 16 out of 19 Colombian MPS IVA unrelated alleles account for 84 .", "sentence_char_start_global": 16180, "sentence_char_end_global": 16338, "entities": [{"text": "MPS IVA", "type": "ENTITY", "char_start": 116, "char_end": 123, "token_start": 18, "token_end": 19}], "entities_global": [{"text": "MPS IVA", "type": "ENTITY", "char_start": 16296, "char_end": 16303, "token_start": 18, "token_end": 19, "note": null}]}
+{"sentence_id": 112, "sentence_text": "2 % of the alleles in this study .", "sentence_char_start_global": 16339, "sentence_char_end_global": 16373, "entities": [], "entities_global": []}
+{"sentence_id": 113, "sentence_text": "The G301C and S162F mutations account for 68 .", "sentence_char_start_global": 16374, "sentence_char_end_global": 16420, "entities": [], "entities_global": []}
+{"sentence_id": 114, "sentence_text": "4 % and 10 .", "sentence_char_start_global": 16421, "sentence_char_end_global": 16433, "entities": [], "entities_global": []}
+{"sentence_id": 115, "sentence_text": "5 % of mutations , respectively , whereas the remaining F69V is limited to a single allele .", "sentence_char_start_global": 16434, "sentence_char_end_global": 16526, "entities": [], "entities_global": []}
+{"sentence_id": 116, "sentence_text": "The skewed prevalence of G301C in only Colombian patients and haplotype analysis by restriction fragment length polymorphisms in the GALNS gene suggest that G301C originated from a common ancestor .", "sentence_char_start_global": 16527, "sentence_char_end_global": 16725, "entities": [], "entities_global": []}
+{"sentence_id": 117, "sentence_text": "Investigation of the genetic background by means of mtDNA lineages indicate that all our patients are probably of native American descent", "sentence_char_start_global": 16726, "sentence_char_end_global": 16863, "entities": [], "entities_global": []}
+{"sentence_id": 118, "sentence_text": "Low frequency of BRCA1 germline mutations in 45 German breast / ovarian cancer families .", "sentence_char_start_global": 16864, "sentence_char_end_global": 16953, "entities": [{"text": "breast / ovarian cancer", "type": "ENTITY", "char_start": 55, "char_end": 78, "token_start": 9, "token_end": 12}], "entities_global": [{"text": "breast / ovarian cancer", "type": "ENTITY", "char_start": 16919, "char_end": 16942, "token_start": 9, "token_end": 12, "note": null}]}
+{"sentence_id": 119, "sentence_text": "In this study we investigated 45 German breast / ovarian cancer families for germline mutations in the BRCA1 gene .", "sentence_char_start_global": 16954, "sentence_char_end_global": 17069, "entities": [{"text": "breast / ovarian cancer", "type": "ENTITY", "char_start": 40, "char_end": 63, "token_start": 7, "token_end": 10}], "entities_global": [{"text": "breast / ovarian cancer", "type": "ENTITY", "char_start": 16994, "char_end": 17017, "token_start": 7, "token_end": 10, "note": null}]}
+{"sentence_id": 120, "sentence_text": "We identified four germline mutations in three breast cancer families and in one breast - ovarian cancer family . among these were one frameshift mutation , one nonsense mutation , one novel splice site mutation , and one missense mutation .", "sentence_char_start_global": 17070, "sentence_char_end_global": 17311, "entities": [{"text": "breast cancer", "type": "ENTITY", "char_start": 47, "char_end": 60, "token_start": 7, "token_end": 8}, {"text": "breast - ovarian cancer", "type": "ENTITY", "char_start": 81, "char_end": 104, "token_start": 13, "token_end": 16}], "entities_global": [{"text": "breast cancer", "type": "ENTITY", "char_start": 17117, "char_end": 17130, "token_start": 7, "token_end": 8, "note": null}, {"text": "breast - ovarian cancer", "type": "ENTITY", "char_start": 17151, "char_end": 17174, "token_start": 13, "token_end": 16, "note": null}]}
+{"sentence_id": 121, "sentence_text": "The missense mutation was also found in 2 .", "sentence_char_start_global": 17312, "sentence_char_end_global": 17355, "entities": [], "entities_global": []}
+{"sentence_id": 122, "sentence_text": "8 % of the general population , suggesting that it is not disease associated .", "sentence_char_start_global": 17356, "sentence_char_end_global": 17434, "entities": [], "entities_global": []}
+{"sentence_id": 123, "sentence_text": "The average age of disease onset in those families harbouring causative mutations was between 32 .", "sentence_char_start_global": 17435, "sentence_char_end_global": 17533, "entities": [], "entities_global": []}
+{"sentence_id": 124, "sentence_text": "3 and 37 .", "sentence_char_start_global": 17534, "sentence_char_end_global": 17544, "entities": [], "entities_global": []}
+{"sentence_id": 125, "sentence_text": "4 years , whereas the family harbouring the missense mutation had an average age of onset of 51 .", "sentence_char_start_global": 17545, "sentence_char_end_global": 17642, "entities": [], "entities_global": []}
+{"sentence_id": 126, "sentence_text": "2 years .", "sentence_char_start_global": 17643, "sentence_char_end_global": 17652, "entities": [], "entities_global": []}
+{"sentence_id": 127, "sentence_text": "These findings show that BRCA1 is implicated in a small fraction of breast / ovarian cancer families suggesting the involvement of another susceptibility gene ( s )", "sentence_char_start_global": 17653, "sentence_char_end_global": 17817, "entities": [{"text": "breast / ovarian cancer", "type": "ENTITY", "char_start": 68, "char_end": 91, "token_start": 12, "token_end": 15}], "entities_global": [{"text": "breast / ovarian cancer", "type": "ENTITY", "char_start": 17721, "char_end": 17744, "token_start": 12, "token_end": 15, "note": null}]}
+{"sentence_id": 128, "sentence_text": "Paternal transmission of congenital myotonic dystrophy .", "sentence_char_start_global": 17818, "sentence_char_end_global": 17874, "entities": [{"text": "congenital myotonic dystrophy", "type": "ENTITY", "char_start": 25, "char_end": 54, "token_start": 3, "token_end": 5}], "entities_global": [{"text": "congenital myotonic dystrophy", "type": "ENTITY", "char_start": 17843, "char_end": 17872, "token_start": 3, "token_end": 5, "note": null}]}
+{"sentence_id": 129, "sentence_text": "We report a rare case of paternally transmitted congenital myotonic dystrophy ( DM ) .", "sentence_char_start_global": 17875, "sentence_char_end_global": 17961, "entities": [{"text": "congenital myotonic dystrophy", "type": "ENTITY", "char_start": 48, "char_end": 77, "token_start": 8, "token_end": 10}, {"text": "DM", "type": "ENTITY", "char_start": 80, "char_end": 82, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "congenital myotonic dystrophy", "type": "ENTITY", "char_start": 17923, "char_end": 17952, "token_start": 8, "token_end": 10, "note": null}, {"text": "DM", "type": "ENTITY", "char_start": 17955, "char_end": 17957, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 130, "sentence_text": "The proband is a 23 year old , mentally retarded male who suffers severe muscular weakness .", "sentence_char_start_global": 17962, "sentence_char_end_global": 18054, "entities": [{"text": "mentally retarded", "type": "ENTITY", "char_start": 31, "char_end": 48, "token_start": 8, "token_end": 9}, {"text": "muscular weakness", "type": "ENTITY", "char_start": 73, "char_end": 90, "token_start": 14, "token_end": 15}], "entities_global": [{"text": "mentally retarded", "type": "ENTITY", "char_start": 17993, "char_end": 18010, "token_start": 8, "token_end": 9, "note": null}, {"text": "muscular weakness", "type": "ENTITY", "char_start": 18035, "char_end": 18052, "token_start": 14, "token_end": 15, "note": null}]}
+{"sentence_id": 131, "sentence_text": "He presented with respiratory and feeding difficulties at birth .", "sentence_char_start_global": 18055, "sentence_char_end_global": 18120, "entities": [], "entities_global": []}
+{"sentence_id": 132, "sentence_text": "His two sibs suffer from childhood onset DM .", "sentence_char_start_global": 18121, "sentence_char_end_global": 18166, "entities": [{"text": "DM", "type": "ENTITY", "char_start": 41, "char_end": 43, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "DM", "type": "ENTITY", "char_start": 18162, "char_end": 18164, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 133, "sentence_text": "Their late father had the adult type of DM , with onset around 30 years .", "sentence_char_start_global": 18167, "sentence_char_end_global": 18240, "entities": [{"text": "DM", "type": "ENTITY", "char_start": 40, "char_end": 42, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "DM", "type": "ENTITY", "char_start": 18207, "char_end": 18209, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 134, "sentence_text": "Only six other cases of paternal transmission of congenital DM have been reported recently .", "sentence_char_start_global": 18241, "sentence_char_end_global": 18333, "entities": [{"text": "congenital DM", "type": "ENTITY", "char_start": 49, "char_end": 62, "token_start": 8, "token_end": 9}], "entities_global": [{"text": "congenital DM", "type": "ENTITY", "char_start": 18290, "char_end": 18303, "token_start": 8, "token_end": 9, "note": null}]}
+{"sentence_id": 135, "sentence_text": "We review the sex related effects on transmission of congenital DM .", "sentence_char_start_global": 18334, "sentence_char_end_global": 18402, "entities": [{"text": "congenital DM", "type": "ENTITY", "char_start": 53, "char_end": 66, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "congenital DM", "type": "ENTITY", "char_start": 18387, "char_end": 18400, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 136, "sentence_text": "Decreased fertility of males with adult onset DM and contraction of the repeat upon male transmission contribute to the almost absent occurrence of paternal transmission of congenital DM .", "sentence_char_start_global": 18403, "sentence_char_end_global": 18591, "entities": [{"text": "DM", "type": "ENTITY", "char_start": 46, "char_end": 48, "token_start": 7, "token_end": 7}, {"text": "congenital DM", "type": "ENTITY", "char_start": 173, "char_end": 186, "token_start": 26, "token_end": 27}], "entities_global": [{"text": "DM", "type": "ENTITY", "char_start": 18449, "char_end": 18451, "token_start": 7, "token_end": 7, "note": null}, {"text": "congenital DM", "type": "ENTITY", "char_start": 18576, "char_end": 18589, "token_start": 26, "token_end": 27, "note": null}]}
+{"sentence_id": 137, "sentence_text": "Also the fathers of the reported congenitally affected children showed , on average , shorter CTG repeat lengths and hence less severe clinical symptoms than the mothers of children with congenital DM .", "sentence_char_start_global": 18592, "sentence_char_end_global": 18794, "entities": [{"text": "congenital DM", "type": "ENTITY", "char_start": 187, "char_end": 200, "token_start": 30, "token_end": 31}], "entities_global": [{"text": "congenital DM", "type": "ENTITY", "char_start": 18779, "char_end": 18792, "token_start": 30, "token_end": 31, "note": null}]}
+{"sentence_id": 138, "sentence_text": "We conclude that paternal transmission of congenital DM is rare and preferentially occurs with onset of DM past 30 years in the father . .", "sentence_char_start_global": 18795, "sentence_char_end_global": 18933, "entities": [{"text": "congenital DM", "type": "ENTITY", "char_start": 42, "char_end": 55, "token_start": 6, "token_end": 7}, {"text": "DM", "type": "ENTITY", "char_start": 104, "char_end": 106, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "congenital DM", "type": "ENTITY", "char_start": 18837, "char_end": 18850, "token_start": 6, "token_end": 7, "note": null}, {"text": "DM", "type": "ENTITY", "char_start": 18899, "char_end": 18901, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 139, "sentence_text": "The RB1 gene mutation in a child with ectopic intracranial retinoblastoma .", "sentence_char_start_global": 18934, "sentence_char_end_global": 19009, "entities": [{"text": "ectopic intracranial retinoblastoma", "type": "ENTITY", "char_start": 38, "char_end": 73, "token_start": 8, "token_end": 10}], "entities_global": [{"text": "ectopic intracranial retinoblastoma", "type": "ENTITY", "char_start": 18972, "char_end": 19007, "token_start": 8, "token_end": 10, "note": null}]}
+{"sentence_id": 140, "sentence_text": "The RB1 gene mutation was investigated in a child with ectopic intracranial retinoblastoma using DNA obtained from both the pineal and retinal tumours of the patient .", "sentence_char_start_global": 19010, "sentence_char_end_global": 19177, "entities": [{"text": "ectopic intracranial retinoblastoma", "type": "ENTITY", "char_start": 55, "char_end": 90, "token_start": 10, "token_end": 12}, {"text": "pineal and retinal tumours", "type": "ENTITY", "char_start": 124, "char_end": 150, "token_start": 19, "token_end": 22}], "entities_global": [{"text": "ectopic intracranial retinoblastoma", "type": "ENTITY", "char_start": 19065, "char_end": 19100, "token_start": 10, "token_end": 12, "note": null}, {"text": "pineal and retinal tumours", "type": "ENTITY", "char_start": 19134, "char_end": 19160, "token_start": 19, "token_end": 22, "note": null}]}
+{"sentence_id": 141, "sentence_text": "A nonsense mutation in exon 17 ( codon 556 ) of the RB1 gene was found to be present homozygously in both the retinal and the pineal tumours .", "sentence_char_start_global": 19178, "sentence_char_end_global": 19320, "entities": [{"text": "retinal and the pineal tumours", "type": "ENTITY", "char_start": 110, "char_end": 140, "token_start": 23, "token_end": 27}], "entities_global": [{"text": "retinal and the pineal tumours", "type": "ENTITY", "char_start": 19288, "char_end": 19318, "token_start": 23, "token_end": 27, "note": null}]}
+{"sentence_id": 142, "sentence_text": "The same mutation was present heterozygously in the DNA from the constitutional cells of the patient , proving it to be of germline origin .", "sentence_char_start_global": 19321, "sentence_char_end_global": 19461, "entities": [], "entities_global": []}
+{"sentence_id": 143, "sentence_text": "The initial mutation was shown to have occurred in the paternally derived RB1 allele .", "sentence_char_start_global": 19462, "sentence_char_end_global": 19548, "entities": [], "entities_global": []}
+{"sentence_id": 144, "sentence_text": "The mutation is in an area of the gene that encodes the protein - binding region known as the pocket region and has been detected in other cases of retinoblastoma . .", "sentence_char_start_global": 19549, "sentence_char_end_global": 19715, "entities": [{"text": "retinoblastoma", "type": "ENTITY", "char_start": 148, "char_end": 162, "token_start": 29, "token_end": 29}], "entities_global": [{"text": "retinoblastoma", "type": "ENTITY", "char_start": 19697, "char_end": 19711, "token_start": 29, "token_end": 29, "note": null}]}
+{"sentence_id": 145, "sentence_text": "Low levels of beta hexosaminidase A in healthy individuals with apparent deficiency of this enzyme .", "sentence_char_start_global": 19716, "sentence_char_end_global": 19816, "entities": [], "entities_global": []}
+{"sentence_id": 146, "sentence_text": "Appreciable beta hexosaminidase A ( hex A ) activity has been detected in cultured skin fibroblasts and melanoma tissue from healthy individuals previously reported as having deficiency of hex A activity indistinguishable from that of patients with Tay - Sachs disease ( TSD ) .", "sentence_char_start_global": 19817, "sentence_char_end_global": 20095, "entities": [{"text": "melanoma", "type": "ENTITY", "char_start": 104, "char_end": 112, "token_start": 17, "token_end": 17}, {"text": "deficiency of hex A", "type": "ENTITY", "char_start": 175, "char_end": 194, "token_start": 26, "token_end": 29}, {"text": "Tay - Sachs disease", "type": "ENTITY", "char_start": 249, "char_end": 268, "token_start": 37, "token_end": 40}, {"text": "TSD", "type": "ENTITY", "char_start": 271, "char_end": 274, "token_start": 42, "token_end": 42}], "entities_global": [{"text": "melanoma", "type": "ENTITY", "char_start": 19921, "char_end": 19929, "token_start": 17, "token_end": 17, "note": null}, {"text": "deficiency of hex A", "type": "ENTITY", "char_start": 19992, "char_end": 20011, "token_start": 26, "token_end": 29, "note": null}, {"text": "Tay - Sachs disease", "type": "ENTITY", "char_start": 20066, "char_end": 20085, "token_start": 37, "token_end": 40, "note": null}, {"text": "TSD", "type": "ENTITY", "char_start": 20088, "char_end": 20091, "token_start": 42, "token_end": 42, "note": null}]}
+{"sentence_id": 147, "sentence_text": "Identification and quantitation of hex A , amounting to 3 .", "sentence_char_start_global": 20096, "sentence_char_end_global": 20155, "entities": [], "entities_global": []}
+{"sentence_id": 148, "sentence_text": "5 % - 6 .", "sentence_char_start_global": 20156, "sentence_char_end_global": 20165, "entities": [], "entities_global": []}
+{"sentence_id": 149, "sentence_text": "9 % of total beta hexosaminidase activity , has been obtained by cellulose acetate gel electrophoresis , DEAE - cellulose ion - exchange chromatography , radial immunodiffusion , and radioimmunoassay .", "sentence_char_start_global": 20166, "sentence_char_end_global": 20367, "entities": [], "entities_global": []}
+{"sentence_id": 150, "sentence_text": "Previous family studies suggested that these individuals may be compound heterozygotes for the common mutant TSD gene and a rare ( allelic ) mutant gene .", "sentence_char_start_global": 20368, "sentence_char_end_global": 20522, "entities": [{"text": "TSD", "type": "ENTITY", "char_start": 109, "char_end": 112, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "TSD", "type": "ENTITY", "char_start": 20477, "char_end": 20480, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 151, "sentence_text": "Thus , the postulated rate mutant gene appears to code for the expression of low amounts of hex A .", "sentence_char_start_global": 20523, "sentence_char_end_global": 20622, "entities": [], "entities_global": []}
+{"sentence_id": 152, "sentence_text": "Heterozygotes for the rare mutant may be indistinguishable from heterozygotes for the common TSD mutant .", "sentence_char_start_global": 20623, "sentence_char_end_global": 20728, "entities": [{"text": "TSD", "type": "ENTITY", "char_start": 93, "char_end": 96, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "TSD", "type": "ENTITY", "char_start": 20716, "char_end": 20719, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 153, "sentence_text": "However , direct visualization and quantitation of hex A by the methods described may prevent false - positive prenatal diagnosis of TSD in fetuses having the incomplete hex A deficiency of the type described in the four healthy individuals", "sentence_char_start_global": 20729, "sentence_char_end_global": 20969, "entities": [{"text": "TSD", "type": "ENTITY", "char_start": 133, "char_end": 136, "token_start": 21, "token_end": 21}, {"text": "hex A deficiency", "type": "ENTITY", "char_start": 170, "char_end": 186, "token_start": 27, "token_end": 29}], "entities_global": [{"text": "TSD", "type": "ENTITY", "char_start": 20862, "char_end": 20865, "token_start": 21, "token_end": 21, "note": null}, {"text": "hex A deficiency", "type": "ENTITY", "char_start": 20899, "char_end": 20915, "token_start": 27, "token_end": 29, "note": null}]}
+{"sentence_id": 154, "sentence_text": "The tumor suppressor gene Smad4 / Dpc4 is required for gastrulation and later for anterior development of the mouse embryo .", "sentence_char_start_global": 20970, "sentence_char_end_global": 21094, "entities": [{"text": "tumor", "type": "ENTITY", "char_start": 4, "char_end": 9, "token_start": 1, "token_end": 1}], "entities_global": [{"text": "tumor", "type": "ENTITY", "char_start": 20974, "char_end": 20979, "token_start": 1, "token_end": 1, "note": null}]}
+{"sentence_id": 155, "sentence_text": "Mutations in the SMAD4 / DPC4 tumor suppressor gene , a key signal transducer in most TGFbeta - related pathways , are involved in 50 % of pancreatic cancers .", "sentence_char_start_global": 21095, "sentence_char_end_global": 21254, "entities": [{"text": "tumor", "type": "ENTITY", "char_start": 30, "char_end": 35, "token_start": 6, "token_end": 6}, {"text": "pancreatic cancers", "type": "ENTITY", "char_start": 139, "char_end": 157, "token_start": 27, "token_end": 28}], "entities_global": [{"text": "tumor", "type": "ENTITY", "char_start": 21125, "char_end": 21130, "token_start": 6, "token_end": 6, "note": null}, {"text": "pancreatic cancers", "type": "ENTITY", "char_start": 21234, "char_end": 21252, "token_start": 27, "token_end": 28, "note": null}]}
+{"sentence_id": 156, "sentence_text": "Homozygous Smad4 mutant mice die before day 7 .", "sentence_char_start_global": 21255, "sentence_char_end_global": 21302, "entities": [], "entities_global": []}
+{"sentence_id": 157, "sentence_text": "5 of embryogenesis .", "sentence_char_start_global": 21303, "sentence_char_end_global": 21323, "entities": [], "entities_global": []}
+{"sentence_id": 158, "sentence_text": "Mutant embryos have reduced size , fail to gastrulate or express a mesodermal marker , and show abnormal visceral endoderm development .", "sentence_char_start_global": 21324, "sentence_char_end_global": 21460, "entities": [], "entities_global": []}
+{"sentence_id": 159, "sentence_text": "Growth retardation of the Smad4 - deficient embryos results from reduced cell proliferation rather than increased apoptosis .", "sentence_char_start_global": 21461, "sentence_char_end_global": 21586, "entities": [{"text": "Growth retardation", "type": "ENTITY", "char_start": 0, "char_end": 18, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "Growth retardation", "type": "ENTITY", "char_start": 21461, "char_end": 21479, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 160, "sentence_text": "Aggregation of mutant Smad4 ES cells with wild - type tetraploid morulae rescues the gastrulation defect .", "sentence_char_start_global": 21587, "sentence_char_end_global": 21693, "entities": [{"text": "gastrulation defect", "type": "ENTITY", "char_start": 85, "char_end": 104, "token_start": 14, "token_end": 15}], "entities_global": [{"text": "gastrulation defect", "type": "ENTITY", "char_start": 21672, "char_end": 21691, "token_start": 14, "token_end": 15, "note": null}]}
+{"sentence_id": 161, "sentence_text": "These results indicate that Smad4 is initially required for the differentiation of the visceral endoderm and that the gastrulation defect in the epiblast is secondary and non - cell autonomous .", "sentence_char_start_global": 21694, "sentence_char_end_global": 21888, "entities": [{"text": "gastrulation defect", "type": "ENTITY", "char_start": 118, "char_end": 137, "token_start": 18, "token_end": 19}], "entities_global": [{"text": "gastrulation defect", "type": "ENTITY", "char_start": 21812, "char_end": 21831, "token_start": 18, "token_end": 19, "note": null}]}
+{"sentence_id": 162, "sentence_text": "Rescued embryos show severe anterior truncations , indicating a second important role for Smad4 in anterior patterning during embryogenesis .", "sentence_char_start_global": 21889, "sentence_char_end_global": 22030, "entities": [], "entities_global": []}
+{"sentence_id": 163, "sentence_text": "Prevalence of p16 and CDK4 germline mutations in 48 melanoma - prone families in France .", "sentence_char_start_global": 22031, "sentence_char_end_global": 22120, "entities": [{"text": "melanoma", "type": "ENTITY", "char_start": 52, "char_end": 60, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "melanoma", "type": "ENTITY", "char_start": 22083, "char_end": 22091, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 164, "sentence_text": "The French Familial Melanoma Study Group .", "sentence_char_start_global": 22121, "sentence_char_end_global": 22163, "entities": [{"text": "Familial Melanoma", "type": "ENTITY", "char_start": 11, "char_end": 28, "token_start": 2, "token_end": 3}], "entities_global": [{"text": "Familial Melanoma", "type": "ENTITY", "char_start": 22132, "char_end": 22149, "token_start": 2, "token_end": 3, "note": null}]}
+{"sentence_id": 165, "sentence_text": "Germline mutations in the p16 and CDK4 genes have been reported in a subset of melanoma pedigrees , but their prevalence is not well known .", "sentence_char_start_global": 22164, "sentence_char_end_global": 22304, "entities": [{"text": "melanoma", "type": "ENTITY", "char_start": 79, "char_end": 87, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "melanoma", "type": "ENTITY", "char_start": 22243, "char_end": 22251, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 166, "sentence_text": "We searched for such germline mutations in 48 French melanoma - prone families selected according to two major criteria families with at least three affected members ( n = 20 ) or families with two affected members , one of them affected before the age of 50 ( n = 28 ) , and one additional minor criterion .", "sentence_char_start_global": 22305, "sentence_char_end_global": 22613, "entities": [{"text": "melanoma", "type": "ENTITY", "char_start": 53, "char_end": 61, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "melanoma", "type": "ENTITY", "char_start": 22358, "char_end": 22366, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 167, "sentence_text": "Sixteen different p16 germline mutations were found in 21 families , while one germline mutation , Arg24His , was detected in the CDK4 gene .", "sentence_char_start_global": 22614, "sentence_char_end_global": 22755, "entities": [], "entities_global": []}
+{"sentence_id": 168, "sentence_text": "The frequency of p16 gene mutation in our sample ( 44 % ) is among the highest rates yet reported and the CDK4 mutation is the second mutation detected in this gene worldwide .", "sentence_char_start_global": 22756, "sentence_char_end_global": 22932, "entities": [], "entities_global": []}
+{"sentence_id": 169, "sentence_text": "In summary , our results show frequent involvement of the p16 gene in familial melanoma and confirm the role of the CDK4 gene as a melanoma - predisposing gene . .", "sentence_char_start_global": 22933, "sentence_char_end_global": 23096, "entities": [{"text": "familial melanoma", "type": "ENTITY", "char_start": 70, "char_end": 87, "token_start": 13, "token_end": 14}, {"text": "melanoma", "type": "ENTITY", "char_start": 131, "char_end": 139, "token_start": 25, "token_end": 25}], "entities_global": [{"text": "familial melanoma", "type": "ENTITY", "char_start": 23003, "char_end": 23020, "token_start": 13, "token_end": 14, "note": null}, {"text": "melanoma", "type": "ENTITY", "char_start": 23064, "char_end": 23072, "token_start": 25, "token_end": 25, "note": null}]}
+{"sentence_id": 170, "sentence_text": "Progression of somatic CTG repeat length heterogeneity in the blood cells of myotonic dystrophy patients .", "sentence_char_start_global": 23097, "sentence_char_end_global": 23203, "entities": [{"text": "myotonic dystrophy", "type": "ENTITY", "char_start": 77, "char_end": 95, "token_start": 12, "token_end": 13}], "entities_global": [{"text": "myotonic dystrophy", "type": "ENTITY", "char_start": 23174, "char_end": 23192, "token_start": 12, "token_end": 13, "note": null}]}
+{"sentence_id": 171, "sentence_text": "The genetic basis of myotonic dystrophy ( DM ) is the expansion of an unstable CTG repeat in the 34 UTR of the DM protein kinase gene on chromosome 19 .", "sentence_char_start_global": 23204, "sentence_char_end_global": 23356, "entities": [{"text": "myotonic dystrophy", "type": "ENTITY", "char_start": 21, "char_end": 39, "token_start": 4, "token_end": 5}, {"text": "DM", "type": "ENTITY", "char_start": 42, "char_end": 44, "token_start": 7, "token_end": 7}, {"text": "DM", "type": "ENTITY", "char_start": 111, "char_end": 113, "token_start": 23, "token_end": 23}], "entities_global": [{"text": "myotonic dystrophy", "type": "ENTITY", "char_start": 23225, "char_end": 23243, "token_start": 4, "token_end": 5, "note": null}, {"text": "DM", "type": "ENTITY", "char_start": 23246, "char_end": 23248, "token_start": 7, "token_end": 7, "note": null}, {"text": "DM", "type": "ENTITY", "char_start": 23315, "char_end": 23317, "token_start": 23, "token_end": 23, "note": null}]}
+{"sentence_id": 172, "sentence_text": "One of the principal features of the DM mutation is an extraordinarily high level of somatic mosaicism , due to an extremely high degree of somatic instability both within and between different tissues .", "sentence_char_start_global": 23357, "sentence_char_end_global": 23560, "entities": [{"text": "DM", "type": "ENTITY", "char_start": 37, "char_end": 39, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "DM", "type": "ENTITY", "char_start": 23394, "char_end": 23396, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 173, "sentence_text": "This instability appears to be biased towards further expansion and continuous throughout the life of an individual , features that could be associated with the progressive nature of the disease .", "sentence_char_start_global": 23561, "sentence_char_end_global": 23757, "entities": [], "entities_global": []}
+{"sentence_id": 174, "sentence_text": "Although increasing measured allele size between patients clearly correlates with an increased severity of symptoms and an earlier age of onset , this correlation is not precise and measured allele length cannot be used as an accurate predictor of age of onset .", "sentence_char_start_global": 23758, "sentence_char_end_global": 24020, "entities": [], "entities_global": []}
+{"sentence_id": 175, "sentence_text": "In order to further characterize the dynamics of DM CTG repeat somatic instability , we have studied repeat length changes over time in 111 myotonic dystrophy patients with varying clinical severity and CTG repeat size over time intervals of 1 - 7 years .", "sentence_char_start_global": 24021, "sentence_char_end_global": 24276, "entities": [{"text": "DM", "type": "ENTITY", "char_start": 49, "char_end": 51, "token_start": 8, "token_end": 8}, {"text": "myotonic dystrophy", "type": "ENTITY", "char_start": 140, "char_end": 158, "token_start": 24, "token_end": 25}], "entities_global": [{"text": "DM", "type": "ENTITY", "char_start": 24070, "char_end": 24072, "token_start": 8, "token_end": 8, "note": null}, {"text": "myotonic dystrophy", "type": "ENTITY", "char_start": 24161, "char_end": 24179, "token_start": 24, "token_end": 25, "note": null}]}
+{"sentence_id": 176, "sentence_text": "We have found a direct progression of the size heterogeneity over time related to initial CTG repeat size and the time interval and always biased towards further expansion .", "sentence_char_start_global": 24277, "sentence_char_end_global": 24450, "entities": [], "entities_global": []}
+{"sentence_id": 177, "sentence_text": "Attempts to mathematically model the dynamics have proved only partially successful suggesting that individual specific genetic and / or environmental factors also play a role in somatic mosaicism . .", "sentence_char_start_global": 24451, "sentence_char_end_global": 24651, "entities": [], "entities_global": []}
+{"sentence_id": 178, "sentence_text": "Aspartylglucosaminuria among Palestinian Arabs .", "sentence_char_start_global": 24652, "sentence_char_end_global": 24700, "entities": [{"text": "Aspartylglucosaminuria", "type": "ENTITY", "char_start": 0, "char_end": 22, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "Aspartylglucosaminuria", "type": "ENTITY", "char_start": 24652, "char_end": 24674, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 179, "sentence_text": "Aspartylglucosaminuria ( AGU ) is a rare disorder of glycoprotein metabolism caused by the deficiency of the lysosomal enzyme aspartylglucosaminidase ( AGA ) .", "sentence_char_start_global": 24701, "sentence_char_end_global": 24860, "entities": [{"text": "Aspartylglucosaminuria", "type": "ENTITY", "char_start": 0, "char_end": 22, "token_start": 0, "token_end": 0}, {"text": "AGU", "type": "ENTITY", "char_start": 25, "char_end": 28, "token_start": 2, "token_end": 2}, {"text": "disorder of glycoprotein metabolism", "type": "ENTITY", "char_start": 41, "char_end": 76, "token_start": 7, "token_end": 10}, {"text": "deficiency of the lysosomal enzyme aspartylglucosaminidase", "type": "ENTITY", "char_start": 91, "char_end": 149, "token_start": 14, "token_end": 19}], "entities_global": [{"text": "Aspartylglucosaminuria", "type": "ENTITY", "char_start": 24701, "char_end": 24723, "token_start": 0, "token_end": 0, "note": null}, {"text": "AGU", "type": "ENTITY", "char_start": 24726, "char_end": 24729, "token_start": 2, "token_end": 2, "note": null}, {"text": "disorder of glycoprotein metabolism", "type": "ENTITY", "char_start": 24742, "char_end": 24777, "token_start": 7, "token_end": 10, "note": null}, {"text": "deficiency of the lysosomal enzyme aspartylglucosaminidase", "type": "ENTITY", "char_start": 24792, "char_end": 24850, "token_start": 14, "token_end": 19, "note": null}]}
+{"sentence_id": 180, "sentence_text": "AGU is inherited as an autosomal recessive trait and occurs with a high frequency in Finland because of a founder effect .", "sentence_char_start_global": 24861, "sentence_char_end_global": 24983, "entities": [{"text": "AGU", "type": "ENTITY", "char_start": 0, "char_end": 3, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "AGU", "type": "ENTITY", "char_start": 24861, "char_end": 24864, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 181, "sentence_text": "While very few patients with AGU have been reported from non - Finnish origin , we diagnosed the disorder in 8 patients originating from 3 unrelated families , all Palestinian Arabs from the region of Jerusalem .", "sentence_char_start_global": 24984, "sentence_char_end_global": 25196, "entities": [{"text": "AGU", "type": "ENTITY", "char_start": 29, "char_end": 32, "token_start": 5, "token_end": 5}], "entities_global": [{"text": "AGU", "type": "ENTITY", "char_start": 25013, "char_end": 25016, "token_start": 5, "token_end": 5, "note": null}]}
+{"sentence_id": 182, "sentence_text": "The clinical diagnosis of AGU is often difficult , in particular early in the course of the disease , and most of the patients are diagnosed after the age of 5 years .", "sentence_char_start_global": 25197, "sentence_char_end_global": 25364, "entities": [{"text": "AGU", "type": "ENTITY", "char_start": 26, "char_end": 29, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "AGU", "type": "ENTITY", "char_start": 25223, "char_end": 25226, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 183, "sentence_text": "However , since these patients excrete early large amounts of aspartylglucosamine in urine , biochemical screening is easy by urine chromatography . .", "sentence_char_start_global": 25365, "sentence_char_end_global": 25515, "entities": [], "entities_global": []}
+{"sentence_id": 184, "sentence_text": "Detection of heterozygous carriers of the ataxia - telangiectasia ( ATM ) gene by G2 phase chromosomal radiosensitivity of peripheral blood lymphocytes .", "sentence_char_start_global": 25516, "sentence_char_end_global": 25669, "entities": [{"text": "ataxia - telangiectasia", "type": "ENTITY", "char_start": 42, "char_end": 65, "token_start": 6, "token_end": 8}], "entities_global": [{"text": "ataxia - telangiectasia", "type": "ENTITY", "char_start": 25558, "char_end": 25581, "token_start": 6, "token_end": 8, "note": null}]}
+{"sentence_id": 185, "sentence_text": "In ataxia - telangiectasia ( A - T ) patients , mutations in a single gene , ATM , result in an autosomal recessive syndrome that embraces a variety of clinical features and manifests extreme radiosensitivity and a strong pre - disposition to malignancy .", "sentence_char_start_global": 25670, "sentence_char_end_global": 25925, "entities": [{"text": "ataxia - telangiectasia", "type": "ENTITY", "char_start": 3, "char_end": 26, "token_start": 1, "token_end": 3}, {"text": "A - T", "type": "ENTITY", "char_start": 29, "char_end": 34, "token_start": 5, "token_end": 7}, {"text": "autosomal recessive syndrome", "type": "ENTITY", "char_start": 96, "char_end": 124, "token_start": 22, "token_end": 24}, {"text": "malignancy", "type": "ENTITY", "char_start": 243, "char_end": 253, "token_start": 43, "token_end": 43}], "entities_global": [{"text": "ataxia - telangiectasia", "type": "ENTITY", "char_start": 25673, "char_end": 25696, "token_start": 1, "token_end": 3, "note": null}, {"text": "A - T", "type": "ENTITY", "char_start": 25699, "char_end": 25704, "token_start": 5, "token_end": 7, "note": null}, {"text": "autosomal recessive syndrome", "type": "ENTITY", "char_start": 25766, "char_end": 25794, "token_start": 22, "token_end": 24, "note": null}, {"text": "malignancy", "type": "ENTITY", "char_start": 25913, "char_end": 25923, "token_start": 43, "token_end": 43, "note": null}]}
+{"sentence_id": 186, "sentence_text": "Heterozygotes for the ATM gene have no clinical expression of A - T but may be cancer prone with a moderate increase in in vitro radiosensitivity .", "sentence_char_start_global": 25926, "sentence_char_end_global": 26073, "entities": [{"text": "A - T", "type": "ENTITY", "char_start": 62, "char_end": 67, "token_start": 10, "token_end": 12}, {"text": "cancer", "type": "ENTITY", "char_start": 79, "char_end": 85, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "A - T", "type": "ENTITY", "char_start": 25988, "char_end": 25993, "token_start": 10, "token_end": 12, "note": null}, {"text": "cancer", "type": "ENTITY", "char_start": 26005, "char_end": 26011, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 187, "sentence_text": "We performed a blind chromosomal analysis on G2 - phase lymphocytes from 7 unrelated A - T patients , 13 obligate A - T heterozygotes ( parents of the patients ) , and 14 normal controls following X - irradiation with 1 Gy in order to evaluate this cytogenetic method as a tool for detection of ATM carriers .", "sentence_char_start_global": 26074, "sentence_char_end_global": 26383, "entities": [{"text": "A - T", "type": "ENTITY", "char_start": 85, "char_end": 90, "token_start": 14, "token_end": 16}, {"text": "A - T", "type": "ENTITY", "char_start": 114, "char_end": 119, "token_start": 21, "token_end": 23}], "entities_global": [{"text": "A - T", "type": "ENTITY", "char_start": 26159, "char_end": 26164, "token_start": 14, "token_end": 16, "note": null}, {"text": "A - T", "type": "ENTITY", "char_start": 26188, "char_end": 26193, "token_start": 21, "token_end": 23, "note": null}]}
+{"sentence_id": 188, "sentence_text": "Both A - T homozygotes and heterozygotes showed significantly increased levels of radiation - induced chromatid damage relative to that of normal controls .", "sentence_char_start_global": 26384, "sentence_char_end_global": 26540, "entities": [{"text": "A - T", "type": "ENTITY", "char_start": 5, "char_end": 10, "token_start": 1, "token_end": 3}], "entities_global": [{"text": "A - T", "type": "ENTITY", "char_start": 26389, "char_end": 26394, "token_start": 1, "token_end": 3, "note": null}]}
+{"sentence_id": 189, "sentence_text": "These results show that the G2 - phase chromosomal radiosensitivity assay can be used for the detection of A - T heterozygotes .", "sentence_char_start_global": 26541, "sentence_char_end_global": 26669, "entities": [{"text": "A - T", "type": "ENTITY", "char_start": 107, "char_end": 112, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "A - T", "type": "ENTITY", "char_start": 26648, "char_end": 26653, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 190, "sentence_text": "In combination with molecular genetic analyses , this test may be of value in studies of familial and sporadic cancers aimed at determination of the potential involvement of ATM mutations in tumor risk or development . .", "sentence_char_start_global": 26670, "sentence_char_end_global": 26890, "entities": [{"text": "familial and sporadic cancers", "type": "ENTITY", "char_start": 89, "char_end": 118, "token_start": 16, "token_end": 19}, {"text": "tumor", "type": "ENTITY", "char_start": 191, "char_end": 196, "token_start": 31, "token_end": 31}], "entities_global": [{"text": "familial and sporadic cancers", "type": "ENTITY", "char_start": 26759, "char_end": 26788, "token_start": 16, "token_end": 19, "note": null}, {"text": "tumor", "type": "ENTITY", "char_start": 26861, "char_end": 26866, "token_start": 31, "token_end": 31, "note": null}]}
+{"sentence_id": 191, "sentence_text": "Ataxia - telangiectasia : identification and detection of founder - effect mutations in the ATM gene in ethnic populations .", "sentence_char_start_global": 26891, "sentence_char_end_global": 27015, "entities": [{"text": "Ataxia - telangiectasia", "type": "ENTITY", "char_start": 0, "char_end": 23, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "Ataxia - telangiectasia", "type": "ENTITY", "char_start": 26891, "char_end": 26914, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 192, "sentence_text": "To facilitate the evaluation of ATM heterozygotes for susceptibility to other diseases , such as breast cancer , we have attempted to define the most common mutations and their frequencies in ataxia - telangiectasia ( A - T ) homozygotes from 10 ethnic populations .", "sentence_char_start_global": 27016, "sentence_char_end_global": 27282, "entities": [{"text": "breast cancer", "type": "ENTITY", "char_start": 97, "char_end": 110, "token_start": 15, "token_end": 16}, {"text": "ataxia - telangiectasia", "type": "ENTITY", "char_start": 192, "char_end": 215, "token_start": 31, "token_end": 33}, {"text": "A - T", "type": "ENTITY", "char_start": 218, "char_end": 223, "token_start": 35, "token_end": 37}], "entities_global": [{"text": "breast cancer", "type": "ENTITY", "char_start": 27113, "char_end": 27126, "token_start": 15, "token_end": 16, "note": null}, {"text": "ataxia - telangiectasia", "type": "ENTITY", "char_start": 27208, "char_end": 27231, "token_start": 31, "token_end": 33, "note": null}, {"text": "A - T", "type": "ENTITY", "char_start": 27234, "char_end": 27239, "token_start": 35, "token_end": 37, "note": null}]}
+{"sentence_id": 193, "sentence_text": "Both genomic mutations and their effects on cDNA were characterized .", "sentence_char_start_global": 27283, "sentence_char_end_global": 27352, "entities": [], "entities_global": []}
+{"sentence_id": 194, "sentence_text": "Protein - truncation testing of the entire ATM cDNA detected 92 ( 66 % ) truncating mutations in 140 mutant alleles screened .", "sentence_char_start_global": 27353, "sentence_char_end_global": 27479, "entities": [], "entities_global": []}
+{"sentence_id": 195, "sentence_text": "The haplotyping of patients with identical mutations indicates that almost all of these represent common ancestry and that very few spontaneously recurring ATM mutations exist .", "sentence_char_start_global": 27480, "sentence_char_end_global": 27657, "entities": [], "entities_global": []}
+{"sentence_id": 196, "sentence_text": "Assays requiring minimal amounts of genomic DNA were designed to allow rapid screening for common ethnic mutations .", "sentence_char_start_global": 27658, "sentence_char_end_global": 27774, "entities": [], "entities_global": []}
+{"sentence_id": 197, "sentence_text": "These rapid assays detected mutations in 76 % of Costa Rican patients ( 3 ) , 50 % of Norwegian patients ( 1 ) , 25 % of Polish patients ( 4 ) , and 14 % of Italian patients ( 1 ) , as well as in patients of Amish / Mennonite and Irish English backgrounds .", "sentence_char_start_global": 27775, "sentence_char_end_global": 28032, "entities": [], "entities_global": []}
+{"sentence_id": 198, "sentence_text": "Additional mutations were observed in Japanese , Utah Mormon , and African American patients .", "sentence_char_start_global": 28033, "sentence_char_end_global": 28127, "entities": [], "entities_global": []}
+{"sentence_id": 199, "sentence_text": "These assays should facilitate screening for A - T heterozygotes in the populations studied . .", "sentence_char_start_global": 28128, "sentence_char_end_global": 28223, "entities": [{"text": "A - T", "type": "ENTITY", "char_start": 45, "char_end": 50, "token_start": 6, "token_end": 8}], "entities_global": [{"text": "A - T", "type": "ENTITY", "char_start": 28173, "char_end": 28178, "token_start": 6, "token_end": 8, "note": null}]}
+{"sentence_id": 200, "sentence_text": "The von Hippel - Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal .", "sentence_char_start_global": 28224, "sentence_char_end_global": 28325, "entities": [{"text": "von Hippel - Lindau tumor", "type": "ENTITY", "char_start": 4, "char_end": 29, "token_start": 1, "token_end": 5}], "entities_global": [{"text": "von Hippel - Lindau tumor", "type": "ENTITY", "char_start": 28228, "char_end": 28253, "token_start": 1, "token_end": 5, "note": null}]}
+{"sentence_id": 201, "sentence_text": "The inactivation of the von Hippel - Lindau ( VHL ) tumor suppressor gene predisposes affected individuals to the human VHL cancer syndrome and is associated with sporadic renal cell carcinomas ( RCC ) and brain hemangioblastomas .", "sentence_char_start_global": 28326, "sentence_char_end_global": 28557, "entities": [{"text": "von Hippel - Lindau ( VHL ) tumor", "type": "ENTITY", "char_start": 24, "char_end": 57, "token_start": 4, "token_end": 11}, {"text": "VHL cancer syndrome", "type": "ENTITY", "char_start": 120, "char_end": 139, "token_start": 20, "token_end": 22}, {"text": "sporadic renal cell carcinomas", "type": "ENTITY", "char_start": 163, "char_end": 193, "token_start": 27, "token_end": 30}, {"text": "RCC", "type": "ENTITY", "char_start": 196, "char_end": 199, "token_start": 32, "token_end": 32}, {"text": "brain hemangioblastomas", "type": "ENTITY", "char_start": 206, "char_end": 229, "token_start": 35, "token_end": 36}], "entities_global": [{"text": "von Hippel - Lindau ( VHL ) tumor", "type": "ENTITY", "char_start": 28350, "char_end": 28383, "token_start": 4, "token_end": 11, "note": null}, {"text": "VHL cancer syndrome", "type": "ENTITY", "char_start": 28446, "char_end": 28465, "token_start": 20, "token_end": 22, "note": null}, {"text": "sporadic renal cell carcinomas", "type": "ENTITY", "char_start": 28489, "char_end": 28519, "token_start": 27, "token_end": 30, "note": null}, {"text": "RCC", "type": "ENTITY", "char_start": 28522, "char_end": 28525, "token_start": 32, "token_end": 32, "note": null}, {"text": "brain hemangioblastomas", "type": "ENTITY", "char_start": 28532, "char_end": 28555, "token_start": 35, "token_end": 36, "note": null}]}
+{"sentence_id": 202, "sentence_text": "VHL - negative 786 - 0 RCC cells are tumorigenic in nude mice which is suppressed by the reintroduction of VHL .", "sentence_char_start_global": 28558, "sentence_char_end_global": 28670, "entities": [{"text": "RCC", "type": "ENTITY", "char_start": 23, "char_end": 26, "token_start": 6, "token_end": 6}, {"text": "VHL", "type": "ENTITY", "char_start": 107, "char_end": 110, "token_start": 20, "token_end": 20}], "entities_global": [{"text": "RCC", "type": "ENTITY", "char_start": 28581, "char_end": 28584, "token_start": 6, "token_end": 6, "note": null}, {"text": "VHL", "type": "ENTITY", "char_start": 28665, "char_end": 28668, "token_start": 20, "token_end": 20, "note": null}]}
+{"sentence_id": 203, "sentence_text": "Remarkably , this occurs without affecting the growth rate and cell cycle profile of these cells in culture .", "sentence_char_start_global": 28671, "sentence_char_end_global": 28780, "entities": [], "entities_global": []}
+{"sentence_id": 204, "sentence_text": "The 786 - 0 cell line , like many cancer cells , fails to exit the cell cycle upon serum withdrawal .", "sentence_char_start_global": 28781, "sentence_char_end_global": 28882, "entities": [{"text": "cancer", "type": "ENTITY", "char_start": 34, "char_end": 40, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "cancer", "type": "ENTITY", "char_start": 28815, "char_end": 28821, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 205, "sentence_text": "Here , it is shown that reintroduction of the wild - type VHL gene restores the ability of VHL - negative RCC cancer cells to exit the cell cycle and enter G0 / quiescence in low serum .", "sentence_char_start_global": 28883, "sentence_char_end_global": 29069, "entities": [{"text": "VHL", "type": "ENTITY", "char_start": 58, "char_end": 61, "token_start": 12, "token_end": 12}, {"text": "RCC cancer", "type": "ENTITY", "char_start": 106, "char_end": 116, "token_start": 21, "token_end": 22}], "entities_global": [{"text": "VHL", "type": "ENTITY", "char_start": 28941, "char_end": 28944, "token_start": 12, "token_end": 12, "note": null}, {"text": "RCC cancer", "type": "ENTITY", "char_start": 28989, "char_end": 28999, "token_start": 21, "token_end": 22, "note": null}]}
+{"sentence_id": 206, "sentence_text": "Both VHL - positive and VHL - negative RCC cells exit the cell cycle by contact inhibition .", "sentence_char_start_global": 29070, "sentence_char_end_global": 29162, "entities": [{"text": "RCC", "type": "ENTITY", "char_start": 39, "char_end": 42, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "RCC", "type": "ENTITY", "char_start": 29109, "char_end": 29112, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 207, "sentence_text": "The cyclin - dependent kinase inhibitor , p27 , accumulates upon serum withdrawal , only in the presence of VHL , as a result of the stabilization of the protein .", "sentence_char_start_global": 29163, "sentence_char_end_global": 29326, "entities": [{"text": "VHL", "type": "ENTITY", "char_start": 108, "char_end": 111, "token_start": 19, "token_end": 19}], "entities_global": [{"text": "VHL", "type": "ENTITY", "char_start": 29271, "char_end": 29274, "token_start": 19, "token_end": 19, "note": null}]}
+{"sentence_id": 208, "sentence_text": "We propose that the loss of wild - type VHL gene results in a specific cellular defect in serum - dependent growth control , which may initiate tumor formation .", "sentence_char_start_global": 29327, "sentence_char_end_global": 29488, "entities": [{"text": "VHL", "type": "ENTITY", "char_start": 40, "char_end": 43, "token_start": 9, "token_end": 9}, {"text": "tumor", "type": "ENTITY", "char_start": 144, "char_end": 149, "token_start": 27, "token_end": 27}], "entities_global": [{"text": "VHL", "type": "ENTITY", "char_start": 29367, "char_end": 29370, "token_start": 9, "token_end": 9, "note": null}, {"text": "tumor", "type": "ENTITY", "char_start": 29471, "char_end": 29476, "token_start": 27, "token_end": 27, "note": null}]}
+{"sentence_id": 209, "sentence_text": "This is corrected by the reintroduction of wild - type VHL , implicating VHL as the first tumor suppressor involved in the regulation of cell cycle exit , which is consistent with its gatekeeper function in the kidney . .", "sentence_char_start_global": 29489, "sentence_char_end_global": 29710, "entities": [{"text": "VHL", "type": "ENTITY", "char_start": 55, "char_end": 58, "token_start": 10, "token_end": 10}, {"text": "VHL", "type": "ENTITY", "char_start": 73, "char_end": 76, "token_start": 13, "token_end": 13}, {"text": "tumor", "type": "ENTITY", "char_start": 90, "char_end": 95, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "VHL", "type": "ENTITY", "char_start": 29544, "char_end": 29547, "token_start": 10, "token_end": 10, "note": null}, {"text": "VHL", "type": "ENTITY", "char_start": 29562, "char_end": 29565, "token_start": 13, "token_end": 13, "note": null}, {"text": "tumor", "type": "ENTITY", "char_start": 29579, "char_end": 29584, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 210, "sentence_text": "Piebaldism with deafness : molecular evidence for an expanded syndrome .", "sentence_char_start_global": 29711, "sentence_char_end_global": 29783, "entities": [{"text": "Piebaldism", "type": "ENTITY", "char_start": 0, "char_end": 10, "token_start": 0, "token_end": 0}, {"text": "deafness", "type": "ENTITY", "char_start": 16, "char_end": 24, "token_start": 2, "token_end": 2}], "entities_global": [{"text": "Piebaldism", "type": "ENTITY", "char_start": 29711, "char_end": 29721, "token_start": 0, "token_end": 0, "note": null}, {"text": "deafness", "type": "ENTITY", "char_start": 29727, "char_end": 29735, "token_start": 2, "token_end": 2, "note": null}]}
+{"sentence_id": 211, "sentence_text": "In a South African girl of Xhosa stock with severe piebaldism and profound congenital sensorineural deafness we identified a novel missense substitution at a highly conserved residue in the intracellular kinase domain of the KIT proto - oncogene , R796G .", "sentence_char_start_global": 29784, "sentence_char_end_global": 30039, "entities": [{"text": "piebaldism", "type": "ENTITY", "char_start": 51, "char_end": 61, "token_start": 10, "token_end": 10}, {"text": "sensorineural deafness", "type": "ENTITY", "char_start": 86, "char_end": 108, "token_start": 14, "token_end": 15}], "entities_global": [{"text": "piebaldism", "type": "ENTITY", "char_start": 29835, "char_end": 29845, "token_start": 10, "token_end": 10, "note": null}, {"text": "sensorineural deafness", "type": "ENTITY", "char_start": 29870, "char_end": 29892, "token_start": 14, "token_end": 15, "note": null}]}
+{"sentence_id": 212, "sentence_text": "Though auditory anomalies have been observed in mice with dominant white spotting ( W ) due to KIT mutations , deafness is not typical in human piebaldism .", "sentence_char_start_global": 30040, "sentence_char_end_global": 30196, "entities": [{"text": "auditory anomalies", "type": "ENTITY", "char_start": 7, "char_end": 25, "token_start": 1, "token_end": 2}, {"text": "deafness", "type": "ENTITY", "char_start": 111, "char_end": 119, "token_start": 20, "token_end": 20}, {"text": "piebaldism", "type": "ENTITY", "char_start": 144, "char_end": 154, "token_start": 26, "token_end": 26}], "entities_global": [{"text": "auditory anomalies", "type": "ENTITY", "char_start": 30047, "char_end": 30065, "token_start": 1, "token_end": 2, "note": null}, {"text": "deafness", "type": "ENTITY", "char_start": 30151, "char_end": 30159, "token_start": 20, "token_end": 20, "note": null}, {"text": "piebaldism", "type": "ENTITY", "char_start": 30184, "char_end": 30194, "token_start": 26, "token_end": 26, "note": null}]}
+{"sentence_id": 213, "sentence_text": "Thus , the occurrence of sensorineural deafness in this patient extends considerably the phenotypic range of piebaldism due to KIT gene mutation in humans and tightens the clinical similarity between piebaldism and the various forms of Waardenburg syndrome . .", "sentence_char_start_global": 30197, "sentence_char_end_global": 30457, "entities": [{"text": "sensorineural deafness", "type": "ENTITY", "char_start": 25, "char_end": 47, "token_start": 5, "token_end": 6}, {"text": "piebaldism", "type": "ENTITY", "char_start": 109, "char_end": 119, "token_start": 16, "token_end": 16}, {"text": "piebaldism", "type": "ENTITY", "char_start": 200, "char_end": 210, "token_start": 30, "token_end": 30}, {"text": "Waardenburg syndrome", "type": "ENTITY", "char_start": 236, "char_end": 256, "token_start": 36, "token_end": 37}], "entities_global": [{"text": "sensorineural deafness", "type": "ENTITY", "char_start": 30222, "char_end": 30244, "token_start": 5, "token_end": 6, "note": null}, {"text": "piebaldism", "type": "ENTITY", "char_start": 30306, "char_end": 30316, "token_start": 16, "token_end": 16, "note": null}, {"text": "piebaldism", "type": "ENTITY", "char_start": 30397, "char_end": 30407, "token_start": 30, "token_end": 30, "note": null}, {"text": "Waardenburg syndrome", "type": "ENTITY", "char_start": 30433, "char_end": 30453, "token_start": 36, "token_end": 37, "note": null}]}
+{"sentence_id": 214, "sentence_text": "Cycloheximide facilitates the identification of aberrant transcripts resulting from a novel splice - site mutation in COL17A1 in a patient with generalized atrophic benign epidermolysis bullosa .", "sentence_char_start_global": 30458, "sentence_char_end_global": 30653, "entities": [{"text": "atrophic benign epidermolysis bullosa", "type": "ENTITY", "char_start": 156, "char_end": 193, "token_start": 22, "token_end": 25}], "entities_global": [{"text": "atrophic benign epidermolysis bullosa", "type": "ENTITY", "char_start": 30614, "char_end": 30651, "token_start": 22, "token_end": 25, "note": null}]}
+{"sentence_id": 215, "sentence_text": "Patients with generalized atrophic benign epidermolysis bullosa often show decreased expression of type XVII collagen , a transmembrane hemidesmosomal protein encoded by COL17A1 .", "sentence_char_start_global": 30654, "sentence_char_end_global": 30833, "entities": [{"text": "atrophic benign epidermolysis bullosa", "type": "ENTITY", "char_start": 26, "char_end": 63, "token_start": 3, "token_end": 6}], "entities_global": [{"text": "atrophic benign epidermolysis bullosa", "type": "ENTITY", "char_start": 30680, "char_end": 30717, "token_start": 3, "token_end": 6, "note": null}]}
+{"sentence_id": 216, "sentence_text": "This report documents a novel splice - site mutation in COL17A1 in a patient with generalized atrophic benign epidermolysis bullosa , and applies a new methodology to define and characterize the resulting mRNA splice variants .", "sentence_char_start_global": 30834, "sentence_char_end_global": 31061, "entities": [{"text": "atrophic benign epidermolysis bullosa", "type": "ENTITY", "char_start": 94, "char_end": 131, "token_start": 16, "token_end": 19}], "entities_global": [{"text": "atrophic benign epidermolysis bullosa", "type": "ENTITY", "char_start": 30928, "char_end": 30965, "token_start": 16, "token_end": 19, "note": null}]}
+{"sentence_id": 217, "sentence_text": "Mutational analysis of COL17A1 identified a maternally inherited G - to - T transversion at the - 1 position of exon 32 .", "sentence_char_start_global": 31062, "sentence_char_end_global": 31183, "entities": [], "entities_global": []}
+{"sentence_id": 218, "sentence_text": "This acceptor splice - site mutation led to the formation of aberrant transcripts present at extremely low levels .", "sentence_char_start_global": 31184, "sentence_char_end_global": 31299, "entities": [], "entities_global": []}
+{"sentence_id": 219, "sentence_text": "Based on our recent finding that cycloheximide stabilized mutant COL17A1 transcripts in keratinocytes homozygous for a frameshift mutation , the effects of the splice - site mutation on splicing of COL17A1 transcripts were determined using reverse transcriptase polymerase chain reaction of total RNA from keratinocytes incubated for 2 .", "sentence_char_start_global": 31300, "sentence_char_end_global": 31637, "entities": [], "entities_global": []}
+{"sentence_id": 220, "sentence_text": "5 h in the presence or absence of 10 microg cycloheximide per ml .", "sentence_char_start_global": 31638, "sentence_char_end_global": 31704, "entities": [], "entities_global": []}
+{"sentence_id": 221, "sentence_text": "Using this approach , an abnormally spliced transcript was identified that contains an extra 264 bases upstream from exon 32 , resulting in a premature termination codon 27 bp downstream from the cryptic splice site .", "sentence_char_start_global": 31705, "sentence_char_end_global": 31922, "entities": [], "entities_global": []}
+{"sentence_id": 222, "sentence_text": "Three other splice variants , including one derived from the skipping of exon 32 , were also identified .", "sentence_char_start_global": 31923, "sentence_char_end_global": 32028, "entities": [], "entities_global": []}
+{"sentence_id": 223, "sentence_text": "These results indicate the usefulness of cycloheximide treatment in evaluating the abnormal processing of mRNA due to splice - site mutations , because ( i ) aberrant splicing often generates a premature termination codon , ( ii ) transcripts with premature termination codons can occur at low or undetectable levels due to nonsense - mediated mRNA decay , and ( iii ) the levels of these transcripts can be increased by cycloheximide .", "sentence_char_start_global": 32029, "sentence_char_end_global": 32465, "entities": [], "entities_global": []}
+{"sentence_id": 224, "sentence_text": "A deletion mutation in COL17A1 in five Austrian families with generalized atrophic benign epidermolysis bullosa represents propagation of an ancestral allele .", "sentence_char_start_global": 32466, "sentence_char_end_global": 32625, "entities": [{"text": "atrophic benign epidermolysis bullosa", "type": "ENTITY", "char_start": 74, "char_end": 111, "token_start": 11, "token_end": 14}], "entities_global": [{"text": "atrophic benign epidermolysis bullosa", "type": "ENTITY", "char_start": 32540, "char_end": 32577, "token_start": 11, "token_end": 14, "note": null}]}
+{"sentence_id": 225, "sentence_text": "Patients with generalized atrophic benign epidermolysis bullosa , a usually nonlethal form of junctional epidermolysis bullosa , have generalized blistering , nail dystrophy , patchy alopecia , and dental abnormalities .", "sentence_char_start_global": 32626, "sentence_char_end_global": 32846, "entities": [{"text": "atrophic benign epidermolysis bullosa", "type": "ENTITY", "char_start": 26, "char_end": 63, "token_start": 3, "token_end": 6}, {"text": "junctional epidermolysis bullosa", "type": "ENTITY", "char_start": 94, "char_end": 126, "token_start": 13, "token_end": 15}, {"text": "blistering", "type": "ENTITY", "char_start": 146, "char_end": 156, "token_start": 19, "token_end": 19}, {"text": "nail dystrophy", "type": "ENTITY", "char_start": 159, "char_end": 173, "token_start": 21, "token_end": 22}, {"text": "patchy alopecia", "type": "ENTITY", "char_start": 176, "char_end": 191, "token_start": 24, "token_end": 25}, {"text": "dental abnormalities", "type": "ENTITY", "char_start": 198, "char_end": 218, "token_start": 28, "token_end": 29}], "entities_global": [{"text": "atrophic benign epidermolysis bullosa", "type": "ENTITY", "char_start": 32652, "char_end": 32689, "token_start": 3, "token_end": 6, "note": null}, {"text": "junctional epidermolysis bullosa", "type": "ENTITY", "char_start": 32720, "char_end": 32752, "token_start": 13, "token_end": 15, "note": null}, {"text": "blistering", "type": "ENTITY", "char_start": 32772, "char_end": 32782, "token_start": 19, "token_end": 19, "note": null}, {"text": "nail dystrophy", "type": "ENTITY", "char_start": 32785, "char_end": 32799, "token_start": 21, "token_end": 22, "note": null}, {"text": "patchy alopecia", "type": "ENTITY", "char_start": 32802, "char_end": 32817, "token_start": 24, "token_end": 25, "note": null}, {"text": "dental abnormalities", "type": "ENTITY", "char_start": 32824, "char_end": 32844, "token_start": 28, "token_end": 29, "note": null}]}
+{"sentence_id": 226, "sentence_text": "Skin fragility in most cases is due to mutations in the gene encoding type XVII collagen ( COL17A1 ) .", "sentence_char_start_global": 32847, "sentence_char_end_global": 32949, "entities": [{"text": "Skin fragility", "type": "ENTITY", "char_start": 0, "char_end": 14, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "Skin fragility", "type": "ENTITY", "char_start": 32847, "char_end": 32861, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 227, "sentence_text": "Recently , we reported five Austrian families with generalized atrophic benign epidermolysis bullosa who share the same COL17A1 mutation .", "sentence_char_start_global": 32950, "sentence_char_end_global": 33088, "entities": [{"text": "atrophic benign epidermolysis bullosa", "type": "ENTITY", "char_start": 63, "char_end": 100, "token_start": 9, "token_end": 12}], "entities_global": [{"text": "atrophic benign epidermolysis bullosa", "type": "ENTITY", "char_start": 33013, "char_end": 33050, "token_start": 9, "token_end": 12, "note": null}]}
+{"sentence_id": 228, "sentence_text": "Affected individuals in three families are homozygous for 4003delTC , whereas those in two others are compound heterozygotes .", "sentence_char_start_global": 33089, "sentence_char_end_global": 33215, "entities": [], "entities_global": []}
+{"sentence_id": 229, "sentence_text": "To determine if the occurrence of 4003delTC in these unrelated families signifies propagation of an ancestral allele or a mutational hot spot , haplotypes were determined for polymorphisms both within and flanking COL17A1 .", "sentence_char_start_global": 33216, "sentence_char_end_global": 33439, "entities": [], "entities_global": []}
+{"sentence_id": 230, "sentence_text": "Five intragenic polymorphisms were chosen based on their informativeness .", "sentence_char_start_global": 33440, "sentence_char_end_global": 33514, "entities": [], "entities_global": []}
+{"sentence_id": 231, "sentence_text": "One of these , not previously reported , was 2988 A or C that introduces a new restriction site for Eco0109 I .", "sentence_char_start_global": 33515, "sentence_char_end_global": 33626, "entities": [], "entities_global": []}
+{"sentence_id": 232, "sentence_text": "All the 4003delTC alleles showed the same haplotype for these five polymorphic markers .", "sentence_char_start_global": 33627, "sentence_char_end_global": 33715, "entities": [], "entities_global": []}
+{"sentence_id": 233, "sentence_text": "Fourteen microsatellite polymorphisms were selected based on their high heterozygosity and their location within 10q23 - q25 near COL17A1 .", "sentence_char_start_global": 33716, "sentence_char_end_global": 33855, "entities": [], "entities_global": []}
+{"sentence_id": 234, "sentence_text": "Three families shared microsatellite polymorphisms covering at most 19 cM , whereas the others shared smaller regions consistent with cross - over events during passage of this mutation through several generations .", "sentence_char_start_global": 33856, "sentence_char_end_global": 34071, "entities": [], "entities_global": []}
+{"sentence_id": 235, "sentence_text": "These results indicate that 4003delTC occurs on a single ancestral allele . .", "sentence_char_start_global": 34072, "sentence_char_end_global": 34149, "entities": [], "entities_global": []}
+{"sentence_id": 236, "sentence_text": "The haptoglobin - gene deletion responsible for anhaptoglobinemia .", "sentence_char_start_global": 34150, "sentence_char_end_global": 34217, "entities": [{"text": "anhaptoglobinemia", "type": "ENTITY", "char_start": 48, "char_end": 65, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "anhaptoglobinemia", "type": "ENTITY", "char_start": 34198, "char_end": 34215, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 237, "sentence_text": "We have found an allelic deletion of the haptoglobin ( Hp ) gene from an individual with anhaptoglobinemia .", "sentence_char_start_global": 34218, "sentence_char_end_global": 34326, "entities": [{"text": "anhaptoglobinemia", "type": "ENTITY", "char_start": 89, "char_end": 106, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "anhaptoglobinemia", "type": "ENTITY", "char_start": 34307, "char_end": 34324, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 238, "sentence_text": "The Hp gene cluster consists of coding regions of the alpha chain and beta chain of the haptoglobin gene ( Hp ) and of the alpha chain and beta chain of the haptoglobin - related gene ( Hpr ) , in tandem from the 5 side .", "sentence_char_start_global": 34327, "sentence_char_end_global": 34548, "entities": [], "entities_global": []}
+{"sentence_id": 239, "sentence_text": "Southern blot and PCR analyses have indicated that the individual with anhaptoglobinemia was homozygous for the gene deletion and that the gene deletion was included at least from the promoter region of Hp to Hpr alpha but not to Hpr beta ( Hpdel ) .", "sentence_char_start_global": 34549, "sentence_char_end_global": 34799, "entities": [{"text": "anhaptoglobinemia", "type": "ENTITY", "char_start": 71, "char_end": 88, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "anhaptoglobinemia", "type": "ENTITY", "char_start": 34620, "char_end": 34637, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 240, "sentence_text": "In addition , we found seven individuals with hypohaptoglobinemia in three families , and the genotypes of six of the seven individuals were found to be Hp2 / Hpdel .", "sentence_char_start_global": 34800, "sentence_char_end_global": 34966, "entities": [{"text": "hypohaptoglobinemia", "type": "ENTITY", "char_start": 46, "char_end": 65, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "hypohaptoglobinemia", "type": "ENTITY", "char_start": 34846, "char_end": 34865, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 241, "sentence_text": "The phenotypes and genotypes in one of these three families showed the father to be hypohaptoglobinemic ( Hp2 ) and Hp2 / Hpdel , the mother to be Hp2 - 1 and Hp1 / Hp2 , one of the two children to be hypohaptoglobinemic ( Hp2 ) and Hp2 / Hpdel , and the other child to be Hp1 and Hp1 / Hpdel , showing an anomalous inheritance of Hp phenotypes in the child with Hp1 .", "sentence_char_start_global": 34967, "sentence_char_end_global": 35335, "entities": [{"text": "hypohaptoglobinemic", "type": "ENTITY", "char_start": 84, "char_end": 103, "token_start": 15, "token_end": 15}, {"text": "hypohaptoglobinemic", "type": "ENTITY", "char_start": 201, "char_end": 220, "token_start": 43, "token_end": 43}], "entities_global": [{"text": "hypohaptoglobinemic", "type": "ENTITY", "char_start": 35051, "char_end": 35070, "token_start": 15, "token_end": 15, "note": null}, {"text": "hypohaptoglobinemic", "type": "ENTITY", "char_start": 35168, "char_end": 35187, "token_start": 43, "token_end": 43, "note": null}]}
+{"sentence_id": 242, "sentence_text": "The Hp2 / Hpdel individuals had an extremely low level of Hp ( mean + / - SD = 0 . 049 + / - 0 . 043 mg / ml ; n = 6 ) , compared with the level ( 1 . 64 + / - 1 . 07 mg / ml ) obtained from 52 healthy volunteers having phenotype Hp2 , whereas the serum Hp level of an individual with Hp1 / Hpdel was 0 .", "sentence_char_start_global": 35336, "sentence_char_end_global": 35640, "entities": [], "entities_global": []}
+{"sentence_id": 243, "sentence_text": "50 mg / ml , which was approximately half the level of Hp in control sera from the Hp1 phenotype ( 1 . 26 + / - 0 . 33 mg / ml ; n = 9 ) , showing a gene - dosage effect .", "sentence_char_start_global": 35641, "sentence_char_end_global": 35812, "entities": [], "entities_global": []}
+{"sentence_id": 244, "sentence_text": "The other allele ( Hp2 ) of individuals with Hp2 / Hpdel was found to have , in all exons , no mutation , by DNA sequencing .", "sentence_char_start_global": 35813, "sentence_char_end_global": 35938, "entities": [], "entities_global": []}
+{"sentence_id": 245, "sentence_text": "On the basis of the present study , the mechanism of anhaptoglobinemia and the mechanism of anomalous inheritance of Hp phenotypes were well explained .", "sentence_char_start_global": 35939, "sentence_char_end_global": 36091, "entities": [{"text": "anhaptoglobinemia", "type": "ENTITY", "char_start": 53, "char_end": 70, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "anhaptoglobinemia", "type": "ENTITY", "char_start": 35992, "char_end": 36009, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 246, "sentence_text": "However , the mechanism of hypohaptoglobinemia remains unknown", "sentence_char_start_global": 36092, "sentence_char_end_global": 36154, "entities": [{"text": "hypohaptoglobinemia", "type": "ENTITY", "char_start": 27, "char_end": 46, "token_start": 5, "token_end": 5}], "entities_global": [{"text": "hypohaptoglobinemia", "type": "ENTITY", "char_start": 36119, "char_end": 36138, "token_start": 5, "token_end": 5, "note": null}]}
+{"sentence_id": 247, "sentence_text": "ATM mutations and phenotypes in ataxia - telangiectasia families in the British Isles : expression of mutant ATM and the risk of leukemia , lymphoma , and breast cancer .", "sentence_char_start_global": 36155, "sentence_char_end_global": 36325, "entities": [{"text": "ataxia - telangiectasia", "type": "ENTITY", "char_start": 32, "char_end": 55, "token_start": 5, "token_end": 7}, {"text": "leukemia", "type": "ENTITY", "char_start": 129, "char_end": 137, "token_start": 22, "token_end": 22}, {"text": "lymphoma", "type": "ENTITY", "char_start": 140, "char_end": 148, "token_start": 24, "token_end": 24}, {"text": "breast cancer", "type": "ENTITY", "char_start": 155, "char_end": 168, "token_start": 27, "token_end": 28}], "entities_global": [{"text": "ataxia - telangiectasia", "type": "ENTITY", "char_start": 36187, "char_end": 36210, "token_start": 5, "token_end": 7, "note": null}, {"text": "leukemia", "type": "ENTITY", "char_start": 36284, "char_end": 36292, "token_start": 22, "token_end": 22, "note": null}, {"text": "lymphoma", "type": "ENTITY", "char_start": 36295, "char_end": 36303, "token_start": 24, "token_end": 24, "note": null}, {"text": "breast cancer", "type": "ENTITY", "char_start": 36310, "char_end": 36323, "token_start": 27, "token_end": 28, "note": null}]}
+{"sentence_id": 248, "sentence_text": "We report the spectrum of 59 ATM mutations observed in ataxia - telangiectasia ( A - T ) patients in the British Isles .", "sentence_char_start_global": 36326, "sentence_char_end_global": 36446, "entities": [{"text": "ataxia - telangiectasia", "type": "ENTITY", "char_start": 55, "char_end": 78, "token_start": 10, "token_end": 12}, {"text": "A - T", "type": "ENTITY", "char_start": 81, "char_end": 86, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "ataxia - telangiectasia", "type": "ENTITY", "char_start": 36381, "char_end": 36404, "token_start": 10, "token_end": 12, "note": null}, {"text": "A - T", "type": "ENTITY", "char_start": 36407, "char_end": 36412, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 249, "sentence_text": "Of 51 ATM mutations identified in families native to the British Isles , 11 were founder mutations , and 2 of these 11 conferred a milder clinical phenotype with respect to both cerebellar degeneration and cellular features .", "sentence_char_start_global": 36447, "sentence_char_end_global": 36672, "entities": [{"text": "cerebellar degeneration", "type": "ENTITY", "char_start": 178, "char_end": 201, "token_start": 32, "token_end": 33}], "entities_global": [{"text": "cerebellar degeneration", "type": "ENTITY", "char_start": 36625, "char_end": 36648, "token_start": 32, "token_end": 33, "note": null}]}
+{"sentence_id": 250, "sentence_text": "We report , in two A - T families , an ATM mutation ( 7271T - - > G ) that may be associated with an increased risk of breast cancer in both homozygotes and heterozygotes ( relative risk 12 . 7 ; P = . 0025 ) , although there is a less severe A - T phenotype in terms of the degree of cerebellar degeneration .", "sentence_char_start_global": 36673, "sentence_char_end_global": 36983, "entities": [{"text": "A - T", "type": "ENTITY", "char_start": 19, "char_end": 24, "token_start": 5, "token_end": 7}, {"text": "breast cancer", "type": "ENTITY", "char_start": 119, "char_end": 132, "token_start": 29, "token_end": 30}, {"text": "A - T", "type": "ENTITY", "char_start": 243, "char_end": 248, "token_start": 55, "token_end": 57}, {"text": "cerebellar degeneration", "type": "ENTITY", "char_start": 285, "char_end": 308, "token_start": 65, "token_end": 66}], "entities_global": [{"text": "A - T", "type": "ENTITY", "char_start": 36692, "char_end": 36697, "token_start": 5, "token_end": 7, "note": null}, {"text": "breast cancer", "type": "ENTITY", "char_start": 36792, "char_end": 36805, "token_start": 29, "token_end": 30, "note": null}, {"text": "A - T", "type": "ENTITY", "char_start": 36916, "char_end": 36921, "token_start": 55, "token_end": 57, "note": null}, {"text": "cerebellar degeneration", "type": "ENTITY", "char_start": 36958, "char_end": 36981, "token_start": 65, "token_end": 66, "note": null}]}
+{"sentence_id": 251, "sentence_text": "This mutation ( 7271T - - > G ) also allows expression of full - length ATM protein at a level comparable with that in unaffected individuals .", "sentence_char_start_global": 36984, "sentence_char_end_global": 37127, "entities": [], "entities_global": []}
+{"sentence_id": 252, "sentence_text": "In addition , we have studied 18 A - T patients , in 15 families , who developed leukemia , lymphoma , preleukemic T - cell proliferation , or Hodgkin lymphoma , mostly in childhood .", "sentence_char_start_global": 37128, "sentence_char_end_global": 37311, "entities": [{"text": "A - T", "type": "ENTITY", "char_start": 33, "char_end": 38, "token_start": 7, "token_end": 9}, {"text": "leukemia", "type": "ENTITY", "char_start": 81, "char_end": 89, "token_start": 18, "token_end": 18}, {"text": "lymphoma", "type": "ENTITY", "char_start": 92, "char_end": 100, "token_start": 20, "token_end": 20}, {"text": "Hodgkin lymphoma", "type": "ENTITY", "char_start": 143, "char_end": 159, "token_start": 29, "token_end": 30}], "entities_global": [{"text": "A - T", "type": "ENTITY", "char_start": 37161, "char_end": 37166, "token_start": 7, "token_end": 9, "note": null}, {"text": "leukemia", "type": "ENTITY", "char_start": 37209, "char_end": 37217, "token_start": 18, "token_end": 18, "note": null}, {"text": "lymphoma", "type": "ENTITY", "char_start": 37220, "char_end": 37228, "token_start": 20, "token_end": 20, "note": null}, {"text": "Hodgkin lymphoma", "type": "ENTITY", "char_start": 37271, "char_end": 37287, "token_start": 29, "token_end": 30, "note": null}]}
+{"sentence_id": 253, "sentence_text": "A wide variety of ATM mutation types , including missense mutations and in - frame deletions , were seen in these patients .", "sentence_char_start_global": 37312, "sentence_char_end_global": 37436, "entities": [], "entities_global": []}
+{"sentence_id": 254, "sentence_text": "We also show that 25 % of all A - T patients carried in - frame deletions or missense mutations , many of which were also associated with expression of mutant ATM protein .", "sentence_char_start_global": 37437, "sentence_char_end_global": 37609, "entities": [{"text": "A - T", "type": "ENTITY", "char_start": 30, "char_end": 35, "token_start": 8, "token_end": 10}], "entities_global": [{"text": "A - T", "type": "ENTITY", "char_start": 37467, "char_end": 37472, "token_start": 8, "token_end": 10, "note": null}]}
+{"sentence_id": 255, "sentence_text": "The DMPK gene of severely affected myotonic dystrophy patients is hypermethylated proximal to the largely expanded CTG repeat .", "sentence_char_start_global": 37610, "sentence_char_end_global": 37737, "entities": [{"text": "myotonic dystrophy", "type": "ENTITY", "char_start": 35, "char_end": 53, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "myotonic dystrophy", "type": "ENTITY", "char_start": 37645, "char_end": 37663, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 256, "sentence_text": "Using methylation - sensitive restriction enzymes , we characterized the methylation pattern on the 5 side of the CTG repeat in the DMPK gene of normal individuals and of patients affected with myotonic dystrophy , showing expansions of the repetitive sequence .", "sentence_char_start_global": 37738, "sentence_char_end_global": 38000, "entities": [{"text": "myotonic dystrophy", "type": "ENTITY", "char_start": 194, "char_end": 212, "token_start": 32, "token_end": 33}], "entities_global": [{"text": "myotonic dystrophy", "type": "ENTITY", "char_start": 37932, "char_end": 37950, "token_start": 32, "token_end": 33, "note": null}]}
+{"sentence_id": 257, "sentence_text": "The gene segment analyzed corresponds to the genomic SacI - HindIII fragment carrying exons 11 - 15 .", "sentence_char_start_global": 38001, "sentence_char_end_global": 38102, "entities": [], "entities_global": []}
+{"sentence_id": 258, "sentence_text": "There is constitutive methylation in intron 12 at restriction sites of SacII and HhaI , localized 1 , 159 - 1 , 232 bp upstream of the CTG repeat , whereas most , if not all , of the other sites of SacII , HhaI , and HpaII in this region are unmethylated , in normal individuals and most of the patients .", "sentence_char_start_global": 38103, "sentence_char_end_global": 38408, "entities": [], "entities_global": []}
+{"sentence_id": 259, "sentence_text": "In a number of young and severely affected patients , however , complete methylation of these restriction sites was found in the mutated allele .", "sentence_char_start_global": 38409, "sentence_char_end_global": 38554, "entities": [], "entities_global": []}
+{"sentence_id": 260, "sentence_text": "In most of these patients , the onset of the disease was congenital .", "sentence_char_start_global": 38555, "sentence_char_end_global": 38624, "entities": [], "entities_global": []}
+{"sentence_id": 261, "sentence_text": "Preliminary in vivo footprinting data gave evidence for protein - DNA contact in normal genes at an Sp1 consensus binding site upstream of the CTG repeat and for a significant reduction of this interaction in cells with a hypermethylated DMPK gene . .", "sentence_char_start_global": 38625, "sentence_char_end_global": 38876, "entities": [], "entities_global": []}
+{"sentence_id": 262, "sentence_text": "The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding .", "sentence_char_start_global": 38877, "sentence_char_end_global": 38994, "entities": [{"text": "hemochromatosis", "type": "ENTITY", "char_start": 4, "char_end": 19, "token_start": 1, "token_end": 1}], "entities_global": [{"text": "hemochromatosis", "type": "ENTITY", "char_start": 38881, "char_end": 38896, "token_start": 1, "token_end": 1, "note": null}]}
+{"sentence_id": 263, "sentence_text": "We recently reported the positional cloning of a candidate gene for hereditary hemochromatosis called HFE .", "sentence_char_start_global": 38995, "sentence_char_end_global": 39102, "entities": [{"text": "hereditary hemochromatosis", "type": "ENTITY", "char_start": 68, "char_end": 94, "token_start": 11, "token_end": 12}], "entities_global": [{"text": "hereditary hemochromatosis", "type": "ENTITY", "char_start": 39063, "char_end": 39089, "token_start": 11, "token_end": 12, "note": null}]}
+{"sentence_id": 264, "sentence_text": "The gene product , a member of the major histocompatibility complex class I - like family , was found to have a mutation , Cys - 282 - - > Tyr ( C282Y ) , in 85 % of patient chromosomes .", "sentence_char_start_global": 39103, "sentence_char_end_global": 39290, "entities": [], "entities_global": []}
+{"sentence_id": 265, "sentence_text": "This mutation eliminates the ability of HFE to associate with beta2 - microglobulin ( beta2m ) and prevents cell - surface expression .", "sentence_char_start_global": 39291, "sentence_char_end_global": 39426, "entities": [], "entities_global": []}
+{"sentence_id": 266, "sentence_text": "A second mutation that has no effect on beta2m association , H63D , was found in eight out of nine patients heterozygous for the C282Y mutant .", "sentence_char_start_global": 39427, "sentence_char_end_global": 39570, "entities": [], "entities_global": []}
+{"sentence_id": 267, "sentence_text": "In this report , we demonstrate in cultured 293 cells overexpressing wild - type or mutant HFE proteins that both the wild - type and H63D HFE proteins form stable complexes with the transferrin receptor ( TfR ) .", "sentence_char_start_global": 39571, "sentence_char_end_global": 39784, "entities": [], "entities_global": []}
+{"sentence_id": 268, "sentence_text": "The C282Y mutation nearly completely prevents the association of the mutant HFE protein with the TfR .", "sentence_char_start_global": 39785, "sentence_char_end_global": 39887, "entities": [], "entities_global": []}
+{"sentence_id": 269, "sentence_text": "Studies on cell - associated transferrin at 37 degrees C suggest that the overexpressed wild - type HFE protein decreases the affinity of the TfR for transferrin .", "sentence_char_start_global": 39888, "sentence_char_end_global": 40051, "entities": [], "entities_global": []}
+{"sentence_id": 270, "sentence_text": "The overexpressed H63D protein does not have this effect , providing the first direct evidence for a functional consequence of the H63D mutation .", "sentence_char_start_global": 40052, "sentence_char_end_global": 40198, "entities": [], "entities_global": []}
+{"sentence_id": 271, "sentence_text": "Addition of soluble wild - type HFE / beta2m heterodimers to cultured cells also decreased the apparent affinity of the TfR for its ligand under steady - state conditions , both in 293 cells and in HeLa cells .", "sentence_char_start_global": 40199, "sentence_char_end_global": 40409, "entities": [], "entities_global": []}
+{"sentence_id": 272, "sentence_text": "Furthermore , at 4 degrees C , the added soluble complex of HFE / beta2m inhibited binding of transferrin to HeLa cell TfR in a concentration - dependent manner .", "sentence_char_start_global": 40410, "sentence_char_end_global": 40572, "entities": [], "entities_global": []}
+{"sentence_id": 273, "sentence_text": "Scatchard plots of these data indicate that the added heterodimer substantially reduced the affinity of TfR for transferrin .", "sentence_char_start_global": 40573, "sentence_char_end_global": 40698, "entities": [], "entities_global": []}
+{"sentence_id": 274, "sentence_text": "These results establish a molecular link between HFE and a key protein involved in iron transport , the TfR , and raise the possibility that alterations in this regulatory mechanism may play a role in the pathogenesis of hereditary hemochromatosis . .", "sentence_char_start_global": 40699, "sentence_char_end_global": 40950, "entities": [{"text": "hereditary hemochromatosis", "type": "ENTITY", "char_start": 221, "char_end": 247, "token_start": 38, "token_end": 39}], "entities_global": [{"text": "hereditary hemochromatosis", "type": "ENTITY", "char_start": 40920, "char_end": 40946, "token_start": 38, "token_end": 39, "note": null}]}
+{"sentence_id": 275, "sentence_text": "Genomic organization of the UBE3A / E6 - AP gene and related pseudogenes .", "sentence_char_start_global": 40951, "sentence_char_end_global": 41025, "entities": [], "entities_global": []}
+{"sentence_id": 276, "sentence_text": "The UBE3A gene encodes the E6 - AP ubiquitin - protein ligase and has recently been shown to be mutated in Angelman syndrome patients who lack 15q11 - q13 deletions or chromosome 15 paternal uniparental disomy .", "sentence_char_start_global": 41026, "sentence_char_end_global": 41237, "entities": [{"text": "Angelman syndrome", "type": "ENTITY", "char_start": 107, "char_end": 124, "token_start": 21, "token_end": 22}, {"text": "uniparental disomy", "type": "ENTITY", "char_start": 191, "char_end": 209, "token_start": 34, "token_end": 35}], "entities_global": [{"text": "Angelman syndrome", "type": "ENTITY", "char_start": 41133, "char_end": 41150, "token_start": 21, "token_end": 22, "note": null}, {"text": "uniparental disomy", "type": "ENTITY", "char_start": 41217, "char_end": 41235, "token_start": 34, "token_end": 35, "note": null}]}
+{"sentence_id": 277, "sentence_text": "Previous UBE3A cDNA analysis has shown a coding region of approximately 2 .", "sentence_char_start_global": 41238, "sentence_char_end_global": 41313, "entities": [], "entities_global": []}
+{"sentence_id": 278, "sentence_text": "6 kb and a 3 - untranslated region ( UTR ) of < 50 bp , whereas Northern analysis has indicated mRNA sizes of 5 - 8 kb .", "sentence_char_start_global": 41314, "sentence_char_end_global": 41434, "entities": [], "entities_global": []}
+{"sentence_id": 279, "sentence_text": "We have analyzed additional cDNA clones and provide evidence for an additional 0 .", "sentence_char_start_global": 41435, "sentence_char_end_global": 41517, "entities": [], "entities_global": []}
+{"sentence_id": 280, "sentence_text": "5 kb of 5 - UTR and > 2 kb of 3 - UTR .", "sentence_char_start_global": 41518, "sentence_char_end_global": 41557, "entities": [], "entities_global": []}
+{"sentence_id": 281, "sentence_text": "We have established the genomic organization of UBE3A and the sequence of intron - exon borders .", "sentence_char_start_global": 41558, "sentence_char_end_global": 41655, "entities": [], "entities_global": []}
+{"sentence_id": 282, "sentence_text": "We have also mapped two highly homologous processed pseudogenes , UBE3AP1 and UBE3AP2 , to chromosomes 2 and 21 , respectively , and determined their genomic organization .", "sentence_char_start_global": 41656, "sentence_char_end_global": 41828, "entities": [], "entities_global": []}
+{"sentence_id": 283, "sentence_text": "These results will form the basis for studies of mutation and imprinting of UBE3A .", "sentence_char_start_global": 41829, "sentence_char_end_global": 41912, "entities": [], "entities_global": []}
+{"sentence_id": 284, "sentence_text": "Mutation spectrum and genotype - phenotype analyses in Cowden disease and Bannayan - Zonana syndrome , two hamartoma syndromes with germline PTEN mutation .", "sentence_char_start_global": 41913, "sentence_char_end_global": 42069, "entities": [{"text": "Cowden disease", "type": "ENTITY", "char_start": 55, "char_end": 69, "token_start": 8, "token_end": 9}, {"text": "Bannayan - Zonana syndrome", "type": "ENTITY", "char_start": 74, "char_end": 100, "token_start": 11, "token_end": 14}, {"text": "hamartoma syndromes", "type": "ENTITY", "char_start": 107, "char_end": 126, "token_start": 17, "token_end": 18}], "entities_global": [{"text": "Cowden disease", "type": "ENTITY", "char_start": 41968, "char_end": 41982, "token_start": 8, "token_end": 9, "note": null}, {"text": "Bannayan - Zonana syndrome", "type": "ENTITY", "char_start": 41987, "char_end": 42013, "token_start": 11, "token_end": 14, "note": null}, {"text": "hamartoma syndromes", "type": "ENTITY", "char_start": 42020, "char_end": 42039, "token_start": 17, "token_end": 18, "note": null}]}
+{"sentence_id": 285, "sentence_text": "The tumour suppressor gene PTEN , which maps to 10q23 .", "sentence_char_start_global": 42070, "sentence_char_end_global": 42125, "entities": [{"text": "tumour", "type": "ENTITY", "char_start": 4, "char_end": 10, "token_start": 1, "token_end": 1}], "entities_global": [{"text": "tumour", "type": "ENTITY", "char_start": 42074, "char_end": 42080, "token_start": 1, "token_end": 1, "note": null}]}
+{"sentence_id": 286, "sentence_text": "3 and encodes a 403 amino acid dual specificity phosphatase ( protein tyrosine phosphatase ; PTPase ) , was shown recently to play a broad role in human malignancy .", "sentence_char_start_global": 42126, "sentence_char_end_global": 42291, "entities": [{"text": "malignancy", "type": "ENTITY", "char_start": 153, "char_end": 163, "token_start": 28, "token_end": 28}], "entities_global": [{"text": "malignancy", "type": "ENTITY", "char_start": 42279, "char_end": 42289, "token_start": 28, "token_end": 28, "note": null}]}
+{"sentence_id": 287, "sentence_text": "Somatic PTEN deletions and mutations were observed in sporadic breast , brain , prostate and kidney cancer cell lines and in several primary tumours such as endometrial carcinomas , malignant melanoma and thyroid tumours .", "sentence_char_start_global": 42292, "sentence_char_end_global": 42514, "entities": [{"text": "sporadic breast , brain , prostate and kidney cancer", "type": "ENTITY", "char_start": 54, "char_end": 106, "token_start": 8, "token_end": 16}, {"text": "tumours", "type": "ENTITY", "char_start": 141, "char_end": 148, "token_start": 23, "token_end": 23}, {"text": "endometrial carcinomas", "type": "ENTITY", "char_start": 157, "char_end": 179, "token_start": 26, "token_end": 27}, {"text": "malignant melanoma", "type": "ENTITY", "char_start": 182, "char_end": 200, "token_start": 29, "token_end": 30}, {"text": "thyroid tumours", "type": "ENTITY", "char_start": 205, "char_end": 220, "token_start": 32, "token_end": 33}], "entities_global": [{"text": "sporadic breast , brain , prostate and kidney cancer", "type": "ENTITY", "char_start": 42346, "char_end": 42398, "token_start": 8, "token_end": 16, "note": null}, {"text": "tumours", "type": "ENTITY", "char_start": 42433, "char_end": 42440, "token_start": 23, "token_end": 23, "note": null}, {"text": "endometrial carcinomas", "type": "ENTITY", "char_start": 42449, "char_end": 42471, "token_start": 26, "token_end": 27, "note": null}, {"text": "malignant melanoma", "type": "ENTITY", "char_start": 42474, "char_end": 42492, "token_start": 29, "token_end": 30, "note": null}, {"text": "thyroid tumours", "type": "ENTITY", "char_start": 42497, "char_end": 42512, "token_start": 32, "token_end": 33, "note": null}]}
+{"sentence_id": 288, "sentence_text": "In addition , PTEN was identified as the susceptibility gene for two hamartoma syndromes Cowden disease ( CD ; MIM 158350 ) and Bannayan - Zonana ( BZS ) or Ruvalcaba - Riley - Smith syndrome ( MIM 153480 ) .", "sentence_char_start_global": 42515, "sentence_char_end_global": 42723, "entities": [{"text": "hamartoma syndromes", "type": "ENTITY", "char_start": 69, "char_end": 88, "token_start": 12, "token_end": 13}, {"text": "Cowden disease", "type": "ENTITY", "char_start": 89, "char_end": 103, "token_start": 14, "token_end": 15}, {"text": "CD", "type": "ENTITY", "char_start": 106, "char_end": 108, "token_start": 17, "token_end": 17}, {"text": "Bannayan - Zonana ( BZS ) or Ruvalcaba - Riley - Smith syndrome", "type": "ENTITY", "char_start": 128, "char_end": 191, "token_start": 23, "token_end": 35}], "entities_global": [{"text": "hamartoma syndromes", "type": "ENTITY", "char_start": 42584, "char_end": 42603, "token_start": 12, "token_end": 13, "note": null}, {"text": "Cowden disease", "type": "ENTITY", "char_start": 42604, "char_end": 42618, "token_start": 14, "token_end": 15, "note": null}, {"text": "CD", "type": "ENTITY", "char_start": 42621, "char_end": 42623, "token_start": 17, "token_end": 17, "note": null}, {"text": "Bannayan - Zonana ( BZS ) or Ruvalcaba - Riley - Smith syndrome", "type": "ENTITY", "char_start": 42643, "char_end": 42706, "token_start": 23, "token_end": 35, "note": null}]}
+{"sentence_id": 289, "sentence_text": "Constitutive DNA from 37 CD families and seven BZS families was screened for germline PTEN mutations .", "sentence_char_start_global": 42724, "sentence_char_end_global": 42826, "entities": [{"text": "CD", "type": "ENTITY", "char_start": 25, "char_end": 27, "token_start": 4, "token_end": 4}, {"text": "BZS", "type": "ENTITY", "char_start": 47, "char_end": 50, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "CD", "type": "ENTITY", "char_start": 42749, "char_end": 42751, "token_start": 4, "token_end": 4, "note": null}, {"text": "BZS", "type": "ENTITY", "char_start": 42771, "char_end": 42774, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 290, "sentence_text": "PTEN mutations were identified in 30 of 37 ( 81 % ) CD families , including missense and nonsense point mutations , deletions , insertions , a deletion / insertion and splice site mutations .", "sentence_char_start_global": 42827, "sentence_char_end_global": 43018, "entities": [{"text": "CD", "type": "ENTITY", "char_start": 52, "char_end": 54, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "CD", "type": "ENTITY", "char_start": 42879, "char_end": 42881, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 291, "sentence_text": "These mutations were scattered over the entire length of PTEN , with the exception of the first , fourth and last exons .", "sentence_char_start_global": 43019, "sentence_char_end_global": 43140, "entities": [], "entities_global": []}
+{"sentence_id": 292, "sentence_text": "A hot spot for PTEN mutation in CD was identified in exon 5 that contains the PTPase core motif , with 13 of 30 ( 43 % ) CD mutations identified in this exon .", "sentence_char_start_global": 43141, "sentence_char_end_global": 43300, "entities": [{"text": "CD", "type": "ENTITY", "char_start": 32, "char_end": 34, "token_start": 7, "token_end": 7}, {"text": "CD", "type": "ENTITY", "char_start": 121, "char_end": 123, "token_start": 28, "token_end": 28}], "entities_global": [{"text": "CD", "type": "ENTITY", "char_start": 43173, "char_end": 43175, "token_start": 7, "token_end": 7, "note": null}, {"text": "CD", "type": "ENTITY", "char_start": 43262, "char_end": 43264, "token_start": 28, "token_end": 28, "note": null}]}
+{"sentence_id": 293, "sentence_text": "Seven of 30 ( 23 % ) were within the core motif , the majority ( five of seven ) of which were missense mutations , possibly pointing to the functional significance of this region .", "sentence_char_start_global": 43301, "sentence_char_end_global": 43482, "entities": [], "entities_global": []}
+{"sentence_id": 294, "sentence_text": "Germline PTEN mutations were identified in four of seven ( 57 % ) BZS families studied .", "sentence_char_start_global": 43483, "sentence_char_end_global": 43571, "entities": [{"text": "BZS", "type": "ENTITY", "char_start": 66, "char_end": 69, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "BZS", "type": "ENTITY", "char_start": 43549, "char_end": 43552, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 295, "sentence_text": "Interestingly , none of these mutations was observed in the PTPase core motif .", "sentence_char_start_global": 43572, "sentence_char_end_global": 43651, "entities": [], "entities_global": []}
+{"sentence_id": 296, "sentence_text": "It is also worthy of note that a single nonsense point mutation , R233X , was observed in the germline DNA from two unrelated CD families and one BZS family .", "sentence_char_start_global": 43652, "sentence_char_end_global": 43810, "entities": [{"text": "CD", "type": "ENTITY", "char_start": 126, "char_end": 128, "token_start": 24, "token_end": 24}, {"text": "BZS", "type": "ENTITY", "char_start": 146, "char_end": 149, "token_start": 28, "token_end": 28}], "entities_global": [{"text": "CD", "type": "ENTITY", "char_start": 43778, "char_end": 43780, "token_start": 24, "token_end": 24, "note": null}, {"text": "BZS", "type": "ENTITY", "char_start": 43798, "char_end": 43801, "token_start": 28, "token_end": 28, "note": null}]}
+{"sentence_id": 297, "sentence_text": "Genotype - phenotype studies were not performed on this small group of BZS families .", "sentence_char_start_global": 43811, "sentence_char_end_global": 43896, "entities": [{"text": "BZS", "type": "ENTITY", "char_start": 71, "char_end": 74, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "BZS", "type": "ENTITY", "char_start": 43882, "char_end": 43885, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 298, "sentence_text": "However , genotype - phenotype analysis inthe group of CD families revealed two possible associations worthy of follow - up in independent analyses .", "sentence_char_start_global": 43897, "sentence_char_end_global": 44046, "entities": [{"text": "CD", "type": "ENTITY", "char_start": 55, "char_end": 57, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "CD", "type": "ENTITY", "char_start": 43952, "char_end": 43954, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 299, "sentence_text": "The first was an association noted in the group of CD families with breast disease .", "sentence_char_start_global": 44047, "sentence_char_end_global": 44131, "entities": [{"text": "CD", "type": "ENTITY", "char_start": 51, "char_end": 53, "token_start": 10, "token_end": 10}, {"text": "breast disease", "type": "ENTITY", "char_start": 68, "char_end": 82, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "CD", "type": "ENTITY", "char_start": 44098, "char_end": 44100, "token_start": 10, "token_end": 10, "note": null}, {"text": "breast disease", "type": "ENTITY", "char_start": 44115, "char_end": 44129, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 300, "sentence_text": "A correlation was observed between the presence / absence of a PTEN mutation and the type of breast involvement ( unaffected versus benign versus malignant ) .", "sentence_char_start_global": 44132, "sentence_char_end_global": 44291, "entities": [], "entities_global": []}
+{"sentence_id": 301, "sentence_text": "Specifically and more directly , an association was also observed between the presence of a PTEN mutation and malignant breast disease .", "sentence_char_start_global": 44292, "sentence_char_end_global": 44428, "entities": [{"text": "malignant breast disease", "type": "ENTITY", "char_start": 110, "char_end": 134, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "malignant breast disease", "type": "ENTITY", "char_start": 44402, "char_end": 44426, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 302, "sentence_text": "Secondly , there appeared to be an interdependent association between mutations upstream and within the PTPase core motif , the core motif containing the majority of missense mutations , and the involvement of all major organ systems ( central nervous system , thyroid , breast , skin and gastrointestinal tract ) .", "sentence_char_start_global": 44429, "sentence_char_end_global": 44744, "entities": [], "entities_global": []}
+{"sentence_id": 303, "sentence_text": "However , these observations would need to be confirmed by studying a larger number of CD families .", "sentence_char_start_global": 44745, "sentence_char_end_global": 44845, "entities": [{"text": "CD", "type": "ENTITY", "char_start": 87, "char_end": 89, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "CD", "type": "ENTITY", "char_start": 44832, "char_end": 44834, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 304, "sentence_text": "Molecular defects leading to human complement component C6 deficiency in an African - American family .", "sentence_char_start_global": 44846, "sentence_char_end_global": 44949, "entities": [{"text": "complement component C6 deficiency", "type": "ENTITY", "char_start": 35, "char_end": 69, "token_start": 5, "token_end": 8}], "entities_global": [{"text": "complement component C6 deficiency", "type": "ENTITY", "char_start": 44881, "char_end": 44915, "token_start": 5, "token_end": 8, "note": null}]}
+{"sentence_id": 305, "sentence_text": "Complement component C6 deficiency ( C6D ) was diagnosed in a 16 - year - old African - American male with meningococcal meningitis .", "sentence_char_start_global": 44950, "sentence_char_end_global": 45083, "entities": [{"text": "Complement component C6 deficiency", "type": "ENTITY", "char_start": 0, "char_end": 34, "token_start": 0, "token_end": 3}, {"text": "C6D", "type": "ENTITY", "char_start": 37, "char_end": 40, "token_start": 5, "token_end": 5}, {"text": "meningococcal meningitis", "type": "ENTITY", "char_start": 107, "char_end": 131, "token_start": 21, "token_end": 22}], "entities_global": [{"text": "Complement component C6 deficiency", "type": "ENTITY", "char_start": 44950, "char_end": 44984, "token_start": 0, "token_end": 3, "note": null}, {"text": "C6D", "type": "ENTITY", "char_start": 44987, "char_end": 44990, "token_start": 5, "token_end": 5, "note": null}, {"text": "meningococcal meningitis", "type": "ENTITY", "char_start": 45057, "char_end": 45081, "token_start": 21, "token_end": 22, "note": null}]}
+{"sentence_id": 306, "sentence_text": "The patients father and two brothers also had C6D , but gave no history of meningitis or other neisserial infection .", "sentence_char_start_global": 45084, "sentence_char_end_global": 45201, "entities": [{"text": "C6D", "type": "ENTITY", "char_start": 46, "char_end": 49, "token_start": 8, "token_end": 8}, {"text": "meningitis", "type": "ENTITY", "char_start": 75, "char_end": 85, "token_start": 15, "token_end": 15}, {"text": "neisserial infection", "type": "ENTITY", "char_start": 95, "char_end": 115, "token_start": 18, "token_end": 19}], "entities_global": [{"text": "C6D", "type": "ENTITY", "char_start": 45130, "char_end": 45133, "token_start": 8, "token_end": 8, "note": null}, {"text": "meningitis", "type": "ENTITY", "char_start": 45159, "char_end": 45169, "token_start": 15, "token_end": 15, "note": null}, {"text": "neisserial infection", "type": "ENTITY", "char_start": 45179, "char_end": 45199, "token_start": 18, "token_end": 19, "note": null}]}
+{"sentence_id": 307, "sentence_text": "By using exon - specific polymerase chain reaction ( PCR ) / single - strand conformation polymorphism as a screening step and nucleotide sequencing of target exons , we determined that the proband was a compound heterozygote for two C6 gene mutations .", "sentence_char_start_global": 45202, "sentence_char_end_global": 45455, "entities": [], "entities_global": []}
+{"sentence_id": 308, "sentence_text": "The first , 1195delC located in exon 7 , is a novel mutation , while the second , 1936delG in exon 12 , has been described before to cause C6D in an unrelated African - American individual .", "sentence_char_start_global": 45456, "sentence_char_end_global": 45646, "entities": [{"text": "C6D", "type": "ENTITY", "char_start": 139, "char_end": 142, "token_start": 29, "token_end": 29}], "entities_global": [{"text": "C6D", "type": "ENTITY", "char_start": 45595, "char_end": 45598, "token_start": 29, "token_end": 29, "note": null}]}
+{"sentence_id": 309, "sentence_text": "Both mutations result in premature termination codons and C6 null alleles .", "sentence_char_start_global": 45647, "sentence_char_end_global": 45722, "entities": [], "entities_global": []}
+{"sentence_id": 310, "sentence_text": "Allele - specific PCR indicated that the probands two brothers also inherited the 1195delC mutation from their heterozygous mother and the 1936delG mutation from their homozygous father . .", "sentence_char_start_global": 45723, "sentence_char_end_global": 45912, "entities": [], "entities_global": []}
+{"sentence_id": 311, "sentence_text": "PAX6 mutations reviewed .", "sentence_char_start_global": 45913, "sentence_char_end_global": 45938, "entities": [], "entities_global": []}
+{"sentence_id": 312, "sentence_text": "Mutations in PAX6 are responsible for human aniridia and have also been found in patients with Peters anomaly , with congenital cataracts , with autosomal dominant keratitis , and with isolated foveal hypoplasia .", "sentence_char_start_global": 45939, "sentence_char_end_global": 46152, "entities": [{"text": "aniridia", "type": "ENTITY", "char_start": 44, "char_end": 52, "token_start": 7, "token_end": 7}, {"text": "Peters anomaly", "type": "ENTITY", "char_start": 95, "char_end": 109, "token_start": 16, "token_end": 17}, {"text": "congenital cataracts", "type": "ENTITY", "char_start": 117, "char_end": 137, "token_start": 20, "token_end": 21}, {"text": "autosomal dominant keratitis", "type": "ENTITY", "char_start": 145, "char_end": 173, "token_start": 24, "token_end": 26}, {"text": "isolated foveal hypoplasia", "type": "ENTITY", "char_start": 185, "char_end": 211, "token_start": 30, "token_end": 32}], "entities_global": [{"text": "aniridia", "type": "ENTITY", "char_start": 45983, "char_end": 45991, "token_start": 7, "token_end": 7, "note": null}, {"text": "Peters anomaly", "type": "ENTITY", "char_start": 46034, "char_end": 46048, "token_start": 16, "token_end": 17, "note": null}, {"text": "congenital cataracts", "type": "ENTITY", "char_start": 46056, "char_end": 46076, "token_start": 20, "token_end": 21, "note": null}, {"text": "autosomal dominant keratitis", "type": "ENTITY", "char_start": 46084, "char_end": 46112, "token_start": 24, "token_end": 26, "note": null}, {"text": "isolated foveal hypoplasia", "type": "ENTITY", "char_start": 46124, "char_end": 46150, "token_start": 30, "token_end": 32, "note": null}]}
+{"sentence_id": 313, "sentence_text": "No locus other than chromosome 11p13 has been implicated in aniridia , and PAX6 is clearly the major , if not only , gene responsible .", "sentence_char_start_global": 46153, "sentence_char_end_global": 46288, "entities": [{"text": "aniridia", "type": "ENTITY", "char_start": 60, "char_end": 68, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "aniridia", "type": "ENTITY", "char_start": 46213, "char_end": 46221, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 314, "sentence_text": "Twenty - eight percent of identified PAX6 mutations are C - T changes at CpG dinucleotides , 20 % are splicing errors , and more than 30 % are deletion or insertion events .", "sentence_char_start_global": 46289, "sentence_char_end_global": 46462, "entities": [], "entities_global": []}
+{"sentence_id": 315, "sentence_text": "There is a noticeably elevated level of mutation in the paired domain compared with the rest of the gene .", "sentence_char_start_global": 46463, "sentence_char_end_global": 46569, "entities": [], "entities_global": []}
+{"sentence_id": 316, "sentence_text": "Increased mutation in the homeodomain is accounted for by the hypermutable CpG dinucleotide in codon 240 .", "sentence_char_start_global": 46570, "sentence_char_end_global": 46676, "entities": [], "entities_global": []}
+{"sentence_id": 317, "sentence_text": "Very nearly all mutations appear to cause loss of function of the mutant allele , and more than 80 % of exonic substitutions result in nonsense codons .", "sentence_char_start_global": 46677, "sentence_char_end_global": 46829, "entities": [], "entities_global": []}
+{"sentence_id": 318, "sentence_text": "In a gene with such extraordinarily high sequence conservation throughout evolution , there are presumed undiscovered missense mutations , these are hypothesized to exist in as - yet unidentified phenotypes . .", "sentence_char_start_global": 46830, "sentence_char_end_global": 47040, "entities": [], "entities_global": []}
+{"sentence_id": 319, "sentence_text": "Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families .", "sentence_char_start_global": 47041, "sentence_char_end_global": 47143, "entities": [{"text": "breast cancer", "type": "ENTITY", "char_start": 78, "char_end": 91, "token_start": 12, "token_end": 13}], "entities_global": [{"text": "breast cancer", "type": "ENTITY", "char_start": 47119, "char_end": 47132, "token_start": 12, "token_end": 13, "note": null}]}
+{"sentence_id": 320, "sentence_text": "The Breast Cancer Linkage Consortium .", "sentence_char_start_global": 47144, "sentence_char_end_global": 47182, "entities": [{"text": "Breast Cancer", "type": "ENTITY", "char_start": 4, "char_end": 17, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "Breast Cancer", "type": "ENTITY", "char_start": 47148, "char_end": 47161, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 321, "sentence_text": "The contribution of BRCA1 and BRCA2 to inherited breast cancer was assessed by linkage and mutation analysis in 237 families , each with at least four cases of breast cancer , collected by the Breast Cancer Linkage Consortium .", "sentence_char_start_global": 47183, "sentence_char_end_global": 47410, "entities": [{"text": "inherited breast cancer", "type": "ENTITY", "char_start": 39, "char_end": 62, "token_start": 7, "token_end": 9}, {"text": "breast cancer", "type": "ENTITY", "char_start": 160, "char_end": 173, "token_start": 28, "token_end": 29}, {"text": "Breast Cancer", "type": "ENTITY", "char_start": 193, "char_end": 206, "token_start": 34, "token_end": 35}], "entities_global": [{"text": "inherited breast cancer", "type": "ENTITY", "char_start": 47222, "char_end": 47245, "token_start": 7, "token_end": 9, "note": null}, {"text": "breast cancer", "type": "ENTITY", "char_start": 47343, "char_end": 47356, "token_start": 28, "token_end": 29, "note": null}, {"text": "Breast Cancer", "type": "ENTITY", "char_start": 47376, "char_end": 47389, "token_start": 34, "token_end": 35, "note": null}]}
+{"sentence_id": 322, "sentence_text": "Families were included without regard to the occurrence of ovarian or other cancers .", "sentence_char_start_global": 47411, "sentence_char_end_global": 47496, "entities": [{"text": "ovarian or other cancers", "type": "ENTITY", "char_start": 59, "char_end": 83, "token_start": 9, "token_end": 12}], "entities_global": [{"text": "ovarian or other cancers", "type": "ENTITY", "char_start": 47470, "char_end": 47494, "token_start": 9, "token_end": 12, "note": null}]}
+{"sentence_id": 323, "sentence_text": "Overall , disease was linked to BRCA1 in an estimated 52 % of families , to BRCA2 in 32 % of families , and to neither gene in 16 % ( 95 % confidence interval [ CI ] 6 % - 28 % ) , suggesting other predisposition genes .", "sentence_char_start_global": 47497, "sentence_char_end_global": 47717, "entities": [], "entities_global": []}
+{"sentence_id": 324, "sentence_text": "The majority ( 81 % ) of the breast - ovarian cancer families were due to BRCA1 , with most others ( 14 % ) due to BRCA2 .", "sentence_char_start_global": 47718, "sentence_char_end_global": 47840, "entities": [{"text": "breast - ovarian cancer", "type": "ENTITY", "char_start": 29, "char_end": 52, "token_start": 8, "token_end": 11}], "entities_global": [{"text": "breast - ovarian cancer", "type": "ENTITY", "char_start": 47747, "char_end": 47770, "token_start": 8, "token_end": 11, "note": null}]}
+{"sentence_id": 325, "sentence_text": "Conversely , the majority of families with male and female breast cancer were due to BRCA2 ( 76 % ) .", "sentence_char_start_global": 47841, "sentence_char_end_global": 47942, "entities": [{"text": "male and female breast cancer", "type": "ENTITY", "char_start": 43, "char_end": 72, "token_start": 7, "token_end": 11}], "entities_global": [{"text": "male and female breast cancer", "type": "ENTITY", "char_start": 47884, "char_end": 47913, "token_start": 7, "token_end": 11, "note": null}]}
+{"sentence_id": 326, "sentence_text": "The largest proportion ( 67 % ) of families due to other genes was found in families with four or five cases of female breast cancer only .", "sentence_char_start_global": 47943, "sentence_char_end_global": 48082, "entities": [{"text": "breast cancer", "type": "ENTITY", "char_start": 119, "char_end": 132, "token_start": 24, "token_end": 25}], "entities_global": [{"text": "breast cancer", "type": "ENTITY", "char_start": 48062, "char_end": 48075, "token_start": 24, "token_end": 25, "note": null}]}
+{"sentence_id": 327, "sentence_text": "These estimates were not substantially affected either by changing the assumed penetrance model for BRCA1 or by including or excluding BRCA1 mutation data .", "sentence_char_start_global": 48083, "sentence_char_end_global": 48239, "entities": [], "entities_global": []}
+{"sentence_id": 328, "sentence_text": "Among those families with disease due to BRCA1 that were tested by one of the standard screening methods , mutations were detected in the coding sequence or splice sites in an estimated 63 % ( 95 % CI 51 % - 77 % ) .", "sentence_char_start_global": 48240, "sentence_char_end_global": 48456, "entities": [], "entities_global": []}
+{"sentence_id": 329, "sentence_text": "The estimated sensitivity was identical for direct sequencing and other techniques .", "sentence_char_start_global": 48457, "sentence_char_end_global": 48541, "entities": [], "entities_global": []}
+{"sentence_id": 330, "sentence_text": "The penetrance of BRCA2 was estimated by maximizing the LOD score in BRCA2 - mutation families , over all possible penetrance functions .", "sentence_char_start_global": 48542, "sentence_char_end_global": 48679, "entities": [], "entities_global": []}
+{"sentence_id": 331, "sentence_text": "The estimated cumulative risk of breast cancer reached 28 % ( 95 % CI 9 % - 44 % ) by age 50 years and 84 % ( 95 % CI 43 % - 95 % ) by age 70 years .", "sentence_char_start_global": 48680, "sentence_char_end_global": 48829, "entities": [{"text": "breast cancer", "type": "ENTITY", "char_start": 33, "char_end": 46, "token_start": 5, "token_end": 6}], "entities_global": [{"text": "breast cancer", "type": "ENTITY", "char_start": 48713, "char_end": 48726, "token_start": 5, "token_end": 6, "note": null}]}
+{"sentence_id": 332, "sentence_text": "The corresponding ovarian cancer risks were 0 .", "sentence_char_start_global": 48830, "sentence_char_end_global": 48877, "entities": [{"text": "ovarian cancer", "type": "ENTITY", "char_start": 18, "char_end": 32, "token_start": 2, "token_end": 3}], "entities_global": [{"text": "ovarian cancer", "type": "ENTITY", "char_start": 48848, "char_end": 48862, "token_start": 2, "token_end": 3, "note": null}]}
+{"sentence_id": 333, "sentence_text": "4 % ( 95 % CI 0 % - 1 % ) by age 50 years and 27 % ( 95 % CI 0 % - 47 % ) by age 70 years .", "sentence_char_start_global": 48878, "sentence_char_end_global": 48969, "entities": [], "entities_global": []}
+{"sentence_id": 334, "sentence_text": "The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers , but there was some suggestion of a lower risk in BRCA2 carriers < 50 years of age .", "sentence_char_start_global": 48970, "sentence_char_end_global": 49136, "entities": [{"text": "breast cancer", "type": "ENTITY", "char_start": 21, "char_end": 34, "token_start": 4, "token_end": 5}], "entities_global": [{"text": "breast cancer", "type": "ENTITY", "char_start": 48991, "char_end": 49004, "token_start": 4, "token_end": 5, "note": null}]}
+{"sentence_id": 335, "sentence_text": "Eye movement abnormalities correlate with genotype in autosomal dominant cerebellar ataxia type I .", "sentence_char_start_global": 49137, "sentence_char_end_global": 49236, "entities": [{"text": "Eye movement abnormalities", "type": "ENTITY", "char_start": 0, "char_end": 26, "token_start": 0, "token_end": 2}, {"text": "cerebellar ataxia type I", "type": "ENTITY", "char_start": 73, "char_end": 97, "token_start": 9, "token_end": 12}], "entities_global": [{"text": "Eye movement abnormalities", "type": "ENTITY", "char_start": 49137, "char_end": 49163, "token_start": 0, "token_end": 2, "note": null}, {"text": "cerebellar ataxia type I", "type": "ENTITY", "char_start": 49210, "char_end": 49234, "token_start": 9, "token_end": 12, "note": null}]}
+{"sentence_id": 336, "sentence_text": "We compared horizontal eye movements ( visually guided saccades , antisaccades , and smooth pursuit ) in control subjects ( n = 14 ) and patients with three forms of autosomal dominant cerebellar ataxias type I spinocerebellar ataxias 1 and 2 ( SCA1 , n = 11 ; SCA2 , n = 10 ) and SCA3 / Machado - Joseph disease ( MJD ) ( n = 16 ) .", "sentence_char_start_global": 49237, "sentence_char_end_global": 49570, "entities": [{"text": "cerebellar ataxias type I", "type": "ENTITY", "char_start": 185, "char_end": 210, "token_start": 32, "token_end": 35}, {"text": "spinocerebellar ataxias 1 and 2", "type": "ENTITY", "char_start": 211, "char_end": 242, "token_start": 36, "token_end": 40}, {"text": "SCA1", "type": "ENTITY", "char_start": 245, "char_end": 249, "token_start": 42, "token_end": 42}, {"text": "SCA2", "type": "ENTITY", "char_start": 261, "char_end": 265, "token_start": 48, "token_end": 48}, {"text": "SCA3", "type": "ENTITY", "char_start": 281, "char_end": 285, "token_start": 55, "token_end": 55}, {"text": "Machado - Joseph disease", "type": "ENTITY", "char_start": 288, "char_end": 312, "token_start": 57, "token_end": 60}, {"text": "MJD", "type": "ENTITY", "char_start": 315, "char_end": 318, "token_start": 62, "token_end": 62}], "entities_global": [{"text": "cerebellar ataxias type I", "type": "ENTITY", "char_start": 49422, "char_end": 49447, "token_start": 32, "token_end": 35, "note": null}, {"text": "spinocerebellar ataxias 1 and 2", "type": "ENTITY", "char_start": 49448, "char_end": 49479, "token_start": 36, "token_end": 40, "note": null}, {"text": "SCA1", "type": "ENTITY", "char_start": 49482, "char_end": 49486, "token_start": 42, "token_end": 42, "note": null}, {"text": "SCA2", "type": "ENTITY", "char_start": 49498, "char_end": 49502, "token_start": 48, "token_end": 48, "note": null}, {"text": "SCA3", "type": "ENTITY", "char_start": 49518, "char_end": 49522, "token_start": 55, "token_end": 55, "note": null}, {"text": "Machado - Joseph disease", "type": "ENTITY", "char_start": 49525, "char_end": 49549, "token_start": 57, "token_end": 60, "note": null}, {"text": "MJD", "type": "ENTITY", "char_start": 49552, "char_end": 49555, "token_start": 62, "token_end": 62, "note": null}]}
+{"sentence_id": 337, "sentence_text": "In SCA1 , saccade amplitude was significantly increased , resulting in hypermetria .", "sentence_char_start_global": 49571, "sentence_char_end_global": 49655, "entities": [{"text": "SCA1", "type": "ENTITY", "char_start": 3, "char_end": 7, "token_start": 1, "token_end": 1}, {"text": "hypermetria", "type": "ENTITY", "char_start": 71, "char_end": 82, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "SCA1", "type": "ENTITY", "char_start": 49574, "char_end": 49578, "token_start": 1, "token_end": 1, "note": null}, {"text": "hypermetria", "type": "ENTITY", "char_start": 49642, "char_end": 49653, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 338, "sentence_text": "The smooth pursuit gain was decreased .", "sentence_char_start_global": 49656, "sentence_char_end_global": 49695, "entities": [], "entities_global": []}
+{"sentence_id": 339, "sentence_text": "In SCA2 , saccade velocity was markedly decreased .", "sentence_char_start_global": 49696, "sentence_char_end_global": 49747, "entities": [{"text": "SCA2", "type": "ENTITY", "char_start": 3, "char_end": 7, "token_start": 1, "token_end": 1}], "entities_global": [{"text": "SCA2", "type": "ENTITY", "char_start": 49699, "char_end": 49703, "token_start": 1, "token_end": 1, "note": null}]}
+{"sentence_id": 340, "sentence_text": "The percentage of errors in antisaccades was greatly increased and was significantly correlated with age at disease onset .", "sentence_char_start_global": 49748, "sentence_char_end_global": 49871, "entities": [], "entities_global": []}
+{"sentence_id": 341, "sentence_text": "In addition , a correlation between smooth pursuit gain and the number of trinucleotide repeats was found .", "sentence_char_start_global": 49872, "sentence_char_end_global": 49979, "entities": [], "entities_global": []}
+{"sentence_id": 342, "sentence_text": "In SCA3 , gaze - evoked nystagmus was often present as was saccade hypometria and smooth pursuit gain was markedly decreased .", "sentence_char_start_global": 49980, "sentence_char_end_global": 50106, "entities": [{"text": "SCA3", "type": "ENTITY", "char_start": 3, "char_end": 7, "token_start": 1, "token_end": 1}, {"text": "gaze - evoked nystagmus", "type": "ENTITY", "char_start": 10, "char_end": 33, "token_start": 3, "token_end": 6}], "entities_global": [{"text": "SCA3", "type": "ENTITY", "char_start": 49983, "char_end": 49987, "token_start": 1, "token_end": 1, "note": null}, {"text": "gaze - evoked nystagmus", "type": "ENTITY", "char_start": 49990, "char_end": 50013, "token_start": 3, "token_end": 6, "note": null}]}
+{"sentence_id": 343, "sentence_text": "Three major criteria , saccade amplitude , saccade velocity , and presence of gaze - evoked nystagmus , permitted the correct assignment of 90 % of the SCA1 , 90 % of the SCA2 , and 93 % of the patients with SCA3 to their genetically confirmed patient group and , therefore , may help orient diagnoses of SCA1 , SCA2 , and SCA3 at early clinical stages of the diseases . .", "sentence_char_start_global": 50107, "sentence_char_end_global": 50479, "entities": [{"text": "gaze - evoked nystagmus", "type": "ENTITY", "char_start": 78, "char_end": 101, "token_start": 13, "token_end": 16}, {"text": "SCA1", "type": "ENTITY", "char_start": 152, "char_end": 156, "token_start": 27, "token_end": 27}, {"text": "SCA2", "type": "ENTITY", "char_start": 171, "char_end": 175, "token_start": 33, "token_end": 33}, {"text": "SCA3", "type": "ENTITY", "char_start": 208, "char_end": 212, "token_start": 42, "token_end": 42}, {"text": "SCA1", "type": "ENTITY", "char_start": 305, "char_end": 309, "token_start": 58, "token_end": 58}, {"text": "SCA2", "type": "ENTITY", "char_start": 312, "char_end": 316, "token_start": 60, "token_end": 60}, {"text": "SCA3", "type": "ENTITY", "char_start": 323, "char_end": 327, "token_start": 63, "token_end": 63}], "entities_global": [{"text": "gaze - evoked nystagmus", "type": "ENTITY", "char_start": 50185, "char_end": 50208, "token_start": 13, "token_end": 16, "note": null}, {"text": "SCA1", "type": "ENTITY", "char_start": 50259, "char_end": 50263, "token_start": 27, "token_end": 27, "note": null}, {"text": "SCA2", "type": "ENTITY", "char_start": 50278, "char_end": 50282, "token_start": 33, "token_end": 33, "note": null}, {"text": "SCA3", "type": "ENTITY", "char_start": 50315, "char_end": 50319, "token_start": 42, "token_end": 42, "note": null}, {"text": "SCA1", "type": "ENTITY", "char_start": 50412, "char_end": 50416, "token_start": 58, "token_end": 58, "note": null}, {"text": "SCA2", "type": "ENTITY", "char_start": 50419, "char_end": 50423, "token_start": 60, "token_end": 60, "note": null}, {"text": "SCA3", "type": "ENTITY", "char_start": 50430, "char_end": 50434, "token_start": 63, "token_end": 63, "note": null}]}
+{"sentence_id": 344, "sentence_text": "Genetic basis and molecular mechanism for idiopathic ventricular fibrillation .", "sentence_char_start_global": 50480, "sentence_char_end_global": 50559, "entities": [{"text": "idiopathic ventricular fibrillation", "type": "ENTITY", "char_start": 42, "char_end": 77, "token_start": 6, "token_end": 8}], "entities_global": [{"text": "idiopathic ventricular fibrillation", "type": "ENTITY", "char_start": 50522, "char_end": 50557, "token_start": 6, "token_end": 8, "note": null}]}
+{"sentence_id": 345, "sentence_text": "Ventricular fibrillation causes more than 300 , 000 sudden deaths each year in the USA alone .", "sentence_char_start_global": 50560, "sentence_char_end_global": 50654, "entities": [{"text": "Ventricular fibrillation", "type": "ENTITY", "char_start": 0, "char_end": 24, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "Ventricular fibrillation", "type": "ENTITY", "char_start": 50560, "char_end": 50584, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 346, "sentence_text": "In approximately 5 - 12 % of these cases , there are no demonstrable cardiac or non - cardiac causes to account for the episode , which is therefore classified as idiopathic ventricular fibrillation ( IVF ) .", "sentence_char_start_global": 50655, "sentence_char_end_global": 50863, "entities": [{"text": "idiopathic ventricular fibrillation", "type": "ENTITY", "char_start": 163, "char_end": 198, "token_start": 31, "token_end": 33}, {"text": "IVF", "type": "ENTITY", "char_start": 201, "char_end": 204, "token_start": 35, "token_end": 35}], "entities_global": [{"text": "idiopathic ventricular fibrillation", "type": "ENTITY", "char_start": 50818, "char_end": 50853, "token_start": 31, "token_end": 33, "note": null}, {"text": "IVF", "type": "ENTITY", "char_start": 50856, "char_end": 50859, "token_start": 35, "token_end": 35, "note": null}]}
+{"sentence_id": 347, "sentence_text": "A distinct group of IVF patients has been found to present with a characteristic electrocardiographic pattern .", "sentence_char_start_global": 50864, "sentence_char_end_global": 50975, "entities": [{"text": "IVF", "type": "ENTITY", "char_start": 20, "char_end": 23, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "IVF", "type": "ENTITY", "char_start": 50884, "char_end": 50887, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 348, "sentence_text": "Because of the small size of most pedigrees and the high incidence of sudden death , however , molecular genetic studies of IVF have not yet been done .", "sentence_char_start_global": 50976, "sentence_char_end_global": 51128, "entities": [{"text": "sudden death", "type": "ENTITY", "char_start": 70, "char_end": 82, "token_start": 13, "token_end": 14}, {"text": "IVF", "type": "ENTITY", "char_start": 124, "char_end": 127, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "sudden death", "type": "ENTITY", "char_start": 51046, "char_end": 51058, "token_start": 13, "token_end": 14, "note": null}, {"text": "IVF", "type": "ENTITY", "char_start": 51100, "char_end": 51103, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 349, "sentence_text": "Because IVF causes cardiac rhythm disturbance , we investigated whether malfunction of ion channels could cause the disorder by studying mutations in the cardiac sodium channel gene SCN5A .", "sentence_char_start_global": 51129, "sentence_char_end_global": 51318, "entities": [{"text": "IVF", "type": "ENTITY", "char_start": 8, "char_end": 11, "token_start": 1, "token_end": 1}], "entities_global": [{"text": "IVF", "type": "ENTITY", "char_start": 51137, "char_end": 51140, "token_start": 1, "token_end": 1, "note": null}]}
+{"sentence_id": 350, "sentence_text": "We have now identified a missense mutation , a splice - donor mutation , and a frameshift mutation in the coding region of SCN5A in three IVF families .", "sentence_char_start_global": 51319, "sentence_char_end_global": 51471, "entities": [{"text": "IVF", "type": "ENTITY", "char_start": 138, "char_end": 141, "token_start": 26, "token_end": 26}], "entities_global": [{"text": "IVF", "type": "ENTITY", "char_start": 51457, "char_end": 51460, "token_start": 26, "token_end": 26, "note": null}]}
+{"sentence_id": 351, "sentence_text": "We show that sodium channels with the missense mutation recover from inactivation more rapidly than normal and that the frameshift mutation causes the sodium channel to be non - functional .", "sentence_char_start_global": 51472, "sentence_char_end_global": 51662, "entities": [], "entities_global": []}
+{"sentence_id": 352, "sentence_text": "Our results indicate that mutations in cardiac ion - channel genes contribute to the risk of developing IVF . .", "sentence_char_start_global": 51663, "sentence_char_end_global": 51774, "entities": [{"text": "IVF", "type": "ENTITY", "char_start": 104, "char_end": 107, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "IVF", "type": "ENTITY", "char_start": 51767, "char_end": 51770, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 353, "sentence_text": "Molecular heterogeneity in mucopolysaccharidosis IVA in Australia and Northern Ireland : nine novel mutations including T312S , a common allele that confers a mild phenotype .", "sentence_char_start_global": 51775, "sentence_char_end_global": 51950, "entities": [{"text": "mucopolysaccharidosis IVA", "type": "ENTITY", "char_start": 27, "char_end": 52, "token_start": 3, "token_end": 4}], "entities_global": [{"text": "mucopolysaccharidosis IVA", "type": "ENTITY", "char_start": 51802, "char_end": 51827, "token_start": 3, "token_end": 4, "note": null}]}
+{"sentence_id": 354, "sentence_text": "Mucopolysaccharidosis IVA ( MPS IVA ) is an autosomal recessive lysosomal storage disorder caused by a genetic defect in N - acetylgalactosamine - 6 - sulfate sulfatase ( GALNS ) .", "sentence_char_start_global": 51951, "sentence_char_end_global": 52131, "entities": [{"text": "Mucopolysaccharidosis IVA", "type": "ENTITY", "char_start": 0, "char_end": 25, "token_start": 0, "token_end": 1}, {"text": "MPS IVA", "type": "ENTITY", "char_start": 28, "char_end": 35, "token_start": 3, "token_end": 4}, {"text": "autosomal recessive lysosomal storage disorder", "type": "ENTITY", "char_start": 44, "char_end": 90, "token_start": 8, "token_end": 12}, {"text": "genetic defect", "type": "ENTITY", "char_start": 103, "char_end": 117, "token_start": 16, "token_end": 17}], "entities_global": [{"text": "Mucopolysaccharidosis IVA", "type": "ENTITY", "char_start": 51951, "char_end": 51976, "token_start": 0, "token_end": 1, "note": null}, {"text": "MPS IVA", "type": "ENTITY", "char_start": 51979, "char_end": 51986, "token_start": 3, "token_end": 4, "note": null}, {"text": "autosomal recessive lysosomal storage disorder", "type": "ENTITY", "char_start": 51995, "char_end": 52041, "token_start": 8, "token_end": 12, "note": null}, {"text": "genetic defect", "type": "ENTITY", "char_start": 52054, "char_end": 52068, "token_start": 16, "token_end": 17, "note": null}]}
+{"sentence_id": 355, "sentence_text": "Previous studies of patients from a British - Irish population showed that the I113F mutation is the most common single mutation among MPS IVA patients and produces a severe clinical phenotype .", "sentence_char_start_global": 52132, "sentence_char_end_global": 52326, "entities": [{"text": "MPS IVA", "type": "ENTITY", "char_start": 135, "char_end": 142, "token_start": 22, "token_end": 23}], "entities_global": [{"text": "MPS IVA", "type": "ENTITY", "char_start": 52267, "char_end": 52274, "token_start": 22, "token_end": 23, "note": null}]}
+{"sentence_id": 356, "sentence_text": "We studied mutations in the GALNS gene from 23 additional MPS IVA patients ( 15 from Australia , 8 from Northern Ireland ) , with various clinical phenotypes ( severe , 16 cases ; intermediate , 4 cases ; mild , 3 cases ) .", "sentence_char_start_global": 52327, "sentence_char_end_global": 52550, "entities": [{"text": "MPS IVA", "type": "ENTITY", "char_start": 58, "char_end": 65, "token_start": 10, "token_end": 11}], "entities_global": [{"text": "MPS IVA", "type": "ENTITY", "char_start": 52385, "char_end": 52392, "token_start": 10, "token_end": 11, "note": null}]}
+{"sentence_id": 357, "sentence_text": "We found two common mutations that together accounted for 32 % of the 44 unrelated alleles in these patients .", "sentence_char_start_global": 52551, "sentence_char_end_global": 52661, "entities": [], "entities_global": []}
+{"sentence_id": 358, "sentence_text": "One is the T312S mutation , a novel mutation found exclusively in milder patients .", "sentence_char_start_global": 52662, "sentence_char_end_global": 52745, "entities": [], "entities_global": []}
+{"sentence_id": 359, "sentence_text": "The other is the previously described I113F that produces a severe phenotype .", "sentence_char_start_global": 52746, "sentence_char_end_global": 52824, "entities": [], "entities_global": []}
+{"sentence_id": 360, "sentence_text": "The I113F and T312S mutations accounted for 8 ( 18 % ) and 6 ( 14 % ) of 44 unrelated alleles , respectively .", "sentence_char_start_global": 52825, "sentence_char_end_global": 52935, "entities": [], "entities_global": []}
+{"sentence_id": 361, "sentence_text": "The relatively high residual GALNS activity seen when the T312S mutant cDNA is overexpressed in mutant cells provides an explanation for the mild phenotype in patients with this mutation .", "sentence_char_start_global": 52936, "sentence_char_end_global": 53124, "entities": [], "entities_global": []}
+{"sentence_id": 362, "sentence_text": "The distribution and relative frequencies of the I113F and T312S mutations in Australia corresponded to those observed in Northern Ireland and are unique to these two populations , suggesting that both mutations were probably introduced to Australia by Irish migrants during the 19th century .", "sentence_char_start_global": 53125, "sentence_char_end_global": 53418, "entities": [], "entities_global": []}
+{"sentence_id": 363, "sentence_text": "Haplotype analysis using 6 RFLPs provides additional data that the I113F mutation originated from a common ancestor .", "sentence_char_start_global": 53419, "sentence_char_end_global": 53536, "entities": [], "entities_global": []}
+{"sentence_id": 364, "sentence_text": "The other 9 novel mutations identified in these 23 patients were each limited to a single family .", "sentence_char_start_global": 53537, "sentence_char_end_global": 53635, "entities": [], "entities_global": []}
+{"sentence_id": 365, "sentence_text": "These data provide further evidence for extensive allelic heterogeneity in MPS IVA in British - Irish patients and provide evidence for their transmission to Australia by British - Irish migrants . .", "sentence_char_start_global": 53636, "sentence_char_end_global": 53835, "entities": [{"text": "MPS IVA", "type": "ENTITY", "char_start": 75, "char_end": 82, "token_start": 10, "token_end": 11}], "entities_global": [{"text": "MPS IVA", "type": "ENTITY", "char_start": 53711, "char_end": 53718, "token_start": 10, "token_end": 11, "note": null}]}
+{"sentence_id": 366, "sentence_text": "Identification of constitutional WT1 mutations , in patients with isolated diffuse mesangial sclerosis , and analysis of genotype / phenotype correlations by use of a computerized mutation database .", "sentence_char_start_global": 53836, "sentence_char_end_global": 54035, "entities": [{"text": "diffuse mesangial sclerosis", "type": "ENTITY", "char_start": 75, "char_end": 102, "token_start": 10, "token_end": 12}], "entities_global": [{"text": "diffuse mesangial sclerosis", "type": "ENTITY", "char_start": 53911, "char_end": 53938, "token_start": 10, "token_end": 12, "note": null}]}
+{"sentence_id": 367, "sentence_text": "Constitutional mutations of the WT1 gene , encoding a zinc - finger transcription factor involved in renal and gonadal development , are found in most patients with Denys - Drash syndrome ( DDS ) , or diffuse mesangial sclerosis ( DMS ) associated with pseudohermaphroditism and / or Wilms tumor ( WT ) .", "sentence_char_start_global": 54036, "sentence_char_end_global": 54340, "entities": [{"text": "Denys - Drash syndrome", "type": "ENTITY", "char_start": 165, "char_end": 187, "token_start": 27, "token_end": 30}, {"text": "DDS", "type": "ENTITY", "char_start": 190, "char_end": 193, "token_start": 32, "token_end": 32}, {"text": "diffuse mesangial sclerosis", "type": "ENTITY", "char_start": 201, "char_end": 228, "token_start": 36, "token_end": 38}, {"text": "DMS", "type": "ENTITY", "char_start": 231, "char_end": 234, "token_start": 40, "token_end": 40}, {"text": "pseudohermaphroditism", "type": "ENTITY", "char_start": 253, "char_end": 274, "token_start": 44, "token_end": 44}, {"text": "Wilms tumor", "type": "ENTITY", "char_start": 284, "char_end": 295, "token_start": 48, "token_end": 49}, {"text": "WT", "type": "ENTITY", "char_start": 298, "char_end": 300, "token_start": 51, "token_end": 51}], "entities_global": [{"text": "Denys - Drash syndrome", "type": "ENTITY", "char_start": 54201, "char_end": 54223, "token_start": 27, "token_end": 30, "note": null}, {"text": "DDS", "type": "ENTITY", "char_start": 54226, "char_end": 54229, "token_start": 32, "token_end": 32, "note": null}, {"text": "diffuse mesangial sclerosis", "type": "ENTITY", "char_start": 54237, "char_end": 54264, "token_start": 36, "token_end": 38, "note": null}, {"text": "DMS", "type": "ENTITY", "char_start": 54267, "char_end": 54270, "token_start": 40, "token_end": 40, "note": null}, {"text": "pseudohermaphroditism", "type": "ENTITY", "char_start": 54289, "char_end": 54310, "token_start": 44, "token_end": 44, "note": null}, {"text": "Wilms tumor", "type": "ENTITY", "char_start": 54320, "char_end": 54331, "token_start": 48, "token_end": 49, "note": null}, {"text": "WT", "type": "ENTITY", "char_start": 54334, "char_end": 54336, "token_start": 51, "token_end": 51, "note": null}]}
+{"sentence_id": 368, "sentence_text": "Most mutations in DDS patients lie in exon 8 or exon 9 , encoding zinc finger 2 or zinc finger 3 , respectively , with a hot spot ( R394W ) in exon 9 .", "sentence_char_start_global": 54341, "sentence_char_end_global": 54492, "entities": [{"text": "DDS", "type": "ENTITY", "char_start": 18, "char_end": 21, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "DDS", "type": "ENTITY", "char_start": 54359, "char_end": 54362, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 369, "sentence_text": "We analyzed a series of 24 patients , 10 with isolated DMS ( IDMS ) , 10 with DDS , and 4 with urogenital abnormalities and / or WT .", "sentence_char_start_global": 54493, "sentence_char_end_global": 54626, "entities": [{"text": "isolated DMS", "type": "ENTITY", "char_start": 46, "char_end": 58, "token_start": 10, "token_end": 11}, {"text": "IDMS", "type": "ENTITY", "char_start": 61, "char_end": 65, "token_start": 13, "token_end": 13}, {"text": "DDS", "type": "ENTITY", "char_start": 78, "char_end": 81, "token_start": 18, "token_end": 18}, {"text": "urogenital abnormalities", "type": "ENTITY", "char_start": 95, "char_end": 119, "token_start": 23, "token_end": 24}, {"text": "WT", "type": "ENTITY", "char_start": 129, "char_end": 131, "token_start": 28, "token_end": 28}], "entities_global": [{"text": "isolated DMS", "type": "ENTITY", "char_start": 54539, "char_end": 54551, "token_start": 10, "token_end": 11, "note": null}, {"text": "IDMS", "type": "ENTITY", "char_start": 54554, "char_end": 54558, "token_start": 13, "token_end": 13, "note": null}, {"text": "DDS", "type": "ENTITY", "char_start": 54571, "char_end": 54574, "token_start": 18, "token_end": 18, "note": null}, {"text": "urogenital abnormalities", "type": "ENTITY", "char_start": 54588, "char_end": 54612, "token_start": 23, "token_end": 24, "note": null}, {"text": "WT", "type": "ENTITY", "char_start": 54622, "char_end": 54624, "token_start": 28, "token_end": 28, "note": null}]}
+{"sentence_id": 370, "sentence_text": "We report WT1 heterozygous mutations in 16 patients , 4 of whom presented with IDMS .", "sentence_char_start_global": 54627, "sentence_char_end_global": 54712, "entities": [{"text": "IDMS", "type": "ENTITY", "char_start": 79, "char_end": 83, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "IDMS", "type": "ENTITY", "char_start": 54706, "char_end": 54710, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 371, "sentence_text": "One male and two female IDMS patients with WT1 mutations underwent normal puberty .", "sentence_char_start_global": 54713, "sentence_char_end_global": 54796, "entities": [{"text": "IDMS", "type": "ENTITY", "char_start": 24, "char_end": 28, "token_start": 5, "token_end": 5}], "entities_global": [{"text": "IDMS", "type": "ENTITY", "char_start": 54737, "char_end": 54741, "token_start": 5, "token_end": 5, "note": null}]}
+{"sentence_id": 372, "sentence_text": "Two mutations associated with IDMS are different from those described in DDS patients .", "sentence_char_start_global": 54797, "sentence_char_end_global": 54884, "entities": [{"text": "IDMS", "type": "ENTITY", "char_start": 30, "char_end": 34, "token_start": 4, "token_end": 4}, {"text": "DDS", "type": "ENTITY", "char_start": 73, "char_end": 76, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "IDMS", "type": "ENTITY", "char_start": 54827, "char_end": 54831, "token_start": 4, "token_end": 4, "note": null}, {"text": "DDS", "type": "ENTITY", "char_start": 54870, "char_end": 54873, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 373, "sentence_text": "No WT1 mutations were detected in the six other IDMS patients , suggesting genetic heterogeneity of this disease .", "sentence_char_start_global": 54885, "sentence_char_end_global": 54999, "entities": [{"text": "IDMS", "type": "ENTITY", "char_start": 48, "char_end": 52, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "IDMS", "type": "ENTITY", "char_start": 54933, "char_end": 54937, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 374, "sentence_text": "We analyzed genotype / phenotype correlations , on the basis of the constitution of a WT1 mutation database of 84 germ - line mutations , to compare the distribution and type of mutations , according to the different symptoms .", "sentence_char_start_global": 55000, "sentence_char_end_global": 55227, "entities": [], "entities_global": []}
+{"sentence_id": 375, "sentence_text": "This demonstrated ( 1 ) the association between mutations in exons 8 and 9 and DMS ; ( 2 ) among patients with DMS , a higher frequency of exon 8 mutations among 46 , XY patients with female phenotype than among 46 , XY patients with sexual ambiguity or male phenotype ; and ( 3 ) statistically significant evidence that mutations in exons 8 and 9 preferentially affect amino acids with different functions . .", "sentence_char_start_global": 55228, "sentence_char_end_global": 55638, "entities": [{"text": "DMS", "type": "ENTITY", "char_start": 79, "char_end": 82, "token_start": 15, "token_end": 15}, {"text": "DMS", "type": "ENTITY", "char_start": 111, "char_end": 114, "token_start": 23, "token_end": 23}], "entities_global": [{"text": "DMS", "type": "ENTITY", "char_start": 55307, "char_end": 55310, "token_start": 15, "token_end": 15, "note": null}, {"text": "DMS", "type": "ENTITY", "char_start": 55339, "char_end": 55342, "token_start": 23, "token_end": 23, "note": null}]}
+{"sentence_id": 376, "sentence_text": "The 185delAG BRCA1 mutation originated before the dispersion of Jews in the diaspora and is not limited to Ashkenazim .", "sentence_char_start_global": 55639, "sentence_char_end_global": 55758, "entities": [], "entities_global": []}
+{"sentence_id": 377, "sentence_text": "The 185delAG mutation in BRCA1 is detected in Ashkenazi Jews both in familial breast and ovarian cancer and in the general population .", "sentence_char_start_global": 55759, "sentence_char_end_global": 55894, "entities": [{"text": "familial breast and ovarian cancer", "type": "ENTITY", "char_start": 69, "char_end": 103, "token_start": 12, "token_end": 16}], "entities_global": [{"text": "familial breast and ovarian cancer", "type": "ENTITY", "char_start": 55828, "char_end": 55862, "token_start": 12, "token_end": 16, "note": null}]}
+{"sentence_id": 378, "sentence_text": "All tested Ashkenazi mutation carriers share the same allelic pattern at the BRCA1 locus .", "sentence_char_start_global": 55895, "sentence_char_end_global": 55985, "entities": [], "entities_global": []}
+{"sentence_id": 379, "sentence_text": "Our previous study showed that this Ashkenazi mutation also occurs in Iraqi Jews with a similar allelic pattern .", "sentence_char_start_global": 55986, "sentence_char_end_global": 56099, "entities": [], "entities_global": []}
+{"sentence_id": 380, "sentence_text": "We extended our analysis to other non - Ashkenazi subsets 354 of Moroccan origin , 200 Yemenites and 150 Iranian Jews .", "sentence_char_start_global": 56100, "sentence_char_end_global": 56219, "entities": [], "entities_global": []}
+{"sentence_id": 381, "sentence_text": "Heteroduplex analysis complemented by direct DNA sequencing of abnormally migrating bands were employed .", "sentence_char_start_global": 56220, "sentence_char_end_global": 56325, "entities": [], "entities_global": []}
+{"sentence_id": 382, "sentence_text": "Four of Moroccan origin ( 1 . 1 % ) and none of the Yemenites or Iranians was a carrier of the 185delAG mutation .", "sentence_char_start_global": 56326, "sentence_char_end_global": 56440, "entities": [], "entities_global": []}
+{"sentence_id": 383, "sentence_text": "BRCA1 allelic patterns were determined for four of these individuals and for 12 additional non - Ashkenazi 185delAG mutation carriers who had breast / ovarian cancer .", "sentence_char_start_global": 56441, "sentence_char_end_global": 56608, "entities": [{"text": "breast / ovarian cancer", "type": "ENTITY", "char_start": 142, "char_end": 165, "token_start": 22, "token_end": 25}], "entities_global": [{"text": "breast / ovarian cancer", "type": "ENTITY", "char_start": 56583, "char_end": 56606, "token_start": 22, "token_end": 25, "note": null}]}
+{"sentence_id": 384, "sentence_text": "Six non - Ashkenazi individuals shared the common Ashkenazi haplotype , four had a closely related pattern , and the rest ( n = 6 ) displayed a distinct BRCA1 allelic pattern .", "sentence_char_start_global": 56609, "sentence_char_end_global": 56785, "entities": [], "entities_global": []}
+{"sentence_id": 385, "sentence_text": "We conclude that the 185delAG BRCA1 mutation occurs in some non - Ashkenazi populations at rates comparable with that of Ashkenazim .", "sentence_char_start_global": 56786, "sentence_char_end_global": 56919, "entities": [], "entities_global": []}
+{"sentence_id": 386, "sentence_text": "The majority of Jewish 185delAG mutation carriers have a common allelic pattern , supporting the founder effect notion , but dating the mutations origin to an earlier date than currently estimated .", "sentence_char_start_global": 56920, "sentence_char_end_global": 57118, "entities": [], "entities_global": []}
+{"sentence_id": 387, "sentence_text": "However , the different allelic pattern at the BRCA1 locus even in some Jewish mutation carriers , might suggest that the mutation arose independently . .", "sentence_char_start_global": 57119, "sentence_char_end_global": 57273, "entities": [], "entities_global": []}
+{"sentence_id": 388, "sentence_text": "Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor .", "sentence_char_start_global": 57274, "sentence_char_end_global": 57394, "entities": [{"text": "hemochromatosis", "type": "ENTITY", "char_start": 25, "char_end": 40, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "hemochromatosis", "type": "ENTITY", "char_start": 57299, "char_end": 57314, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 389, "sentence_text": "HFE is an MHC - related protein that is mutated in the iron - overload disease hereditary hemochromatosis .", "sentence_char_start_global": 57395, "sentence_char_end_global": 57502, "entities": [{"text": "iron - overload disease", "type": "ENTITY", "char_start": 55, "char_end": 78, "token_start": 12, "token_end": 15}, {"text": "hereditary hemochromatosis", "type": "ENTITY", "char_start": 79, "char_end": 105, "token_start": 16, "token_end": 17}], "entities_global": [{"text": "iron - overload disease", "type": "ENTITY", "char_start": 57450, "char_end": 57473, "token_start": 12, "token_end": 15, "note": null}, {"text": "hereditary hemochromatosis", "type": "ENTITY", "char_start": 57474, "char_end": 57500, "token_start": 16, "token_end": 17, "note": null}]}
+{"sentence_id": 390, "sentence_text": "HFE binds to transferrin receptor ( TfR ) and reduces its affinity for iron - loaded transferrin , implicating HFE in iron metabolism .", "sentence_char_start_global": 57503, "sentence_char_end_global": 57638, "entities": [], "entities_global": []}
+{"sentence_id": 391, "sentence_text": "The 2 .", "sentence_char_start_global": 57639, "sentence_char_end_global": 57646, "entities": [], "entities_global": []}
+{"sentence_id": 392, "sentence_text": "6 A crystal structure of HFE reveals the locations of hemochromatosis mutations and a patch of histidines that could be involved in pH - dependent interactions .", "sentence_char_start_global": 57647, "sentence_char_end_global": 57808, "entities": [{"text": "hemochromatosis", "type": "ENTITY", "char_start": 54, "char_end": 69, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "hemochromatosis", "type": "ENTITY", "char_start": 57701, "char_end": 57716, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 393, "sentence_text": "We also demonstrate that soluble TfR and HFE bind tightly at the basic pH of the cell surface , but not at the acidic pH of intracellular vesicles .", "sentence_char_start_global": 57809, "sentence_char_end_global": 57957, "entities": [], "entities_global": []}
+{"sentence_id": 394, "sentence_text": "TfR HFE stoichiometry ( 2 1 ) differs from TfR transferrin stoichiometry ( 2 2 ) , implying a different mode of binding for HFE and transferrin to TfR , consistent with our demonstration that HFE , transferrin , and TfR form a ternary complex .", "sentence_char_start_global": 57958, "sentence_char_end_global": 58202, "entities": [], "entities_global": []}
+{"sentence_id": 395, "sentence_text": "Identification of three novel mutations and a high frequency of the Arg778Leu mutation in Korean patients with Wilson disease .", "sentence_char_start_global": 58203, "sentence_char_end_global": 58330, "entities": [{"text": "Wilson disease", "type": "ENTITY", "char_start": 111, "char_end": 125, "token_start": 17, "token_end": 18}], "entities_global": [{"text": "Wilson disease", "type": "ENTITY", "char_start": 58314, "char_end": 58328, "token_start": 17, "token_end": 18, "note": null}]}
+{"sentence_id": 396, "sentence_text": "Four mutations - - R778L , A874V , L1083F , and 2304delC - - in the copper - transporting enzyme , P - type ATPase ( ATP7B ) , were identified in Korean Patients with Wilson disease .", "sentence_char_start_global": 58331, "sentence_char_end_global": 58514, "entities": [{"text": "Wilson disease", "type": "ENTITY", "char_start": 167, "char_end": 181, "token_start": 35, "token_end": 36}], "entities_global": [{"text": "Wilson disease", "type": "ENTITY", "char_start": 58498, "char_end": 58512, "token_start": 35, "token_end": 36, "note": null}]}
+{"sentence_id": 397, "sentence_text": "Arg778Leu , the most frequently reported mutation of this enzyme , was found in six of eight unrelated patients studied , an allele frequency of 37 .", "sentence_char_start_global": 58515, "sentence_char_end_global": 58664, "entities": [], "entities_global": []}
+{"sentence_id": 398, "sentence_text": "5 % , which is considerably higher than those in other Asian populations .", "sentence_char_start_global": 58665, "sentence_char_end_global": 58739, "entities": [], "entities_global": []}
+{"sentence_id": 399, "sentence_text": "The novel single nucleotide deletion , 2304delC , was found in one patient .", "sentence_char_start_global": 58740, "sentence_char_end_global": 58816, "entities": [], "entities_global": []}
+{"sentence_id": 400, "sentence_text": "Since a mutation at cDNA nucleotide 2302 ( 2302insC ) had been previously described , this region of the ATP7B gene may be susceptible to gene rearrangements causing Wilson disease .", "sentence_char_start_global": 58817, "sentence_char_end_global": 58999, "entities": [{"text": "Wilson disease", "type": "ENTITY", "char_start": 166, "char_end": 180, "token_start": 28, "token_end": 29}], "entities_global": [{"text": "Wilson disease", "type": "ENTITY", "char_start": 58983, "char_end": 58997, "token_start": 28, "token_end": 29, "note": null}]}
+{"sentence_id": 401, "sentence_text": "Disruption of splicing regulated by a CUG - binding protein in myotonic dystrophy .", "sentence_char_start_global": 59000, "sentence_char_end_global": 59083, "entities": [{"text": "myotonic dystrophy", "type": "ENTITY", "char_start": 63, "char_end": 81, "token_start": 11, "token_end": 12}], "entities_global": [{"text": "myotonic dystrophy", "type": "ENTITY", "char_start": 59063, "char_end": 59081, "token_start": 11, "token_end": 12, "note": null}]}
+{"sentence_id": 402, "sentence_text": "Myotonic dystrophy ( DM ) is caused by a CTG expansion in the 3 untranslated region of the DM gene .", "sentence_char_start_global": 59084, "sentence_char_end_global": 59184, "entities": [{"text": "Myotonic dystrophy", "type": "ENTITY", "char_start": 0, "char_end": 18, "token_start": 0, "token_end": 1}, {"text": "DM", "type": "ENTITY", "char_start": 21, "char_end": 23, "token_start": 3, "token_end": 3}, {"text": "DM", "type": "ENTITY", "char_start": 91, "char_end": 93, "token_start": 18, "token_end": 18}], "entities_global": [{"text": "Myotonic dystrophy", "type": "ENTITY", "char_start": 59084, "char_end": 59102, "token_start": 0, "token_end": 1, "note": null}, {"text": "DM", "type": "ENTITY", "char_start": 59105, "char_end": 59107, "token_start": 3, "token_end": 3, "note": null}, {"text": "DM", "type": "ENTITY", "char_start": 59175, "char_end": 59177, "token_start": 18, "token_end": 18, "note": null}]}
+{"sentence_id": 403, "sentence_text": "One model of DM pathogenesis suggests that RNAs from the expanded allele create a gain - of - function mutation by the inappropriate binding of proteins to the CUG repeats .", "sentence_char_start_global": 59185, "sentence_char_end_global": 59358, "entities": [{"text": "DM", "type": "ENTITY", "char_start": 13, "char_end": 15, "token_start": 3, "token_end": 3}], "entities_global": [{"text": "DM", "type": "ENTITY", "char_start": 59198, "char_end": 59200, "token_start": 3, "token_end": 3, "note": null}]}
+{"sentence_id": 404, "sentence_text": "Data presented here indicate that the conserved heterogeneous nuclear ribonucleoprotein , CUG - binding protein ( CUG - BP ) , may mediate the trans - dominant effect of the RNA .", "sentence_char_start_global": 59359, "sentence_char_end_global": 59538, "entities": [], "entities_global": []}
+{"sentence_id": 405, "sentence_text": "CUG - BP was found to bind to the human cardiac troponin T ( cTNT ) pre - messenger RNA and regulate its alternative splicing .", "sentence_char_start_global": 59539, "sentence_char_end_global": 59666, "entities": [], "entities_global": []}
+{"sentence_id": 406, "sentence_text": "Splicing of cTNT was disrupted in DM striated muscle and in normal cells expressing transcripts that contain CUG repeats .", "sentence_char_start_global": 59667, "sentence_char_end_global": 59789, "entities": [{"text": "DM", "type": "ENTITY", "char_start": 34, "char_end": 36, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "DM", "type": "ENTITY", "char_start": 59701, "char_end": 59703, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 407, "sentence_text": "Altered expression of genes regulated posttranscriptionally by CUG - BP therefore may contribute to DM pathogenesis . .", "sentence_char_start_global": 59790, "sentence_char_end_global": 59909, "entities": [{"text": "DM", "type": "ENTITY", "char_start": 100, "char_end": 102, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "DM", "type": "ENTITY", "char_start": 59890, "char_end": 59892, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 408, "sentence_text": "Identification of a novel nonsense mutation and a missense substitution in the vasopressin - neurophysin II gene in two Spanish kindreds with familial neurohypophyseal diabetes insipidus .", "sentence_char_start_global": 59910, "sentence_char_end_global": 60098, "entities": [{"text": "familial neurohypophyseal diabetes insipidus", "type": "ENTITY", "char_start": 142, "char_end": 186, "token_start": 22, "token_end": 25}], "entities_global": [{"text": "familial neurohypophyseal diabetes insipidus", "type": "ENTITY", "char_start": 60052, "char_end": 60096, "token_start": 22, "token_end": 25, "note": null}]}
+{"sentence_id": 409, "sentence_text": "Familial neurohypophyseal diabetes insipidus ( FNDI ) is an autosomal dominant disease caused by deficiency in the antidiuretic hormone arginine vasopressin ( AVP ) encoded by the AVP - neurophysin II ( AVP - NPII ) gene on chromosome 20p13 .", "sentence_char_start_global": 60099, "sentence_char_end_global": 60341, "entities": [{"text": "Familial neurohypophyseal diabetes insipidus", "type": "ENTITY", "char_start": 0, "char_end": 44, "token_start": 0, "token_end": 3}, {"text": "FNDI", "type": "ENTITY", "char_start": 47, "char_end": 51, "token_start": 5, "token_end": 5}, {"text": "autosomal dominant disease", "type": "ENTITY", "char_start": 60, "char_end": 86, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "Familial neurohypophyseal diabetes insipidus", "type": "ENTITY", "char_start": 60099, "char_end": 60143, "token_start": 0, "token_end": 3, "note": null}, {"text": "FNDI", "type": "ENTITY", "char_start": 60146, "char_end": 60150, "token_start": 5, "token_end": 5, "note": null}, {"text": "autosomal dominant disease", "type": "ENTITY", "char_start": 60159, "char_end": 60185, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 410, "sentence_text": "In this study , we analyzed two families with FNDI using direct automated fluorescent , solid phase , single - stranded DNA sequencing of PCR - amplified AVP - NPII DNA .", "sentence_char_start_global": 60342, "sentence_char_end_global": 60512, "entities": [{"text": "FNDI", "type": "ENTITY", "char_start": 46, "char_end": 50, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "FNDI", "type": "ENTITY", "char_start": 60388, "char_end": 60392, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 411, "sentence_text": "In one of the families , affected individuals presented a novel nonsense mutation in exon 3 of the gene , consisting in a G to T transition at nucleotide 2101 , which produces a stop signal in codon 82 ( Glu ) of NPII .", "sentence_char_start_global": 60513, "sentence_char_end_global": 60732, "entities": [], "entities_global": []}
+{"sentence_id": 412, "sentence_text": "The premature termination eliminates part of the C - terminal domain of NPII , including a cysteine residue in position 85 , which could be involved in the correct folding of the prohormone .", "sentence_char_start_global": 60733, "sentence_char_end_global": 60924, "entities": [], "entities_global": []}
+{"sentence_id": 413, "sentence_text": "In the second family , a G279A substitution at position - 1 of the signal peptide was observed in all affected individuals .", "sentence_char_start_global": 60925, "sentence_char_end_global": 61049, "entities": [], "entities_global": []}
+{"sentence_id": 414, "sentence_text": "This missense mutation , which replaces Ala with Thr , is frequent among FNDI patients and is thought to reduce the efficiency of cleavage by signal peptidases . .", "sentence_char_start_global": 61050, "sentence_char_end_global": 61213, "entities": [{"text": "FNDI", "type": "ENTITY", "char_start": 73, "char_end": 77, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "FNDI", "type": "ENTITY", "char_start": 61123, "char_end": 61127, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 415, "sentence_text": "Genetic heterogeneity of Saethre - Chotzen syndrome , due to TWIST and FGFR mutations .", "sentence_char_start_global": 61214, "sentence_char_end_global": 61301, "entities": [{"text": "Saethre - Chotzen syndrome", "type": "ENTITY", "char_start": 25, "char_end": 51, "token_start": 3, "token_end": 6}], "entities_global": [{"text": "Saethre - Chotzen syndrome", "type": "ENTITY", "char_start": 61239, "char_end": 61265, "token_start": 3, "token_end": 6, "note": null}]}
+{"sentence_id": 416, "sentence_text": "Thirty - two unrelated patients with features of Saethre - Chotzen syndrome , a common autosomal dominant condition of craniosynostosis and limb anomalies , were screened for mutations in TWIST , FGFR2 , and FGFR3 .", "sentence_char_start_global": 61302, "sentence_char_end_global": 61517, "entities": [{"text": "Saethre - Chotzen syndrome", "type": "ENTITY", "char_start": 49, "char_end": 75, "token_start": 8, "token_end": 11}, {"text": "autosomal dominant condition", "type": "ENTITY", "char_start": 87, "char_end": 115, "token_start": 15, "token_end": 17}, {"text": "craniosynostosis", "type": "ENTITY", "char_start": 119, "char_end": 135, "token_start": 19, "token_end": 19}, {"text": "limb anomalies", "type": "ENTITY", "char_start": 140, "char_end": 154, "token_start": 21, "token_end": 22}], "entities_global": [{"text": "Saethre - Chotzen syndrome", "type": "ENTITY", "char_start": 61351, "char_end": 61377, "token_start": 8, "token_end": 11, "note": null}, {"text": "autosomal dominant condition", "type": "ENTITY", "char_start": 61389, "char_end": 61417, "token_start": 15, "token_end": 17, "note": null}, {"text": "craniosynostosis", "type": "ENTITY", "char_start": 61421, "char_end": 61437, "token_start": 19, "token_end": 19, "note": null}, {"text": "limb anomalies", "type": "ENTITY", "char_start": 61442, "char_end": 61456, "token_start": 21, "token_end": 22, "note": null}]}
+{"sentence_id": 417, "sentence_text": "Nine novel and three recurrent TWIST mutations were found in 12 families .", "sentence_char_start_global": 61518, "sentence_char_end_global": 61592, "entities": [], "entities_global": []}
+{"sentence_id": 418, "sentence_text": "Seven families were found to have the FGFR3 P250R mutation , and one individual was found to have an FGFR2 VV269 - 270 deletion .", "sentence_char_start_global": 61593, "sentence_char_end_global": 61722, "entities": [], "entities_global": []}
+{"sentence_id": 419, "sentence_text": "To date , our detection rate for TWIST or FGFR mutations is 68 % in our Saethre - Chotzen syndrome patients , including our five patients elsewhere reported with TWIST mutations .", "sentence_char_start_global": 61723, "sentence_char_end_global": 61902, "entities": [{"text": "Saethre - Chotzen syndrome", "type": "ENTITY", "char_start": 72, "char_end": 98, "token_start": 16, "token_end": 19}], "entities_global": [{"text": "Saethre - Chotzen syndrome", "type": "ENTITY", "char_start": 61795, "char_end": 61821, "token_start": 16, "token_end": 19, "note": null}]}
+{"sentence_id": 420, "sentence_text": "More than 35 different TWIST mutations are now known in the literature .", "sentence_char_start_global": 61903, "sentence_char_end_global": 61975, "entities": [], "entities_global": []}
+{"sentence_id": 421, "sentence_text": "The most common phenotypic features , present in more than a third of our patients with TWIST mutations , are coronal synostosis , brachycephaly , low frontal hairline , facial asymmetry , ptosis , hypertelorism , broad great toes , and clinodactyly .", "sentence_char_start_global": 61976, "sentence_char_end_global": 62227, "entities": [{"text": "coronal synostosis", "type": "ENTITY", "char_start": 110, "char_end": 128, "token_start": 20, "token_end": 21}, {"text": "brachycephaly", "type": "ENTITY", "char_start": 131, "char_end": 144, "token_start": 23, "token_end": 23}, {"text": "low frontal hairline", "type": "ENTITY", "char_start": 147, "char_end": 167, "token_start": 25, "token_end": 27}, {"text": "facial asymmetry", "type": "ENTITY", "char_start": 170, "char_end": 186, "token_start": 29, "token_end": 30}, {"text": "ptosis", "type": "ENTITY", "char_start": 189, "char_end": 195, "token_start": 32, "token_end": 32}, {"text": "hypertelorism", "type": "ENTITY", "char_start": 198, "char_end": 211, "token_start": 34, "token_end": 34}, {"text": "broad great toes", "type": "ENTITY", "char_start": 214, "char_end": 230, "token_start": 36, "token_end": 38}, {"text": "clinodactyly", "type": "ENTITY", "char_start": 237, "char_end": 249, "token_start": 41, "token_end": 41}], "entities_global": [{"text": "coronal synostosis", "type": "ENTITY", "char_start": 62086, "char_end": 62104, "token_start": 20, "token_end": 21, "note": null}, {"text": "brachycephaly", "type": "ENTITY", "char_start": 62107, "char_end": 62120, "token_start": 23, "token_end": 23, "note": null}, {"text": "low frontal hairline", "type": "ENTITY", "char_start": 62123, "char_end": 62143, "token_start": 25, "token_end": 27, "note": null}, {"text": "facial asymmetry", "type": "ENTITY", "char_start": 62146, "char_end": 62162, "token_start": 29, "token_end": 30, "note": null}, {"text": "ptosis", "type": "ENTITY", "char_start": 62165, "char_end": 62171, "token_start": 32, "token_end": 32, "note": null}, {"text": "hypertelorism", "type": "ENTITY", "char_start": 62174, "char_end": 62187, "token_start": 34, "token_end": 34, "note": null}, {"text": "broad great toes", "type": "ENTITY", "char_start": 62190, "char_end": 62206, "token_start": 36, "token_end": 38, "note": null}, {"text": "clinodactyly", "type": "ENTITY", "char_start": 62213, "char_end": 62225, "token_start": 41, "token_end": 41, "note": null}]}
+{"sentence_id": 422, "sentence_text": "Significant intra - and interfamilial phenotypic variability is present for either TWIST mutations or FGFR mutations .", "sentence_char_start_global": 62228, "sentence_char_end_global": 62346, "entities": [], "entities_global": []}
+{"sentence_id": 423, "sentence_text": "The overlap in clinical features and the presence , in the same genes , of mutations for more than one craniosynostotic condition - such as Saethre - Chotzen , Crouzon , and Pfeiffer syndromes - support the hypothesis that TWIST and FGFRs are components of the same molecular pathway involved in the modulation of craniofacial and limb development in humans . .", "sentence_char_start_global": 62347, "sentence_char_end_global": 62708, "entities": [{"text": "craniosynostotic condition", "type": "ENTITY", "char_start": 103, "char_end": 129, "token_start": 20, "token_end": 21}, {"text": "Saethre - Chotzen , Crouzon , and Pfeiffer syndromes", "type": "ENTITY", "char_start": 140, "char_end": 192, "token_start": 25, "token_end": 33}], "entities_global": [{"text": "craniosynostotic condition", "type": "ENTITY", "char_start": 62450, "char_end": 62476, "token_start": 20, "token_end": 21, "note": null}, {"text": "Saethre - Chotzen , Crouzon , and Pfeiffer syndromes", "type": "ENTITY", "char_start": 62487, "char_end": 62539, "token_start": 25, "token_end": 33, "note": null}]}
+{"sentence_id": 424, "sentence_text": "Mutation analysis of UBE3A in Angelman syndrome patients .", "sentence_char_start_global": 62709, "sentence_char_end_global": 62767, "entities": [{"text": "Angelman syndrome", "type": "ENTITY", "char_start": 30, "char_end": 47, "token_start": 5, "token_end": 6}], "entities_global": [{"text": "Angelman syndrome", "type": "ENTITY", "char_start": 62739, "char_end": 62756, "token_start": 5, "token_end": 6, "note": null}]}
+{"sentence_id": 425, "sentence_text": "Angelman syndrome ( AS ) is caused by chromosome 15q11 - q13 deletions of maternal origin , by paternal uniparental disomy ( UPD ) 15 , by imprinting defects , and by mutations in the UBE3A gene .", "sentence_char_start_global": 62768, "sentence_char_end_global": 62964, "entities": [{"text": "Angelman syndrome", "type": "ENTITY", "char_start": 0, "char_end": 17, "token_start": 0, "token_end": 1}, {"text": "AS", "type": "ENTITY", "char_start": 20, "char_end": 22, "token_start": 3, "token_end": 3}, {"text": "uniparental disomy", "type": "ENTITY", "char_start": 104, "char_end": 122, "token_start": 19, "token_end": 20}, {"text": "UPD", "type": "ENTITY", "char_start": 125, "char_end": 128, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "Angelman syndrome", "type": "ENTITY", "char_start": 62768, "char_end": 62785, "token_start": 0, "token_end": 1, "note": null}, {"text": "AS", "type": "ENTITY", "char_start": 62788, "char_end": 62790, "token_start": 3, "token_end": 3, "note": null}, {"text": "uniparental disomy", "type": "ENTITY", "char_start": 62872, "char_end": 62890, "token_start": 19, "token_end": 20, "note": null}, {"text": "UPD", "type": "ENTITY", "char_start": 62893, "char_end": 62896, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 426, "sentence_text": "UBE3A encodes a ubiquitin - protein ligase and shows brain - specific imprinting .", "sentence_char_start_global": 62965, "sentence_char_end_global": 63047, "entities": [], "entities_global": []}
+{"sentence_id": 427, "sentence_text": "Here we describe UBE3A coding - region mutations detected by SSCP analysis in 13 AS individuals or families .", "sentence_char_start_global": 63048, "sentence_char_end_global": 63157, "entities": [{"text": "AS", "type": "ENTITY", "char_start": 81, "char_end": 83, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "AS", "type": "ENTITY", "char_start": 63129, "char_end": 63131, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 428, "sentence_text": "Two identical de novo 5 - bp duplications in exon 16 were found .", "sentence_char_start_global": 63158, "sentence_char_end_global": 63223, "entities": [], "entities_global": []}
+{"sentence_id": 429, "sentence_text": "Among the other 11 unique mutations , 8 were small deletions or insertions predicted to cause frameshifts , 1 was a mutation to a stop codon , 1 was a missense mutation , and 1 was predicted to cause insertion of an isoleucine in the hect domain of the UBE3A protein , which functions in E2 binding and ubiquitin transfer .", "sentence_char_start_global": 63224, "sentence_char_end_global": 63547, "entities": [], "entities_global": []}
+{"sentence_id": 430, "sentence_text": "Eight of the cases were familial , and five were sporadic .", "sentence_char_start_global": 63548, "sentence_char_end_global": 63607, "entities": [], "entities_global": []}
+{"sentence_id": 431, "sentence_text": "In two familial cases and one sporadic case , mosaicism for UBE3A mutations was detected in the mother of three AS sons , in the maternal grandfather of two AS first cousins , and in the mother of an AS daughter .", "sentence_char_start_global": 63608, "sentence_char_end_global": 63821, "entities": [{"text": "AS", "type": "ENTITY", "char_start": 112, "char_end": 114, "token_start": 20, "token_end": 20}, {"text": "AS", "type": "ENTITY", "char_start": 157, "char_end": 159, "token_start": 29, "token_end": 29}, {"text": "AS", "type": "ENTITY", "char_start": 200, "char_end": 202, "token_start": 39, "token_end": 39}], "entities_global": [{"text": "AS", "type": "ENTITY", "char_start": 63720, "char_end": 63722, "token_start": 20, "token_end": 20, "note": null}, {"text": "AS", "type": "ENTITY", "char_start": 63765, "char_end": 63767, "token_start": 29, "token_end": 29, "note": null}, {"text": "AS", "type": "ENTITY", "char_start": 63808, "char_end": 63810, "token_start": 39, "token_end": 39, "note": null}]}
+{"sentence_id": 432, "sentence_text": "The frequencies with which we detected mutations were 5 ( 14 % ) of 35 in sporadic cases and 8 ( 80 % ) of 10 in familial cases . .", "sentence_char_start_global": 63822, "sentence_char_end_global": 63953, "entities": [], "entities_global": []}
+{"sentence_id": 433, "sentence_text": "The hemochromatosis 845 G - - > A and 187 C - - > G mutations : prevalence in non - Caucasian populations .", "sentence_char_start_global": 63954, "sentence_char_end_global": 64061, "entities": [{"text": "hemochromatosis", "type": "ENTITY", "char_start": 4, "char_end": 19, "token_start": 1, "token_end": 1}], "entities_global": [{"text": "hemochromatosis", "type": "ENTITY", "char_start": 63958, "char_end": 63973, "token_start": 1, "token_end": 1, "note": null}]}
+{"sentence_id": 434, "sentence_text": "Hemochromatosis , the inherited disorder of iron metabolism , leads , if untreated , to progressive iron overload and premature death .", "sentence_char_start_global": 64062, "sentence_char_end_global": 64197, "entities": [{"text": "Hemochromatosis", "type": "ENTITY", "char_start": 0, "char_end": 15, "token_start": 0, "token_end": 0}, {"text": "inherited disorder of iron metabolism", "type": "ENTITY", "char_start": 22, "char_end": 59, "token_start": 3, "token_end": 7}, {"text": "iron overload", "type": "ENTITY", "char_start": 100, "char_end": 113, "token_start": 16, "token_end": 17}, {"text": "premature death", "type": "ENTITY", "char_start": 118, "char_end": 133, "token_start": 19, "token_end": 20}], "entities_global": [{"text": "Hemochromatosis", "type": "ENTITY", "char_start": 64062, "char_end": 64077, "token_start": 0, "token_end": 0, "note": null}, {"text": "inherited disorder of iron metabolism", "type": "ENTITY", "char_start": 64084, "char_end": 64121, "token_start": 3, "token_end": 7, "note": null}, {"text": "iron overload", "type": "ENTITY", "char_start": 64162, "char_end": 64175, "token_start": 16, "token_end": 17, "note": null}, {"text": "premature death", "type": "ENTITY", "char_start": 64180, "char_end": 64195, "token_start": 19, "token_end": 20, "note": null}]}
+{"sentence_id": 435, "sentence_text": "The hemochromatosis gene , HFE , recently has been identified , and characterization of this gene has shown that it contains two mutations that result in amino acid substitutions - cDNA nucleotides 845 G - - > A ( C282Y ) and 187 C - - > G ( H63D ) .", "sentence_char_start_global": 64198, "sentence_char_end_global": 64448, "entities": [{"text": "hemochromatosis", "type": "ENTITY", "char_start": 4, "char_end": 19, "token_start": 1, "token_end": 1}], "entities_global": [{"text": "hemochromatosis", "type": "ENTITY", "char_start": 64202, "char_end": 64217, "token_start": 1, "token_end": 1, "note": null}]}
+{"sentence_id": 436, "sentence_text": "Although hemochromatosis is common in Caucasians , affecting > = 1 / 300 individuals of northern European origin , it has not been recognized in other populations .", "sentence_char_start_global": 64449, "sentence_char_end_global": 64613, "entities": [{"text": "hemochromatosis", "type": "ENTITY", "char_start": 9, "char_end": 24, "token_start": 1, "token_end": 1}], "entities_global": [{"text": "hemochromatosis", "type": "ENTITY", "char_start": 64458, "char_end": 64473, "token_start": 1, "token_end": 1, "note": null}]}
+{"sentence_id": 437, "sentence_text": "The present study used PCR and restriction - enzyme digestion to analyze the frequency of the 845 G - - > A and 187 C - - > G mutations in HLA - typed samples from non - Caucasian populations , comprising Australian Aboriginal , Chinese , and Pacific Islanders .", "sentence_char_start_global": 64614, "sentence_char_end_global": 64876, "entities": [], "entities_global": []}
+{"sentence_id": 438, "sentence_text": "Results showed that the 845 G - - > A mutation was present in these populations ( allele frequency 0 . 32 % ) , and , furthermore , it was always seen in conjunction with HLA haplotypes common in Caucasians , suggesting that 845 G - - > A may have been introduced into these populations by Caucasian admixture .", "sentence_char_start_global": 64877, "sentence_char_end_global": 65188, "entities": [], "entities_global": []}
+{"sentence_id": 439, "sentence_text": "187 C - - > G was present at an allele frequency of 2 .", "sentence_char_start_global": 65189, "sentence_char_end_global": 65244, "entities": [], "entities_global": []}
+{"sentence_id": 440, "sentence_text": "68 % in the two populations analyzed ( Australian Aboriginal and Chinese ) .", "sentence_char_start_global": 65245, "sentence_char_end_global": 65321, "entities": [], "entities_global": []}
+{"sentence_id": 441, "sentence_text": "In the Australian Aboriginal samples , 187 C - - > G was found to be associated with HLA haplotypes common in Caucasians , suggesting that it was introduced by recent admixture .", "sentence_char_start_global": 65322, "sentence_char_end_global": 65500, "entities": [], "entities_global": []}
+{"sentence_id": 442, "sentence_text": "In the Chinese samples analyzed , 187 C - - > G was present in association with a wide variety of HLA haplotypes , showing this mutation to be widespread and likely to predate the more genetically restricted 845 G - - > A mutation .", "sentence_char_start_global": 65501, "sentence_char_end_global": 65733, "entities": [], "entities_global": []}
+{"sentence_id": 443, "sentence_text": "Genotype - phenotype correlations in attenuated adenomatous polyposis coli .", "sentence_char_start_global": 65734, "sentence_char_end_global": 65810, "entities": [{"text": "attenuated adenomatous polyposis coli", "type": "ENTITY", "char_start": 37, "char_end": 74, "token_start": 5, "token_end": 8}], "entities_global": [{"text": "attenuated adenomatous polyposis coli", "type": "ENTITY", "char_start": 65771, "char_end": 65808, "token_start": 5, "token_end": 8, "note": null}]}
+{"sentence_id": 444, "sentence_text": "Germ - line mutations of the tumor suppressor APC are implicated in attenuated adenomatous polyposis coli ( AAPC ) , a variant of familial adenomatous polyposis ( FAP ) .", "sentence_char_start_global": 65811, "sentence_char_end_global": 65981, "entities": [{"text": "tumor", "type": "ENTITY", "char_start": 29, "char_end": 34, "token_start": 6, "token_end": 6}, {"text": "attenuated adenomatous polyposis coli", "type": "ENTITY", "char_start": 68, "char_end": 105, "token_start": 12, "token_end": 15}, {"text": "AAPC", "type": "ENTITY", "char_start": 108, "char_end": 112, "token_start": 17, "token_end": 17}, {"text": "familial adenomatous polyposis", "type": "ENTITY", "char_start": 130, "char_end": 160, "token_start": 23, "token_end": 25}, {"text": "FAP", "type": "ENTITY", "char_start": 163, "char_end": 166, "token_start": 27, "token_end": 27}], "entities_global": [{"text": "tumor", "type": "ENTITY", "char_start": 65840, "char_end": 65845, "token_start": 6, "token_end": 6, "note": null}, {"text": "attenuated adenomatous polyposis coli", "type": "ENTITY", "char_start": 65879, "char_end": 65916, "token_start": 12, "token_end": 15, "note": null}, {"text": "AAPC", "type": "ENTITY", "char_start": 65919, "char_end": 65923, "token_start": 17, "token_end": 17, "note": null}, {"text": "familial adenomatous polyposis", "type": "ENTITY", "char_start": 65941, "char_end": 65971, "token_start": 23, "token_end": 25, "note": null}, {"text": "FAP", "type": "ENTITY", "char_start": 65974, "char_end": 65977, "token_start": 27, "token_end": 27, "note": null}]}
+{"sentence_id": 445, "sentence_text": "AAPC is recognized by the occurrence of < 100 colonic adenomas and a later onset of colorectal cancer ( age > 40 years ) .", "sentence_char_start_global": 65982, "sentence_char_end_global": 66104, "entities": [{"text": "AAPC", "type": "ENTITY", "char_start": 0, "char_end": 4, "token_start": 0, "token_end": 0}, {"text": "colonic adenomas", "type": "ENTITY", "char_start": 46, "char_end": 62, "token_start": 9, "token_end": 10}, {"text": "colorectal cancer", "type": "ENTITY", "char_start": 84, "char_end": 101, "token_start": 16, "token_end": 17}], "entities_global": [{"text": "AAPC", "type": "ENTITY", "char_start": 65982, "char_end": 65986, "token_start": 0, "token_end": 0, "note": null}, {"text": "colonic adenomas", "type": "ENTITY", "char_start": 66028, "char_end": 66044, "token_start": 9, "token_end": 10, "note": null}, {"text": "colorectal cancer", "type": "ENTITY", "char_start": 66066, "char_end": 66083, "token_start": 16, "token_end": 17, "note": null}]}
+{"sentence_id": 446, "sentence_text": "The aim of this study was to assess genotype - phenotype correlations in AAPC families .", "sentence_char_start_global": 66105, "sentence_char_end_global": 66193, "entities": [{"text": "AAPC", "type": "ENTITY", "char_start": 73, "char_end": 77, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "AAPC", "type": "ENTITY", "char_start": 66178, "char_end": 66182, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 447, "sentence_text": "By protein - truncation test ( PTT ) assay , the entire coding region of the APC gene was screened in affected individuals from 11 AAPC kindreds , and their phenotypic differences were examined .", "sentence_char_start_global": 66194, "sentence_char_end_global": 66389, "entities": [{"text": "APC", "type": "ENTITY", "char_start": 77, "char_end": 80, "token_start": 16, "token_end": 16}, {"text": "AAPC", "type": "ENTITY", "char_start": 131, "char_end": 135, "token_start": 25, "token_end": 25}], "entities_global": [{"text": "APC", "type": "ENTITY", "char_start": 66271, "char_end": 66274, "token_start": 16, "token_end": 16, "note": null}, {"text": "AAPC", "type": "ENTITY", "char_start": 66325, "char_end": 66329, "token_start": 25, "token_end": 25, "note": null}]}
+{"sentence_id": 448, "sentence_text": "Five novel germ - line APC mutations were identified in seven kindreds .", "sentence_char_start_global": 66390, "sentence_char_end_global": 66462, "entities": [{"text": "APC", "type": "ENTITY", "char_start": 23, "char_end": 26, "token_start": 5, "token_end": 5}], "entities_global": [{"text": "APC", "type": "ENTITY", "char_start": 66413, "char_end": 66416, "token_start": 5, "token_end": 5, "note": null}]}
+{"sentence_id": 449, "sentence_text": "Mutations were located in three different regions of the APC gene ( 1 ) at the 5 end spanning exons 4 and 5 , ( 2 ) within exon 9 , and ( 3 ) at the 3 distal end of the gene .", "sentence_char_start_global": 66463, "sentence_char_end_global": 66638, "entities": [{"text": "APC", "type": "ENTITY", "char_start": 57, "char_end": 60, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "APC", "type": "ENTITY", "char_start": 66520, "char_end": 66523, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 450, "sentence_text": "Variability in the number of colorectal adenomas was most apparent in individuals with mutations in region 1 , and upper - gastrointestinal manifestations were more severe in them .", "sentence_char_start_global": 66639, "sentence_char_end_global": 66820, "entities": [{"text": "colorectal adenomas", "type": "ENTITY", "char_start": 29, "char_end": 48, "token_start": 5, "token_end": 6}], "entities_global": [{"text": "colorectal adenomas", "type": "ENTITY", "char_start": 66668, "char_end": 66687, "token_start": 5, "token_end": 6, "note": null}]}
+{"sentence_id": 451, "sentence_text": "In individuals with mutations in either region 2 or region 3 , the average number of adenomas tended to be lower than those in individuals with mutations in region 1 , although age at diagnosis was similar .", "sentence_char_start_global": 66821, "sentence_char_end_global": 67028, "entities": [{"text": "adenomas", "type": "ENTITY", "char_start": 85, "char_end": 93, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "adenomas", "type": "ENTITY", "char_start": 66906, "char_end": 66914, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 452, "sentence_text": "In all AAPC kindreds , a predominance of right - sided colorectal adenomas and rectal polyp sparing was observed .", "sentence_char_start_global": 67029, "sentence_char_end_global": 67143, "entities": [{"text": "AAPC", "type": "ENTITY", "char_start": 7, "char_end": 11, "token_start": 2, "token_end": 2}, {"text": "colorectal adenomas", "type": "ENTITY", "char_start": 55, "char_end": 74, "token_start": 11, "token_end": 12}, {"text": "rectal polyp", "type": "ENTITY", "char_start": 79, "char_end": 91, "token_start": 14, "token_end": 15}], "entities_global": [{"text": "AAPC", "type": "ENTITY", "char_start": 67036, "char_end": 67040, "token_start": 2, "token_end": 2, "note": null}, {"text": "colorectal adenomas", "type": "ENTITY", "char_start": 67084, "char_end": 67103, "token_start": 11, "token_end": 12, "note": null}, {"text": "rectal polyp", "type": "ENTITY", "char_start": 67108, "char_end": 67120, "token_start": 14, "token_end": 15, "note": null}]}
+{"sentence_id": 453, "sentence_text": "No desmoid tumors were found in these kindreds .", "sentence_char_start_global": 67144, "sentence_char_end_global": 67192, "entities": [{"text": "desmoid tumors", "type": "ENTITY", "char_start": 3, "char_end": 17, "token_start": 1, "token_end": 2}], "entities_global": [{"text": "desmoid tumors", "type": "ENTITY", "char_start": 67147, "char_end": 67161, "token_start": 1, "token_end": 2, "note": null}]}
+{"sentence_id": 454, "sentence_text": "Our data suggest that , in AAPC families , the location of the APC mutation may partially predict specific phenotypic expression .", "sentence_char_start_global": 67193, "sentence_char_end_global": 67323, "entities": [{"text": "AAPC", "type": "ENTITY", "char_start": 27, "char_end": 31, "token_start": 6, "token_end": 6}, {"text": "APC", "type": "ENTITY", "char_start": 63, "char_end": 66, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "AAPC", "type": "ENTITY", "char_start": 67220, "char_end": 67224, "token_start": 6, "token_end": 6, "note": null}, {"text": "APC", "type": "ENTITY", "char_start": 67256, "char_end": 67259, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 455, "sentence_text": "This should help in the design of tailored clinical - management protocols in this subset of FAP patients . .", "sentence_char_start_global": 67324, "sentence_char_end_global": 67433, "entities": [{"text": "FAP", "type": "ENTITY", "char_start": 93, "char_end": 96, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "FAP", "type": "ENTITY", "char_start": 67417, "char_end": 67420, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 456, "sentence_text": "Wilms ' tumor 1 and Dax - 1 modulate the orphan nuclear receptor SF - 1 in sex - specific gene expression .", "sentence_char_start_global": 67434, "sentence_char_end_global": 67541, "entities": [{"text": "Wilms ' tumor", "type": "ENTITY", "char_start": 0, "char_end": 13, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "Wilms ' tumor", "type": "ENTITY", "char_start": 67434, "char_end": 67447, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 457, "sentence_text": "Products of steroidogenic factor 1 ( SF - 1 ) and Wilms tumor 1 ( WT1 ) genes are essential for mammalian gonadogenesis prior to sexual differentiation .", "sentence_char_start_global": 67542, "sentence_char_end_global": 67695, "entities": [{"text": "Wilms tumor", "type": "ENTITY", "char_start": 50, "char_end": 61, "token_start": 11, "token_end": 12}], "entities_global": [{"text": "Wilms tumor", "type": "ENTITY", "char_start": 67592, "char_end": 67603, "token_start": 11, "token_end": 12, "note": null}]}
+{"sentence_id": 458, "sentence_text": "In males , SF - 1 participates in sexual development by regulating expression of the polypeptide hormone Mullerian inhibiting substance ( MIS ) .", "sentence_char_start_global": 67696, "sentence_char_end_global": 67841, "entities": [], "entities_global": []}
+{"sentence_id": 459, "sentence_text": "Here , we show that WT1 - KTS isoforms associate and synergize with SF - 1 to promote MIS expression .", "sentence_char_start_global": 67842, "sentence_char_end_global": 67944, "entities": [], "entities_global": []}
+{"sentence_id": 460, "sentence_text": "In contrast , WT1 missense mutations , associated with male pseudohermaphroditism in Denys - Drash syndrome , fail to synergize with SF - 1 .", "sentence_char_start_global": 67945, "sentence_char_end_global": 68086, "entities": [{"text": "male pseudohermaphroditism", "type": "ENTITY", "char_start": 55, "char_end": 81, "token_start": 9, "token_end": 10}, {"text": "Denys - Drash syndrome", "type": "ENTITY", "char_start": 85, "char_end": 107, "token_start": 12, "token_end": 15}], "entities_global": [{"text": "male pseudohermaphroditism", "type": "ENTITY", "char_start": 68000, "char_end": 68026, "token_start": 9, "token_end": 10, "note": null}, {"text": "Denys - Drash syndrome", "type": "ENTITY", "char_start": 68030, "char_end": 68052, "token_start": 12, "token_end": 15, "note": null}]}
+{"sentence_id": 461, "sentence_text": "Additionally , the X - linked , candidate dosage - sensitive sex - reversal gene , Dax - 1 , antagonizes synergy between SF - 1 and WT1 , most likely through a direct interaction with SF - 1 .", "sentence_char_start_global": 68087, "sentence_char_end_global": 68279, "entities": [], "entities_global": []}
+{"sentence_id": 462, "sentence_text": "We propose that WT1 and Dax - 1 functionally oppose each other in testis development by modulating SF - 1 - mediated transactivation . .", "sentence_char_start_global": 68280, "sentence_char_end_global": 68416, "entities": [], "entities_global": []}
+{"sentence_id": 463, "sentence_text": "A mouse model for Prader - Willi syndrome imprinting - centre mutations .", "sentence_char_start_global": 68417, "sentence_char_end_global": 68490, "entities": [{"text": "Prader - Willi syndrome", "type": "ENTITY", "char_start": 18, "char_end": 41, "token_start": 4, "token_end": 7}], "entities_global": [{"text": "Prader - Willi syndrome", "type": "ENTITY", "char_start": 68435, "char_end": 68458, "token_start": 4, "token_end": 7, "note": null}]}
+{"sentence_id": 464, "sentence_text": "Imprinting in the 15q11 - q13 region involves an imprinting centre ( IC ) , mapping in part to the promoter and first exon of SNRPN .", "sentence_char_start_global": 68491, "sentence_char_end_global": 68624, "entities": [], "entities_global": []}
+{"sentence_id": 465, "sentence_text": "Deletion of this IC abolishes local paternally derived gene expression and results in Prader - Willi syndrome ( PWS ) .", "sentence_char_start_global": 68625, "sentence_char_end_global": 68744, "entities": [{"text": "Prader - Willi syndrome", "type": "ENTITY", "char_start": 86, "char_end": 109, "token_start": 13, "token_end": 16}, {"text": "PWS", "type": "ENTITY", "char_start": 112, "char_end": 115, "token_start": 18, "token_end": 18}], "entities_global": [{"text": "Prader - Willi syndrome", "type": "ENTITY", "char_start": 68711, "char_end": 68734, "token_start": 13, "token_end": 16, "note": null}, {"text": "PWS", "type": "ENTITY", "char_start": 68737, "char_end": 68740, "token_start": 18, "token_end": 18, "note": null}]}
+{"sentence_id": 466, "sentence_text": "We have created two deletion mutations in mice to understand PWS and the mechanism of this IC .", "sentence_char_start_global": 68745, "sentence_char_end_global": 68840, "entities": [{"text": "PWS", "type": "ENTITY", "char_start": 61, "char_end": 64, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "PWS", "type": "ENTITY", "char_start": 68806, "char_end": 68809, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 467, "sentence_text": "Mice harbouring an intragenic deletion in Snrpn are phenotypically normal , suggesting that mutations of SNRPN are not sufficient to induce PWS .", "sentence_char_start_global": 68841, "sentence_char_end_global": 68986, "entities": [{"text": "PWS", "type": "ENTITY", "char_start": 140, "char_end": 143, "token_start": 21, "token_end": 21}], "entities_global": [{"text": "PWS", "type": "ENTITY", "char_start": 68981, "char_end": 68984, "token_start": 21, "token_end": 21, "note": null}]}
+{"sentence_id": 468, "sentence_text": "Mice with a larger deletion involving both Snrpn and the putative PWS - IC lack expression of the imprinted genes Zfp127 ( mouse homologue of ZNF127 ) , Ndn and Ipw , and manifest several phenotypes common to PWS infants .", "sentence_char_start_global": 68987, "sentence_char_end_global": 69209, "entities": [{"text": "PWS", "type": "ENTITY", "char_start": 209, "char_end": 212, "token_start": 38, "token_end": 38}], "entities_global": [{"text": "PWS", "type": "ENTITY", "char_start": 69196, "char_end": 69199, "token_start": 38, "token_end": 38, "note": null}]}
+{"sentence_id": 469, "sentence_text": "These data demonstrate that both the position of the IC and its role in the coordinate expression of genes is conserved between mouse and human , and indicate that the mouse is a suitable model system in which to investigate the molecular mechanisms of imprinting in this region of the genome . .", "sentence_char_start_global": 69210, "sentence_char_end_global": 69506, "entities": [], "entities_global": []}
+{"sentence_id": 470, "sentence_text": "Mutations of the ATM gene detected in Japanese ataxia - telangiectasia patients : possible preponderance of the two founder mutations 4612del165 and 7883del5 .", "sentence_char_start_global": 69507, "sentence_char_end_global": 69666, "entities": [{"text": "ataxia - telangiectasia", "type": "ENTITY", "char_start": 47, "char_end": 70, "token_start": 8, "token_end": 10}], "entities_global": [{"text": "ataxia - telangiectasia", "type": "ENTITY", "char_start": 69554, "char_end": 69577, "token_start": 8, "token_end": 10, "note": null}]}
+{"sentence_id": 471, "sentence_text": "The ATM ( A - T , mutated ) gene on human chromosome 11q22 .", "sentence_char_start_global": 69667, "sentence_char_end_global": 69727, "entities": [], "entities_global": []}
+{"sentence_id": 472, "sentence_text": "3 has recently been identified as the gene responsible for the human recessive disease ataxia - telangiectasia ( A - T ) .", "sentence_char_start_global": 69728, "sentence_char_end_global": 69850, "entities": [{"text": "recessive disease", "type": "ENTITY", "char_start": 69, "char_end": 86, "token_start": 12, "token_end": 13}, {"text": "ataxia - telangiectasia", "type": "ENTITY", "char_start": 87, "char_end": 110, "token_start": 14, "token_end": 16}, {"text": "A - T", "type": "ENTITY", "char_start": 113, "char_end": 118, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "recessive disease", "type": "ENTITY", "char_start": 69797, "char_end": 69814, "token_start": 12, "token_end": 13, "note": null}, {"text": "ataxia - telangiectasia", "type": "ENTITY", "char_start": 69815, "char_end": 69838, "token_start": 14, "token_end": 16, "note": null}, {"text": "A - T", "type": "ENTITY", "char_start": 69841, "char_end": 69846, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 473, "sentence_text": "In order to define the types of disease - causing ATM mutations in Japanese A - T patients as well as to look for possible mutational hotspots , reverse - transcribed RNA derived from ten patients belonging to eight unrelated Japanese A - T families was analyzed for mutations by the restriction endonuclease fingerprinting method .", "sentence_char_start_global": 69851, "sentence_char_end_global": 70183, "entities": [{"text": "A - T", "type": "ENTITY", "char_start": 76, "char_end": 81, "token_start": 14, "token_end": 16}, {"text": "A - T", "type": "ENTITY", "char_start": 235, "char_end": 240, "token_start": 41, "token_end": 43}], "entities_global": [{"text": "A - T", "type": "ENTITY", "char_start": 69927, "char_end": 69932, "token_start": 14, "token_end": 16, "note": null}, {"text": "A - T", "type": "ENTITY", "char_start": 70086, "char_end": 70091, "token_start": 41, "token_end": 43, "note": null}]}
+{"sentence_id": 474, "sentence_text": "As has been reported by others , mutations that lead to exon skipping or premature protein truncation were also predominant in our mutants .", "sentence_char_start_global": 70184, "sentence_char_end_global": 70324, "entities": [], "entities_global": []}
+{"sentence_id": 475, "sentence_text": "Six different mutations were identified on 12 of the 16 alleles examined .", "sentence_char_start_global": 70325, "sentence_char_end_global": 70399, "entities": [], "entities_global": []}
+{"sentence_id": 476, "sentence_text": "Four were deletions involving a loss of a single exon exon 7 , exon 16 , exon 33 or exon 35 .", "sentence_char_start_global": 70400, "sentence_char_end_global": 70493, "entities": [], "entities_global": []}
+{"sentence_id": 477, "sentence_text": "The others were minute deletions , 4649delA in exon 33 and 7883del5 in exon 55 .", "sentence_char_start_global": 70494, "sentence_char_end_global": 70574, "entities": [], "entities_global": []}
+{"sentence_id": 478, "sentence_text": "The mutations 4612del165 and 7883del5 were found in more than two unrelated families ; 44 % ( 7 of 16 ) of the mutant alleles had one of the two mutations .", "sentence_char_start_global": 70575, "sentence_char_end_global": 70731, "entities": [], "entities_global": []}
+{"sentence_id": 479, "sentence_text": "The 4612del165 mutations in three different families were all ascribed to the same T - - > A substitution at the splice donor site in intron 33 .", "sentence_char_start_global": 70732, "sentence_char_end_global": 70877, "entities": [], "entities_global": []}
+{"sentence_id": 480, "sentence_text": "Microsatellite genotyping around the ATM locus also indicated that a common haplotype was shared by the mutant alleles in both mutations .", "sentence_char_start_global": 70878, "sentence_char_end_global": 71016, "entities": [], "entities_global": []}
+{"sentence_id": 481, "sentence_text": "This suggests that these two founder mutations may be predominant among Japanese ATM mutant alleles .", "sentence_char_start_global": 71017, "sentence_char_end_global": 71118, "entities": [], "entities_global": []}
+{"sentence_id": 482, "sentence_text": "W474C amino acid substitution affects early processing of the alpha - subunit of beta - hexosaminidase A and is associated with subacute G ( M2 ) gangliosidosis .", "sentence_char_start_global": 71119, "sentence_char_end_global": 71281, "entities": [{"text": "G ( M2 ) gangliosidosis", "type": "ENTITY", "char_start": 137, "char_end": 160, "token_start": 22, "token_end": 26}], "entities_global": [{"text": "G ( M2 ) gangliosidosis", "type": "ENTITY", "char_start": 71256, "char_end": 71279, "token_start": 22, "token_end": 26, "note": null}]}
+{"sentence_id": 483, "sentence_text": "Mutations in the HEXA gene , encoding the alpha - subunit of beta - hexosaminidase A ( Hex A ) , that abolish Hex A enzyme activity cause Tay - Sachs disease ( TSD ) , the fatal infantile form of G ( M2 ) gangliosidosis , Type 1 .", "sentence_char_start_global": 71282, "sentence_char_end_global": 71512, "entities": [{"text": "Tay - Sachs disease", "type": "ENTITY", "char_start": 138, "char_end": 157, "token_start": 28, "token_end": 31}, {"text": "TSD", "type": "ENTITY", "char_start": 160, "char_end": 163, "token_start": 33, "token_end": 33}, {"text": "infantile form of G ( M2 ) gangliosidosis , Type 1", "type": "ENTITY", "char_start": 178, "char_end": 228, "token_start": 38, "token_end": 48}], "entities_global": [{"text": "Tay - Sachs disease", "type": "ENTITY", "char_start": 71420, "char_end": 71439, "token_start": 28, "token_end": 31, "note": null}, {"text": "TSD", "type": "ENTITY", "char_start": 71442, "char_end": 71445, "token_start": 33, "token_end": 33, "note": null}, {"text": "infantile form of G ( M2 ) gangliosidosis , Type 1", "type": "ENTITY", "char_start": 71460, "char_end": 71510, "token_start": 38, "token_end": 48, "note": null}]}
+{"sentence_id": 484, "sentence_text": "Less severe , subacute ( juvenile - onset ) and chronic ( adult - onset ) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity .", "sentence_char_start_global": 71513, "sentence_char_end_global": 71727, "entities": [], "entities_global": []}
+{"sentence_id": 485, "sentence_text": "We identified a 1422 G - - > C ( amino acid W474C ) substitution in the first position of exon 13 of HEXA of a non - Jewish proband who manifested a subacute variant of G ( M2 ) gangliosidosis .", "sentence_char_start_global": 71728, "sentence_char_end_global": 71922, "entities": [{"text": "G ( M2 ) gangliosidosis", "type": "ENTITY", "char_start": 169, "char_end": 192, "token_start": 36, "token_end": 40}], "entities_global": [{"text": "G ( M2 ) gangliosidosis", "type": "ENTITY", "char_start": 71897, "char_end": 71920, "token_start": 36, "token_end": 40, "note": null}]}
+{"sentence_id": 486, "sentence_text": "On the second maternally inherited allele , we identified the common infantile disease - causing 4 - bp insertion , + TATC 1278 , in exon 11 .", "sentence_char_start_global": 71923, "sentence_char_end_global": 72065, "entities": [], "entities_global": []}
+{"sentence_id": 487, "sentence_text": "Pulse - chase analysis using proband fibroblasts revealed that the W474C - containing alpha - subunit precursor was normally synthesized , but not phosphorylated or secreted , and the mature lysosomal alpha - subunit was not detected .", "sentence_char_start_global": 72066, "sentence_char_end_global": 72301, "entities": [], "entities_global": []}
+{"sentence_id": 488, "sentence_text": "When the W474C - containing alpha - subunit was transiently co - expressed with the beta - subunit to produce Hex A ( alphabeta ) in COS - 7 cells , the mature alpha - subunit was present , but its level was much lower than that from normal alpha - subunit transfections , although higher than in those cells transfected with an alpha - subunit associated with infantile TSD .", "sentence_char_start_global": 72302, "sentence_char_end_global": 72678, "entities": [{"text": "TSD", "type": "ENTITY", "char_start": 371, "char_end": 374, "token_start": 69, "token_end": 69}], "entities_global": [{"text": "TSD", "type": "ENTITY", "char_start": 72673, "char_end": 72676, "token_start": 69, "token_end": 69, "note": null}]}
+{"sentence_id": 489, "sentence_text": "Furthermore , the precursor level of the W474C alpha - subunit was found to accumulate in comparison to the normal alpha - subunit precursor levels .", "sentence_char_start_global": 72679, "sentence_char_end_global": 72828, "entities": [], "entities_global": []}
+{"sentence_id": 490, "sentence_text": "We conclude that the 1422 G - - > C mutation is the cause of Hex A enzyme deficiency in the proband .", "sentence_char_start_global": 72829, "sentence_char_end_global": 72930, "entities": [{"text": "Hex A enzyme deficiency", "type": "ENTITY", "char_start": 61, "char_end": 84, "token_start": 15, "token_end": 18}], "entities_global": [{"text": "Hex A enzyme deficiency", "type": "ENTITY", "char_start": 72890, "char_end": 72913, "token_start": 15, "token_end": 18, "note": null}]}
+{"sentence_id": 491, "sentence_text": "The resulting W474C substitution clearly interferes with alpha - subunit processing , but because the base substitution falls at the first position of exon 13 , aberrant splicing may also contribute to Hex A deficiency in this proband . .", "sentence_char_start_global": 72931, "sentence_char_end_global": 73169, "entities": [{"text": "Hex A deficiency", "type": "ENTITY", "char_start": 202, "char_end": 218, "token_start": 32, "token_end": 34}], "entities_global": [{"text": "Hex A deficiency", "type": "ENTITY", "char_start": 73133, "char_end": 73149, "token_start": 32, "token_end": 34, "note": null}]}
+{"sentence_id": 492, "sentence_text": "Two frequent missense mutations in Pendred syndrome .", "sentence_char_start_global": 73170, "sentence_char_end_global": 73223, "entities": [{"text": "Pendred syndrome", "type": "ENTITY", "char_start": 35, "char_end": 51, "token_start": 5, "token_end": 6}], "entities_global": [{"text": "Pendred syndrome", "type": "ENTITY", "char_start": 73205, "char_end": 73221, "token_start": 5, "token_end": 6, "note": null}]}
+{"sentence_id": 493, "sentence_text": "Pendred syndrome is an autosomal recessive disorder characterized by early childhood deafness and goiter .", "sentence_char_start_global": 73224, "sentence_char_end_global": 73330, "entities": [{"text": "Pendred syndrome", "type": "ENTITY", "char_start": 0, "char_end": 16, "token_start": 0, "token_end": 1}, {"text": "autosomal recessive disorder", "type": "ENTITY", "char_start": 23, "char_end": 51, "token_start": 4, "token_end": 6}, {"text": "deafness", "type": "ENTITY", "char_start": 85, "char_end": 93, "token_start": 11, "token_end": 11}, {"text": "goiter", "type": "ENTITY", "char_start": 98, "char_end": 104, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "Pendred syndrome", "type": "ENTITY", "char_start": 73224, "char_end": 73240, "token_start": 0, "token_end": 1, "note": null}, {"text": "autosomal recessive disorder", "type": "ENTITY", "char_start": 73247, "char_end": 73275, "token_start": 4, "token_end": 6, "note": null}, {"text": "deafness", "type": "ENTITY", "char_start": 73309, "char_end": 73317, "token_start": 11, "token_end": 11, "note": null}, {"text": "goiter", "type": "ENTITY", "char_start": 73322, "char_end": 73328, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 494, "sentence_text": "A century after its recognition as a syndrome by Vaughan Pendred , the disease gene ( PDS ) was mapped to chromosome 7q22 - q31 .", "sentence_char_start_global": 73331, "sentence_char_end_global": 73460, "entities": [], "entities_global": []}
+{"sentence_id": 495, "sentence_text": "1 and , recently , found to encode a putative sulfate transporter .", "sentence_char_start_global": 73461, "sentence_char_end_global": 73528, "entities": [], "entities_global": []}
+{"sentence_id": 496, "sentence_text": "We performed mutation analysis of the PDS gene in patients from 14 Pendred families originating from seven countries and identified all mutations .", "sentence_char_start_global": 73529, "sentence_char_end_global": 73676, "entities": [{"text": "PDS", "type": "ENTITY", "char_start": 38, "char_end": 41, "token_start": 6, "token_end": 6}, {"text": "Pendred", "type": "ENTITY", "char_start": 67, "char_end": 74, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "PDS", "type": "ENTITY", "char_start": 73567, "char_end": 73570, "token_start": 6, "token_end": 6, "note": null}, {"text": "Pendred", "type": "ENTITY", "char_start": 73596, "char_end": 73603, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 497, "sentence_text": "The mutations include three single base deletions , one splice site mutation and 10 missense mutations .", "sentence_char_start_global": 73677, "sentence_char_end_global": 73781, "entities": [], "entities_global": []}
+{"sentence_id": 498, "sentence_text": "One missense mutation ( L236P ) was found in a homozygous state in two consanguineous families and in a heterozygous state in five additional non - consanguineous families .", "sentence_char_start_global": 73782, "sentence_char_end_global": 73955, "entities": [], "entities_global": []}
+{"sentence_id": 499, "sentence_text": "Another missense mutation ( T416P ) was found in a homozygous state in one family and in a heterozygous state in four families .", "sentence_char_start_global": 73956, "sentence_char_end_global": 74084, "entities": [], "entities_global": []}
+{"sentence_id": 500, "sentence_text": "Pendred patients in three non - consanguineous families were shown to be compound heterozygotes for L236P and T416P .", "sentence_char_start_global": 74085, "sentence_char_end_global": 74202, "entities": [{"text": "Pendred", "type": "ENTITY", "char_start": 0, "char_end": 7, "token_start": 0, "token_end": 0}], "entities_global": [{"text": "Pendred", "type": "ENTITY", "char_start": 74085, "char_end": 74092, "token_start": 0, "token_end": 0, "note": null}]}
+{"sentence_id": 501, "sentence_text": "In total , one or both of these mutations were found in nine of the 14 families analyzed .", "sentence_char_start_global": 74203, "sentence_char_end_global": 74293, "entities": [], "entities_global": []}
+{"sentence_id": 502, "sentence_text": "The identification of two frequent PDS mutations will facilitate the molecular diagnosis of Pendred syndrome .", "sentence_char_start_global": 74294, "sentence_char_end_global": 74404, "entities": [{"text": "PDS", "type": "ENTITY", "char_start": 35, "char_end": 38, "token_start": 5, "token_end": 5}, {"text": "Pendred syndrome", "type": "ENTITY", "char_start": 92, "char_end": 108, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "PDS", "type": "ENTITY", "char_start": 74329, "char_end": 74332, "token_start": 5, "token_end": 5, "note": null}, {"text": "Pendred syndrome", "type": "ENTITY", "char_start": 74386, "char_end": 74402, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 503, "sentence_text": "Insertional mutation by transposable element , L1 , in the DMD gene results in X - linked dilated cardiomyopathy .", "sentence_char_start_global": 74405, "sentence_char_end_global": 74519, "entities": [{"text": "DMD", "type": "ENTITY", "char_start": 59, "char_end": 62, "token_start": 10, "token_end": 10}, {"text": "X - linked dilated cardiomyopathy", "type": "ENTITY", "char_start": 79, "char_end": 112, "token_start": 14, "token_end": 18}], "entities_global": [{"text": "DMD", "type": "ENTITY", "char_start": 74464, "char_end": 74467, "token_start": 10, "token_end": 10, "note": null}, {"text": "X - linked dilated cardiomyopathy", "type": "ENTITY", "char_start": 74484, "char_end": 74517, "token_start": 14, "token_end": 18, "note": null}]}
+{"sentence_id": 504, "sentence_text": "X - linked dilated cardiomyopathy ( XLDCM ) is a clinical phenotype of dystrophinopathy which is characterized by preferential myocardial involvement without any overt clinical signs of skeletal myopathy .", "sentence_char_start_global": 74520, "sentence_char_end_global": 74725, "entities": [{"text": "X - linked dilated cardiomyopathy", "type": "ENTITY", "char_start": 0, "char_end": 33, "token_start": 0, "token_end": 4}, {"text": "XLDCM", "type": "ENTITY", "char_start": 36, "char_end": 41, "token_start": 6, "token_end": 6}, {"text": "dystrophinopathy", "type": "ENTITY", "char_start": 71, "char_end": 87, "token_start": 13, "token_end": 13}, {"text": "myocardial involvement", "type": "ENTITY", "char_start": 127, "char_end": 149, "token_start": 19, "token_end": 20}, {"text": "skeletal myopathy", "type": "ENTITY", "char_start": 186, "char_end": 203, "token_start": 27, "token_end": 28}], "entities_global": [{"text": "X - linked dilated cardiomyopathy", "type": "ENTITY", "char_start": 74520, "char_end": 74553, "token_start": 0, "token_end": 4, "note": null}, {"text": "XLDCM", "type": "ENTITY", "char_start": 74556, "char_end": 74561, "token_start": 6, "token_end": 6, "note": null}, {"text": "dystrophinopathy", "type": "ENTITY", "char_start": 74591, "char_end": 74607, "token_start": 13, "token_end": 13, "note": null}, {"text": "myocardial involvement", "type": "ENTITY", "char_start": 74647, "char_end": 74669, "token_start": 19, "token_end": 20, "note": null}, {"text": "skeletal myopathy", "type": "ENTITY", "char_start": 74706, "char_end": 74723, "token_start": 27, "token_end": 28, "note": null}]}
+{"sentence_id": 505, "sentence_text": "To date , several mutations in the Duchenne muscular dystrophy gene , DMD , have been identified in patients with XLDCM , but a pathogenic correlation of these cardiospecific mutations in DMD with the XLDCM phenotype has remained to be elucidated .", "sentence_char_start_global": 74726, "sentence_char_end_global": 74974, "entities": [{"text": "Duchenne muscular dystrophy", "type": "ENTITY", "char_start": 35, "char_end": 62, "token_start": 7, "token_end": 9}, {"text": "XLDCM", "type": "ENTITY", "char_start": 114, "char_end": 119, "token_start": 20, "token_end": 20}, {"text": "XLDCM", "type": "ENTITY", "char_start": 201, "char_end": 206, "token_start": 34, "token_end": 34}], "entities_global": [{"text": "Duchenne muscular dystrophy", "type": "ENTITY", "char_start": 74761, "char_end": 74788, "token_start": 7, "token_end": 9, "note": null}, {"text": "XLDCM", "type": "ENTITY", "char_start": 74840, "char_end": 74845, "token_start": 20, "token_end": 20, "note": null}, {"text": "XLDCM", "type": "ENTITY", "char_start": 74927, "char_end": 74932, "token_start": 34, "token_end": 34, "note": null}]}
+{"sentence_id": 506, "sentence_text": "We report here the identification of a unique de novo L1 insertion in the muscle exon 1 in DMD in three XLDCM patients from two unrelated Japanese families .", "sentence_char_start_global": 74975, "sentence_char_end_global": 75132, "entities": [{"text": "XLDCM", "type": "ENTITY", "char_start": 104, "char_end": 109, "token_start": 21, "token_end": 21}], "entities_global": [{"text": "XLDCM", "type": "ENTITY", "char_start": 75079, "char_end": 75084, "token_start": 21, "token_end": 21, "note": null}]}
+{"sentence_id": 507, "sentence_text": "The insertion was a 5 - truncated form of human L1 inversely integrated in the 5 - untranslated region in the muscle exon 1 , which affected the transcription or the stability of the muscle form of dystrophin transcripts but not that of the brain or Purkinje cell form , probably due to its unique site of integration .", "sentence_char_start_global": 75133, "sentence_char_end_global": 75452, "entities": [], "entities_global": []}
+{"sentence_id": 508, "sentence_text": "We speculate that this insertion of an L1 sequence in DMD is responsible for some of the population of Japanese patients with XLDCM . .", "sentence_char_start_global": 75453, "sentence_char_end_global": 75588, "entities": [{"text": "XLDCM", "type": "ENTITY", "char_start": 126, "char_end": 131, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "XLDCM", "type": "ENTITY", "char_start": 75579, "char_end": 75584, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 509, "sentence_text": "Severe early - onset obesity , adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans .", "sentence_char_start_global": 75589, "sentence_char_end_global": 75704, "entities": [{"text": "obesity", "type": "ENTITY", "char_start": 21, "char_end": 28, "token_start": 4, "token_end": 4}, {"text": "adrenal insufficiency", "type": "ENTITY", "char_start": 31, "char_end": 52, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "obesity", "type": "ENTITY", "char_start": 75610, "char_end": 75617, "token_start": 4, "token_end": 4, "note": null}, {"text": "adrenal insufficiency", "type": "ENTITY", "char_start": 75620, "char_end": 75641, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 510, "sentence_text": "Sequential cleavage of the precursor protein pre - pro - opiomelanocortin ( POMC ) generates the melanocortin peptides adrenocorticotrophin ( ACTH ) , melanocyte - stimulating hormones ( MSH ) alpha , beta and gamma as well as the opioid - receptor ligand beta - endorphin .", "sentence_char_start_global": 75705, "sentence_char_end_global": 75979, "entities": [], "entities_global": []}
+{"sentence_id": 511, "sentence_text": "While a few cases of isolated ACTH deficiency have been reported ( OMIM 201400 ) , an inherited POMC defect has not been described so far .", "sentence_char_start_global": 75980, "sentence_char_end_global": 76119, "entities": [{"text": "ACTH deficiency", "type": "ENTITY", "char_start": 30, "char_end": 45, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "ACTH deficiency", "type": "ENTITY", "char_start": 76010, "char_end": 76025, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 512, "sentence_text": "Recent studies in animal models elucidated a central role of alpha - MSH in the regulation of food intake by activation of the brain melanocortin - 4 - receptor ( MC4 - R ; refs 3 - 5 ) and the linkage of human obesity to chromosome 2 in close proximity to the POMC locus , led to the proposal of an association of POMC with human obesity .", "sentence_char_start_global": 76120, "sentence_char_end_global": 76460, "entities": [{"text": "obesity", "type": "ENTITY", "char_start": 211, "char_end": 218, "token_start": 44, "token_end": 44}, {"text": "obesity", "type": "ENTITY", "char_start": 331, "char_end": 338, "token_start": 67, "token_end": 67}], "entities_global": [{"text": "obesity", "type": "ENTITY", "char_start": 76331, "char_end": 76338, "token_start": 44, "token_end": 44, "note": null}, {"text": "obesity", "type": "ENTITY", "char_start": 76451, "char_end": 76458, "token_start": 67, "token_end": 67, "note": null}]}
+{"sentence_id": 513, "sentence_text": "The dual role of alpha - MSH in regulating food intake and influencing hair pigmentation predicts that the phenotype associated with a defect in POMC function would include obesity , alteration in pigmentation and ACTH deficiency .", "sentence_char_start_global": 76461, "sentence_char_end_global": 76692, "entities": [{"text": "obesity", "type": "ENTITY", "char_start": 173, "char_end": 180, "token_start": 28, "token_end": 28}, {"text": "ACTH deficiency", "type": "ENTITY", "char_start": 214, "char_end": 229, "token_start": 34, "token_end": 35}], "entities_global": [{"text": "obesity", "type": "ENTITY", "char_start": 76634, "char_end": 76641, "token_start": 28, "token_end": 28, "note": null}, {"text": "ACTH deficiency", "type": "ENTITY", "char_start": 76675, "char_end": 76690, "token_start": 34, "token_end": 35, "note": null}]}
+{"sentence_id": 514, "sentence_text": "The observation of these symptoms in two probands prompted us to search for mutations within their POMC genes .", "sentence_char_start_global": 76693, "sentence_char_end_global": 76804, "entities": [], "entities_global": []}
+{"sentence_id": 515, "sentence_text": "Patient 1 was found to be a compound heterozygote for two mutations in exon 3 ( G7013T , C7133delta ) which interfere with appropriate synthesis of ACTH and alpha - MSH .", "sentence_char_start_global": 76805, "sentence_char_end_global": 76975, "entities": [], "entities_global": []}
+{"sentence_id": 516, "sentence_text": "Patient 2 was homozygous for a mutation in exon 2 ( C3804A ) which abolishes POMC translation .", "sentence_char_start_global": 76976, "sentence_char_end_global": 77071, "entities": [], "entities_global": []}
+{"sentence_id": 517, "sentence_text": "These findings represent the first examples of a genetic defect within the POMC gene and define a new monogenic endocrine disorder resulting in early - onset obesity , adrenal insufficiency and red hair pigmentation . .", "sentence_char_start_global": 77072, "sentence_char_end_global": 77291, "entities": [{"text": "genetic defect", "type": "ENTITY", "char_start": 49, "char_end": 63, "token_start": 8, "token_end": 9}, {"text": "monogenic endocrine disorder", "type": "ENTITY", "char_start": 102, "char_end": 130, "token_start": 18, "token_end": 20}, {"text": "obesity", "type": "ENTITY", "char_start": 158, "char_end": 165, "token_start": 26, "token_end": 26}, {"text": "adrenal insufficiency", "type": "ENTITY", "char_start": 168, "char_end": 189, "token_start": 28, "token_end": 29}], "entities_global": [{"text": "genetic defect", "type": "ENTITY", "char_start": 77121, "char_end": 77135, "token_start": 8, "token_end": 9, "note": null}, {"text": "monogenic endocrine disorder", "type": "ENTITY", "char_start": 77174, "char_end": 77202, "token_start": 18, "token_end": 20, "note": null}, {"text": "obesity", "type": "ENTITY", "char_start": 77230, "char_end": 77237, "token_start": 26, "token_end": 26, "note": null}, {"text": "adrenal insufficiency", "type": "ENTITY", "char_start": 77240, "char_end": 77261, "token_start": 28, "token_end": 29, "note": null}]}
+{"sentence_id": 518, "sentence_text": "A European multicenter study of phenylalanine hydroxylase deficiency : classification of 105 mutations and a general system for genotype - based prediction of metabolic phenotype .", "sentence_char_start_global": 77292, "sentence_char_end_global": 77472, "entities": [{"text": "phenylalanine hydroxylase deficiency", "type": "ENTITY", "char_start": 32, "char_end": 68, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "phenylalanine hydroxylase deficiency", "type": "ENTITY", "char_start": 77324, "char_end": 77360, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 519, "sentence_text": "Phenylketonuria ( PKU ) and mild hyperphenylalaninemia ( MHP ) are allelic disorders caused by mutations in the gene encoding phenylalanine hydroxylase ( PAH ) .", "sentence_char_start_global": 77473, "sentence_char_end_global": 77634, "entities": [{"text": "Phenylketonuria", "type": "ENTITY", "char_start": 0, "char_end": 15, "token_start": 0, "token_end": 0}, {"text": "PKU", "type": "ENTITY", "char_start": 18, "char_end": 21, "token_start": 2, "token_end": 2}, {"text": "mild hyperphenylalaninemia", "type": "ENTITY", "char_start": 28, "char_end": 54, "token_start": 5, "token_end": 6}, {"text": "MHP", "type": "ENTITY", "char_start": 57, "char_end": 60, "token_start": 8, "token_end": 8}, {"text": "allelic disorders", "type": "ENTITY", "char_start": 67, "char_end": 84, "token_start": 11, "token_end": 12}], "entities_global": [{"text": "Phenylketonuria", "type": "ENTITY", "char_start": 77473, "char_end": 77488, "token_start": 0, "token_end": 0, "note": null}, {"text": "PKU", "type": "ENTITY", "char_start": 77491, "char_end": 77494, "token_start": 2, "token_end": 2, "note": null}, {"text": "mild hyperphenylalaninemia", "type": "ENTITY", "char_start": 77501, "char_end": 77527, "token_start": 5, "token_end": 6, "note": null}, {"text": "MHP", "type": "ENTITY", "char_start": 77530, "char_end": 77533, "token_start": 8, "token_end": 8, "note": null}, {"text": "allelic disorders", "type": "ENTITY", "char_start": 77540, "char_end": 77557, "token_start": 11, "token_end": 12, "note": null}]}
+{"sentence_id": 520, "sentence_text": "Previous studies have suggested that the highly variable metabolic phenotypes of PAH deficiency correlate with PAH genotypes .", "sentence_char_start_global": 77635, "sentence_char_end_global": 77761, "entities": [{"text": "PAH deficiency", "type": "ENTITY", "char_start": 81, "char_end": 95, "token_start": 11, "token_end": 12}], "entities_global": [{"text": "PAH deficiency", "type": "ENTITY", "char_start": 77716, "char_end": 77730, "token_start": 11, "token_end": 12, "note": null}]}
+{"sentence_id": 521, "sentence_text": "We identified both causative mutations in 686 patients from seven European centers .", "sentence_char_start_global": 77762, "sentence_char_end_global": 77846, "entities": [], "entities_global": []}
+{"sentence_id": 522, "sentence_text": "On the basis of the phenotypic characteristics of 297 functionally hemizygous patients , 105 of the mutations were assigned to one of four arbitrary phenotype categories .", "sentence_char_start_global": 77847, "sentence_char_end_global": 78018, "entities": [], "entities_global": []}
+{"sentence_id": 523, "sentence_text": "We proposed and tested a simple model for correlation between genotype and phenotypic outcome .", "sentence_char_start_global": 78019, "sentence_char_end_global": 78114, "entities": [], "entities_global": []}
+{"sentence_id": 524, "sentence_text": "The observed phenotype matched the predicted phenotype in 79 % of the cases , and in only 5 of 184 patients was the observed phenotype more than one category away from that expected .", "sentence_char_start_global": 78115, "sentence_char_end_global": 78298, "entities": [], "entities_global": []}
+{"sentence_id": 525, "sentence_text": "Among the seven contributing centers , the proportion of patients for whom the observed phenotype did not match the predicted phenotype was 4 % - 23 % ( P < . 0001 ) , suggesting that differences in methods used for mutation detection or phenotype classification may account for a considerable proportion of genotype - phenotype inconsistencies .", "sentence_char_start_global": 78299, "sentence_char_end_global": 78645, "entities": [], "entities_global": []}
+{"sentence_id": 526, "sentence_text": "Our data indicate that the PAH - mutation genotype is the main determinant of metabolic phenotype in most patients with PAH deficiency .", "sentence_char_start_global": 78646, "sentence_char_end_global": 78782, "entities": [{"text": "PAH deficiency", "type": "ENTITY", "char_start": 120, "char_end": 134, "token_start": 20, "token_end": 21}], "entities_global": [{"text": "PAH deficiency", "type": "ENTITY", "char_start": 78766, "char_end": 78780, "token_start": 20, "token_end": 21, "note": null}]}
+{"sentence_id": 527, "sentence_text": "In the present study , the classification of 105 PAH mutations may allow the prediction of the biochemical phenotype in > 10 , 000 genotypes , which may be useful for the management of hyperphenylalaninemia in newborns .", "sentence_char_start_global": 78783, "sentence_char_end_global": 79003, "entities": [{"text": "hyperphenylalaninemia", "type": "ENTITY", "char_start": 185, "char_end": 206, "token_start": 34, "token_end": 34}], "entities_global": [{"text": "hyperphenylalaninemia", "type": "ENTITY", "char_start": 78968, "char_end": 78989, "token_start": 34, "token_end": 34, "note": null}]}
+{"sentence_id": 528, "sentence_text": "Somatic instability of the CTG repeat in mice transgenic for the myotonic dystrophy region is age dependent but not correlated to the relative intertissue transcription levels and proliferative capacities .", "sentence_char_start_global": 79004, "sentence_char_end_global": 79210, "entities": [{"text": "myotonic dystrophy", "type": "ENTITY", "char_start": 65, "char_end": 83, "token_start": 11, "token_end": 12}], "entities_global": [{"text": "myotonic dystrophy", "type": "ENTITY", "char_start": 79069, "char_end": 79087, "token_start": 11, "token_end": 12, "note": null}]}
+{"sentence_id": 529, "sentence_text": "A ( CTG ) nexpansion in the 3 - untranslated region ( UTR ) of the DM protein kinase gene ( DMPK ) is responsible for causing myotonic dystrophy ( DM ) .", "sentence_char_start_global": 79211, "sentence_char_end_global": 79364, "entities": [{"text": "myotonic dystrophy", "type": "ENTITY", "char_start": 126, "char_end": 144, "token_start": 27, "token_end": 28}, {"text": "DM", "type": "ENTITY", "char_start": 147, "char_end": 149, "token_start": 30, "token_end": 30}], "entities_global": [{"text": "myotonic dystrophy", "type": "ENTITY", "char_start": 79337, "char_end": 79355, "token_start": 27, "token_end": 28, "note": null}, {"text": "DM", "type": "ENTITY", "char_start": 79358, "char_end": 79360, "token_start": 30, "token_end": 30, "note": null}]}
+{"sentence_id": 530, "sentence_text": "Major instability , with very large expansions between generations and high levels of somatic mosaicism , is observed in patients .", "sentence_char_start_global": 79365, "sentence_char_end_global": 79496, "entities": [], "entities_global": []}
+{"sentence_id": 531, "sentence_text": "There is a good correlation between repeat size ( at least in leucocytes ) , clinical severity and age of onset .", "sentence_char_start_global": 79497, "sentence_char_end_global": 79610, "entities": [], "entities_global": []}
+{"sentence_id": 532, "sentence_text": "The trinucleotide repeat instability mechanisms involved in DM and other human genetic diseases are unknown .", "sentence_char_start_global": 79611, "sentence_char_end_global": 79720, "entities": [{"text": "DM", "type": "ENTITY", "char_start": 60, "char_end": 62, "token_start": 7, "token_end": 7}, {"text": "genetic diseases", "type": "ENTITY", "char_start": 79, "char_end": 95, "token_start": 11, "token_end": 12}], "entities_global": [{"text": "DM", "type": "ENTITY", "char_start": 79671, "char_end": 79673, "token_start": 7, "token_end": 7, "note": null}, {"text": "genetic diseases", "type": "ENTITY", "char_start": 79690, "char_end": 79706, "token_start": 11, "token_end": 12, "note": null}]}
+{"sentence_id": 533, "sentence_text": "We studied somatic instability by measuring the CTG repeat length at several ages in various tissues of transgenic mice carrying a ( CTG ) 55expansion surrounded by 45 kb of the human DM region , using small - pool PCR .", "sentence_char_start_global": 79721, "sentence_char_end_global": 79941, "entities": [{"text": "DM", "type": "ENTITY", "char_start": 184, "char_end": 186, "token_start": 32, "token_end": 32}], "entities_global": [{"text": "DM", "type": "ENTITY", "char_start": 79905, "char_end": 79907, "token_start": 32, "token_end": 32, "note": null}]}
+{"sentence_id": 534, "sentence_text": "These mice have been shown to reproduce the intergenerational and somatic instability of the 55 CTG repeat suggesting that surrounding sequences and the chromatin environment are involved in instability mechanisms .", "sentence_char_start_global": 79942, "sentence_char_end_global": 80157, "entities": [], "entities_global": []}
+{"sentence_id": 535, "sentence_text": "As observed in some of the tissues of DM patients , there is a tendency for repeat length and somatic mosaicism to increase with the age of the mouse .", "sentence_char_start_global": 80158, "sentence_char_end_global": 80309, "entities": [{"text": "DM", "type": "ENTITY", "char_start": 38, "char_end": 40, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "DM", "type": "ENTITY", "char_start": 80196, "char_end": 80198, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 536, "sentence_text": "Furthermore , we observed no correlation between the somatic mutation rate and tissue proliferation capacity .", "sentence_char_start_global": 80310, "sentence_char_end_global": 80420, "entities": [], "entities_global": []}
+{"sentence_id": 537, "sentence_text": "The somatic mutation rates in different tissues were also not correlated to the relative inter - tissue difference in transcriptional levels of the three genes ( DMAHP , DMPK and 59 ) surrounding the repeat . .", "sentence_char_start_global": 80421, "sentence_char_end_global": 80631, "entities": [], "entities_global": []}
+{"sentence_id": 538, "sentence_text": "A novel missense mutation in patients from a retinoblastoma pedigree showing only mild expression of the tumor phenotype .", "sentence_char_start_global": 80632, "sentence_char_end_global": 80754, "entities": [{"text": "retinoblastoma", "type": "ENTITY", "char_start": 45, "char_end": 59, "token_start": 8, "token_end": 8}, {"text": "tumor", "type": "ENTITY", "char_start": 105, "char_end": 110, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "retinoblastoma", "type": "ENTITY", "char_start": 80677, "char_end": 80691, "token_start": 8, "token_end": 8, "note": null}, {"text": "tumor", "type": "ENTITY", "char_start": 80737, "char_end": 80742, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 539, "sentence_text": "We have used single strand conformation polymorphism analysis to study the 27 exons of the RB1 gene in individuals from a family showing mild expression of the retinoblastoma phenotype .", "sentence_char_start_global": 80755, "sentence_char_end_global": 80941, "entities": [{"text": "retinoblastoma", "type": "ENTITY", "char_start": 160, "char_end": 174, "token_start": 27, "token_end": 27}], "entities_global": [{"text": "retinoblastoma", "type": "ENTITY", "char_start": 80915, "char_end": 80929, "token_start": 27, "token_end": 27, "note": null}]}
+{"sentence_id": 540, "sentence_text": "In this family affected individuals developed unilateral tumors and , as a result of linkage analysis , unaffected mutation carriers were also identified within the pedigree .", "sentence_char_start_global": 80942, "sentence_char_end_global": 81117, "entities": [{"text": "unilateral tumors", "type": "ENTITY", "char_start": 46, "char_end": 63, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "unilateral tumors", "type": "ENTITY", "char_start": 80988, "char_end": 81005, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 541, "sentence_text": "A single band shift using SSCP was identified in exon 21 which resulted in a missense mutation converting a cys - - > arg at nucleotide position 28 in the exon .", "sentence_char_start_global": 81118, "sentence_char_end_global": 81279, "entities": [], "entities_global": []}
+{"sentence_id": 542, "sentence_text": "The mutation destroyed an NdeI restriction enzyme site .", "sentence_char_start_global": 81280, "sentence_char_end_global": 81336, "entities": [], "entities_global": []}
+{"sentence_id": 543, "sentence_text": "Analysis of all family members demonstrated that the missense mutation co - segregated with patients with tumors or who , as a result of linkage analysis had been predicted to carry the predisposing mutation .", "sentence_char_start_global": 81337, "sentence_char_end_global": 81546, "entities": [{"text": "tumors", "type": "ENTITY", "char_start": 106, "char_end": 112, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "tumors", "type": "ENTITY", "char_start": 81443, "char_end": 81449, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 544, "sentence_text": "These observations point to another region of the RB1 gene where mutations only modify the function of the gene and raise important questions for genetic counseling in families with these distinctive phenotypes . .", "sentence_char_start_global": 81547, "sentence_char_end_global": 81761, "entities": [], "entities_global": []}
+{"sentence_id": 545, "sentence_text": "Maternal disomy and Prader - Willi syndrome consistent with gamete complementation in a case of familial translocation ( 3 ; 15 ) ( p25 ; q11 . 2 ) .", "sentence_char_start_global": 81762, "sentence_char_end_global": 81911, "entities": [{"text": "Maternal disomy", "type": "ENTITY", "char_start": 0, "char_end": 15, "token_start": 0, "token_end": 1}, {"text": "Prader - Willi syndrome", "type": "ENTITY", "char_start": 20, "char_end": 43, "token_start": 3, "token_end": 6}], "entities_global": [{"text": "Maternal disomy", "type": "ENTITY", "char_start": 81762, "char_end": 81777, "token_start": 0, "token_end": 1, "note": null}, {"text": "Prader - Willi syndrome", "type": "ENTITY", "char_start": 81782, "char_end": 81805, "token_start": 3, "token_end": 6, "note": null}]}
+{"sentence_id": 546, "sentence_text": "Maternal uniparental disomy ( UPD ) for chromosome 15 is responsible for an estimated 30 % of cases of Prader - Willi syndrome ( PWS ) .", "sentence_char_start_global": 81912, "sentence_char_end_global": 82048, "entities": [{"text": "Maternal uniparental disomy ( UPD ) for chromosome 15", "type": "ENTITY", "char_start": 0, "char_end": 53, "token_start": 0, "token_end": 8}, {"text": "Prader - Willi syndrome", "type": "ENTITY", "char_start": 103, "char_end": 126, "token_start": 19, "token_end": 22}, {"text": "PWS", "type": "ENTITY", "char_start": 129, "char_end": 132, "token_start": 24, "token_end": 24}], "entities_global": [{"text": "Maternal uniparental disomy ( UPD ) for chromosome 15", "type": "ENTITY", "char_start": 81912, "char_end": 81965, "token_start": 0, "token_end": 8, "note": null}, {"text": "Prader - Willi syndrome", "type": "ENTITY", "char_start": 82015, "char_end": 82038, "token_start": 19, "token_end": 22, "note": null}, {"text": "PWS", "type": "ENTITY", "char_start": 82041, "char_end": 82044, "token_start": 24, "token_end": 24, "note": null}]}
+{"sentence_id": 547, "sentence_text": "We report on an unusual case of maternal disomy 15 in PWS that is most consistent with adjacent - 1 segregation of a paternal t ( 3 ; 15 ) ( p25 ; q11 . 2 ) with simultaneous maternal meiotic nondisjunction for chromosome 15 .", "sentence_char_start_global": 82049, "sentence_char_end_global": 82275, "entities": [{"text": "maternal disomy 15", "type": "ENTITY", "char_start": 32, "char_end": 50, "token_start": 7, "token_end": 9}, {"text": "PWS", "type": "ENTITY", "char_start": 54, "char_end": 57, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "maternal disomy 15", "type": "ENTITY", "char_start": 82081, "char_end": 82099, "token_start": 7, "token_end": 9, "note": null}, {"text": "PWS", "type": "ENTITY", "char_start": 82103, "char_end": 82106, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 548, "sentence_text": "The patient ( J . B . ) , a 17 - year - old white male with PWS , was found to have 47 chromosomes with a supernumerary , paternal der ( 15 ) consisting of the short arm and the proximal long arm of chromosome 15 , and distal chromosome arm 3p .", "sentence_char_start_global": 82276, "sentence_char_end_global": 82521, "entities": [{"text": "PWS", "type": "ENTITY", "char_start": 60, "char_end": 63, "token_start": 18, "token_end": 18}], "entities_global": [{"text": "PWS", "type": "ENTITY", "char_start": 82336, "char_end": 82339, "token_start": 18, "token_end": 18, "note": null}]}
+{"sentence_id": 549, "sentence_text": "The t ( 3 ; 15 ) was present in the balanced state in the patients father and a sister .", "sentence_char_start_global": 82522, "sentence_char_end_global": 82610, "entities": [], "entities_global": []}
+{"sentence_id": 550, "sentence_text": "Fluorescent in situ hybridization analysis demonstrated that the PWS critical region resided on the derivative chromosome 3 and that there was no deletion of the PWS region on the normal pair of 15s present in J .", "sentence_char_start_global": 82611, "sentence_char_end_global": 82824, "entities": [{"text": "PWS", "type": "ENTITY", "char_start": 65, "char_end": 68, "token_start": 8, "token_end": 8}, {"text": "PWS", "type": "ENTITY", "char_start": 162, "char_end": 165, "token_start": 25, "token_end": 25}], "entities_global": [{"text": "PWS", "type": "ENTITY", "char_start": 82676, "char_end": 82679, "token_start": 8, "token_end": 8, "note": null}, {"text": "PWS", "type": "ENTITY", "char_start": 82773, "char_end": 82776, "token_start": 25, "token_end": 25, "note": null}]}
+{"sentence_id": 551, "sentence_text": "B .", "sentence_char_start_global": 82825, "sentence_char_end_global": 82828, "entities": [], "entities_global": []}
+{"sentence_id": 552, "sentence_text": "Methylation analysis at exon alpha of the small nuclear ribonucleoprotein - associated polypeptide N ( SNRPN ) gene showed a pattern characteristic of only the maternal chromosome 15 in J .", "sentence_char_start_global": 82829, "sentence_char_end_global": 83018, "entities": [], "entities_global": []}
+{"sentence_id": 553, "sentence_text": "B .", "sentence_char_start_global": 83019, "sentence_char_end_global": 83022, "entities": [], "entities_global": []}
+{"sentence_id": 554, "sentence_text": "Maternal disomy was confirmed by polymerase chain reaction analysis of microsatellite repeats at the gamma - aminobutyric acid receptor beta3 subunit ( GABRB3 ) locus .", "sentence_char_start_global": 83023, "sentence_char_end_global": 83191, "entities": [{"text": "Maternal disomy", "type": "ENTITY", "char_start": 0, "char_end": 15, "token_start": 0, "token_end": 1}], "entities_global": [{"text": "Maternal disomy", "type": "ENTITY", "char_start": 83023, "char_end": 83038, "token_start": 0, "token_end": 1, "note": null}]}
+{"sentence_id": 555, "sentence_text": "A niece ( B . B . ) with 45 chromosomes and the derivative 3 but without the der ( 15 ) demonstrated a phenotype consistent with that reported for haploinsufficiency of distal 3 p .", "sentence_char_start_global": 83192, "sentence_char_end_global": 83373, "entities": [], "entities_global": []}
+{"sentence_id": 556, "sentence_text": "Uniparental disomy associated with unbalanced segregation of non - Robertsonian translocations has been reported previously but has not , to our knowledge , been observed in a case of PWS .", "sentence_char_start_global": 83374, "sentence_char_end_global": 83563, "entities": [{"text": "Uniparental disomy", "type": "ENTITY", "char_start": 0, "char_end": 18, "token_start": 0, "token_end": 1}, {"text": "PWS", "type": "ENTITY", "char_start": 184, "char_end": 187, "token_start": 29, "token_end": 29}], "entities_global": [{"text": "Uniparental disomy", "type": "ENTITY", "char_start": 83374, "char_end": 83392, "token_start": 0, "token_end": 1, "note": null}, {"text": "PWS", "type": "ENTITY", "char_start": 83558, "char_end": 83561, "token_start": 29, "token_end": 29, "note": null}]}
+{"sentence_id": 557, "sentence_text": "Furthermore , our findings are best interpreted as true gamete complementation resulting in maternal UPD 15 and PWS", "sentence_char_start_global": 83564, "sentence_char_end_global": 83679, "entities": [{"text": "maternal UPD 15", "type": "ENTITY", "char_start": 92, "char_end": 107, "token_start": 13, "token_end": 15}, {"text": "PWS", "type": "ENTITY", "char_start": 112, "char_end": 115, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "maternal UPD 15", "type": "ENTITY", "char_start": 83656, "char_end": 83671, "token_start": 13, "token_end": 15, "note": null}, {"text": "PWS", "type": "ENTITY", "char_start": 83676, "char_end": 83679, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 558, "sentence_text": "Schwartz - Jampel syndrome type 2 and Stuve - Wiedemann syndrome : a case for \" lumping \" .", "sentence_char_start_global": 83680, "sentence_char_end_global": 83771, "entities": [{"text": "Schwartz - Jampel syndrome type 2", "type": "ENTITY", "char_start": 0, "char_end": 33, "token_start": 0, "token_end": 5}, {"text": "Stuve - Wiedemann syndrome", "type": "ENTITY", "char_start": 38, "char_end": 64, "token_start": 7, "token_end": 10}], "entities_global": [{"text": "Schwartz - Jampel syndrome type 2", "type": "ENTITY", "char_start": 83680, "char_end": 83713, "token_start": 0, "token_end": 5, "note": null}, {"text": "Stuve - Wiedemann syndrome", "type": "ENTITY", "char_start": 83718, "char_end": 83744, "token_start": 7, "token_end": 10, "note": null}]}
+{"sentence_id": 559, "sentence_text": "Recent studies demonstrated the existence of a genetically distinct , usually lethal form of the Schwartz - Jampel syndrome ( SJS ) of myotonia and skeletal dysplasia , which we called SJS type 2 .", "sentence_char_start_global": 83772, "sentence_char_end_global": 83969, "entities": [{"text": "Schwartz - Jampel syndrome", "type": "ENTITY", "char_start": 97, "char_end": 123, "token_start": 15, "token_end": 18}, {"text": "SJS", "type": "ENTITY", "char_start": 126, "char_end": 129, "token_start": 20, "token_end": 20}, {"text": "myotonia", "type": "ENTITY", "char_start": 135, "char_end": 143, "token_start": 23, "token_end": 23}, {"text": "skeletal dysplasia", "type": "ENTITY", "char_start": 148, "char_end": 166, "token_start": 25, "token_end": 26}, {"text": "SJS type 2", "type": "ENTITY", "char_start": 185, "char_end": 195, "token_start": 31, "token_end": 33}], "entities_global": [{"text": "Schwartz - Jampel syndrome", "type": "ENTITY", "char_start": 83869, "char_end": 83895, "token_start": 15, "token_end": 18, "note": null}, {"text": "SJS", "type": "ENTITY", "char_start": 83898, "char_end": 83901, "token_start": 20, "token_end": 20, "note": null}, {"text": "myotonia", "type": "ENTITY", "char_start": 83907, "char_end": 83915, "token_start": 23, "token_end": 23, "note": null}, {"text": "skeletal dysplasia", "type": "ENTITY", "char_start": 83920, "char_end": 83938, "token_start": 25, "token_end": 26, "note": null}, {"text": "SJS type 2", "type": "ENTITY", "char_start": 83957, "char_end": 83967, "token_start": 31, "token_end": 33, "note": null}]}
+{"sentence_id": 560, "sentence_text": "This disorder is reminiscent of another rare condition , the Stuve - Wiedemann syndrome ( SWS ) , which comprises campomelia at birth with skeletal dysplasia , contractures , and early death .", "sentence_char_start_global": 83970, "sentence_char_end_global": 84162, "entities": [{"text": "Stuve - Wiedemann syndrome", "type": "ENTITY", "char_start": 61, "char_end": 87, "token_start": 10, "token_end": 13}, {"text": "SWS", "type": "ENTITY", "char_start": 90, "char_end": 93, "token_start": 15, "token_end": 15}, {"text": "campomelia", "type": "ENTITY", "char_start": 114, "char_end": 124, "token_start": 20, "token_end": 20}, {"text": "skeletal dysplasia", "type": "ENTITY", "char_start": 139, "char_end": 157, "token_start": 24, "token_end": 25}, {"text": "contractures", "type": "ENTITY", "char_start": 160, "char_end": 172, "token_start": 27, "token_end": 27}, {"text": "early death", "type": "ENTITY", "char_start": 179, "char_end": 190, "token_start": 30, "token_end": 31}], "entities_global": [{"text": "Stuve - Wiedemann syndrome", "type": "ENTITY", "char_start": 84031, "char_end": 84057, "token_start": 10, "token_end": 13, "note": null}, {"text": "SWS", "type": "ENTITY", "char_start": 84060, "char_end": 84063, "token_start": 15, "token_end": 15, "note": null}, {"text": "campomelia", "type": "ENTITY", "char_start": 84084, "char_end": 84094, "token_start": 20, "token_end": 20, "note": null}, {"text": "skeletal dysplasia", "type": "ENTITY", "char_start": 84109, "char_end": 84127, "token_start": 24, "token_end": 25, "note": null}, {"text": "contractures", "type": "ENTITY", "char_start": 84130, "char_end": 84142, "token_start": 27, "token_end": 27, "note": null}, {"text": "early death", "type": "ENTITY", "char_start": 84149, "char_end": 84160, "token_start": 30, "token_end": 31, "note": null}]}
+{"sentence_id": 561, "sentence_text": "To test for possible nosologic identity between these disorders , we reviewed the literature and obtained a follow - up of the only two surviving patients , one with SJS type 2 at age 10 years and another with SWS at age 7 years .", "sentence_char_start_global": 84163, "sentence_char_end_global": 84393, "entities": [{"text": "SJS type 2", "type": "ENTITY", "char_start": 166, "char_end": 176, "token_start": 29, "token_end": 31}, {"text": "SWS", "type": "ENTITY", "char_start": 210, "char_end": 213, "token_start": 39, "token_end": 39}], "entities_global": [{"text": "SJS type 2", "type": "ENTITY", "char_start": 84329, "char_end": 84339, "token_start": 29, "token_end": 31, "note": null}, {"text": "SWS", "type": "ENTITY", "char_start": 84373, "char_end": 84376, "token_start": 39, "token_end": 39, "note": null}]}
+{"sentence_id": 562, "sentence_text": "Patients reported as having either neonatal SJS or SWS presented a combination of a severe , prenatal - onset neuromuscular disorder ( with congenital joint contractures , respiratory and feeding difficulties , tendency to hyperthermia , and frequent death in infancy ) with a distinct campomelic - metaphyseal skeletal dysplasia .", "sentence_char_start_global": 84394, "sentence_char_end_global": 84725, "entities": [{"text": "SJS", "type": "ENTITY", "char_start": 44, "char_end": 47, "token_start": 6, "token_end": 6}, {"text": "SWS", "type": "ENTITY", "char_start": 51, "char_end": 54, "token_start": 8, "token_end": 8}, {"text": "neuromuscular disorder", "type": "ENTITY", "char_start": 110, "char_end": 132, "token_start": 19, "token_end": 20}, {"text": "congenital joint contractures", "type": "ENTITY", "char_start": 140, "char_end": 169, "token_start": 23, "token_end": 25}, {"text": "hyperthermia", "type": "ENTITY", "char_start": 223, "char_end": 235, "token_start": 34, "token_end": 34}, {"text": "campomelic - metaphyseal skeletal dysplasia", "type": "ENTITY", "char_start": 286, "char_end": 329, "token_start": 45, "token_end": 49}], "entities_global": [{"text": "SJS", "type": "ENTITY", "char_start": 84438, "char_end": 84441, "token_start": 6, "token_end": 6, "note": null}, {"text": "SWS", "type": "ENTITY", "char_start": 84445, "char_end": 84448, "token_start": 8, "token_end": 8, "note": null}, {"text": "neuromuscular disorder", "type": "ENTITY", "char_start": 84504, "char_end": 84526, "token_start": 19, "token_end": 20, "note": null}, {"text": "congenital joint contractures", "type": "ENTITY", "char_start": 84534, "char_end": 84563, "token_start": 23, "token_end": 25, "note": null}, {"text": "hyperthermia", "type": "ENTITY", "char_start": 84617, "char_end": 84629, "token_start": 34, "token_end": 34, "note": null}, {"text": "campomelic - metaphyseal skeletal dysplasia", "type": "ENTITY", "char_start": 84680, "char_end": 84723, "token_start": 45, "token_end": 49, "note": null}]}
+{"sentence_id": 563, "sentence_text": "The similarity of the clinical and radiographic findings is so extensive that these disorders appear to be a single entity .", "sentence_char_start_global": 84726, "sentence_char_end_global": 84850, "entities": [], "entities_global": []}
+{"sentence_id": 564, "sentence_text": "The follow - up observation of an identical and unique pattern of progressive bone dysplasia in the two patients ( one with SJS type 2 , one with SWS ) surviving beyond infancy adds to the evidence in favor of identity .", "sentence_char_start_global": 84851, "sentence_char_end_global": 85071, "entities": [{"text": "bone dysplasia", "type": "ENTITY", "char_start": 78, "char_end": 92, "token_start": 13, "token_end": 14}, {"text": "SJS type 2", "type": "ENTITY", "char_start": 124, "char_end": 134, "token_start": 22, "token_end": 24}, {"text": "SWS", "type": "ENTITY", "char_start": 146, "char_end": 149, "token_start": 28, "token_end": 28}], "entities_global": [{"text": "bone dysplasia", "type": "ENTITY", "char_start": 84929, "char_end": 84943, "token_start": 13, "token_end": 14, "note": null}, {"text": "SJS type 2", "type": "ENTITY", "char_start": 84975, "char_end": 84985, "token_start": 22, "token_end": 24, "note": null}, {"text": "SWS", "type": "ENTITY", "char_start": 84997, "char_end": 85000, "token_start": 28, "token_end": 28, "note": null}]}
+{"sentence_id": 565, "sentence_text": "The hypothesis that SWS and SJS type 2 are the same disorder should be testable by molecular methods . .", "sentence_char_start_global": 85072, "sentence_char_end_global": 85176, "entities": [{"text": "SWS", "type": "ENTITY", "char_start": 20, "char_end": 23, "token_start": 3, "token_end": 3}, {"text": "SJS type 2", "type": "ENTITY", "char_start": 28, "char_end": 38, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "SWS", "type": "ENTITY", "char_start": 85092, "char_end": 85095, "token_start": 3, "token_end": 3, "note": null}, {"text": "SJS type 2", "type": "ENTITY", "char_start": 85100, "char_end": 85110, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 566, "sentence_text": "A mouse model of severe von Willebrand disease : defects in hemostasis and thrombosis .", "sentence_char_start_global": 85177, "sentence_char_end_global": 85264, "entities": [{"text": "von Willebrand disease", "type": "ENTITY", "char_start": 24, "char_end": 46, "token_start": 5, "token_end": 7}, {"text": "thrombosis", "type": "ENTITY", "char_start": 75, "char_end": 85, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "von Willebrand disease", "type": "ENTITY", "char_start": 85201, "char_end": 85223, "token_start": 5, "token_end": 7, "note": null}, {"text": "thrombosis", "type": "ENTITY", "char_start": 85252, "char_end": 85262, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 567, "sentence_text": "von Willebrand factor ( vWf ) deficiency causes severe von Willebrand disease in humans .", "sentence_char_start_global": 85265, "sentence_char_end_global": 85354, "entities": [{"text": "von Willebrand factor ( vWf ) deficiency", "type": "ENTITY", "char_start": 0, "char_end": 40, "token_start": 0, "token_end": 6}, {"text": "von Willebrand disease", "type": "ENTITY", "char_start": 55, "char_end": 77, "token_start": 9, "token_end": 11}], "entities_global": [{"text": "von Willebrand factor ( vWf ) deficiency", "type": "ENTITY", "char_start": 85265, "char_end": 85305, "token_start": 0, "token_end": 6, "note": null}, {"text": "von Willebrand disease", "type": "ENTITY", "char_start": 85320, "char_end": 85342, "token_start": 9, "token_end": 11, "note": null}]}
+{"sentence_id": 568, "sentence_text": "We generated a mouse model for this disease by using gene targeting .", "sentence_char_start_global": 85355, "sentence_char_end_global": 85424, "entities": [], "entities_global": []}
+{"sentence_id": 569, "sentence_text": "vWf - deficient mice appeared normal at birth ; they were viable and fertile .", "sentence_char_start_global": 85425, "sentence_char_end_global": 85503, "entities": [{"text": "vWf - deficient", "type": "ENTITY", "char_start": 0, "char_end": 15, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "vWf - deficient", "type": "ENTITY", "char_start": 85425, "char_end": 85440, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 570, "sentence_text": "Neither vWf nor vWf propolypeptide ( von Willebrand antigen II ) were detectable in plasma , platelets , or endothelial cells of the homozygous mutant mice .", "sentence_char_start_global": 85504, "sentence_char_end_global": 85661, "entities": [{"text": "von Willebrand", "type": "ENTITY", "char_start": 37, "char_end": 51, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "von Willebrand", "type": "ENTITY", "char_start": 85541, "char_end": 85555, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 571, "sentence_text": "The mutant mice exhibited defects in hemostasis with a highly prolonged bleeding time and spontaneous bleeding events in approximately 10 % of neonates .", "sentence_char_start_global": 85662, "sentence_char_end_global": 85815, "entities": [], "entities_global": []}
+{"sentence_id": 572, "sentence_text": "As in the human disease , the factor VIII level in these mice was reduced strongly as a result of the lack of protection provided by vWf .", "sentence_char_start_global": 85816, "sentence_char_end_global": 85954, "entities": [], "entities_global": []}
+{"sentence_id": 573, "sentence_text": "Defective thrombosis in mutant mice was also evident in an in vivo model of vascular injury .", "sentence_char_start_global": 85955, "sentence_char_end_global": 86048, "entities": [{"text": "thrombosis", "type": "ENTITY", "char_start": 10, "char_end": 20, "token_start": 1, "token_end": 1}, {"text": "vascular injury", "type": "ENTITY", "char_start": 76, "char_end": 91, "token_start": 14, "token_end": 15}], "entities_global": [{"text": "thrombosis", "type": "ENTITY", "char_start": 85965, "char_end": 85975, "token_start": 1, "token_end": 1, "note": null}, {"text": "vascular injury", "type": "ENTITY", "char_start": 86031, "char_end": 86046, "token_start": 14, "token_end": 15, "note": null}]}
+{"sentence_id": 574, "sentence_text": "In this model , the exteriorized mesentery was superfused with ferric chloride and the accumulation of fluorescently labeled platelets was observed by intravital microscopy .", "sentence_char_start_global": 86049, "sentence_char_end_global": 86223, "entities": [], "entities_global": []}
+{"sentence_id": 575, "sentence_text": "We conclude that these mice very closely mimic severe human von Willebrand disease and will be very useful for investigating the role of vWf in normal physiology and in disease models . .", "sentence_char_start_global": 86224, "sentence_char_end_global": 86411, "entities": [{"text": "von Willebrand disease", "type": "ENTITY", "char_start": 60, "char_end": 82, "token_start": 10, "token_end": 12}], "entities_global": [{"text": "von Willebrand disease", "type": "ENTITY", "char_start": 86284, "char_end": 86306, "token_start": 10, "token_end": 12, "note": null}]}
+{"sentence_id": 576, "sentence_text": "Oral contraceptives and the risk of hereditary ovarian cancer .", "sentence_char_start_global": 86412, "sentence_char_end_global": 86475, "entities": [{"text": "hereditary ovarian cancer", "type": "ENTITY", "char_start": 36, "char_end": 61, "token_start": 6, "token_end": 8}], "entities_global": [{"text": "hereditary ovarian cancer", "type": "ENTITY", "char_start": 86448, "char_end": 86473, "token_start": 6, "token_end": 8, "note": null}]}
+{"sentence_id": 577, "sentence_text": "Hereditary Ovarian Cancer Clinical Study Group .", "sentence_char_start_global": 86476, "sentence_char_end_global": 86524, "entities": [{"text": "Hereditary Ovarian Cancer", "type": "ENTITY", "char_start": 0, "char_end": 25, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "Hereditary Ovarian Cancer", "type": "ENTITY", "char_start": 86476, "char_end": 86501, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 578, "sentence_text": "BACKGROUND Women with mutations in either the BRCA1 or the BRCA2 gene have a high lifetime risk of ovarian cancer .", "sentence_char_start_global": 86525, "sentence_char_end_global": 86640, "entities": [{"text": "ovarian cancer", "type": "ENTITY", "char_start": 99, "char_end": 113, "token_start": 18, "token_end": 19}], "entities_global": [{"text": "ovarian cancer", "type": "ENTITY", "char_start": 86624, "char_end": 86638, "token_start": 18, "token_end": 19, "note": null}]}
+{"sentence_id": 579, "sentence_text": "Oral contraceptives protect against ovarian cancer in general , but it is not known whether they also protect against hereditary forms of ovarian cancer .", "sentence_char_start_global": 86641, "sentence_char_end_global": 86795, "entities": [{"text": "ovarian cancer", "type": "ENTITY", "char_start": 36, "char_end": 50, "token_start": 4, "token_end": 5}, {"text": "hereditary forms of ovarian cancer", "type": "ENTITY", "char_start": 118, "char_end": 152, "token_start": 19, "token_end": 23}], "entities_global": [{"text": "ovarian cancer", "type": "ENTITY", "char_start": 86677, "char_end": 86691, "token_start": 4, "token_end": 5, "note": null}, {"text": "hereditary forms of ovarian cancer", "type": "ENTITY", "char_start": 86759, "char_end": 86793, "token_start": 19, "token_end": 23, "note": null}]}
+{"sentence_id": 580, "sentence_text": "METHODS We enrolled 207 women with hereditary ovarian cancer and 161 of their sisters as controls in a case - control study .", "sentence_char_start_global": 86796, "sentence_char_end_global": 86921, "entities": [{"text": "hereditary ovarian cancer", "type": "ENTITY", "char_start": 35, "char_end": 60, "token_start": 6, "token_end": 8}], "entities_global": [{"text": "hereditary ovarian cancer", "type": "ENTITY", "char_start": 86831, "char_end": 86856, "token_start": 6, "token_end": 8, "note": null}]}
+{"sentence_id": 581, "sentence_text": "All the patients carried a pathogenic mutation in either BRCA1 ( 179 women ) or BRCA2 ( 28 women ) .", "sentence_char_start_global": 86922, "sentence_char_end_global": 87022, "entities": [], "entities_global": []}
+{"sentence_id": 582, "sentence_text": "The control women were enrolled regardless of whether or not they had either mutation .", "sentence_char_start_global": 87023, "sentence_char_end_global": 87110, "entities": [], "entities_global": []}
+{"sentence_id": 583, "sentence_text": "Lifetime histories of oral - contraceptive use were obtained by interview or by written questionnaire and were compared between patients and control women , after adjustment for year of birth and parity .", "sentence_char_start_global": 87111, "sentence_char_end_global": 87315, "entities": [], "entities_global": []}
+{"sentence_id": 584, "sentence_text": "RESULTS The adjusted odds ratio for ovarian cancer associated with any past use of oral contraceptives was 0 .", "sentence_char_start_global": 87316, "sentence_char_end_global": 87426, "entities": [{"text": "ovarian cancer", "type": "ENTITY", "char_start": 36, "char_end": 50, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "ovarian cancer", "type": "ENTITY", "char_start": 87352, "char_end": 87366, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 585, "sentence_text": "5 ( 95 percent confidence interval , 0 . 3 to 0 . 8 ) .", "sentence_char_start_global": 87427, "sentence_char_end_global": 87482, "entities": [], "entities_global": []}
+{"sentence_id": 586, "sentence_text": "The risk decreased with increasing duration of use ( P for trend , < 0 . 001 ) ; use for six or more years was associated with a 60 percent reduction in risk .", "sentence_char_start_global": 87483, "sentence_char_end_global": 87642, "entities": [], "entities_global": []}
+{"sentence_id": 587, "sentence_text": "Oral - contraceptive use protected against ovarian cancer both for carriers of the BRCA1 mutation ( odds ratio , 0 . 5 ; 95 percent confidence interval , 0 . 3 to 0 . 9 ) and for carriers of the BRCA2 mutation ( odds ratio , 0 . 4 ; 95 percent confidence interval , 0 . 2 to 1 . 1 ) .", "sentence_char_start_global": 87643, "sentence_char_end_global": 87927, "entities": [{"text": "ovarian cancer", "type": "ENTITY", "char_start": 43, "char_end": 57, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "ovarian cancer", "type": "ENTITY", "char_start": 87686, "char_end": 87700, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 588, "sentence_text": "CONCLUSIONS Oral - contraceptive use may reduce the risk of ovarian cancer in women with pathogenic mutations in the BRCA1 or BRCA2 gene", "sentence_char_start_global": 87928, "sentence_char_end_global": 88064, "entities": [{"text": "ovarian cancer", "type": "ENTITY", "char_start": 60, "char_end": 74, "token_start": 10, "token_end": 11}], "entities_global": [{"text": "ovarian cancer", "type": "ENTITY", "char_start": 87988, "char_end": 88002, "token_start": 10, "token_end": 11, "note": null}]}
+{"sentence_id": 589, "sentence_text": "A Japanese family with adrenoleukodystrophy with a codon 291 deletion : a clinical , biochemical , pathological , and genetic report .", "sentence_char_start_global": 88065, "sentence_char_end_global": 88199, "entities": [{"text": "adrenoleukodystrophy", "type": "ENTITY", "char_start": 23, "char_end": 43, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "adrenoleukodystrophy", "type": "ENTITY", "char_start": 88088, "char_end": 88108, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 590, "sentence_text": "We report a Japanese family with adrenoleukodystrophy ( ALD ) with a three base pair deletion ( delGAG 291 ) in the ALD gene .", "sentence_char_start_global": 88200, "sentence_char_end_global": 88326, "entities": [{"text": "adrenoleukodystrophy", "type": "ENTITY", "char_start": 33, "char_end": 53, "token_start": 6, "token_end": 6}, {"text": "ALD", "type": "ENTITY", "char_start": 56, "char_end": 59, "token_start": 8, "token_end": 8}, {"text": "ALD", "type": "ENTITY", "char_start": 116, "char_end": 119, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "adrenoleukodystrophy", "type": "ENTITY", "char_start": 88233, "char_end": 88253, "token_start": 6, "token_end": 6, "note": null}, {"text": "ALD", "type": "ENTITY", "char_start": 88256, "char_end": 88259, "token_start": 8, "token_end": 8, "note": null}, {"text": "ALD", "type": "ENTITY", "char_start": 88316, "char_end": 88319, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 591, "sentence_text": "A variety of phenotypes were observed within this family .", "sentence_char_start_global": 88327, "sentence_char_end_global": 88385, "entities": [], "entities_global": []}
+{"sentence_id": 592, "sentence_text": "While the proband ( patient 1 ) was classified as having a rare intermediate type of adult cerebral and cerebello - brain stem forms , his younger brother ( patient 2 ) and nephew ( patient 3 ) had a childhood ALD type .", "sentence_char_start_global": 88386, "sentence_char_end_global": 88606, "entities": [{"text": "ALD", "type": "ENTITY", "char_start": 210, "char_end": 213, "token_start": 41, "token_end": 41}], "entities_global": [{"text": "ALD", "type": "ENTITY", "char_start": 88596, "char_end": 88599, "token_start": 41, "token_end": 41, "note": null}]}
+{"sentence_id": 593, "sentence_text": "Another nephew ( patient 4 ) of patient 1 was classified as having an adolescent form .", "sentence_char_start_global": 88607, "sentence_char_end_global": 88694, "entities": [], "entities_global": []}
+{"sentence_id": 594, "sentence_text": "The tau level in the cerebrospinal fluid ( CSF ) in patient 1 was as high as that of patients with Alzheimers disease ( AD ) .", "sentence_char_start_global": 88695, "sentence_char_end_global": 88821, "entities": [{"text": "Alzheimers disease", "type": "ENTITY", "char_start": 99, "char_end": 117, "token_start": 21, "token_end": 22}, {"text": "AD", "type": "ENTITY", "char_start": 120, "char_end": 122, "token_start": 24, "token_end": 24}], "entities_global": [{"text": "Alzheimers disease", "type": "ENTITY", "char_start": 88794, "char_end": 88812, "token_start": 21, "token_end": 22, "note": null}, {"text": "AD", "type": "ENTITY", "char_start": 88815, "char_end": 88817, "token_start": 24, "token_end": 24, "note": null}]}
+{"sentence_id": 595, "sentence_text": "His brain magnetic resonance image ( MRI ) showed abnormalities in the bilateral cerebellar hemispheres and brain stem , but not in the cerebral white matter , where marked reductions of the cerebral blood flow and oxygen metabolism were clearly demonstrated by positron emission tomography ( PET ) .", "sentence_char_start_global": 88822, "sentence_char_end_global": 89122, "entities": [{"text": "abnormalities in the bilateral cerebellar hemispheres", "type": "ENTITY", "char_start": 50, "char_end": 103, "token_start": 9, "token_end": 14}], "entities_global": [{"text": "abnormalities in the bilateral cerebellar hemispheres", "type": "ENTITY", "char_start": 88872, "char_end": 88925, "token_start": 9, "token_end": 14, "note": null}]}
+{"sentence_id": 596, "sentence_text": "In patients 2 and 3 , the autopsy findings showed massive demyelination of the cerebral white matter with sparing of the U - fibers , compatible with the findings of childhood ALD .", "sentence_char_start_global": 89123, "sentence_char_end_global": 89304, "entities": [{"text": "demyelination of the cerebral white matter", "type": "ENTITY", "char_start": 58, "char_end": 100, "token_start": 11, "token_end": 16}, {"text": "ALD", "type": "ENTITY", "char_start": 176, "char_end": 179, "token_start": 31, "token_end": 31}], "entities_global": [{"text": "demyelination of the cerebral white matter", "type": "ENTITY", "char_start": 89181, "char_end": 89223, "token_start": 11, "token_end": 16, "note": null}, {"text": "ALD", "type": "ENTITY", "char_start": 89299, "char_end": 89302, "token_start": 31, "token_end": 31, "note": null}]}
+{"sentence_id": 597, "sentence_text": "Oleic and erucic acids ( Lorenzos Oil ) were administered to patients 1 and 4 , but sufficient effectiveness was not obtained .", "sentence_char_start_global": 89305, "sentence_char_end_global": 89432, "entities": [], "entities_global": []}
+{"sentence_id": 598, "sentence_text": "The findings in this family suggest that delGAG291 is part of the cause of Japanese ALD with phenotypic variations .", "sentence_char_start_global": 89433, "sentence_char_end_global": 89549, "entities": [{"text": "ALD", "type": "ENTITY", "char_start": 84, "char_end": 87, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "ALD", "type": "ENTITY", "char_start": 89517, "char_end": 89520, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 599, "sentence_text": "Moreover , although the scale of the study is limited , there is a possibility that PET can detect an insidious lesion which is undetectable by computed tomogram ( CT ) or MRI analysis , and that the higher level of tau reflects the process of neuronal degeneration in ALD .", "sentence_char_start_global": 89550, "sentence_char_end_global": 89824, "entities": [{"text": "insidious lesion", "type": "ENTITY", "char_start": 102, "char_end": 118, "token_start": 20, "token_end": 21}, {"text": "neuronal degeneration", "type": "ENTITY", "char_start": 244, "char_end": 265, "token_start": 46, "token_end": 47}, {"text": "ALD", "type": "ENTITY", "char_start": 269, "char_end": 272, "token_start": 49, "token_end": 49}], "entities_global": [{"text": "insidious lesion", "type": "ENTITY", "char_start": 89652, "char_end": 89668, "token_start": 20, "token_end": 21, "note": null}, {"text": "neuronal degeneration", "type": "ENTITY", "char_start": 89794, "char_end": 89815, "token_start": 46, "token_end": 47, "note": null}, {"text": "ALD", "type": "ENTITY", "char_start": 89819, "char_end": 89822, "token_start": 49, "token_end": 49, "note": null}]}
+{"sentence_id": 600, "sentence_text": "Lorenzos Oil should be given in the early stage . .", "sentence_char_start_global": 89825, "sentence_char_end_global": 89876, "entities": [], "entities_global": []}
+{"sentence_id": 601, "sentence_text": "Nonsense mutation in exon 4 of human complement C9 gene is the major cause of Japanese complement C9 deficiency .", "sentence_char_start_global": 89877, "sentence_char_end_global": 89990, "entities": [{"text": "complement C9 deficiency", "type": "ENTITY", "char_start": 87, "char_end": 111, "token_start": 16, "token_end": 18}], "entities_global": [{"text": "complement C9 deficiency", "type": "ENTITY", "char_start": 89964, "char_end": 89988, "token_start": 16, "token_end": 18, "note": null}]}
+{"sentence_id": 602, "sentence_text": "Deficiency of the ninth component of human complement ( C9 ) is the most common complement deficiency in Japan but is rare in other countries .", "sentence_char_start_global": 89991, "sentence_char_end_global": 90134, "entities": [{"text": "Deficiency of the ninth component of human complement", "type": "ENTITY", "char_start": 0, "char_end": 53, "token_start": 0, "token_end": 7}, {"text": "complement deficiency", "type": "ENTITY", "char_start": 80, "char_end": 101, "token_start": 15, "token_end": 16}], "entities_global": [{"text": "Deficiency of the ninth component of human complement", "type": "ENTITY", "char_start": 89991, "char_end": 90044, "token_start": 0, "token_end": 7, "note": null}, {"text": "complement deficiency", "type": "ENTITY", "char_start": 90071, "char_end": 90092, "token_start": 15, "token_end": 16, "note": null}]}
+{"sentence_id": 603, "sentence_text": "We studied the molecular basis of C9 deficiency in four Japanese C9 - deficient patients who had suffered from meningococcal meningitis .", "sentence_char_start_global": 90135, "sentence_char_end_global": 90272, "entities": [{"text": "C9 deficiency", "type": "ENTITY", "char_start": 34, "char_end": 47, "token_start": 6, "token_end": 7}, {"text": "C9 - deficient", "type": "ENTITY", "char_start": 65, "char_end": 79, "token_start": 11, "token_end": 13}, {"text": "meningococcal meningitis", "type": "ENTITY", "char_start": 111, "char_end": 135, "token_start": 19, "token_end": 20}], "entities_global": [{"text": "C9 deficiency", "type": "ENTITY", "char_start": 90169, "char_end": 90182, "token_start": 6, "token_end": 7, "note": null}, {"text": "C9 - deficient", "type": "ENTITY", "char_start": 90200, "char_end": 90214, "token_start": 11, "token_end": 13, "note": null}, {"text": "meningococcal meningitis", "type": "ENTITY", "char_start": 90246, "char_end": 90270, "token_start": 19, "token_end": 20, "note": null}]}
+{"sentence_id": 604, "sentence_text": "Direct sequencing of amplified C9 cDNA and DNA revealed a nonsense substitution ( CGA - - > TGA ) at codon 95 in exon 4 in the four C9 - deficient individuals .", "sentence_char_start_global": 90273, "sentence_char_end_global": 90433, "entities": [{"text": "C9 - deficient", "type": "ENTITY", "char_start": 132, "char_end": 146, "token_start": 28, "token_end": 30}], "entities_global": [{"text": "C9 - deficient", "type": "ENTITY", "char_start": 90405, "char_end": 90419, "token_start": 28, "token_end": 30, "note": null}]}
+{"sentence_id": 605, "sentence_text": "An allele - specific polymerase chain reaction system designed to detect exclusively only one of the normal and mutant alleles indicated that all the four patients were homozygous for the mutation in exon 4 and that the parents of patient 2 were heterozygous .", "sentence_char_start_global": 90434, "sentence_char_end_global": 90694, "entities": [], "entities_global": []}
+{"sentence_id": 606, "sentence_text": "The common mutation at codon 95 in exon 4 might be responsible for most Japanese C9 deficiency . .", "sentence_char_start_global": 90695, "sentence_char_end_global": 90793, "entities": [{"text": "C9 deficiency", "type": "ENTITY", "char_start": 81, "char_end": 94, "token_start": 15, "token_end": 16}], "entities_global": [{"text": "C9 deficiency", "type": "ENTITY", "char_start": 90776, "char_end": 90789, "token_start": 15, "token_end": 16, "note": null}]}
+{"sentence_id": 607, "sentence_text": "BRCA1 required for transcription - coupled repair of oxidative DNA damage .", "sentence_char_start_global": 90794, "sentence_char_end_global": 90869, "entities": [], "entities_global": []}
+{"sentence_id": 608, "sentence_text": "The breast and ovarian cancer susceptibility gene BRCA1 encodes a zinc finger protein of unknown function .", "sentence_char_start_global": 90870, "sentence_char_end_global": 90977, "entities": [{"text": "breast and ovarian cancer", "type": "ENTITY", "char_start": 4, "char_end": 29, "token_start": 1, "token_end": 4}], "entities_global": [{"text": "breast and ovarian cancer", "type": "ENTITY", "char_start": 90874, "char_end": 90899, "token_start": 1, "token_end": 4, "note": null}]}
+{"sentence_id": 609, "sentence_text": "Association of the BRCA1 protein with the DNA repair protein Rad51 and changes in the phosphorylation and cellular localization of the protein after exposure to DNA - damaging agents are consistent with a role for BRCA1 in DNA repair .", "sentence_char_start_global": 90978, "sentence_char_end_global": 91213, "entities": [], "entities_global": []}
+{"sentence_id": 610, "sentence_text": "Here , it is shown that mouse embryonic stem cells deficient in BRCA1 are defective in the ability to carry out transcription - coupled repair of oxidative DNA damage , and are hypersensitive to ionizing radiation and hydrogen peroxide .", "sentence_char_start_global": 91214, "sentence_char_end_global": 91451, "entities": [{"text": "deficient in BRCA1", "type": "ENTITY", "char_start": 51, "char_end": 69, "token_start": 10, "token_end": 12}], "entities_global": [{"text": "deficient in BRCA1", "type": "ENTITY", "char_start": 91265, "char_end": 91283, "token_start": 10, "token_end": 12, "note": null}]}
+{"sentence_id": 611, "sentence_text": "These results suggest that BRCA1 participates , directly or indirectly , in transcription - coupled repair of oxidative DNA damage . .", "sentence_char_start_global": 91452, "sentence_char_end_global": 91586, "entities": [], "entities_global": []}
+{"sentence_id": 612, "sentence_text": "Truncation mutations in the transactivation region of PAX6 result in dominant - negative mutants .", "sentence_char_start_global": 91587, "sentence_char_end_global": 91685, "entities": [], "entities_global": []}
+{"sentence_id": 613, "sentence_text": "PAX6 is a transcription factor with two DNA - binding domains ( paired box and homeobox ) and a proline - serine - threonine ( PST ) - rich transactivation domain .", "sentence_char_start_global": 91686, "sentence_char_end_global": 91850, "entities": [], "entities_global": []}
+{"sentence_id": 614, "sentence_text": "PAX6 regulates eye development in animals ranging from jellyfish to Drosophila to humans .", "sentence_char_start_global": 91851, "sentence_char_end_global": 91941, "entities": [], "entities_global": []}
+{"sentence_id": 615, "sentence_text": "Heterozygous mutations in the human PAX6 gene result in various phenotypes , including aniridia , Peters anomaly , autosomal dominant keratitis , and familial foveal dysplasia .", "sentence_char_start_global": 91942, "sentence_char_end_global": 92119, "entities": [{"text": "aniridia", "type": "ENTITY", "char_start": 87, "char_end": 95, "token_start": 13, "token_end": 13}, {"text": "Peters anomaly", "type": "ENTITY", "char_start": 98, "char_end": 112, "token_start": 15, "token_end": 16}, {"text": "autosomal dominant keratitis", "type": "ENTITY", "char_start": 115, "char_end": 143, "token_start": 18, "token_end": 20}, {"text": "familial foveal dysplasia", "type": "ENTITY", "char_start": 150, "char_end": 175, "token_start": 23, "token_end": 25}], "entities_global": [{"text": "aniridia", "type": "ENTITY", "char_start": 92029, "char_end": 92037, "token_start": 13, "token_end": 13, "note": null}, {"text": "Peters anomaly", "type": "ENTITY", "char_start": 92040, "char_end": 92054, "token_start": 15, "token_end": 16, "note": null}, {"text": "autosomal dominant keratitis", "type": "ENTITY", "char_start": 92057, "char_end": 92085, "token_start": 18, "token_end": 20, "note": null}, {"text": "familial foveal dysplasia", "type": "ENTITY", "char_start": 92092, "char_end": 92117, "token_start": 23, "token_end": 25, "note": null}]}
+{"sentence_id": 616, "sentence_text": "It is believed that the mutated allele of PAX6 produces an inactive protein and aniridia is caused due to genetic haploinsufficiency .", "sentence_char_start_global": 92120, "sentence_char_end_global": 92254, "entities": [{"text": "aniridia", "type": "ENTITY", "char_start": 80, "char_end": 88, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "aniridia", "type": "ENTITY", "char_start": 92200, "char_end": 92208, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 617, "sentence_text": "However , several truncation mutations have been found to occur in the C - terminal half of PAX6 in patients with Aniridia resulting in mutant proteins that retain the DNA - binding domains but have lost most of the transactivation domain .", "sentence_char_start_global": 92255, "sentence_char_end_global": 92495, "entities": [{"text": "Aniridia", "type": "ENTITY", "char_start": 114, "char_end": 122, "token_start": 21, "token_end": 21}], "entities_global": [{"text": "Aniridia", "type": "ENTITY", "char_start": 92369, "char_end": 92377, "token_start": 21, "token_end": 21, "note": null}]}
+{"sentence_id": 618, "sentence_text": "It is not clear whether such mutants really behave as loss - of - function mutants as predicted by haploinsufficiency .", "sentence_char_start_global": 92496, "sentence_char_end_global": 92615, "entities": [], "entities_global": []}
+{"sentence_id": 619, "sentence_text": "Contrary to this theory , our data showed that these mutants are dominant - negative in transient transfection assays when they are coexpressed with wild - type PAX6 .", "sentence_char_start_global": 92616, "sentence_char_end_global": 92783, "entities": [], "entities_global": []}
+{"sentence_id": 620, "sentence_text": "We found that the dominant - negative effects result from the enhanced DNA binding ability of these mutants .", "sentence_char_start_global": 92784, "sentence_char_end_global": 92893, "entities": [], "entities_global": []}
+{"sentence_id": 621, "sentence_text": "Kinetic studies of binding and dissociation revealed that various truncation mutants have 3 - 5 - fold higher affinity to various DNA - binding sites when compared with the wild - type PAX6 .", "sentence_char_start_global": 92894, "sentence_char_end_global": 93085, "entities": [], "entities_global": []}
+{"sentence_id": 622, "sentence_text": "These results provide a new insight into the role of mutant PAX6 in causing aniridia . .", "sentence_char_start_global": 93086, "sentence_char_end_global": 93174, "entities": [{"text": "aniridia", "type": "ENTITY", "char_start": 76, "char_end": 84, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "aniridia", "type": "ENTITY", "char_start": 93162, "char_end": 93170, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 623, "sentence_text": "Reversal of severe hypertrophic cardiomyopathy and excellent neuropsychologic outcome in very - long - chain acyl - coenzyme A dehydrogenase deficiency .", "sentence_char_start_global": 93175, "sentence_char_end_global": 93328, "entities": [{"text": "hypertrophic cardiomyopathy", "type": "ENTITY", "char_start": 19, "char_end": 46, "token_start": 3, "token_end": 4}, {"text": "very - long - chain acyl - coenzyme A dehydrogenase deficiency", "type": "ENTITY", "char_start": 89, "char_end": 151, "token_start": 10, "token_end": 20}], "entities_global": [{"text": "hypertrophic cardiomyopathy", "type": "ENTITY", "char_start": 93194, "char_end": 93221, "token_start": 3, "token_end": 4, "note": null}, {"text": "very - long - chain acyl - coenzyme A dehydrogenase deficiency", "type": "ENTITY", "char_start": 93264, "char_end": 93326, "token_start": 10, "token_end": 20, "note": null}]}
+{"sentence_id": 624, "sentence_text": "Very - long - chain acyl - coenzyme A dehydrogenase ( VLCAD ) deficiency is a disorder of fatty acid beta oxidation that reportedly has high rates of morbidity and mortality .", "sentence_char_start_global": 93329, "sentence_char_end_global": 93504, "entities": [{"text": "Very - long - chain acyl - coenzyme A dehydrogenase ( VLCAD ) deficiency", "type": "ENTITY", "char_start": 0, "char_end": 72, "token_start": 0, "token_end": 13}], "entities_global": [{"text": "Very - long - chain acyl - coenzyme A dehydrogenase ( VLCAD ) deficiency", "type": "ENTITY", "char_start": 93329, "char_end": 93401, "token_start": 0, "token_end": 13, "note": null}]}
+{"sentence_id": 625, "sentence_text": "We describe the outcome of a 5 - year - old girl with VLCAD deficiency who was first seen at 5 months of age with severe hypertrophic cardiomyopathy , hepatomegaly , encephalopathy , and hypotonia .", "sentence_char_start_global": 93505, "sentence_char_end_global": 93703, "entities": [{"text": "VLCAD deficiency", "type": "ENTITY", "char_start": 54, "char_end": 70, "token_start": 13, "token_end": 14}, {"text": "hypertrophic cardiomyopathy", "type": "ENTITY", "char_start": 121, "char_end": 148, "token_start": 26, "token_end": 27}, {"text": "hepatomegaly", "type": "ENTITY", "char_start": 151, "char_end": 163, "token_start": 29, "token_end": 29}, {"text": "encephalopathy", "type": "ENTITY", "char_start": 166, "char_end": 180, "token_start": 31, "token_end": 31}, {"text": "hypotonia", "type": "ENTITY", "char_start": 187, "char_end": 196, "token_start": 34, "token_end": 34}], "entities_global": [{"text": "VLCAD deficiency", "type": "ENTITY", "char_start": 93559, "char_end": 93575, "token_start": 13, "token_end": 14, "note": null}, {"text": "hypertrophic cardiomyopathy", "type": "ENTITY", "char_start": 93626, "char_end": 93653, "token_start": 26, "token_end": 27, "note": null}, {"text": "hepatomegaly", "type": "ENTITY", "char_start": 93656, "char_end": 93668, "token_start": 29, "token_end": 29, "note": null}, {"text": "encephalopathy", "type": "ENTITY", "char_start": 93671, "char_end": 93685, "token_start": 31, "token_end": 31, "note": null}, {"text": "hypotonia", "type": "ENTITY", "char_start": 93692, "char_end": 93701, "token_start": 34, "token_end": 34, "note": null}]}
+{"sentence_id": 626, "sentence_text": "Biochemical studies indicated VLCAD deficiency caused by a stable yet inactive enzyme .", "sentence_char_start_global": 93704, "sentence_char_end_global": 93791, "entities": [{"text": "VLCAD deficiency", "type": "ENTITY", "char_start": 30, "char_end": 46, "token_start": 3, "token_end": 4}], "entities_global": [{"text": "VLCAD deficiency", "type": "ENTITY", "char_start": 93734, "char_end": 93750, "token_start": 3, "token_end": 4, "note": null}]}
+{"sentence_id": 627, "sentence_text": "Molecular genetic analysis of her VLCAD gene revealed a T1372C ( F458L ) missense mutation and a 1668 ACAG 1669 splice site mutation .", "sentence_char_start_global": 93792, "sentence_char_end_global": 93926, "entities": [], "entities_global": []}
+{"sentence_id": 628, "sentence_text": "After initial treatment with intravenous glucose and carnitine , the patient has thrived on a low - fat diet supplemented with medium - chain triglyceride oil and carnitine and avoidance of fasting .", "sentence_char_start_global": 93927, "sentence_char_end_global": 94126, "entities": [], "entities_global": []}
+{"sentence_id": 629, "sentence_text": "Her ventricular hypertrophy resolved significantly over 1 year , and cognitively , she is in the superior range for age .", "sentence_char_start_global": 94127, "sentence_char_end_global": 94248, "entities": [], "entities_global": []}
+{"sentence_id": 630, "sentence_text": "Clinical recognition of VLCAD deficiency is important because it is one of the few directly treatable causes of cardiomyopathy in children . .", "sentence_char_start_global": 94249, "sentence_char_end_global": 94391, "entities": [{"text": "VLCAD deficiency", "type": "ENTITY", "char_start": 24, "char_end": 40, "token_start": 3, "token_end": 4}, {"text": "cardiomyopathy", "type": "ENTITY", "char_start": 112, "char_end": 126, "token_start": 18, "token_end": 18}], "entities_global": [{"text": "VLCAD deficiency", "type": "ENTITY", "char_start": 94273, "char_end": 94289, "token_start": 3, "token_end": 4, "note": null}, {"text": "cardiomyopathy", "type": "ENTITY", "char_start": 94361, "char_end": 94375, "token_start": 18, "token_end": 18, "note": null}]}
+{"sentence_id": 631, "sentence_text": "Cloning of a novel member of the low - density lipoprotein receptor family .", "sentence_char_start_global": 94392, "sentence_char_end_global": 94468, "entities": [], "entities_global": []}
+{"sentence_id": 632, "sentence_text": "A gene encoding a novel transmembrane protein was identified by DNA sequence analysis within the insulin - dependent diabetes mellitus ( IDDM ) locus IDDM4 on chromosome 11q13 .", "sentence_char_start_global": 94469, "sentence_char_end_global": 94646, "entities": [{"text": "insulin - dependent diabetes mellitus", "type": "ENTITY", "char_start": 97, "char_end": 134, "token_start": 15, "token_end": 19}, {"text": "IDDM", "type": "ENTITY", "char_start": 137, "char_end": 141, "token_start": 21, "token_end": 21}], "entities_global": [{"text": "insulin - dependent diabetes mellitus", "type": "ENTITY", "char_start": 94566, "char_end": 94603, "token_start": 15, "token_end": 19, "note": null}, {"text": "IDDM", "type": "ENTITY", "char_start": 94606, "char_end": 94610, "token_start": 21, "token_end": 21, "note": null}]}
+{"sentence_id": 633, "sentence_text": "Based on its chromosomal position , this gene is a candidate for conferring susceptibility to diabetes .", "sentence_char_start_global": 94647, "sentence_char_end_global": 94751, "entities": [{"text": "diabetes", "type": "ENTITY", "char_start": 94, "char_end": 102, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "diabetes", "type": "ENTITY", "char_start": 94741, "char_end": 94749, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 634, "sentence_text": "The gene , termed low - density lipoprotein receptor related protein 5 ( LRP5 ) , encodes a protein of 1615 amino acids that contains conserved modules which are characteristic of the low - density lipoprotein ( LDL ) receptor family .", "sentence_char_start_global": 94752, "sentence_char_end_global": 94987, "entities": [], "entities_global": []}
+{"sentence_id": 635, "sentence_text": "These modules include a putative signal peptide for protein export , four epidermal growth factor ( EGF ) repeats with associated spacer domains , three LDL - receptor ( LDLR ) repeats , a single transmembrane spanning domain , and a cytoplasmic domain .", "sentence_char_start_global": 94988, "sentence_char_end_global": 95242, "entities": [], "entities_global": []}
+{"sentence_id": 636, "sentence_text": "The encoded protein has a unique organization of EGF and LDLR repeats ; therefore , LRP5 likely represents a new category of the LDLR family .", "sentence_char_start_global": 95243, "sentence_char_end_global": 95385, "entities": [], "entities_global": []}
+{"sentence_id": 637, "sentence_text": "Both human and mouse LRP5 cDNAs have been isolated and the encoded mature proteins are 95 % identical , indicating a high degree of evolutionary conservation . .", "sentence_char_start_global": 95386, "sentence_char_end_global": 95547, "entities": [], "entities_global": []}
+{"sentence_id": 638, "sentence_text": "The APC variants I1307K and E1317Q are associated with colorectal tumors , but not always with a family history .", "sentence_char_start_global": 95548, "sentence_char_end_global": 95661, "entities": [{"text": "APC", "type": "ENTITY", "char_start": 4, "char_end": 7, "token_start": 1, "token_end": 1}, {"text": "colorectal tumors", "type": "ENTITY", "char_start": 55, "char_end": 72, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "APC", "type": "ENTITY", "char_start": 95552, "char_end": 95555, "token_start": 1, "token_end": 1, "note": null}, {"text": "colorectal tumors", "type": "ENTITY", "char_start": 95603, "char_end": 95620, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 639, "sentence_text": "Classical familial adenomatous polyposis ( FAP ) is a high - penetrance autosomal dominant disease that predisposes to hundreds or thousands of colorectal adenomas and carcinoma and that results from truncating mutations in the APC gene .", "sentence_char_start_global": 95662, "sentence_char_end_global": 95900, "entities": [{"text": "familial adenomatous polyposis", "type": "ENTITY", "char_start": 10, "char_end": 40, "token_start": 1, "token_end": 3}, {"text": "FAP", "type": "ENTITY", "char_start": 43, "char_end": 46, "token_start": 5, "token_end": 5}, {"text": "autosomal dominant disease", "type": "ENTITY", "char_start": 72, "char_end": 98, "token_start": 12, "token_end": 14}, {"text": "colorectal adenomas and carcinoma", "type": "ENTITY", "char_start": 144, "char_end": 177, "token_start": 22, "token_end": 25}, {"text": "APC", "type": "ENTITY", "char_start": 228, "char_end": 231, "token_start": 34, "token_end": 34}], "entities_global": [{"text": "familial adenomatous polyposis", "type": "ENTITY", "char_start": 95672, "char_end": 95702, "token_start": 1, "token_end": 3, "note": null}, {"text": "FAP", "type": "ENTITY", "char_start": 95705, "char_end": 95708, "token_start": 5, "token_end": 5, "note": null}, {"text": "autosomal dominant disease", "type": "ENTITY", "char_start": 95734, "char_end": 95760, "token_start": 12, "token_end": 14, "note": null}, {"text": "colorectal adenomas and carcinoma", "type": "ENTITY", "char_start": 95806, "char_end": 95839, "token_start": 22, "token_end": 25, "note": null}, {"text": "APC", "type": "ENTITY", "char_start": 95890, "char_end": 95893, "token_start": 34, "token_end": 34, "note": null}]}
+{"sentence_id": 640, "sentence_text": "A variant of FAP is attenuated adenomatous polyposis coli , which results from germ - line mutations in the 5 and 3 regions of the APC gene .", "sentence_char_start_global": 95901, "sentence_char_end_global": 96042, "entities": [{"text": "FAP", "type": "ENTITY", "char_start": 13, "char_end": 16, "token_start": 3, "token_end": 3}, {"text": "attenuated adenomatous polyposis coli", "type": "ENTITY", "char_start": 20, "char_end": 57, "token_start": 5, "token_end": 8}, {"text": "APC", "type": "ENTITY", "char_start": 131, "char_end": 134, "token_start": 25, "token_end": 25}], "entities_global": [{"text": "FAP", "type": "ENTITY", "char_start": 95914, "char_end": 95917, "token_start": 3, "token_end": 3, "note": null}, {"text": "attenuated adenomatous polyposis coli", "type": "ENTITY", "char_start": 95921, "char_end": 95958, "token_start": 5, "token_end": 8, "note": null}, {"text": "APC", "type": "ENTITY", "char_start": 96032, "char_end": 96035, "token_start": 25, "token_end": 25, "note": null}]}
+{"sentence_id": 641, "sentence_text": "Attenuated adenomatous polyposis coli patients have \" multiple \" colorectal adenomas ( typically fewer than 100 ) without the florid phenotype of classical FAP .", "sentence_char_start_global": 96043, "sentence_char_end_global": 96204, "entities": [{"text": "Attenuated adenomatous polyposis coli", "type": "ENTITY", "char_start": 0, "char_end": 37, "token_start": 0, "token_end": 3}, {"text": "colorectal adenomas", "type": "ENTITY", "char_start": 65, "char_end": 84, "token_start": 9, "token_end": 10}, {"text": "FAP", "type": "ENTITY", "char_start": 156, "char_end": 159, "token_start": 23, "token_end": 23}], "entities_global": [{"text": "Attenuated adenomatous polyposis coli", "type": "ENTITY", "char_start": 96043, "char_end": 96080, "token_start": 0, "token_end": 3, "note": null}, {"text": "colorectal adenomas", "type": "ENTITY", "char_start": 96108, "char_end": 96127, "token_start": 9, "token_end": 10, "note": null}, {"text": "FAP", "type": "ENTITY", "char_start": 96199, "char_end": 96202, "token_start": 23, "token_end": 23, "note": null}]}
+{"sentence_id": 642, "sentence_text": "Another group of patients with multiple adenomas has no mutations in the APC gene , and their phenotype probably results from variation at a locus , or loci , elsewhere in the genome .", "sentence_char_start_global": 96205, "sentence_char_end_global": 96389, "entities": [{"text": "adenomas", "type": "ENTITY", "char_start": 40, "char_end": 48, "token_start": 6, "token_end": 6}, {"text": "APC", "type": "ENTITY", "char_start": 73, "char_end": 76, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "adenomas", "type": "ENTITY", "char_start": 96245, "char_end": 96253, "token_start": 6, "token_end": 6, "note": null}, {"text": "APC", "type": "ENTITY", "char_start": 96278, "char_end": 96281, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 643, "sentence_text": "Recently , however , a missense variant of APC ( I1307K ) was described that confers an increased risk of colorectal tumors , including multiple adenomas , in Ashkenazim .", "sentence_char_start_global": 96390, "sentence_char_end_global": 96561, "entities": [{"text": "APC", "type": "ENTITY", "char_start": 43, "char_end": 46, "token_start": 8, "token_end": 8}, {"text": "colorectal tumors", "type": "ENTITY", "char_start": 106, "char_end": 123, "token_start": 20, "token_end": 21}, {"text": "adenomas", "type": "ENTITY", "char_start": 145, "char_end": 153, "token_start": 25, "token_end": 25}], "entities_global": [{"text": "APC", "type": "ENTITY", "char_start": 96433, "char_end": 96436, "token_start": 8, "token_end": 8, "note": null}, {"text": "colorectal tumors", "type": "ENTITY", "char_start": 96496, "char_end": 96513, "token_start": 20, "token_end": 21, "note": null}, {"text": "adenomas", "type": "ENTITY", "char_start": 96535, "char_end": 96543, "token_start": 25, "token_end": 25, "note": null}]}
+{"sentence_id": 644, "sentence_text": "We have studied a set of 164 patients with multiple colorectal adenomas and / or carcinoma and analyzed codons 1263 - 1377 ( exon 15G ) of the APC gene for germ - line variants .", "sentence_char_start_global": 96562, "sentence_char_end_global": 96740, "entities": [{"text": "colorectal adenomas and / or carcinoma", "type": "ENTITY", "char_start": 52, "char_end": 90, "token_start": 10, "token_end": 15}, {"text": "APC", "type": "ENTITY", "char_start": 143, "char_end": 146, "token_start": 28, "token_end": 28}], "entities_global": [{"text": "colorectal adenomas and / or carcinoma", "type": "ENTITY", "char_start": 96614, "char_end": 96652, "token_start": 10, "token_end": 15, "note": null}, {"text": "APC", "type": "ENTITY", "char_start": 96705, "char_end": 96708, "token_start": 28, "token_end": 28, "note": null}]}
+{"sentence_id": 645, "sentence_text": "Three patients with the I1307K allele were detected , each of Ashkenazi descent .", "sentence_char_start_global": 96741, "sentence_char_end_global": 96822, "entities": [], "entities_global": []}
+{"sentence_id": 646, "sentence_text": "Four patients had a germ - line E1317Q missense variant of APC that was not present in controls ; one of these individuals had an unusually large number of metaplastic polyps of the colorectum .", "sentence_char_start_global": 96823, "sentence_char_end_global": 97017, "entities": [{"text": "metaplastic polyps of the colorectum", "type": "ENTITY", "char_start": 156, "char_end": 192, "token_start": 29, "token_end": 33}], "entities_global": [{"text": "metaplastic polyps of the colorectum", "type": "ENTITY", "char_start": 96979, "char_end": 97015, "token_start": 29, "token_end": 33, "note": null}]}
+{"sentence_id": 647, "sentence_text": "There is increasing evidence that there exist germ - line variants of the APC gene that predispose to the development of multiple colorectal adenomas and carcinoma , but without the florid phenotype of classical FAP , and possibly with importance for colorectal cancer risk in the general population . .", "sentence_char_start_global": 97018, "sentence_char_end_global": 97321, "entities": [{"text": "APC", "type": "ENTITY", "char_start": 74, "char_end": 77, "token_start": 13, "token_end": 13}, {"text": "colorectal adenomas and carcinoma", "type": "ENTITY", "char_start": 130, "char_end": 163, "token_start": 22, "token_end": 25}, {"text": "FAP", "type": "ENTITY", "char_start": 212, "char_end": 215, "token_start": 34, "token_end": 34}, {"text": "colorectal cancer", "type": "ENTITY", "char_start": 251, "char_end": 268, "token_start": 41, "token_end": 42}], "entities_global": [{"text": "APC", "type": "ENTITY", "char_start": 97092, "char_end": 97095, "token_start": 13, "token_end": 13, "note": null}, {"text": "colorectal adenomas and carcinoma", "type": "ENTITY", "char_start": 97148, "char_end": 97181, "token_start": 22, "token_end": 25, "note": null}, {"text": "FAP", "type": "ENTITY", "char_start": 97230, "char_end": 97233, "token_start": 34, "token_end": 34, "note": null}, {"text": "colorectal cancer", "type": "ENTITY", "char_start": 97269, "char_end": 97286, "token_start": 41, "token_end": 42, "note": null}]}
+{"sentence_id": 648, "sentence_text": "Genomic structure of the human congenital chloride diarrhea ( CLD ) gene .", "sentence_char_start_global": 97322, "sentence_char_end_global": 97396, "entities": [{"text": "congenital chloride diarrhea", "type": "ENTITY", "char_start": 31, "char_end": 59, "token_start": 5, "token_end": 7}, {"text": "CLD", "type": "ENTITY", "char_start": 62, "char_end": 65, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "congenital chloride diarrhea", "type": "ENTITY", "char_start": 97353, "char_end": 97381, "token_start": 5, "token_end": 7, "note": null}, {"text": "CLD", "type": "ENTITY", "char_start": 97384, "char_end": 97387, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 649, "sentence_text": "Congenital chloride diarrhea ( CLD ) is caused by mutations in a gene which encodes an intestinal anion transporter .", "sentence_char_start_global": 97397, "sentence_char_end_global": 97514, "entities": [{"text": "Congenital chloride diarrhea", "type": "ENTITY", "char_start": 0, "char_end": 28, "token_start": 0, "token_end": 2}, {"text": "CLD", "type": "ENTITY", "char_start": 31, "char_end": 34, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "Congenital chloride diarrhea", "type": "ENTITY", "char_start": 97397, "char_end": 97425, "token_start": 0, "token_end": 2, "note": null}, {"text": "CLD", "type": "ENTITY", "char_start": 97428, "char_end": 97431, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 650, "sentence_text": "We report here the complete genomic organization of the human CLD gene which spans approximately 39kb , and comprises 21 exons .", "sentence_char_start_global": 97515, "sentence_char_end_global": 97643, "entities": [{"text": "CLD", "type": "ENTITY", "char_start": 62, "char_end": 65, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "CLD", "type": "ENTITY", "char_start": 97577, "char_end": 97580, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 651, "sentence_text": "All exon / intron boundaries conform to the GT / AG rule .", "sentence_char_start_global": 97644, "sentence_char_end_global": 97702, "entities": [], "entities_global": []}
+{"sentence_id": 652, "sentence_text": "An analysis of the putative promoter region sequence shows a putative TATA box and predicts multiple transcription factor binding sites .", "sentence_char_start_global": 97703, "sentence_char_end_global": 97840, "entities": [], "entities_global": []}
+{"sentence_id": 653, "sentence_text": "The genomic structure was determined using DNA from several sources including multiple large - insert libaries and genomic DNA from Finnish CLD patients and controls .", "sentence_char_start_global": 97841, "sentence_char_end_global": 98008, "entities": [{"text": "CLD", "type": "ENTITY", "char_start": 140, "char_end": 143, "token_start": 21, "token_end": 21}], "entities_global": [{"text": "CLD", "type": "ENTITY", "char_start": 97981, "char_end": 97984, "token_start": 21, "token_end": 21, "note": null}]}
+{"sentence_id": 654, "sentence_text": "Exon - specific primers developed in this study will facilitate mutation screening studies of patients with the disease .", "sentence_char_start_global": 98009, "sentence_char_end_global": 98130, "entities": [], "entities_global": []}
+{"sentence_id": 655, "sentence_text": "Genomic sequencing of a BAC clone H _ RG364P16 revealed the presence of another , highly homologous gene 3 of the CLD gene , with a similar genomic structure , recently identified as the Pendred syndrome gene ( PDS ) . .", "sentence_char_start_global": 98131, "sentence_char_end_global": 98351, "entities": [{"text": "CLD", "type": "ENTITY", "char_start": 114, "char_end": 117, "token_start": 21, "token_end": 21}, {"text": "Pendred syndrome", "type": "ENTITY", "char_start": 187, "char_end": 203, "token_start": 34, "token_end": 35}, {"text": "PDS", "type": "ENTITY", "char_start": 211, "char_end": 214, "token_start": 38, "token_end": 38}], "entities_global": [{"text": "CLD", "type": "ENTITY", "char_start": 98245, "char_end": 98248, "token_start": 21, "token_end": 21, "note": null}, {"text": "Pendred syndrome", "type": "ENTITY", "char_start": 98318, "char_end": 98334, "token_start": 34, "token_end": 35, "note": null}, {"text": "PDS", "type": "ENTITY", "char_start": 98342, "char_end": 98345, "token_start": 38, "token_end": 38, "note": null}]}
+{"sentence_id": 656, "sentence_text": "The APCI1307K allele and cancer risk in a community - based study of Ashkenazi Jews .", "sentence_char_start_global": 98352, "sentence_char_end_global": 98437, "entities": [{"text": "cancer", "type": "ENTITY", "char_start": 25, "char_end": 31, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "cancer", "type": "ENTITY", "char_start": 98377, "char_end": 98383, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 657, "sentence_text": "Mutations in APC are classically associated with familial adenomatous polyposis ( FAP ) , a highly penetrant autosomal dominant disorder characterized by multiple intestinal polyps and , without surgical intervention , the development of colorectal cancer ( CRC ) .", "sentence_char_start_global": 98438, "sentence_char_end_global": 98703, "entities": [{"text": "familial adenomatous polyposis", "type": "ENTITY", "char_start": 49, "char_end": 79, "token_start": 7, "token_end": 9}, {"text": "FAP", "type": "ENTITY", "char_start": 82, "char_end": 85, "token_start": 11, "token_end": 11}, {"text": "autosomal dominant disorder", "type": "ENTITY", "char_start": 109, "char_end": 136, "token_start": 17, "token_end": 19}, {"text": "polyps", "type": "ENTITY", "char_start": 174, "char_end": 180, "token_start": 24, "token_end": 24}, {"text": "colorectal cancer", "type": "ENTITY", "char_start": 238, "char_end": 255, "token_start": 34, "token_end": 35}, {"text": "CRC", "type": "ENTITY", "char_start": 258, "char_end": 261, "token_start": 37, "token_end": 37}], "entities_global": [{"text": "familial adenomatous polyposis", "type": "ENTITY", "char_start": 98487, "char_end": 98517, "token_start": 7, "token_end": 9, "note": null}, {"text": "FAP", "type": "ENTITY", "char_start": 98520, "char_end": 98523, "token_start": 11, "token_end": 11, "note": null}, {"text": "autosomal dominant disorder", "type": "ENTITY", "char_start": 98547, "char_end": 98574, "token_start": 17, "token_end": 19, "note": null}, {"text": "polyps", "type": "ENTITY", "char_start": 98612, "char_end": 98618, "token_start": 24, "token_end": 24, "note": null}, {"text": "colorectal cancer", "type": "ENTITY", "char_start": 98676, "char_end": 98693, "token_start": 34, "token_end": 35, "note": null}, {"text": "CRC", "type": "ENTITY", "char_start": 98696, "char_end": 98699, "token_start": 37, "token_end": 37, "note": null}]}
+{"sentence_id": 658, "sentence_text": "APC is a tumour - suppressor gene , and somatic loss occurs in tumours .", "sentence_char_start_global": 98704, "sentence_char_end_global": 98776, "entities": [{"text": "APC", "type": "ENTITY", "char_start": 0, "char_end": 3, "token_start": 0, "token_end": 0}, {"text": "tumours", "type": "ENTITY", "char_start": 63, "char_end": 70, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "APC", "type": "ENTITY", "char_start": 98704, "char_end": 98707, "token_start": 0, "token_end": 0, "note": null}, {"text": "tumours", "type": "ENTITY", "char_start": 98767, "char_end": 98774, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 659, "sentence_text": "The germline T - to - A transversion responsible for the APC I1307K allele converts the wild - type sequence to a homopolymer tract ( A8 ) that is genetically unstable and prone to somatic mutation .", "sentence_char_start_global": 98777, "sentence_char_end_global": 98976, "entities": [], "entities_global": []}
+{"sentence_id": 660, "sentence_text": "The I1307K allele was found in 6 .", "sentence_char_start_global": 98977, "sentence_char_end_global": 99011, "entities": [], "entities_global": []}
+{"sentence_id": 661, "sentence_text": "1 % of unselected Ashkenazi Jews and higher proportions of Ashkenazim with family or personal histories of CRC ( ref . 2 ) .", "sentence_char_start_global": 99012, "sentence_char_end_global": 99136, "entities": [{"text": "CRC", "type": "ENTITY", "char_start": 107, "char_end": 110, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "CRC", "type": "ENTITY", "char_start": 99119, "char_end": 99122, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 662, "sentence_text": "To evaluate the role of I1307K in cancer , we genotyped 5 , 081 Ashkenazi volunteers in a community survey .", "sentence_char_start_global": 99137, "sentence_char_end_global": 99245, "entities": [{"text": "cancer", "type": "ENTITY", "char_start": 34, "char_end": 40, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "cancer", "type": "ENTITY", "char_start": 99171, "char_end": 99177, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 663, "sentence_text": "Risk of developing colorectal , breast and other cancers were compared between genotyped I1307K carriers and non - carriers and their first - degree relatives .", "sentence_char_start_global": 99246, "sentence_char_end_global": 99406, "entities": [{"text": "colorectal , breast and other cancers", "type": "ENTITY", "char_start": 19, "char_end": 56, "token_start": 3, "token_end": 8}], "entities_global": [{"text": "colorectal , breast and other cancers", "type": "ENTITY", "char_start": 99265, "char_end": 99302, "token_start": 3, "token_end": 8, "note": null}]}
+{"sentence_id": 664, "sentence_text": "Sperm DNA analysis in a Friedreich ataxia premutation carrier suggests both meiotic and mitotic expansion in the FRDA gene .", "sentence_char_start_global": 99407, "sentence_char_end_global": 99531, "entities": [{"text": "Friedreich ataxia", "type": "ENTITY", "char_start": 24, "char_end": 41, "token_start": 5, "token_end": 6}, {"text": "FRDA", "type": "ENTITY", "char_start": 113, "char_end": 117, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "Friedreich ataxia", "type": "ENTITY", "char_start": 99431, "char_end": 99448, "token_start": 5, "token_end": 6, "note": null}, {"text": "FRDA", "type": "ENTITY", "char_start": 99520, "char_end": 99524, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 665, "sentence_text": "Friedreich ataxia is usually caused by an expansion of a GAA trinucleotide repeat in intron 1 of the FRDA gene .", "sentence_char_start_global": 99532, "sentence_char_end_global": 99644, "entities": [{"text": "Friedreich ataxia", "type": "ENTITY", "char_start": 0, "char_end": 17, "token_start": 0, "token_end": 1}, {"text": "FRDA", "type": "ENTITY", "char_start": 101, "char_end": 105, "token_start": 18, "token_end": 18}], "entities_global": [{"text": "Friedreich ataxia", "type": "ENTITY", "char_start": 99532, "char_end": 99549, "token_start": 0, "token_end": 1, "note": null}, {"text": "FRDA", "type": "ENTITY", "char_start": 99633, "char_end": 99637, "token_start": 18, "token_end": 18, "note": null}]}
+{"sentence_id": 666, "sentence_text": "Occasionally , a fully expanded allele has been found to arise from a premutation of 100 or less triplet repeats .", "sentence_char_start_global": 99645, "sentence_char_end_global": 99759, "entities": [], "entities_global": []}
+{"sentence_id": 667, "sentence_text": "We have examined the sperm DNA of a premutation carrier .", "sentence_char_start_global": 99760, "sentence_char_end_global": 99817, "entities": [], "entities_global": []}
+{"sentence_id": 668, "sentence_text": "This mans leucocyte DNA showed one normal allele and one allele of approximately 100 repeats .", "sentence_char_start_global": 99818, "sentence_char_end_global": 99912, "entities": [], "entities_global": []}
+{"sentence_id": 669, "sentence_text": "His sperm showed an expanded allele in a tight range centering on a size of approximately 320 trinucleotide repeats .", "sentence_char_start_global": 99913, "sentence_char_end_global": 100030, "entities": [], "entities_global": []}
+{"sentence_id": 670, "sentence_text": "His affected son has repeat sizes of 1040 and 540 .", "sentence_char_start_global": 100031, "sentence_char_end_global": 100082, "entities": [], "entities_global": []}
+{"sentence_id": 671, "sentence_text": "These data suggest that expansion occurs in two stages , the first during meiosis followed by a second mitotic expansion .", "sentence_char_start_global": 100083, "sentence_char_end_global": 100205, "entities": [], "entities_global": []}
+{"sentence_id": 672, "sentence_text": "We also show that in all informative carrier father to affected child transmissions , with the notable exception of the premutation carrier , the expansion size decreases . .", "sentence_char_start_global": 100206, "sentence_char_end_global": 100380, "entities": [], "entities_global": []}
+{"sentence_id": 673, "sentence_text": "The R496H mutation of arylsulfatase A does not cause metachromatic leukodystrophy .", "sentence_char_start_global": 100381, "sentence_char_end_global": 100464, "entities": [{"text": "metachromatic leukodystrophy", "type": "ENTITY", "char_start": 53, "char_end": 81, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "metachromatic leukodystrophy", "type": "ENTITY", "char_start": 100434, "char_end": 100462, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 674, "sentence_text": "Deficiency of arylsulfatase A ( ARSA ) enzyme activity causes metachromatic leukodystrophy ( MLD ) .", "sentence_char_start_global": 100465, "sentence_char_end_global": 100565, "entities": [{"text": "Deficiency of arylsulfatase A", "type": "ENTITY", "char_start": 0, "char_end": 29, "token_start": 0, "token_end": 3}, {"text": "metachromatic leukodystrophy", "type": "ENTITY", "char_start": 62, "char_end": 90, "token_start": 10, "token_end": 11}, {"text": "MLD", "type": "ENTITY", "char_start": 93, "char_end": 96, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "Deficiency of arylsulfatase A", "type": "ENTITY", "char_start": 100465, "char_end": 100494, "token_start": 0, "token_end": 3, "note": null}, {"text": "metachromatic leukodystrophy", "type": "ENTITY", "char_start": 100527, "char_end": 100555, "token_start": 10, "token_end": 11, "note": null}, {"text": "MLD", "type": "ENTITY", "char_start": 100558, "char_end": 100561, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 675, "sentence_text": "A number of ARSA gene mutations responsible for MLD have been identified .", "sentence_char_start_global": 100566, "sentence_char_end_global": 100640, "entities": [{"text": "MLD", "type": "ENTITY", "char_start": 48, "char_end": 51, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "MLD", "type": "ENTITY", "char_start": 100614, "char_end": 100617, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 676, "sentence_text": "Recently , the R496H mutation of ARSA was proposed to be a cause of MLD ( Draghia et al . , 1997 ) .", "sentence_char_start_global": 100641, "sentence_char_end_global": 100741, "entities": [{"text": "MLD", "type": "ENTITY", "char_start": 68, "char_end": 71, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "MLD", "type": "ENTITY", "char_start": 100709, "char_end": 100712, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 677, "sentence_text": "We have investigated the R496H mutation and found this mutation at a relatively high frequency in an African American population ( f = 0 . 09 , n = 61 subjects ) .", "sentence_char_start_global": 100742, "sentence_char_end_global": 100905, "entities": [], "entities_global": []}
+{"sentence_id": 678, "sentence_text": "The ARSA enzyme activity in subjects with and without the R496H mutation was determined and found to be normal .", "sentence_char_start_global": 100906, "sentence_char_end_global": 101018, "entities": [], "entities_global": []}
+{"sentence_id": 679, "sentence_text": "It is therefore concluded that the R496H mutation of ARSA does not negatively influence the activity of ARSA and is not a cause of MLD", "sentence_char_start_global": 101019, "sentence_char_end_global": 101153, "entities": [{"text": "MLD", "type": "ENTITY", "char_start": 131, "char_end": 134, "token_start": 24, "token_end": 24}], "entities_global": [{"text": "MLD", "type": "ENTITY", "char_start": 101150, "char_end": 101153, "token_start": 24, "token_end": 24, "note": null}]}
+{"sentence_id": 680, "sentence_text": "Down - regulation of transmembrane carbonic anhydrases in renal cell carcinoma cell lines by wild - type von Hippel - Lindau transgenes .", "sentence_char_start_global": 101154, "sentence_char_end_global": 101291, "entities": [{"text": "renal cell carcinoma", "type": "ENTITY", "char_start": 58, "char_end": 78, "token_start": 8, "token_end": 10}, {"text": "von Hippel - Lindau", "type": "ENTITY", "char_start": 105, "char_end": 124, "token_start": 17, "token_end": 20}], "entities_global": [{"text": "renal cell carcinoma", "type": "ENTITY", "char_start": 101212, "char_end": 101232, "token_start": 8, "token_end": 10, "note": null}, {"text": "von Hippel - Lindau", "type": "ENTITY", "char_start": 101259, "char_end": 101278, "token_start": 17, "token_end": 20, "note": null}]}
+{"sentence_id": 681, "sentence_text": "To discover genes involved in von Hippel - Lindau ( VHL ) - mediated carcinogenesis , we used renal cell carcinoma cell lines stably transfected with wild - type VHL - expressing transgenes .", "sentence_char_start_global": 101292, "sentence_char_end_global": 101483, "entities": [{"text": "von Hippel - Lindau", "type": "ENTITY", "char_start": 30, "char_end": 49, "token_start": 5, "token_end": 8}, {"text": "VHL", "type": "ENTITY", "char_start": 52, "char_end": 55, "token_start": 10, "token_end": 10}, {"text": "renal cell carcinoma", "type": "ENTITY", "char_start": 94, "char_end": 114, "token_start": 18, "token_end": 20}], "entities_global": [{"text": "von Hippel - Lindau", "type": "ENTITY", "char_start": 101322, "char_end": 101341, "token_start": 5, "token_end": 8, "note": null}, {"text": "VHL", "type": "ENTITY", "char_start": 101344, "char_end": 101347, "token_start": 10, "token_end": 10, "note": null}, {"text": "renal cell carcinoma", "type": "ENTITY", "char_start": 101386, "char_end": 101406, "token_start": 18, "token_end": 20, "note": null}]}
+{"sentence_id": 682, "sentence_text": "Large - scale RNA differential display technology applied to these cell lines identified several differentially expressed genes , including an alpha carbonic anhydrase gene , termed CA12 .", "sentence_char_start_global": 101484, "sentence_char_end_global": 101672, "entities": [], "entities_global": []}
+{"sentence_id": 683, "sentence_text": "The deduced protein sequence was classified as a one - pass transmembrane CA possessing an apparently intact catalytic domain in the extracellular CA module .", "sentence_char_start_global": 101673, "sentence_char_end_global": 101831, "entities": [], "entities_global": []}
+{"sentence_id": 684, "sentence_text": "Reintroduced wild - type VHL strongly inhibited the overexpression of the CA12 gene in the parental renal cell carcinoma cell lines .", "sentence_char_start_global": 101832, "sentence_char_end_global": 101965, "entities": [{"text": "VHL", "type": "ENTITY", "char_start": 25, "char_end": 28, "token_start": 4, "token_end": 4}, {"text": "renal cell carcinoma", "type": "ENTITY", "char_start": 100, "char_end": 120, "token_start": 16, "token_end": 18}], "entities_global": [{"text": "VHL", "type": "ENTITY", "char_start": 101857, "char_end": 101860, "token_start": 4, "token_end": 4, "note": null}, {"text": "renal cell carcinoma", "type": "ENTITY", "char_start": 101932, "char_end": 101952, "token_start": 16, "token_end": 18, "note": null}]}
+{"sentence_id": 685, "sentence_text": "Similar results were obtained with CA9 , encoding another transmembrane CA with an intact catalytic domain .", "sentence_char_start_global": 101966, "sentence_char_end_global": 102074, "entities": [], "entities_global": []}
+{"sentence_id": 686, "sentence_text": "Although both domains of the VHL protein contribute to regulation of CA12 expression , the elongin binding domain alone could effectively regulate CA9 expression .", "sentence_char_start_global": 102075, "sentence_char_end_global": 102238, "entities": [{"text": "VHL", "type": "ENTITY", "char_start": 29, "char_end": 32, "token_start": 5, "token_end": 5}], "entities_global": [{"text": "VHL", "type": "ENTITY", "char_start": 102104, "char_end": 102107, "token_start": 5, "token_end": 5, "note": null}]}
+{"sentence_id": 687, "sentence_text": "We mapped CA12 and CA9 loci to chromosome bands 15q22 and 17q21 .", "sentence_char_start_global": 102239, "sentence_char_end_global": 102304, "entities": [], "entities_global": []}
+{"sentence_id": 688, "sentence_text": "2 respectively , regions prone to amplification in some human cancers .", "sentence_char_start_global": 102305, "sentence_char_end_global": 102376, "entities": [{"text": "cancers", "type": "ENTITY", "char_start": 62, "char_end": 69, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "cancers", "type": "ENTITY", "char_start": 102367, "char_end": 102374, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 689, "sentence_text": "Additional experiments are needed to define the role of CA IX and CA XII enzymes in the regulation of pH in the extracellular microenvironment and its potential impact on cancer cell growth .", "sentence_char_start_global": 102377, "sentence_char_end_global": 102568, "entities": [{"text": "cancer", "type": "ENTITY", "char_start": 171, "char_end": 177, "token_start": 29, "token_end": 29}], "entities_global": [{"text": "cancer", "type": "ENTITY", "char_start": 102548, "char_end": 102554, "token_start": 29, "token_end": 29, "note": null}]}
+{"sentence_id": 690, "sentence_text": "A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy ( Wolfram syndrome ) .", "sentence_char_start_global": 102569, "sentence_char_end_global": 102695, "entities": [{"text": "diabetes mellitus", "type": "ENTITY", "char_start": 68, "char_end": 85, "token_start": 11, "token_end": 12}, {"text": "optic atrophy", "type": "ENTITY", "char_start": 90, "char_end": 103, "token_start": 14, "token_end": 15}, {"text": "Wolfram syndrome", "type": "ENTITY", "char_start": 106, "char_end": 122, "token_start": 17, "token_end": 18}], "entities_global": [{"text": "diabetes mellitus", "type": "ENTITY", "char_start": 102637, "char_end": 102654, "token_start": 11, "token_end": 12, "note": null}, {"text": "optic atrophy", "type": "ENTITY", "char_start": 102659, "char_end": 102672, "token_start": 14, "token_end": 15, "note": null}, {"text": "Wolfram syndrome", "type": "ENTITY", "char_start": 102675, "char_end": 102691, "token_start": 17, "token_end": 18, "note": null}]}
+{"sentence_id": 691, "sentence_text": "Wolfram syndrome ( WFS ; OMIM 222300 ) is an autosomal recessive neurodegenerative disorder defined by young - onset non - immune insulin - dependent diabetes mellitus and progressive optic atrophy .", "sentence_char_start_global": 102696, "sentence_char_end_global": 102895, "entities": [{"text": "Wolfram syndrome", "type": "ENTITY", "char_start": 0, "char_end": 16, "token_start": 0, "token_end": 1}, {"text": "WFS", "type": "ENTITY", "char_start": 19, "char_end": 22, "token_start": 3, "token_end": 3}, {"text": "autosomal recessive neurodegenerative disorder", "type": "ENTITY", "char_start": 45, "char_end": 91, "token_start": 10, "token_end": 13}, {"text": "insulin - dependent diabetes mellitus", "type": "ENTITY", "char_start": 130, "char_end": 167, "token_start": 22, "token_end": 26}, {"text": "optic atrophy", "type": "ENTITY", "char_start": 184, "char_end": 197, "token_start": 29, "token_end": 30}], "entities_global": [{"text": "Wolfram syndrome", "type": "ENTITY", "char_start": 102696, "char_end": 102712, "token_start": 0, "token_end": 1, "note": null}, {"text": "WFS", "type": "ENTITY", "char_start": 102715, "char_end": 102718, "token_start": 3, "token_end": 3, "note": null}, {"text": "autosomal recessive neurodegenerative disorder", "type": "ENTITY", "char_start": 102741, "char_end": 102787, "token_start": 10, "token_end": 13, "note": null}, {"text": "insulin - dependent diabetes mellitus", "type": "ENTITY", "char_start": 102826, "char_end": 102863, "token_start": 22, "token_end": 26, "note": null}, {"text": "optic atrophy", "type": "ENTITY", "char_start": 102880, "char_end": 102893, "token_start": 29, "token_end": 30, "note": null}]}
+{"sentence_id": 692, "sentence_text": "Linkage to markers on chromosome 4p was confirmed in five families .", "sentence_char_start_global": 102896, "sentence_char_end_global": 102964, "entities": [], "entities_global": []}
+{"sentence_id": 693, "sentence_text": "On the basis of meiotic recombinants and disease - associated haplotypes , the WFS gene was localized to a BAC / P1 contig of less than 250 kb .", "sentence_char_start_global": 102965, "sentence_char_end_global": 103109, "entities": [{"text": "WFS", "type": "ENTITY", "char_start": 79, "char_end": 82, "token_start": 13, "token_end": 13}], "entities_global": [{"text": "WFS", "type": "ENTITY", "char_start": 103044, "char_end": 103047, "token_start": 13, "token_end": 13, "note": null}]}
+{"sentence_id": 694, "sentence_text": "Mutations in a novel gene ( WFS1 ) encoding a putative transmembrane protein were found in all affected individuals in six WFS families , and these mutations were associated with the disease phenotype .", "sentence_char_start_global": 103110, "sentence_char_end_global": 103312, "entities": [{"text": "WFS", "type": "ENTITY", "char_start": 123, "char_end": 126, "token_start": 21, "token_end": 21}], "entities_global": [{"text": "WFS", "type": "ENTITY", "char_start": 103233, "char_end": 103236, "token_start": 21, "token_end": 21, "note": null}]}
+{"sentence_id": 695, "sentence_text": "WFS1 appears to function in survival of islet beta - cells and neurons . .", "sentence_char_start_global": 103313, "sentence_char_end_global": 103387, "entities": [], "entities_global": []}
+{"sentence_id": 696, "sentence_text": "Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells .", "sentence_char_start_global": 103388, "sentence_char_end_global": 103504, "entities": [{"text": "tumor", "type": "ENTITY", "char_start": 63, "char_end": 68, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "tumor", "type": "ENTITY", "char_start": 103451, "char_end": 103456, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 697, "sentence_text": "BRCA1 and BRCA2 account for most cases of familial , early onset breast and / or ovarian cancer and encode products that each interact with hRAD51 .", "sentence_char_start_global": 103505, "sentence_char_end_global": 103653, "entities": [{"text": "breast and / or ovarian cancer", "type": "ENTITY", "char_start": 65, "char_end": 95, "token_start": 12, "token_end": 17}], "entities_global": [{"text": "breast and / or ovarian cancer", "type": "ENTITY", "char_start": 103570, "char_end": 103600, "token_start": 12, "token_end": 17, "note": null}]}
+{"sentence_id": 698, "sentence_text": "Results presented here show that BRCA1 and BRCA2 coexist in a biochemical complex and colocalize in subnuclear foci in somatic cells and on the axial elements of developing synaptonemal complexes .", "sentence_char_start_global": 103654, "sentence_char_end_global": 103851, "entities": [], "entities_global": []}
+{"sentence_id": 699, "sentence_text": "Like BRCA1 and RAD51 , BRCA2 relocates to PCNA + replication sites following exposure of S phase cells to hydroxyurea or UV irradiation .", "sentence_char_start_global": 103852, "sentence_char_end_global": 103989, "entities": [], "entities_global": []}
+{"sentence_id": 700, "sentence_text": "Thus , BRCA1 and BRCA2 participate , together , in a pathway ( s ) associated with the activation of double - strand break repair and / or homologous recombination .", "sentence_char_start_global": 103990, "sentence_char_end_global": 104155, "entities": [], "entities_global": []}
+{"sentence_id": 701, "sentence_text": "Dysfunction of this pathway may be a general phenomenon in the majority of cases of hereditary breast and / or ovarian cancer . .", "sentence_char_start_global": 104156, "sentence_char_end_global": 104285, "entities": [{"text": "hereditary breast and / or ovarian cancer", "type": "ENTITY", "char_start": 84, "char_end": 125, "token_start": 15, "token_end": 21}], "entities_global": [{"text": "hereditary breast and / or ovarian cancer", "type": "ENTITY", "char_start": 104240, "char_end": 104281, "token_start": 15, "token_end": 21, "note": null}]}
+{"sentence_id": 702, "sentence_text": "A novel Arg362Ser mutation in the sterol 27 - hydroxylase gene ( CYP27 ) : its effects on pre - mRNA splicing and enzyme activity .", "sentence_char_start_global": 104286, "sentence_char_end_global": 104417, "entities": [], "entities_global": []}
+{"sentence_id": 703, "sentence_text": "A novel C to A mutation in the sterol 27 - hydroxylase gene ( CYP27 ) was identified by sequencing amplified CYP27 gene products from a patient with cerebrotendinous xanthomatosis ( CTX ) .", "sentence_char_start_global": 104418, "sentence_char_end_global": 104607, "entities": [{"text": "cerebrotendinous xanthomatosis", "type": "ENTITY", "char_start": 149, "char_end": 179, "token_start": 28, "token_end": 29}, {"text": "CTX", "type": "ENTITY", "char_start": 182, "char_end": 185, "token_start": 31, "token_end": 31}], "entities_global": [{"text": "cerebrotendinous xanthomatosis", "type": "ENTITY", "char_start": 104567, "char_end": 104597, "token_start": 28, "token_end": 29, "note": null}, {"text": "CTX", "type": "ENTITY", "char_start": 104600, "char_end": 104603, "token_start": 31, "token_end": 31, "note": null}]}
+{"sentence_id": 704, "sentence_text": "The mutation changed the adrenodoxin cofactor binding residue 362Arg to 362Ser ( CGT 362Arg to AGT 362Ser ) , and was responsible for deficiency in the sterol 27 - hydroxylase activity , as confirmed by expression of mutant cDNA into COS - 1 cells .", "sentence_char_start_global": 104608, "sentence_char_end_global": 104857, "entities": [], "entities_global": []}
+{"sentence_id": 705, "sentence_text": "Quantitative analysis showed that the expression of CYP27 gene mRNA in the patient represented 52 .", "sentence_char_start_global": 104858, "sentence_char_end_global": 104957, "entities": [], "entities_global": []}
+{"sentence_id": 706, "sentence_text": "5 % of the normal level .", "sentence_char_start_global": 104958, "sentence_char_end_global": 104983, "entities": [], "entities_global": []}
+{"sentence_id": 707, "sentence_text": "As the mutation occurred at the penultimate nucleotide of exon 6 ( - 2 position of exon 6 - intron 6 splice site ) of the gene , we hypothesized that the mutation may partially affect the normal splicing efficiency in exon 6 and cause alternative splicing elsewhere , which resulted in decreased transcript in the patient .", "sentence_char_start_global": 104984, "sentence_char_end_global": 105307, "entities": [], "entities_global": []}
+{"sentence_id": 708, "sentence_text": "Transfection of constructed minigenes , with or without the mutation , into COS - 1 cells confirmed that the mutant minigene was responsible for a mRNA species alternatively spliced at an activated cryptic 5 splice site 88 bp upstream from the 3 end of exon 6 .", "sentence_char_start_global": 105308, "sentence_char_end_global": 105569, "entities": [], "entities_global": []}
+{"sentence_id": 709, "sentence_text": "Our data suggest that the C to A mutation at the penultimate nucleotide of exon 6 of the CYP27 gene not only causes the deficiency in the sterol 27 - hydroxylase activity , but also partially leads to alternative pre - mRNA splicing of the gene .", "sentence_char_start_global": 105570, "sentence_char_end_global": 105816, "entities": [{"text": "deficiency in the sterol 27 - hydroxylase activity", "type": "ENTITY", "char_start": 120, "char_end": 170, "token_start": 24, "token_end": 31}], "entities_global": [{"text": "deficiency in the sterol 27 - hydroxylase activity", "type": "ENTITY", "char_start": 105690, "char_end": 105740, "token_start": 24, "token_end": 31, "note": null}]}
+{"sentence_id": 710, "sentence_text": "To our knowledge , this is the first report regarding effects on pre - mRNA splicing of a mutation at the - 2 position of a 5 splice site .", "sentence_char_start_global": 105817, "sentence_char_end_global": 105956, "entities": [], "entities_global": []}
+{"sentence_id": 711, "sentence_text": "ATM germline mutations in classical ataxia - telangiectasia patients in the Dutch population .", "sentence_char_start_global": 105957, "sentence_char_end_global": 106051, "entities": [{"text": "ataxia - telangiectasia", "type": "ENTITY", "char_start": 36, "char_end": 59, "token_start": 5, "token_end": 7}], "entities_global": [{"text": "ataxia - telangiectasia", "type": "ENTITY", "char_start": 105993, "char_end": 106016, "token_start": 5, "token_end": 7, "note": null}]}
+{"sentence_id": 712, "sentence_text": "Germline mutations in the ATM gene are responsible for the autosomal recessive disorder ataxia - telangiectasia ( A - T ) .", "sentence_char_start_global": 106052, "sentence_char_end_global": 106175, "entities": [{"text": "autosomal recessive disorder", "type": "ENTITY", "char_start": 59, "char_end": 87, "token_start": 10, "token_end": 12}, {"text": "ataxia - telangiectasia", "type": "ENTITY", "char_start": 88, "char_end": 111, "token_start": 13, "token_end": 15}, {"text": "A - T", "type": "ENTITY", "char_start": 114, "char_end": 119, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "autosomal recessive disorder", "type": "ENTITY", "char_start": 106111, "char_end": 106139, "token_start": 10, "token_end": 12, "note": null}, {"text": "ataxia - telangiectasia", "type": "ENTITY", "char_start": 106140, "char_end": 106163, "token_start": 13, "token_end": 15, "note": null}, {"text": "A - T", "type": "ENTITY", "char_start": 106166, "char_end": 106171, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 713, "sentence_text": "In our study , we have determined the ATM mutation spectrum in 19 classical A - T patients , including some immigrant populations , as well as 12 of Dutch ethnic origin .", "sentence_char_start_global": 106176, "sentence_char_end_global": 106346, "entities": [{"text": "A - T", "type": "ENTITY", "char_start": 76, "char_end": 81, "token_start": 14, "token_end": 16}], "entities_global": [{"text": "A - T", "type": "ENTITY", "char_start": 106252, "char_end": 106257, "token_start": 14, "token_end": 16, "note": null}]}
+{"sentence_id": 714, "sentence_text": "Both the protein truncation test ( PTT ) and the restriction endonuclease fingerprinting ( REF ) method were used and compared for their detection efficiency , identifying 76 % and 60 % of the mutations , respectively .", "sentence_char_start_global": 106347, "sentence_char_end_global": 106566, "entities": [], "entities_global": []}
+{"sentence_id": 715, "sentence_text": "Most patients were found to be compound heterozygote .", "sentence_char_start_global": 106567, "sentence_char_end_global": 106621, "entities": [], "entities_global": []}
+{"sentence_id": 716, "sentence_text": "Seventeen mutations were distinct , of which 10 were not reported previously .", "sentence_char_start_global": 106622, "sentence_char_end_global": 106700, "entities": [], "entities_global": []}
+{"sentence_id": 717, "sentence_text": "Mutations are small deletions or point mutations frequently affecting splice sites .", "sentence_char_start_global": 106701, "sentence_char_end_global": 106785, "entities": [], "entities_global": []}
+{"sentence_id": 718, "sentence_text": "Moreover , a 16 .", "sentence_char_start_global": 106786, "sentence_char_end_global": 106803, "entities": [], "entities_global": []}
+{"sentence_id": 719, "sentence_text": "7 - kb genomic deletion of the 3 end of the gene , most likely a result of recombination between two LINE elements , was identified .", "sentence_char_start_global": 106804, "sentence_char_end_global": 106937, "entities": [], "entities_global": []}
+{"sentence_id": 720, "sentence_text": "The most frequently found mutation , identified in three unrelated Turkish A - T individuals , was previously described to be a Turkish A - T founder mutation .", "sentence_char_start_global": 106938, "sentence_char_end_global": 107098, "entities": [{"text": "A - T", "type": "ENTITY", "char_start": 75, "char_end": 80, "token_start": 11, "token_end": 13}, {"text": "A - T", "type": "ENTITY", "char_start": 136, "char_end": 141, "token_start": 23, "token_end": 25}], "entities_global": [{"text": "A - T", "type": "ENTITY", "char_start": 107013, "char_end": 107018, "token_start": 11, "token_end": 13, "note": null}, {"text": "A - T", "type": "ENTITY", "char_start": 107074, "char_end": 107079, "token_start": 23, "token_end": 25, "note": null}]}
+{"sentence_id": 721, "sentence_text": "The presence of a founder mutation among relatively small ethnic population groups in Western Europe could indicate a high carrier frequency in such communities .", "sentence_char_start_global": 107099, "sentence_char_end_global": 107261, "entities": [], "entities_global": []}
+{"sentence_id": 722, "sentence_text": "In patients of Dutch ethnic origin , however , no significant founder effect could be identified .", "sentence_char_start_global": 107262, "sentence_char_end_global": 107360, "entities": [], "entities_global": []}
+{"sentence_id": 723, "sentence_text": "The observed genetic heterogeneity including the relative high percentage of splice - site mutations had no reflection on the phenotype .", "sentence_char_start_global": 107361, "sentence_char_end_global": 107498, "entities": [], "entities_global": []}
+{"sentence_id": 724, "sentence_text": "All patients manifested classical A - T and increased cellular radioresistant DNA synthesis .", "sentence_char_start_global": 107499, "sentence_char_end_global": 107592, "entities": [{"text": "A - T", "type": "ENTITY", "char_start": 34, "char_end": 39, "token_start": 4, "token_end": 6}], "entities_global": [{"text": "A - T", "type": "ENTITY", "char_start": 107533, "char_end": 107538, "token_start": 4, "token_end": 6, "note": null}]}
+{"sentence_id": 725, "sentence_text": "Determination of the genomic structure of the COL4A4 gene and of novel mutations causing autosomal recessive Alport syndrome .", "sentence_char_start_global": 107593, "sentence_char_end_global": 107719, "entities": [{"text": "autosomal recessive Alport syndrome", "type": "ENTITY", "char_start": 89, "char_end": 124, "token_start": 14, "token_end": 17}], "entities_global": [{"text": "autosomal recessive Alport syndrome", "type": "ENTITY", "char_start": 107682, "char_end": 107717, "token_start": 14, "token_end": 17, "note": null}]}
+{"sentence_id": 726, "sentence_text": "Autosomal recessive Alport syndrome is a progressive hematuric glomerulonephritis characterized by glomerular basement membrane abnormalities and associated with mutations in either the COL4A3 or the COL4A4 gene , which encode the alpha3 and alpha4 type IV collagen chains , respectively .", "sentence_char_start_global": 107720, "sentence_char_end_global": 108009, "entities": [{"text": "Autosomal recessive Alport syndrome", "type": "ENTITY", "char_start": 0, "char_end": 35, "token_start": 0, "token_end": 3}, {"text": "hematuric glomerulonephritis", "type": "ENTITY", "char_start": 53, "char_end": 81, "token_start": 7, "token_end": 8}, {"text": "glomerular basement membrane abnormalities", "type": "ENTITY", "char_start": 99, "char_end": 141, "token_start": 11, "token_end": 14}], "entities_global": [{"text": "Autosomal recessive Alport syndrome", "type": "ENTITY", "char_start": 107720, "char_end": 107755, "token_start": 0, "token_end": 3, "note": null}, {"text": "hematuric glomerulonephritis", "type": "ENTITY", "char_start": 107773, "char_end": 107801, "token_start": 7, "token_end": 8, "note": null}, {"text": "glomerular basement membrane abnormalities", "type": "ENTITY", "char_start": 107819, "char_end": 107861, "token_start": 11, "token_end": 14, "note": null}]}
+{"sentence_id": 727, "sentence_text": "To date , mutation screening in the two genes has been hampered by the lack of genomic structure information .", "sentence_char_start_global": 108010, "sentence_char_end_global": 108120, "entities": [], "entities_global": []}
+{"sentence_id": 728, "sentence_text": "We report here the complete characterization of the 48 exons of the COL4A4 gene , a comprehensive gene screen , and the subsequent detection of 10 novel mutations in eight patients diagnosed with autosomal recessive Alport syndrome .", "sentence_char_start_global": 108121, "sentence_char_end_global": 108354, "entities": [{"text": "autosomal recessive Alport syndrome", "type": "ENTITY", "char_start": 196, "char_end": 231, "token_start": 33, "token_end": 36}], "entities_global": [{"text": "autosomal recessive Alport syndrome", "type": "ENTITY", "char_start": 108317, "char_end": 108352, "token_start": 33, "token_end": 36, "note": null}]}
+{"sentence_id": 729, "sentence_text": "Furthermore , we identified a glycine to alanine substitution in the collagenous domain that is apparently silent in the heterozygous carriers , in 11 .", "sentence_char_start_global": 108355, "sentence_char_end_global": 108507, "entities": [], "entities_global": []}
+{"sentence_id": 730, "sentence_text": "5 % of all control individuals , and in one control individual homozygous for this glycine substitution .", "sentence_char_start_global": 108508, "sentence_char_end_global": 108613, "entities": [], "entities_global": []}
+{"sentence_id": 731, "sentence_text": "There has been no previous finding of a glycine substitution that is not associated with any obvious phenotype in homozygous individuals .", "sentence_char_start_global": 108614, "sentence_char_end_global": 108752, "entities": [], "entities_global": []}
+{"sentence_id": 732, "sentence_text": "Founder BRCA1 and BRCA2 mutations in French Canadian breast and ovarian cancer families .", "sentence_char_start_global": 108753, "sentence_char_end_global": 108842, "entities": [{"text": "breast and ovarian cancer", "type": "ENTITY", "char_start": 53, "char_end": 78, "token_start": 8, "token_end": 11}], "entities_global": [{"text": "breast and ovarian cancer", "type": "ENTITY", "char_start": 108806, "char_end": 108831, "token_start": 8, "token_end": 11, "note": null}]}
+{"sentence_id": 733, "sentence_text": "We have identified four mutations in each of the breast cancer - susceptibility genes , BRCA1 and BRCA2 , in French Canadian breast cancer and breast / ovarian cancer families from Quebec .", "sentence_char_start_global": 108843, "sentence_char_end_global": 109032, "entities": [{"text": "breast cancer", "type": "ENTITY", "char_start": 49, "char_end": 62, "token_start": 9, "token_end": 10}, {"text": "breast cancer", "type": "ENTITY", "char_start": 125, "char_end": 138, "token_start": 22, "token_end": 23}, {"text": "breast / ovarian cancer", "type": "ENTITY", "char_start": 143, "char_end": 166, "token_start": 25, "token_end": 28}], "entities_global": [{"text": "breast cancer", "type": "ENTITY", "char_start": 108892, "char_end": 108905, "token_start": 9, "token_end": 10, "note": null}, {"text": "breast cancer", "type": "ENTITY", "char_start": 108968, "char_end": 108981, "token_start": 22, "token_end": 23, "note": null}, {"text": "breast / ovarian cancer", "type": "ENTITY", "char_start": 108986, "char_end": 109009, "token_start": 25, "token_end": 28, "note": null}]}
+{"sentence_id": 734, "sentence_text": "To identify founder effects , we examined independently ascertained French Canadian cancer families for the distribution of these eight mutations .", "sentence_char_start_global": 109033, "sentence_char_end_global": 109180, "entities": [{"text": "cancer", "type": "ENTITY", "char_start": 84, "char_end": 90, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "cancer", "type": "ENTITY", "char_start": 109117, "char_end": 109123, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 735, "sentence_text": "Mutations were found in 41 of 97 families .", "sentence_char_start_global": 109181, "sentence_char_end_global": 109224, "entities": [], "entities_global": []}
+{"sentence_id": 736, "sentence_text": "Six of eight mutations were observed at least twice .", "sentence_char_start_global": 109225, "sentence_char_end_global": 109278, "entities": [], "entities_global": []}
+{"sentence_id": 737, "sentence_text": "The BRCA1 C4446T mutation was the most common mutation found , followed by the BRCA2 8765delAG mutation .", "sentence_char_start_global": 109279, "sentence_char_end_global": 109384, "entities": [], "entities_global": []}
+{"sentence_id": 738, "sentence_text": "Together , these mutations were found in 28 of 41 families identified to have a mutation .", "sentence_char_start_global": 109385, "sentence_char_end_global": 109475, "entities": [], "entities_global": []}
+{"sentence_id": 739, "sentence_text": "The odds of detection of any of the four BRCA1 mutations was 18 .", "sentence_char_start_global": 109476, "sentence_char_end_global": 109541, "entities": [], "entities_global": []}
+{"sentence_id": 740, "sentence_text": "7x greater if one or more cases of ovarian cancer were also present in the family .", "sentence_char_start_global": 109542, "sentence_char_end_global": 109625, "entities": [{"text": "ovarian cancer", "type": "ENTITY", "char_start": 35, "char_end": 49, "token_start": 8, "token_end": 9}], "entities_global": [{"text": "ovarian cancer", "type": "ENTITY", "char_start": 109577, "char_end": 109591, "token_start": 8, "token_end": 9, "note": null}]}
+{"sentence_id": 741, "sentence_text": "The odds of detection of any of the four BRCA2 mutations was 5 .", "sentence_char_start_global": 109626, "sentence_char_end_global": 109690, "entities": [], "entities_global": []}
+{"sentence_id": 742, "sentence_text": "3x greater if there were at least five cases of breast cancer in the family .", "sentence_char_start_global": 109691, "sentence_char_end_global": 109768, "entities": [{"text": "breast cancer", "type": "ENTITY", "char_start": 48, "char_end": 61, "token_start": 10, "token_end": 11}], "entities_global": [{"text": "breast cancer", "type": "ENTITY", "char_start": 109739, "char_end": 109752, "token_start": 10, "token_end": 11, "note": null}]}
+{"sentence_id": 743, "sentence_text": "Interestingly , the presence of a breast cancer case < 36 years of age was strongly predictive of the presence of any of the eight mutations screened .", "sentence_char_start_global": 109769, "sentence_char_end_global": 109920, "entities": [{"text": "breast cancer", "type": "ENTITY", "char_start": 34, "char_end": 47, "token_start": 6, "token_end": 7}], "entities_global": [{"text": "breast cancer", "type": "ENTITY", "char_start": 109803, "char_end": 109816, "token_start": 6, "token_end": 7, "note": null}]}
+{"sentence_id": 744, "sentence_text": "Carriers of the same mutation , from different families , shared similar haplotypes , indicating that the mutant alleles were likely to be identical by descent for a mutation in the founder population .", "sentence_char_start_global": 109921, "sentence_char_end_global": 110123, "entities": [], "entities_global": []}
+{"sentence_id": 745, "sentence_text": "The identification of common BRCA1 and BRCA2 mutations will facilitate carrier detection in French Canadian breast cancer and breast / ovarian cancer families .", "sentence_char_start_global": 110124, "sentence_char_end_global": 110284, "entities": [{"text": "breast cancer", "type": "ENTITY", "char_start": 108, "char_end": 121, "token_start": 15, "token_end": 16}, {"text": "breast / ovarian cancer", "type": "ENTITY", "char_start": 126, "char_end": 149, "token_start": 18, "token_end": 21}], "entities_global": [{"text": "breast cancer", "type": "ENTITY", "char_start": 110232, "char_end": 110245, "token_start": 15, "token_end": 16, "note": null}, {"text": "breast / ovarian cancer", "type": "ENTITY", "char_start": 110250, "char_end": 110273, "token_start": 18, "token_end": 21, "note": null}]}
+{"sentence_id": 746, "sentence_text": "Are Dp71 and Dp140 brain dystrophin isoforms related to cognitive impairment in Duchenne muscular dystrophy ?", "sentence_char_start_global": 110285, "sentence_char_end_global": 110394, "entities": [{"text": "cognitive impairment", "type": "ENTITY", "char_start": 56, "char_end": 76, "token_start": 9, "token_end": 10}, {"text": "Duchenne muscular dystrophy", "type": "ENTITY", "char_start": 80, "char_end": 107, "token_start": 12, "token_end": 14}], "entities_global": [{"text": "cognitive impairment", "type": "ENTITY", "char_start": 110341, "char_end": 110361, "token_start": 9, "token_end": 10, "note": null}, {"text": "Duchenne muscular dystrophy", "type": "ENTITY", "char_start": 110365, "char_end": 110392, "token_start": 12, "token_end": 14, "note": null}]}
+{"sentence_id": 747, "sentence_text": "Molecular study and neuropsychological analysis were performed concurrently on 49 patients with Duchenne muscular dystrophy ( DMD ) in order to find a molecular explanation for the cognitive impairment observed in most DMD patients .", "sentence_char_start_global": 110395, "sentence_char_end_global": 110628, "entities": [{"text": "Duchenne muscular dystrophy", "type": "ENTITY", "char_start": 96, "char_end": 123, "token_start": 12, "token_end": 14}, {"text": "DMD", "type": "ENTITY", "char_start": 126, "char_end": 129, "token_start": 16, "token_end": 16}, {"text": "cognitive impairment", "type": "ENTITY", "char_start": 181, "char_end": 201, "token_start": 27, "token_end": 28}, {"text": "DMD", "type": "ENTITY", "char_start": 219, "char_end": 222, "token_start": 32, "token_end": 32}], "entities_global": [{"text": "Duchenne muscular dystrophy", "type": "ENTITY", "char_start": 110491, "char_end": 110518, "token_start": 12, "token_end": 14, "note": null}, {"text": "DMD", "type": "ENTITY", "char_start": 110521, "char_end": 110524, "token_start": 16, "token_end": 16, "note": null}, {"text": "cognitive impairment", "type": "ENTITY", "char_start": 110576, "char_end": 110596, "token_start": 27, "token_end": 28, "note": null}, {"text": "DMD", "type": "ENTITY", "char_start": 110614, "char_end": 110617, "token_start": 32, "token_end": 32, "note": null}]}
+{"sentence_id": 748, "sentence_text": "Complete analysis of the dystrophin gene was performed to define the localization of deletions and duplications in relation to the different DMD promoters .", "sentence_char_start_global": 110629, "sentence_char_end_global": 110785, "entities": [{"text": "DMD", "type": "ENTITY", "char_start": 141, "char_end": 144, "token_start": 21, "token_end": 21}], "entities_global": [{"text": "DMD", "type": "ENTITY", "char_start": 110770, "char_end": 110773, "token_start": 21, "token_end": 21, "note": null}]}
+{"sentence_id": 749, "sentence_text": "Qualitative analysis of the Dp71 transcript and testing for the specific first exon of Dp140 were also carried out .", "sentence_char_start_global": 110786, "sentence_char_end_global": 110902, "entities": [], "entities_global": []}
+{"sentence_id": 750, "sentence_text": "Neuropsychological analysis assessed verbal and visuospatial intelligence , verbal memory , and reading skills .", "sentence_char_start_global": 110903, "sentence_char_end_global": 111015, "entities": [], "entities_global": []}
+{"sentence_id": 751, "sentence_text": "Comparison of molecular and psychometric findings demonstrated that deletions and duplications that were localized in the distal part of the gene seemed to be preferentially associated with cognitive impairment .", "sentence_char_start_global": 111016, "sentence_char_end_global": 111228, "entities": [{"text": "cognitive impairment", "type": "ENTITY", "char_start": 190, "char_end": 210, "token_start": 27, "token_end": 28}], "entities_global": [{"text": "cognitive impairment", "type": "ENTITY", "char_start": 111206, "char_end": 111226, "token_start": 27, "token_end": 28, "note": null}]}
+{"sentence_id": 752, "sentence_text": "Two altered Dp71 transcripts and two deleted Dp140 DNA sequences were found in four patients with severe cerebral dysfunction .", "sentence_char_start_global": 111229, "sentence_char_end_global": 111356, "entities": [{"text": "cerebral dysfunction", "type": "ENTITY", "char_start": 105, "char_end": 125, "token_start": 17, "token_end": 18}], "entities_global": [{"text": "cerebral dysfunction", "type": "ENTITY", "char_start": 111334, "char_end": 111354, "token_start": 17, "token_end": 18, "note": null}]}
+{"sentence_id": 753, "sentence_text": "These findings suggest that some sequences located in the distal part of the gene and , in particular , some DMD isoforms expressed in the brain may be related to the cognitive impairment associated with DMD . .", "sentence_char_start_global": 111357, "sentence_char_end_global": 111568, "entities": [{"text": "DMD", "type": "ENTITY", "char_start": 109, "char_end": 112, "token_start": 20, "token_end": 20}, {"text": "cognitive impairment", "type": "ENTITY", "char_start": 167, "char_end": 187, "token_start": 31, "token_end": 32}, {"text": "DMD", "type": "ENTITY", "char_start": 204, "char_end": 207, "token_start": 35, "token_end": 35}], "entities_global": [{"text": "DMD", "type": "ENTITY", "char_start": 111466, "char_end": 111469, "token_start": 20, "token_end": 20, "note": null}, {"text": "cognitive impairment", "type": "ENTITY", "char_start": 111524, "char_end": 111544, "token_start": 31, "token_end": 32, "note": null}, {"text": "DMD", "type": "ENTITY", "char_start": 111561, "char_end": 111564, "token_start": 35, "token_end": 35, "note": null}]}
+{"sentence_id": 754, "sentence_text": "I1307K APC and hMLH1 mutations in a non - Jewish family with hereditary non - polyposis colorectal cancer .", "sentence_char_start_global": 111569, "sentence_char_end_global": 111676, "entities": [{"text": "hereditary non - polyposis colorectal cancer", "type": "ENTITY", "char_start": 61, "char_end": 105, "token_start": 12, "token_end": 17}], "entities_global": [{"text": "hereditary non - polyposis colorectal cancer", "type": "ENTITY", "char_start": 111630, "char_end": 111674, "token_start": 12, "token_end": 17, "note": null}]}
+{"sentence_id": 755, "sentence_text": "We describe a French Canadian hereditary non - polyposis colorectal cancer ( HNPCC ) kindred which carries a novel truncating mutation in hMLH1 .", "sentence_char_start_global": 111677, "sentence_char_end_global": 111822, "entities": [{"text": "hereditary non - polyposis colorectal cancer", "type": "ENTITY", "char_start": 30, "char_end": 74, "token_start": 5, "token_end": 10}, {"text": "HNPCC", "type": "ENTITY", "char_start": 77, "char_end": 82, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "hereditary non - polyposis colorectal cancer", "type": "ENTITY", "char_start": 111707, "char_end": 111751, "token_start": 5, "token_end": 10, "note": null}, {"text": "HNPCC", "type": "ENTITY", "char_start": 111754, "char_end": 111759, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 756, "sentence_text": "Interestingly , the I1307K APC polymorphism , associated with an increased risk of colorectal cancer , is also present in this family .", "sentence_char_start_global": 111823, "sentence_char_end_global": 111958, "entities": [{"text": "colorectal cancer", "type": "ENTITY", "char_start": 83, "char_end": 100, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "colorectal cancer", "type": "ENTITY", "char_start": 111906, "char_end": 111923, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 757, "sentence_text": "The I1307K polymorphism has previously only been identified in individuals of self - reported Ashkenazi Jewish origins .", "sentence_char_start_global": 111959, "sentence_char_end_global": 112079, "entities": [], "entities_global": []}
+{"sentence_id": 758, "sentence_text": "In addition , in this family , there appears to be no relationship between the I1307K polymorphism and the presence or absence of cancer . .", "sentence_char_start_global": 112080, "sentence_char_end_global": 112220, "entities": [{"text": "cancer", "type": "ENTITY", "char_start": 130, "char_end": 136, "token_start": 23, "token_end": 23}], "entities_global": [{"text": "cancer", "type": "ENTITY", "char_start": 112210, "char_end": 112216, "token_start": 23, "token_end": 23, "note": null}]}
+{"sentence_id": 759, "sentence_text": "Identification of a novel mutation of the CPO gene in a Japanese hereditary coproporphyria family .", "sentence_char_start_global": 112221, "sentence_char_end_global": 112320, "entities": [{"text": "hereditary coproporphyria", "type": "ENTITY", "char_start": 65, "char_end": 90, "token_start": 12, "token_end": 13}], "entities_global": [{"text": "hereditary coproporphyria", "type": "ENTITY", "char_start": 112286, "char_end": 112311, "token_start": 12, "token_end": 13, "note": null}]}
+{"sentence_id": 760, "sentence_text": "Hereditary coproporphyria ( HCP ) is an autosomal dominant disease characterized by a deficiency of coproporphyrinogen oxidase ( CPO ) caused by a mutation in the CPO gene .", "sentence_char_start_global": 112321, "sentence_char_end_global": 112494, "entities": [{"text": "Hereditary coproporphyria", "type": "ENTITY", "char_start": 0, "char_end": 25, "token_start": 0, "token_end": 1}, {"text": "HCP", "type": "ENTITY", "char_start": 28, "char_end": 31, "token_start": 3, "token_end": 3}, {"text": "autosomal dominant disease", "type": "ENTITY", "char_start": 40, "char_end": 66, "token_start": 7, "token_end": 9}, {"text": "deficiency of coproporphyrinogen oxidase", "type": "ENTITY", "char_start": 86, "char_end": 126, "token_start": 13, "token_end": 16}], "entities_global": [{"text": "Hereditary coproporphyria", "type": "ENTITY", "char_start": 112321, "char_end": 112346, "token_start": 0, "token_end": 1, "note": null}, {"text": "HCP", "type": "ENTITY", "char_start": 112349, "char_end": 112352, "token_start": 3, "token_end": 3, "note": null}, {"text": "autosomal dominant disease", "type": "ENTITY", "char_start": 112361, "char_end": 112387, "token_start": 7, "token_end": 9, "note": null}, {"text": "deficiency of coproporphyrinogen oxidase", "type": "ENTITY", "char_start": 112407, "char_end": 112447, "token_start": 13, "token_end": 16, "note": null}]}
+{"sentence_id": 761, "sentence_text": "Only 11 mutations of the gene have been reported in HCP patients .", "sentence_char_start_global": 112495, "sentence_char_end_global": 112561, "entities": [{"text": "HCP", "type": "ENTITY", "char_start": 52, "char_end": 55, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "HCP", "type": "ENTITY", "char_start": 112547, "char_end": 112550, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 762, "sentence_text": "We report another mutation in a Japanese family .", "sentence_char_start_global": 112562, "sentence_char_end_global": 112611, "entities": [], "entities_global": []}
+{"sentence_id": 763, "sentence_text": "Polymerase chain reaction - single strand conformational polymorphism and direct sequence analyses demonstrated a C to T substitution in exon 1 of the CPO gene at nucleotide position 85 , which lies in the putative presequence for targeting to mitochondria .", "sentence_char_start_global": 112612, "sentence_char_end_global": 112870, "entities": [], "entities_global": []}
+{"sentence_id": 764, "sentence_text": "This mutation changes the codon for glutamine to a termination codon at amino acid position 29 .", "sentence_char_start_global": 112871, "sentence_char_end_global": 112967, "entities": [], "entities_global": []}
+{"sentence_id": 765, "sentence_text": "MaeI restriction analysis showed two other carriers in the family .", "sentence_char_start_global": 112968, "sentence_char_end_global": 113035, "entities": [], "entities_global": []}
+{"sentence_id": 766, "sentence_text": "The C - T mutation is located within a recently proposed putative alternative translation initiation codon ( TIC - 1 ) , supporting that TIC - 1 is the real TIC rather than TIC - 2 . .", "sentence_char_start_global": 113036, "sentence_char_end_global": 113220, "entities": [], "entities_global": []}
+{"sentence_id": 767, "sentence_text": "Human complement factor H deficiency associated with hemolytic uremic syndrome .", "sentence_char_start_global": 113221, "sentence_char_end_global": 113301, "entities": [{"text": "Human complement factor H deficiency", "type": "ENTITY", "char_start": 0, "char_end": 36, "token_start": 0, "token_end": 4}, {"text": "hemolytic uremic syndrome", "type": "ENTITY", "char_start": 53, "char_end": 78, "token_start": 7, "token_end": 9}], "entities_global": [{"text": "Human complement factor H deficiency", "type": "ENTITY", "char_start": 113221, "char_end": 113257, "token_start": 0, "token_end": 4, "note": null}, {"text": "hemolytic uremic syndrome", "type": "ENTITY", "char_start": 113274, "char_end": 113299, "token_start": 7, "token_end": 9, "note": null}]}
+{"sentence_id": 768, "sentence_text": "This study reports on six cases of deficiency in the human complement regulatory protein Factor H ( FH ) in the context of an acute renal disease .", "sentence_char_start_global": 113302, "sentence_char_end_global": 113449, "entities": [{"text": "deficiency in the human complement regulatory protein Factor H", "type": "ENTITY", "char_start": 35, "char_end": 97, "token_start": 7, "token_end": 15}, {"text": "acute renal disease", "type": "ENTITY", "char_start": 126, "char_end": 145, "token_start": 24, "token_end": 26}], "entities_global": [{"text": "deficiency in the human complement regulatory protein Factor H", "type": "ENTITY", "char_start": 113337, "char_end": 113399, "token_start": 7, "token_end": 15, "note": null}, {"text": "acute renal disease", "type": "ENTITY", "char_start": 113428, "char_end": 113447, "token_start": 24, "token_end": 26, "note": null}]}
+{"sentence_id": 769, "sentence_text": "Five of the cases were observed in children presenting with idiopathic hemolytic uremic syndrome ( HUS ) .", "sentence_char_start_global": 113450, "sentence_char_end_global": 113556, "entities": [{"text": "hemolytic uremic syndrome", "type": "ENTITY", "char_start": 71, "char_end": 96, "token_start": 11, "token_end": 13}, {"text": "HUS", "type": "ENTITY", "char_start": 99, "char_end": 102, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "hemolytic uremic syndrome", "type": "ENTITY", "char_start": 113521, "char_end": 113546, "token_start": 11, "token_end": 13, "note": null}, {"text": "HUS", "type": "ENTITY", "char_start": 113549, "char_end": 113552, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 770, "sentence_text": "Two of the children exhibited a homozygous deficiency characterized by the absence of the 150 - kD form of Factor H and the presence , upon immunoblotting , of the 42 - kD Factor H - like protein 1 ( FHL - 1 ) and other FH - related protein ( FHR ) bands .", "sentence_char_start_global": 113557, "sentence_char_end_global": 113813, "entities": [], "entities_global": []}
+{"sentence_id": 771, "sentence_text": "Southern blot and PCR analysis of DNA of one patient with homozygous deficiency ruled out the presence of a large deletion of the FH gene as the underlying defect for the deficiency .", "sentence_char_start_global": 113814, "sentence_char_end_global": 113997, "entities": [], "entities_global": []}
+{"sentence_id": 772, "sentence_text": "The other four children presented with heterozygous deficiency and exhibited a normal immunoblotting pattern of proteins of the FH family .", "sentence_char_start_global": 113998, "sentence_char_end_global": 114137, "entities": [], "entities_global": []}
+{"sentence_id": 773, "sentence_text": "Factor H deficiency is the only complement deficiency associated with HUS .", "sentence_char_start_global": 114138, "sentence_char_end_global": 114213, "entities": [{"text": "Factor H deficiency", "type": "ENTITY", "char_start": 0, "char_end": 19, "token_start": 0, "token_end": 2}, {"text": "complement deficiency", "type": "ENTITY", "char_start": 32, "char_end": 53, "token_start": 6, "token_end": 7}, {"text": "HUS", "type": "ENTITY", "char_start": 70, "char_end": 73, "token_start": 10, "token_end": 10}], "entities_global": [{"text": "Factor H deficiency", "type": "ENTITY", "char_start": 114138, "char_end": 114157, "token_start": 0, "token_end": 2, "note": null}, {"text": "complement deficiency", "type": "ENTITY", "char_start": 114170, "char_end": 114191, "token_start": 6, "token_end": 7, "note": null}, {"text": "HUS", "type": "ENTITY", "char_start": 114208, "char_end": 114211, "token_start": 10, "token_end": 10, "note": null}]}
+{"sentence_id": 774, "sentence_text": "These observations suggest a role for FH and / or FH receptors in the pathogenesis of idiopathic HUS . .", "sentence_char_start_global": 114214, "sentence_char_end_global": 114318, "entities": [{"text": "HUS", "type": "ENTITY", "char_start": 97, "char_end": 100, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "HUS", "type": "ENTITY", "char_start": 114311, "char_end": 114314, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 775, "sentence_text": "Further evidence for a major ancient mutation underlying myotonic dystrophy from linkage disequilibrium studies in the Japanese population .", "sentence_char_start_global": 114319, "sentence_char_end_global": 114459, "entities": [{"text": "myotonic dystrophy", "type": "ENTITY", "char_start": 57, "char_end": 75, "token_start": 8, "token_end": 9}], "entities_global": [{"text": "myotonic dystrophy", "type": "ENTITY", "char_start": 114376, "char_end": 114394, "token_start": 8, "token_end": 9, "note": null}]}
+{"sentence_id": 776, "sentence_text": "The myotonic dystrophy ( DM ) mutation is an unstable ( CTG ) n repeat , present at a copy number of 5 - 37 repeats on normal chromosomes but amplified to 50 - 3000 copies on DM chromosomes .", "sentence_char_start_global": 114460, "sentence_char_end_global": 114651, "entities": [{"text": "myotonic dystrophy", "type": "ENTITY", "char_start": 4, "char_end": 22, "token_start": 1, "token_end": 2}, {"text": "DM", "type": "ENTITY", "char_start": 25, "char_end": 27, "token_start": 4, "token_end": 4}, {"text": "DM", "type": "ENTITY", "char_start": 175, "char_end": 177, "token_start": 37, "token_end": 37}], "entities_global": [{"text": "myotonic dystrophy", "type": "ENTITY", "char_start": 114464, "char_end": 114482, "token_start": 1, "token_end": 2, "note": null}, {"text": "DM", "type": "ENTITY", "char_start": 114485, "char_end": 114487, "token_start": 4, "token_end": 4, "note": null}, {"text": "DM", "type": "ENTITY", "char_start": 114635, "char_end": 114637, "token_start": 37, "token_end": 37, "note": null}]}
+{"sentence_id": 777, "sentence_text": "Previous findings in Caucasian populations of a DM founder chromosome raise a question about the molecular events involved in the expansion mutation .", "sentence_char_start_global": 114652, "sentence_char_end_global": 114802, "entities": [{"text": "DM", "type": "ENTITY", "char_start": 48, "char_end": 50, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "DM", "type": "ENTITY", "char_start": 114700, "char_end": 114702, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 778, "sentence_text": "To investigate whether a founder chromosome for the DM mutation exists in the Japanese population , we genotyped families using polymorphic markers near the ( CTG ) n repeat region and constructed haplotypes .", "sentence_char_start_global": 114803, "sentence_char_end_global": 115012, "entities": [{"text": "DM", "type": "ENTITY", "char_start": 52, "char_end": 54, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "DM", "type": "ENTITY", "char_start": 114855, "char_end": 114857, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 779, "sentence_text": "Six different haplotypes were found and DM alleles were always haplotype A .", "sentence_char_start_global": 115013, "sentence_char_end_global": 115089, "entities": [{"text": "DM", "type": "ENTITY", "char_start": 40, "char_end": 42, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "DM", "type": "ENTITY", "char_start": 115053, "char_end": 115055, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 780, "sentence_text": "To find an origin of the ( CTG ) n repeat mutation and to investigate the mechanism of the expansion mutation in the Japanese population we have studied 90 Japanese DM families comprising 190 affected and 130 unaffected members .", "sentence_char_start_global": 115090, "sentence_char_end_global": 115319, "entities": [{"text": "DM", "type": "ENTITY", "char_start": 165, "char_end": 167, "token_start": 30, "token_end": 30}], "entities_global": [{"text": "DM", "type": "ENTITY", "char_start": 115255, "char_end": 115257, "token_start": 30, "token_end": 30, "note": null}]}
+{"sentence_id": 781, "sentence_text": "The results suggest that a few common ancestral mutations in both Caucasian and Japanese populations have originated by expansion of an ancestral n = 5 repeat to n = 19 - 37 copies .", "sentence_char_start_global": 115320, "sentence_char_end_global": 115502, "entities": [], "entities_global": []}
+{"sentence_id": 782, "sentence_text": "These data support multistep models of triplet repeat expansion that have been proposed for both DM and Friedreichs ataxia . .", "sentence_char_start_global": 115503, "sentence_char_end_global": 115629, "entities": [{"text": "DM", "type": "ENTITY", "char_start": 97, "char_end": 99, "token_start": 15, "token_end": 15}, {"text": "Friedreichs ataxia", "type": "ENTITY", "char_start": 104, "char_end": 122, "token_start": 17, "token_end": 18}], "entities_global": [{"text": "DM", "type": "ENTITY", "char_start": 115600, "char_end": 115602, "token_start": 15, "token_end": 15, "note": null}, {"text": "Friedreichs ataxia", "type": "ENTITY", "char_start": 115607, "char_end": 115625, "token_start": 17, "token_end": 18, "note": null}]}
+{"sentence_id": 783, "sentence_text": "The molecular basis of C6 deficiency in the western Cape , South Africa .", "sentence_char_start_global": 115630, "sentence_char_end_global": 115703, "entities": [{"text": "C6 deficiency", "type": "ENTITY", "char_start": 23, "char_end": 36, "token_start": 4, "token_end": 5}], "entities_global": [{"text": "C6 deficiency", "type": "ENTITY", "char_start": 115653, "char_end": 115666, "token_start": 4, "token_end": 5, "note": null}]}
+{"sentence_id": 784, "sentence_text": "Deficiency of the sixth component of human complement ( C6 ) has been reported in a number of families from the western Cape , South Africa .", "sentence_char_start_global": 115704, "sentence_char_end_global": 115845, "entities": [{"text": "Deficiency of the sixth component of human complement", "type": "ENTITY", "char_start": 0, "char_end": 53, "token_start": 0, "token_end": 7}], "entities_global": [{"text": "Deficiency of the sixth component of human complement", "type": "ENTITY", "char_start": 115704, "char_end": 115757, "token_start": 0, "token_end": 7, "note": null}]}
+{"sentence_id": 785, "sentence_text": "Meningococcal disease is endemic in the Cape and almost all pedigrees of total C6 deficiency ( C6Q0 ) have been ascertained because of recurrent disease .", "sentence_char_start_global": 115846, "sentence_char_end_global": 116000, "entities": [{"text": "Meningococcal disease", "type": "ENTITY", "char_start": 0, "char_end": 21, "token_start": 0, "token_end": 1}, {"text": "C6 deficiency", "type": "ENTITY", "char_start": 79, "char_end": 92, "token_start": 13, "token_end": 14}], "entities_global": [{"text": "Meningococcal disease", "type": "ENTITY", "char_start": 115846, "char_end": 115867, "token_start": 0, "token_end": 1, "note": null}, {"text": "C6 deficiency", "type": "ENTITY", "char_start": 115925, "char_end": 115938, "token_start": 13, "token_end": 14, "note": null}]}
+{"sentence_id": 786, "sentence_text": "We have sequenced the expressed exons of the C6 gene from selected cases and have found three molecular defects leading to total deficiency 879delG , which is the common defect in the Cape and hitherto unreported , and 1195delC and 1936delG , which have been previously reported in African - Americans .", "sentence_char_start_global": 116001, "sentence_char_end_global": 116304, "entities": [], "entities_global": []}
+{"sentence_id": 787, "sentence_text": "We also show that the 879delG and 1195delC defects are associated with characteristic C6 / C7 region DNA marker haplotypes , although small variations were observed .", "sentence_char_start_global": 116305, "sentence_char_end_global": 116471, "entities": [], "entities_global": []}
+{"sentence_id": 788, "sentence_text": "The 1936delG defect was observed only once in the Cape , but its associated haplotype could be deduced .", "sentence_char_start_global": 116472, "sentence_char_end_global": 116576, "entities": [], "entities_global": []}
+{"sentence_id": 789, "sentence_text": "The data from the haplotypes indicate that these three molecular defects account for the defects in all the 38 unrelated C6Q0 individuals we have studied from the Cape .", "sentence_char_start_global": 116577, "sentence_char_end_global": 116746, "entities": [], "entities_global": []}
+{"sentence_id": 790, "sentence_text": "We have also observed the 879delG defect in two Dutch C6 - deficient kindreds , but the 879delG defect in the Cape probably did not come from The Netherlands . .", "sentence_char_start_global": 116747, "sentence_char_end_global": 116908, "entities": [{"text": "C6 - deficient", "type": "ENTITY", "char_start": 54, "char_end": 68, "token_start": 10, "token_end": 12}], "entities_global": [{"text": "C6 - deficient", "type": "ENTITY", "char_start": 116801, "char_end": 116815, "token_start": 10, "token_end": 12, "note": null}]}
+{"sentence_id": 791, "sentence_text": "Complement C7 deficiency : seven further molecular defects and their associated marker haplotypes .", "sentence_char_start_global": 116909, "sentence_char_end_global": 117008, "entities": [{"text": "Complement C7 deficiency", "type": "ENTITY", "char_start": 0, "char_end": 24, "token_start": 0, "token_end": 2}], "entities_global": [{"text": "Complement C7 deficiency", "type": "ENTITY", "char_start": 116909, "char_end": 116933, "token_start": 0, "token_end": 2, "note": null}]}
+{"sentence_id": 792, "sentence_text": "Seven further molecular bases of C7 deficiency are described .", "sentence_char_start_global": 117009, "sentence_char_end_global": 117071, "entities": [{"text": "C7 deficiency", "type": "ENTITY", "char_start": 33, "char_end": 46, "token_start": 5, "token_end": 6}], "entities_global": [{"text": "C7 deficiency", "type": "ENTITY", "char_start": 117042, "char_end": 117055, "token_start": 5, "token_end": 6, "note": null}]}
+{"sentence_id": 793, "sentence_text": "All these new molecular defects involve single - nucleotide events , deletions and substitutions , some of which alter splice sites , and others codons .", "sentence_char_start_global": 117072, "sentence_char_end_global": 117225, "entities": [], "entities_global": []}
+{"sentence_id": 794, "sentence_text": "They are distributed along the C7 gene , but predominantly towards the 3 end .", "sentence_char_start_global": 117226, "sentence_char_end_global": 117304, "entities": [], "entities_global": []}
+{"sentence_id": 795, "sentence_text": "All were found in compound heterozygous individuals .", "sentence_char_start_global": 117305, "sentence_char_end_global": 117358, "entities": [], "entities_global": []}
+{"sentence_id": 796, "sentence_text": "The C6 / C7 marker haplotypes associated with most C7 defects are tabulated . .", "sentence_char_start_global": 117359, "sentence_char_end_global": 117438, "entities": [{"text": "C7 defects", "type": "ENTITY", "char_start": 51, "char_end": 61, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "C7 defects", "type": "ENTITY", "char_start": 117410, "char_end": 117420, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 797, "sentence_text": "A genome - wide search for chromosomal loci linked to mental health wellness in relatives at high risk for bipolar affective disorder among the Old Order Amish .", "sentence_char_start_global": 117439, "sentence_char_end_global": 117600, "entities": [{"text": "bipolar affective disorder", "type": "ENTITY", "char_start": 107, "char_end": 133, "token_start": 19, "token_end": 21}], "entities_global": [{"text": "bipolar affective disorder", "type": "ENTITY", "char_start": 117546, "char_end": 117572, "token_start": 19, "token_end": 21, "note": null}]}
+{"sentence_id": 798, "sentence_text": "Bipolar affective disorder ( BPAD ; manic - depressive illness ) is characterized by episodes of mania and / or hypomania interspersed with periods of depression .", "sentence_char_start_global": 117601, "sentence_char_end_global": 117764, "entities": [{"text": "Bipolar affective disorder", "type": "ENTITY", "char_start": 0, "char_end": 26, "token_start": 0, "token_end": 2}, {"text": "BPAD", "type": "ENTITY", "char_start": 29, "char_end": 33, "token_start": 4, "token_end": 4}, {"text": "manic - depressive illness", "type": "ENTITY", "char_start": 36, "char_end": 62, "token_start": 6, "token_end": 9}, {"text": "mania", "type": "ENTITY", "char_start": 97, "char_end": 102, "token_start": 16, "token_end": 16}, {"text": "hypomania", "type": "ENTITY", "char_start": 112, "char_end": 121, "token_start": 20, "token_end": 20}, {"text": "depression", "type": "ENTITY", "char_start": 151, "char_end": 161, "token_start": 25, "token_end": 25}], "entities_global": [{"text": "Bipolar affective disorder", "type": "ENTITY", "char_start": 117601, "char_end": 117627, "token_start": 0, "token_end": 2, "note": null}, {"text": "BPAD", "type": "ENTITY", "char_start": 117630, "char_end": 117634, "token_start": 4, "token_end": 4, "note": null}, {"text": "manic - depressive illness", "type": "ENTITY", "char_start": 117637, "char_end": 117663, "token_start": 6, "token_end": 9, "note": null}, {"text": "mania", "type": "ENTITY", "char_start": 117698, "char_end": 117703, "token_start": 16, "token_end": 16, "note": null}, {"text": "hypomania", "type": "ENTITY", "char_start": 117713, "char_end": 117722, "token_start": 20, "token_end": 20, "note": null}, {"text": "depression", "type": "ENTITY", "char_start": 117752, "char_end": 117762, "token_start": 25, "token_end": 25, "note": null}]}
+{"sentence_id": 799, "sentence_text": "Compelling evidence supports a significant genetic component in the susceptibility to develop BPAD .", "sentence_char_start_global": 117765, "sentence_char_end_global": 117865, "entities": [{"text": "BPAD", "type": "ENTITY", "char_start": 94, "char_end": 98, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "BPAD", "type": "ENTITY", "char_start": 117859, "char_end": 117863, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 800, "sentence_text": "To date , however , linkage studies have attempted only to identify chromosomal loci that cause or increase the risk of developing BPAD .", "sentence_char_start_global": 117866, "sentence_char_end_global": 118003, "entities": [{"text": "BPAD", "type": "ENTITY", "char_start": 131, "char_end": 135, "token_start": 22, "token_end": 22}], "entities_global": [{"text": "BPAD", "type": "ENTITY", "char_start": 117997, "char_end": 118001, "token_start": 22, "token_end": 22, "note": null}]}
+{"sentence_id": 801, "sentence_text": "To determine whether there could be protective alleles that prevent or reduce the risk of developing BPAD , similar to what is observed in other genetic disorders , we used mental health wellness ( absence of any psychiatric disorder ) as the phenotype in our genome - wide linkage scan of several large multigeneration Old Order Amish pedigrees exhibiting an extremely high incidence of BPAD .", "sentence_char_start_global": 118004, "sentence_char_end_global": 118398, "entities": [{"text": "BPAD", "type": "ENTITY", "char_start": 101, "char_end": 105, "token_start": 16, "token_end": 16}, {"text": "genetic disorders", "type": "ENTITY", "char_start": 145, "char_end": 162, "token_start": 25, "token_end": 26}, {"text": "psychiatric disorder", "type": "ENTITY", "char_start": 213, "char_end": 233, "token_start": 37, "token_end": 38}, {"text": "BPAD", "type": "ENTITY", "char_start": 388, "char_end": 392, "token_start": 64, "token_end": 64}], "entities_global": [{"text": "BPAD", "type": "ENTITY", "char_start": 118105, "char_end": 118109, "token_start": 16, "token_end": 16, "note": null}, {"text": "genetic disorders", "type": "ENTITY", "char_start": 118149, "char_end": 118166, "token_start": 25, "token_end": 26, "note": null}, {"text": "psychiatric disorder", "type": "ENTITY", "char_start": 118217, "char_end": 118237, "token_start": 37, "token_end": 38, "note": null}, {"text": "BPAD", "type": "ENTITY", "char_start": 118392, "char_end": 118396, "token_start": 64, "token_end": 64, "note": null}]}
+{"sentence_id": 802, "sentence_text": "We have found strong evidence for a locus on chromosome 4p at D4S2949 ( maximum GENEHUNTER - PLUS nonparametric linkage score = 4 . 05 , P = 5 . 22 x 10 ( - 4 ) ; SIBPAL Pempirical value < 3 x 10 ( - 5 ) ) and suggestive evidence for a locus on chromosome 4q at D4S397 ( maximum GENEHUNTER - PLUS nonparametric linkage score = 3 . 29 , P = 2 . 57 x 10 ( - 3 ) ; SIBPAL Pempirical value < 1 x 10 ( - 3 ) ) that are linked to mental health wellness .", "sentence_char_start_global": 118399, "sentence_char_end_global": 118847, "entities": [], "entities_global": []}
+{"sentence_id": 803, "sentence_text": "These findings are consistent with the hypothesis that certain alleles could prevent or modify the clinical manifestations of BPAD and perhaps other related affective disorders .", "sentence_char_start_global": 118848, "sentence_char_end_global": 119026, "entities": [{"text": "BPAD", "type": "ENTITY", "char_start": 126, "char_end": 130, "token_start": 18, "token_end": 18}, {"text": "affective disorders", "type": "ENTITY", "char_start": 157, "char_end": 176, "token_start": 23, "token_end": 24}], "entities_global": [{"text": "BPAD", "type": "ENTITY", "char_start": 118974, "char_end": 118978, "token_start": 18, "token_end": 18, "note": null}, {"text": "affective disorders", "type": "ENTITY", "char_start": 119005, "char_end": 119024, "token_start": 23, "token_end": 24, "note": null}]}
+{"sentence_id": 804, "sentence_text": "Segregation distortion in myotonic dystrophy .", "sentence_char_start_global": 119027, "sentence_char_end_global": 119073, "entities": [{"text": "myotonic dystrophy", "type": "ENTITY", "char_start": 26, "char_end": 44, "token_start": 3, "token_end": 4}], "entities_global": [{"text": "myotonic dystrophy", "type": "ENTITY", "char_start": 119053, "char_end": 119071, "token_start": 3, "token_end": 4, "note": null}]}
+{"sentence_id": 805, "sentence_text": "Myotonic dystrophy ( DM ) is an autosomal dominant disease which , in the typical pedigree , shows a three generation anticipation cascade .", "sentence_char_start_global": 119074, "sentence_char_end_global": 119214, "entities": [{"text": "Myotonic dystrophy", "type": "ENTITY", "char_start": 0, "char_end": 18, "token_start": 0, "token_end": 1}, {"text": "DM", "type": "ENTITY", "char_start": 21, "char_end": 23, "token_start": 3, "token_end": 3}, {"text": "autosomal dominant disease", "type": "ENTITY", "char_start": 32, "char_end": 58, "token_start": 7, "token_end": 9}], "entities_global": [{"text": "Myotonic dystrophy", "type": "ENTITY", "char_start": 119074, "char_end": 119092, "token_start": 0, "token_end": 1, "note": null}, {"text": "DM", "type": "ENTITY", "char_start": 119095, "char_end": 119097, "token_start": 3, "token_end": 3, "note": null}, {"text": "autosomal dominant disease", "type": "ENTITY", "char_start": 119106, "char_end": 119132, "token_start": 7, "token_end": 9, "note": null}]}
+{"sentence_id": 806, "sentence_text": "This results in infertility and congenital myotonic dystrophy ( CDM ) with the disappearance of DM in that pedigree .", "sentence_char_start_global": 119215, "sentence_char_end_global": 119332, "entities": [{"text": "infertility", "type": "ENTITY", "char_start": 16, "char_end": 27, "token_start": 3, "token_end": 3}, {"text": "congenital myotonic dystrophy", "type": "ENTITY", "char_start": 32, "char_end": 61, "token_start": 5, "token_end": 7}, {"text": "CDM", "type": "ENTITY", "char_start": 64, "char_end": 67, "token_start": 9, "token_end": 9}, {"text": "DM", "type": "ENTITY", "char_start": 96, "char_end": 98, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "infertility", "type": "ENTITY", "char_start": 119231, "char_end": 119242, "token_start": 3, "token_end": 3, "note": null}, {"text": "congenital myotonic dystrophy", "type": "ENTITY", "char_start": 119247, "char_end": 119276, "token_start": 5, "token_end": 7, "note": null}, {"text": "CDM", "type": "ENTITY", "char_start": 119279, "char_end": 119282, "token_start": 9, "token_end": 9, "note": null}, {"text": "DM", "type": "ENTITY", "char_start": 119311, "char_end": 119313, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 807, "sentence_text": "The concept of segregation distortion , where there is preferential transmission of the larger allele at the DM locus , has been put forward to explain partially the maintenance of DM in the population .", "sentence_char_start_global": 119333, "sentence_char_end_global": 119536, "entities": [{"text": "DM", "type": "ENTITY", "char_start": 109, "char_end": 111, "token_start": 17, "token_end": 17}, {"text": "DM", "type": "ENTITY", "char_start": 181, "char_end": 183, "token_start": 30, "token_end": 30}], "entities_global": [{"text": "DM", "type": "ENTITY", "char_start": 119442, "char_end": 119444, "token_start": 17, "token_end": 17, "note": null}, {"text": "DM", "type": "ENTITY", "char_start": 119514, "char_end": 119516, "token_start": 30, "token_end": 30, "note": null}]}
+{"sentence_id": 808, "sentence_text": "In a survey of DM in Northern Ireland , 59 pedigrees were ascertained .", "sentence_char_start_global": 119537, "sentence_char_end_global": 119608, "entities": [{"text": "DM", "type": "ENTITY", "char_start": 15, "char_end": 17, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "DM", "type": "ENTITY", "char_start": 119552, "char_end": 119554, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 809, "sentence_text": "Sibships where the status of all the members had been identified were examined to determine the transmission of the DM expansion from affected parents to their offspring .", "sentence_char_start_global": 119609, "sentence_char_end_global": 119780, "entities": [{"text": "DM", "type": "ENTITY", "char_start": 116, "char_end": 118, "token_start": 19, "token_end": 19}], "entities_global": [{"text": "DM", "type": "ENTITY", "char_start": 119725, "char_end": 119727, "token_start": 19, "token_end": 19, "note": null}]}
+{"sentence_id": 810, "sentence_text": "Where the transmitting parent was male , 58 .", "sentence_char_start_global": 119781, "sentence_char_end_global": 119826, "entities": [], "entities_global": []}
+{"sentence_id": 811, "sentence_text": "3 % of the offspring were affected , and in the case of a female transmitting parent , 68 .", "sentence_char_start_global": 119827, "sentence_char_end_global": 119918, "entities": [], "entities_global": []}
+{"sentence_id": 812, "sentence_text": "7 % were affected .", "sentence_char_start_global": 119919, "sentence_char_end_global": 119938, "entities": [], "entities_global": []}
+{"sentence_id": 813, "sentence_text": "Studies on meiotic drive in DM have shown increased transmission of the larger allele at the DM locus in non - DM heterozygotes for CTGn .", "sentence_char_start_global": 119939, "sentence_char_end_global": 120077, "entities": [{"text": "DM", "type": "ENTITY", "char_start": 28, "char_end": 30, "token_start": 5, "token_end": 5}, {"text": "DM", "type": "ENTITY", "char_start": 93, "char_end": 95, "token_start": 16, "token_end": 16}], "entities_global": [{"text": "DM", "type": "ENTITY", "char_start": 119967, "char_end": 119969, "token_start": 5, "token_end": 5, "note": null}, {"text": "DM", "type": "ENTITY", "char_start": 120032, "char_end": 120034, "token_start": 16, "token_end": 16, "note": null}]}
+{"sentence_id": 814, "sentence_text": "This study provides further evidence that the DM expansion tends to be transmitted preferentially .", "sentence_char_start_global": 120078, "sentence_char_end_global": 120177, "entities": [{"text": "DM", "type": "ENTITY", "char_start": 46, "char_end": 48, "token_start": 7, "token_end": 7}], "entities_global": [{"text": "DM", "type": "ENTITY", "char_start": 120124, "char_end": 120126, "token_start": 7, "token_end": 7, "note": null}]}
+{"sentence_id": 815, "sentence_text": "Diagnosis of hemochromatosis .", "sentence_char_start_global": 120178, "sentence_char_end_global": 120208, "entities": [{"text": "hemochromatosis", "type": "ENTITY", "char_start": 13, "char_end": 28, "token_start": 2, "token_end": 2}], "entities_global": [{"text": "hemochromatosis", "type": "ENTITY", "char_start": 120191, "char_end": 120206, "token_start": 2, "token_end": 2, "note": null}]}
+{"sentence_id": 816, "sentence_text": "If untreated , hemochromatosis can cause serious illness and early death , but the disease is still substantially under - diagnosed .", "sentence_char_start_global": 120209, "sentence_char_end_global": 120342, "entities": [{"text": "hemochromatosis", "type": "ENTITY", "char_start": 15, "char_end": 30, "token_start": 3, "token_end": 3}, {"text": "early death", "type": "ENTITY", "char_start": 61, "char_end": 72, "token_start": 9, "token_end": 10}], "entities_global": [{"text": "hemochromatosis", "type": "ENTITY", "char_start": 120224, "char_end": 120239, "token_start": 3, "token_end": 3, "note": null}, {"text": "early death", "type": "ENTITY", "char_start": 120270, "char_end": 120281, "token_start": 9, "token_end": 10, "note": null}]}
+{"sentence_id": 817, "sentence_text": "The cornerstone of screening and case detection is the measurement of serum transferrin saturation and the serum ferritin level .", "sentence_char_start_global": 120343, "sentence_char_end_global": 120472, "entities": [], "entities_global": []}
+{"sentence_id": 818, "sentence_text": "Once the diagnosis is suspected , physicians must use serum ferritin levels and hepatic iron stores on liver biopsy specimens to assess patients for the presence of iron overload .", "sentence_char_start_global": 120473, "sentence_char_end_global": 120653, "entities": [{"text": "iron overload", "type": "ENTITY", "char_start": 165, "char_end": 178, "token_start": 27, "token_end": 28}], "entities_global": [{"text": "iron overload", "type": "ENTITY", "char_start": 120638, "char_end": 120651, "token_start": 27, "token_end": 28, "note": null}]}
+{"sentence_id": 819, "sentence_text": "Liver biopsy is also used to establish the presence or absence of cirrhosis , which can affect prognosis and management .", "sentence_char_start_global": 120654, "sentence_char_end_global": 120775, "entities": [{"text": "cirrhosis", "type": "ENTITY", "char_start": 66, "char_end": 75, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "cirrhosis", "type": "ENTITY", "char_start": 120720, "char_end": 120729, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 820, "sentence_text": "A DNA - based test for the HFE gene is commercially available , but its place in the diagnosis of hemochromatosis is still being evaluated .", "sentence_char_start_global": 120776, "sentence_char_end_global": 120916, "entities": [{"text": "hemochromatosis", "type": "ENTITY", "char_start": 98, "char_end": 113, "token_start": 20, "token_end": 20}], "entities_global": [{"text": "hemochromatosis", "type": "ENTITY", "char_start": 120874, "char_end": 120889, "token_start": 20, "token_end": 20, "note": null}]}
+{"sentence_id": 821, "sentence_text": "Currently , the most useful role for this test is in the detection of hemochromatosis in the family members of patients with a proven case of the disease .", "sentence_char_start_global": 120917, "sentence_char_end_global": 121072, "entities": [{"text": "hemochromatosis", "type": "ENTITY", "char_start": 70, "char_end": 85, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "hemochromatosis", "type": "ENTITY", "char_start": 120987, "char_end": 121002, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 822, "sentence_text": "It is crucial to diagnose hemochromatosis before hepatic cirrhosis develops because phlebotomy therapy can avert serious chronic disease and can even lead to normal life expectancy . .", "sentence_char_start_global": 121073, "sentence_char_end_global": 121257, "entities": [{"text": "hemochromatosis", "type": "ENTITY", "char_start": 26, "char_end": 41, "token_start": 5, "token_end": 5}, {"text": "hepatic cirrhosis", "type": "ENTITY", "char_start": 49, "char_end": 66, "token_start": 7, "token_end": 8}], "entities_global": [{"text": "hemochromatosis", "type": "ENTITY", "char_start": 121099, "char_end": 121114, "token_start": 5, "token_end": 5, "note": null}, {"text": "hepatic cirrhosis", "type": "ENTITY", "char_start": 121122, "char_end": 121139, "token_start": 7, "token_end": 8, "note": null}]}
+{"sentence_id": 823, "sentence_text": "Prevalence of the I1307K APC gene variant in Israeli Jews of differing ethnic origin and risk for colorectal cancer .", "sentence_char_start_global": 121258, "sentence_char_end_global": 121375, "entities": [{"text": "APC", "type": "ENTITY", "char_start": 25, "char_end": 28, "token_start": 4, "token_end": 4}, {"text": "colorectal cancer", "type": "ENTITY", "char_start": 98, "char_end": 115, "token_start": 17, "token_end": 18}], "entities_global": [{"text": "APC", "type": "ENTITY", "char_start": 121283, "char_end": 121286, "token_start": 4, "token_end": 4, "note": null}, {"text": "colorectal cancer", "type": "ENTITY", "char_start": 121356, "char_end": 121373, "token_start": 17, "token_end": 18, "note": null}]}
+{"sentence_id": 824, "sentence_text": "BACKGROUND & AIMS Israeli Jews of European birth , i . e . , Ashkenazim , have the highest colorectal cancer incidence of any Israeli ethnic group .", "sentence_char_start_global": 121376, "sentence_char_end_global": 121524, "entities": [{"text": "colorectal cancer", "type": "ENTITY", "char_start": 91, "char_end": 108, "token_start": 19, "token_end": 20}], "entities_global": [{"text": "colorectal cancer", "type": "ENTITY", "char_start": 121467, "char_end": 121484, "token_start": 19, "token_end": 20, "note": null}]}
+{"sentence_id": 825, "sentence_text": "The I1307K APC gene variant was found in 6 .", "sentence_char_start_global": 121525, "sentence_char_end_global": 121569, "entities": [{"text": "APC", "type": "ENTITY", "char_start": 11, "char_end": 14, "token_start": 2, "token_end": 2}], "entities_global": [{"text": "APC", "type": "ENTITY", "char_start": 121536, "char_end": 121539, "token_start": 2, "token_end": 2, "note": null}]}
+{"sentence_id": 826, "sentence_text": "1 % of American Jews , 28 % of their familial colorectal cancer cases , but not in non - Jews .", "sentence_char_start_global": 121570, "sentence_char_end_global": 121665, "entities": [{"text": "colorectal cancer", "type": "ENTITY", "char_start": 46, "char_end": 63, "token_start": 11, "token_end": 12}], "entities_global": [{"text": "colorectal cancer", "type": "ENTITY", "char_start": 121616, "char_end": 121633, "token_start": 11, "token_end": 12, "note": null}]}
+{"sentence_id": 827, "sentence_text": "We assessed the I1307K prevalence in Israeli Jews of differing ethnic origin and risk for colorectal cancer .", "sentence_char_start_global": 121666, "sentence_char_end_global": 121775, "entities": [{"text": "colorectal cancer", "type": "ENTITY", "char_start": 90, "char_end": 107, "token_start": 15, "token_end": 16}], "entities_global": [{"text": "colorectal cancer", "type": "ENTITY", "char_start": 121756, "char_end": 121773, "token_start": 15, "token_end": 16, "note": null}]}
+{"sentence_id": 828, "sentence_text": "METHODS DNA samples from 500 unrelated Jews of European or non - European origin , with or without a personal and / or family history of neoplasia , were examined for the I1307K variant by the allele - specific oligonucleotide ( ASO ) method .", "sentence_char_start_global": 121776, "sentence_char_end_global": 122019, "entities": [{"text": "neoplasia", "type": "ENTITY", "char_start": 137, "char_end": 146, "token_start": 26, "token_end": 26}], "entities_global": [{"text": "neoplasia", "type": "ENTITY", "char_start": 121913, "char_end": 121922, "token_start": 26, "token_end": 26, "note": null}]}
+{"sentence_id": 829, "sentence_text": "RESULTS In persons at average risk for colorectal cancer , I1307K was found in 5 .", "sentence_char_start_global": 122020, "sentence_char_end_global": 122102, "entities": [{"text": "colorectal cancer", "type": "ENTITY", "char_start": 39, "char_end": 56, "token_start": 7, "token_end": 8}], "entities_global": [{"text": "colorectal cancer", "type": "ENTITY", "char_start": 122059, "char_end": 122076, "token_start": 7, "token_end": 8, "note": null}]}
+{"sentence_id": 830, "sentence_text": "0 % of 120 European and 1 .", "sentence_char_start_global": 122103, "sentence_char_end_global": 122130, "entities": [], "entities_global": []}
+{"sentence_id": 831, "sentence_text": "6 % of 188 non - European Jews ( P = 0 . 08 ) .", "sentence_char_start_global": 122131, "sentence_char_end_global": 122178, "entities": [], "entities_global": []}
+{"sentence_id": 832, "sentence_text": "It occurred in 15 .", "sentence_char_start_global": 122179, "sentence_char_end_global": 122198, "entities": [], "entities_global": []}
+{"sentence_id": 833, "sentence_text": "4 % of 52 Ashkenazi Israelis with familial cancer ( P = 0 . 02 ) and was not detected in 51 non - European Jews at increased cancer risk .", "sentence_char_start_global": 122199, "sentence_char_end_global": 122337, "entities": [{"text": "cancer", "type": "ENTITY", "char_start": 43, "char_end": 49, "token_start": 8, "token_end": 8}, {"text": "cancer", "type": "ENTITY", "char_start": 125, "char_end": 131, "token_start": 28, "token_end": 28}], "entities_global": [{"text": "cancer", "type": "ENTITY", "char_start": 122242, "char_end": 122248, "token_start": 8, "token_end": 8, "note": null}, {"text": "cancer", "type": "ENTITY", "char_start": 122324, "char_end": 122330, "token_start": 28, "token_end": 28, "note": null}]}
+{"sentence_id": 834, "sentence_text": "Colorectal neoplasia occurred personally or in the families of 13 of 20 Ashkenazi I1307K carriers , 8 of whom also had a personal or family history of noncolonic neoplasia .", "sentence_char_start_global": 122338, "sentence_char_end_global": 122511, "entities": [{"text": "Colorectal neoplasia", "type": "ENTITY", "char_start": 0, "char_end": 20, "token_start": 0, "token_end": 1}, {"text": "neoplasia", "type": "ENTITY", "char_start": 162, "char_end": 171, "token_start": 28, "token_end": 28}], "entities_global": [{"text": "Colorectal neoplasia", "type": "ENTITY", "char_start": 122338, "char_end": 122358, "token_start": 0, "token_end": 1, "note": null}, {"text": "neoplasia", "type": "ENTITY", "char_start": 122500, "char_end": 122509, "token_start": 28, "token_end": 28, "note": null}]}
+{"sentence_id": 835, "sentence_text": "CONCLUSIONS The I1307K APC variant may represent a susceptibility gene for colorectal , or other , cancers in Ashkenazi Jews , and partially explains the higher incidence of colorectal cancer in European Israelis .", "sentence_char_start_global": 122512, "sentence_char_end_global": 122726, "entities": [{"text": "colorectal , or other , cancers", "type": "ENTITY", "char_start": 75, "char_end": 106, "token_start": 11, "token_end": 16}, {"text": "colorectal cancer", "type": "ENTITY", "char_start": 174, "char_end": 191, "token_start": 28, "token_end": 29}], "entities_global": [{"text": "colorectal , or other , cancers", "type": "ENTITY", "char_start": 122587, "char_end": 122618, "token_start": 11, "token_end": 16, "note": null}, {"text": "colorectal cancer", "type": "ENTITY", "char_start": 122686, "char_end": 122703, "token_start": 28, "token_end": 29, "note": null}]}
+{"sentence_id": 836, "sentence_text": "Systematic analysis of coproporphyrinogen oxidase gene defects in hereditary coproporphyria and mutation update .", "sentence_char_start_global": 122727, "sentence_char_end_global": 122840, "entities": [{"text": "hereditary coproporphyria", "type": "ENTITY", "char_start": 66, "char_end": 91, "token_start": 8, "token_end": 9}], "entities_global": [{"text": "hereditary coproporphyria", "type": "ENTITY", "char_start": 122793, "char_end": 122818, "token_start": 8, "token_end": 9, "note": null}]}
+{"sentence_id": 837, "sentence_text": "Hereditary coproporphyria ( HC ) is an acute hepatic porphyria with autosomal dominant inheritance caused by deficient activity of coproporphyrinogen III oxidase ( CPO ) .", "sentence_char_start_global": 122841, "sentence_char_end_global": 123012, "entities": [{"text": "Hereditary coproporphyria", "type": "ENTITY", "char_start": 0, "char_end": 25, "token_start": 0, "token_end": 1}, {"text": "HC", "type": "ENTITY", "char_start": 28, "char_end": 30, "token_start": 3, "token_end": 3}, {"text": "hepatic porphyria", "type": "ENTITY", "char_start": 45, "char_end": 62, "token_start": 8, "token_end": 9}, {"text": "deficient activity of coproporphyrinogen III oxidase", "type": "ENTITY", "char_start": 109, "char_end": 161, "token_start": 16, "token_end": 21}], "entities_global": [{"text": "Hereditary coproporphyria", "type": "ENTITY", "char_start": 122841, "char_end": 122866, "token_start": 0, "token_end": 1, "note": null}, {"text": "HC", "type": "ENTITY", "char_start": 122869, "char_end": 122871, "token_start": 3, "token_end": 3, "note": null}, {"text": "hepatic porphyria", "type": "ENTITY", "char_start": 122886, "char_end": 122903, "token_start": 8, "token_end": 9, "note": null}, {"text": "deficient activity of coproporphyrinogen III oxidase", "type": "ENTITY", "char_start": 122950, "char_end": 123002, "token_start": 16, "token_end": 21, "note": null}]}
+{"sentence_id": 838, "sentence_text": "Clinical manifestations of the disease are characterized by acute attacks of neurological dysfunction often precipitated by drugs , fasting , cyclical hormonal changes , or infectious diseases .", "sentence_char_start_global": 123013, "sentence_char_end_global": 123207, "entities": [{"text": "neurological dysfunction", "type": "ENTITY", "char_start": 77, "char_end": 101, "token_start": 11, "token_end": 12}, {"text": "infectious diseases", "type": "ENTITY", "char_start": 173, "char_end": 192, "token_start": 25, "token_end": 26}], "entities_global": [{"text": "neurological dysfunction", "type": "ENTITY", "char_start": 123090, "char_end": 123114, "token_start": 11, "token_end": 12, "note": null}, {"text": "infectious diseases", "type": "ENTITY", "char_start": 123186, "char_end": 123205, "token_start": 25, "token_end": 26, "note": null}]}
+{"sentence_id": 839, "sentence_text": "Skin photosensitivity may also be present .", "sentence_char_start_global": 123208, "sentence_char_end_global": 123251, "entities": [], "entities_global": []}
+{"sentence_id": 840, "sentence_text": "The seven exons , the exon / intron boundaries and part of 3 noncoding sequence of the CPO gene were systematically analyzed by an exon - by - exon denaturing gradient gel electrophoresis ( DGGE ) strategy followed by direct sequencing in seven unrelated heterozygous HC patients from France , Holland , and Czech Republic .", "sentence_char_start_global": 123252, "sentence_char_end_global": 123576, "entities": [{"text": "HC", "type": "ENTITY", "char_start": 268, "char_end": 270, "token_start": 45, "token_end": 45}], "entities_global": [{"text": "HC", "type": "ENTITY", "char_start": 123520, "char_end": 123522, "token_start": 45, "token_end": 45, "note": null}]}
+{"sentence_id": 841, "sentence_text": "Seven novel mutations and two new polymorphisms were detected .", "sentence_char_start_global": 123577, "sentence_char_end_global": 123640, "entities": [], "entities_global": []}
+{"sentence_id": 842, "sentence_text": "Among these mutations two are missense ( G197W , W427R ) , two are nonsense ( Q306X , Q385X ) , two are small deletions ( 662de14bp ; 1168del3bp removing a glycine at position 390 ) , and one is a splicing mutation ( IVS1 - 15c - - > g ) which creates a new acceptor splice site .", "sentence_char_start_global": 123641, "sentence_char_end_global": 123921, "entities": [], "entities_global": []}
+{"sentence_id": 843, "sentence_text": "The pathological significance of the point mutations G197W , W427R , and the in - frame deletion 390delGly were assessed by their respective expression in a prokaryotic system using site - directed mutagenesis .", "sentence_char_start_global": 123922, "sentence_char_end_global": 124133, "entities": [], "entities_global": []}
+{"sentence_id": 844, "sentence_text": "These mutations resulted in the absence or a dramatic decrease of CPO activity .", "sentence_char_start_global": 124134, "sentence_char_end_global": 124214, "entities": [], "entities_global": []}
+{"sentence_id": 845, "sentence_text": "The two polymorphisms were localized in noncoding part of the gene 1 ) a C / G polymorphism in the promotor region , 142 bp upstream from the transcriptional initiation site ( - 142C / G ) , and 2 ) a 6 bp deletion polymorphism in the 3 noncoding part of the CPO gene , 574 bp downstream of the last base of the normal termination codon ( + 574 delATTCTT ) .", "sentence_char_start_global": 124215, "sentence_char_end_global": 124573, "entities": [], "entities_global": []}
+{"sentence_id": 846, "sentence_text": "Five intragenic dimorphisms are now well characterized and the high degree of allelic heterogeneity in HC is demonstrated with seven new different mutations making a total of nineteen CPO gene defects reported so far . .", "sentence_char_start_global": 124574, "sentence_char_end_global": 124794, "entities": [{"text": "HC", "type": "ENTITY", "char_start": 103, "char_end": 105, "token_start": 15, "token_end": 15}, {"text": "gene defects", "type": "ENTITY", "char_start": 188, "char_end": 200, "token_start": 29, "token_end": 30}], "entities_global": [{"text": "HC", "type": "ENTITY", "char_start": 124677, "char_end": 124679, "token_start": 15, "token_end": 15, "note": null}, {"text": "gene defects", "type": "ENTITY", "char_start": 124762, "char_end": 124774, "token_start": 29, "token_end": 30, "note": null}]}
+{"sentence_id": 847, "sentence_text": "Coincidence of two novel arylsulfatase A alleles and mutation 459 + 1G > A within a family with metachromatic leukodystrophy : molecular basis of phenotypic heterogeneity .", "sentence_char_start_global": 124795, "sentence_char_end_global": 124967, "entities": [{"text": "metachromatic leukodystrophy", "type": "ENTITY", "char_start": 96, "char_end": 124, "token_start": 18, "token_end": 19}], "entities_global": [{"text": "metachromatic leukodystrophy", "type": "ENTITY", "char_start": 124891, "char_end": 124919, "token_start": 18, "token_end": 19, "note": null}]}
+{"sentence_id": 848, "sentence_text": "In a family with three siblings , one developed classical late infantile metachromatic leukodystrophy ( MLD ) , fatal at age 5 years , with deficient arylsulfatase A ( ARSA ) activity and increased galactosylsulfatide ( GS ) excretion .", "sentence_char_start_global": 124968, "sentence_char_end_global": 125204, "entities": [{"text": "metachromatic leukodystrophy", "type": "ENTITY", "char_start": 73, "char_end": 101, "token_start": 12, "token_end": 13}, {"text": "MLD", "type": "ENTITY", "char_start": 104, "char_end": 107, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "metachromatic leukodystrophy", "type": "ENTITY", "char_start": 125041, "char_end": 125069, "token_start": 12, "token_end": 13, "note": null}, {"text": "MLD", "type": "ENTITY", "char_start": 125072, "char_end": 125075, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 849, "sentence_text": "The two other siblings , apparently healthy at 12 ( 1 / 2 ) and 15 years , respectively , and their father , apparently healthy as well , presented ARSA and GS values within the range of MLD patients .", "sentence_char_start_global": 125205, "sentence_char_end_global": 125406, "entities": [{"text": "MLD", "type": "ENTITY", "char_start": 187, "char_end": 190, "token_start": 38, "token_end": 38}], "entities_global": [{"text": "MLD", "type": "ENTITY", "char_start": 125392, "char_end": 125395, "token_start": 38, "token_end": 38, "note": null}]}
+{"sentence_id": 850, "sentence_text": "Mutation screening and sequence analysis disclosed the involvement of three different ARSA mutations being the molecular basis of intrafamilial phenotypic heterogeneity .", "sentence_char_start_global": 125407, "sentence_char_end_global": 125577, "entities": [], "entities_global": []}
+{"sentence_id": 851, "sentence_text": "The late infantile patient inherited from his mother the frequent 0 - type mutation 459 + 1G > A , and from his father a novel , single basepair microdeletion of guanine at nucleotide 7 in exon 1 ( 7delG ) .", "sentence_char_start_global": 125578, "sentence_char_end_global": 125785, "entities": [], "entities_global": []}
+{"sentence_id": 852, "sentence_text": "The two clinically unaffected siblings carried the maternal mutation 459 + 1G > A and , on their paternal allele , a novel cytosine to thymidine transition at nucleotide 2435 in exon 8 , resulting in substitution of alanine 464 by valine ( A464V ) .", "sentence_char_start_global": 125786, "sentence_char_end_global": 126035, "entities": [], "entities_global": []}
+{"sentence_id": 853, "sentence_text": "The fathers genotype thus was 7delG / A464V .", "sentence_char_start_global": 126036, "sentence_char_end_global": 126081, "entities": [], "entities_global": []}
+{"sentence_id": 854, "sentence_text": "Mutation A464V was not found in 18 unrelated MLD patients and 50 controls .", "sentence_char_start_global": 126082, "sentence_char_end_global": 126157, "entities": [{"text": "MLD", "type": "ENTITY", "char_start": 45, "char_end": 48, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "MLD", "type": "ENTITY", "char_start": 126127, "char_end": 126130, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 855, "sentence_text": "A464V , although clearly modifying ARSA and GS levels , apparently bears little significance for clinical manifestation of MLD , mimicking the frequent ARSA pseudodeficiency allele .", "sentence_char_start_global": 126158, "sentence_char_end_global": 126340, "entities": [{"text": "MLD", "type": "ENTITY", "char_start": 123, "char_end": 126, "token_start": 18, "token_end": 18}], "entities_global": [{"text": "MLD", "type": "ENTITY", "char_start": 126281, "char_end": 126284, "token_start": 18, "token_end": 18, "note": null}]}
+{"sentence_id": 856, "sentence_text": "Our results demonstrate that in certain genetic conditions MLD - like ARSA and GS values need not be paralleled by clinical disease , a finding with serious diagnostic and prognostic implications .", "sentence_char_start_global": 126341, "sentence_char_end_global": 126538, "entities": [{"text": "MLD", "type": "ENTITY", "char_start": 59, "char_end": 62, "token_start": 8, "token_end": 8}], "entities_global": [{"text": "MLD", "type": "ENTITY", "char_start": 126400, "char_end": 126403, "token_start": 8, "token_end": 8, "note": null}]}
+{"sentence_id": 857, "sentence_text": "Moreover , further ARSA alleles functionally similar to A464V might exist which , together with 0 - type mutations , may cause pathological ARSA and GS levels , but not clinical outbreak of the disease . .", "sentence_char_start_global": 126539, "sentence_char_end_global": 126744, "entities": [], "entities_global": []}
+{"sentence_id": 858, "sentence_text": "Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1 .", "sentence_char_start_global": 126745, "sentence_char_end_global": 126837, "entities": [{"text": "hematological malignancy", "type": "ENTITY", "char_start": 37, "char_end": 61, "token_start": 5, "token_end": 6}, {"text": "neurofibromatosis type 1", "type": "ENTITY", "char_start": 66, "char_end": 90, "token_start": 8, "token_end": 10}], "entities_global": [{"text": "hematological malignancy", "type": "ENTITY", "char_start": 126782, "char_end": 126806, "token_start": 5, "token_end": 6, "note": null}, {"text": "neurofibromatosis type 1", "type": "ENTITY", "char_start": 126811, "char_end": 126835, "token_start": 8, "token_end": 10, "note": null}]}
+{"sentence_id": 859, "sentence_text": "Heterozygous germ - line mutations in the DNA mismatch repair genes lead to hereditary nonpolyposis colorectal cancer .", "sentence_char_start_global": 126838, "sentence_char_end_global": 126957, "entities": [{"text": "hereditary nonpolyposis colorectal cancer", "type": "ENTITY", "char_start": 76, "char_end": 117, "token_start": 13, "token_end": 16}], "entities_global": [{"text": "hereditary nonpolyposis colorectal cancer", "type": "ENTITY", "char_start": 126914, "char_end": 126955, "token_start": 13, "token_end": 16, "note": null}]}
+{"sentence_id": 860, "sentence_text": "The disease susceptibility of individuals who constitutionally lack both wild - type alleles is unknown .", "sentence_char_start_global": 126958, "sentence_char_end_global": 127063, "entities": [], "entities_global": []}
+{"sentence_id": 861, "sentence_text": "We have identified three offspring in a hereditary nonpolyposis colorectal cancer family who developed hematological malignancy at a very early age , and at least two of them displayed signs of neurofibromatosis type 1 ( NF1 ) .", "sentence_char_start_global": 127064, "sentence_char_end_global": 127292, "entities": [{"text": "hereditary nonpolyposis colorectal cancer", "type": "ENTITY", "char_start": 40, "char_end": 81, "token_start": 7, "token_end": 10}, {"text": "hematological malignancy", "type": "ENTITY", "char_start": 103, "char_end": 127, "token_start": 14, "token_end": 15}, {"text": "neurofibromatosis type 1", "type": "ENTITY", "char_start": 194, "char_end": 218, "token_start": 31, "token_end": 33}, {"text": "NF1", "type": "ENTITY", "char_start": 221, "char_end": 224, "token_start": 35, "token_end": 35}], "entities_global": [{"text": "hereditary nonpolyposis colorectal cancer", "type": "ENTITY", "char_start": 127104, "char_end": 127145, "token_start": 7, "token_end": 10, "note": null}, {"text": "hematological malignancy", "type": "ENTITY", "char_start": 127167, "char_end": 127191, "token_start": 14, "token_end": 15, "note": null}, {"text": "neurofibromatosis type 1", "type": "ENTITY", "char_start": 127258, "char_end": 127282, "token_start": 31, "token_end": 33, "note": null}, {"text": "NF1", "type": "ENTITY", "char_start": 127285, "char_end": 127288, "token_start": 35, "token_end": 35, "note": null}]}
+{"sentence_id": 862, "sentence_text": "DNA sequence analysis and allele - specific amplification in two siblings revealed a homozygous MLH1 mutation ( C676T - - > Arg226Stop ) .", "sentence_char_start_global": 127293, "sentence_char_end_global": 127431, "entities": [], "entities_global": []}
+{"sentence_id": 863, "sentence_text": "Thus , a homozygous germ - line MLH1 mutation and consequent mismatch repair deficiency results in a mutator phenotype characterized by leukemia and / or lymphoma associated with neurofibromatosis type 1 . .", "sentence_char_start_global": 127432, "sentence_char_end_global": 127639, "entities": [{"text": "leukemia", "type": "ENTITY", "char_start": 136, "char_end": 144, "token_start": 21, "token_end": 21}, {"text": "lymphoma", "type": "ENTITY", "char_start": 154, "char_end": 162, "token_start": 25, "token_end": 25}, {"text": "neurofibromatosis type 1", "type": "ENTITY", "char_start": 179, "char_end": 203, "token_start": 28, "token_end": 30}], "entities_global": [{"text": "leukemia", "type": "ENTITY", "char_start": 127568, "char_end": 127576, "token_start": 21, "token_end": 21, "note": null}, {"text": "lymphoma", "type": "ENTITY", "char_start": 127586, "char_end": 127594, "token_start": 25, "token_end": 25, "note": null}, {"text": "neurofibromatosis type 1", "type": "ENTITY", "char_start": 127611, "char_end": 127635, "token_start": 28, "token_end": 30, "note": null}]}
+{"sentence_id": 864, "sentence_text": "Missense mutations in the most ancient residues of the PAX6 paired domain underlie a spectrum of human congenital eye malformations .", "sentence_char_start_global": 127640, "sentence_char_end_global": 127773, "entities": [{"text": "congenital eye malformations", "type": "ENTITY", "char_start": 103, "char_end": 131, "token_start": 17, "token_end": 19}], "entities_global": [{"text": "congenital eye malformations", "type": "ENTITY", "char_start": 127743, "char_end": 127771, "token_start": 17, "token_end": 19, "note": null}]}
+{"sentence_id": 865, "sentence_text": "Mutations of the human PAX6 gene underlie aniridia ( congenital absence of the iris ) , a rare dominant malformation of the eye .", "sentence_char_start_global": 127774, "sentence_char_end_global": 127903, "entities": [{"text": "aniridia", "type": "ENTITY", "char_start": 42, "char_end": 50, "token_start": 7, "token_end": 7}, {"text": "congenital absence of the iris", "type": "ENTITY", "char_start": 53, "char_end": 83, "token_start": 9, "token_end": 13}, {"text": "malformation of the eye", "type": "ENTITY", "char_start": 104, "char_end": 127, "token_start": 19, "token_end": 22}], "entities_global": [{"text": "aniridia", "type": "ENTITY", "char_start": 127816, "char_end": 127824, "token_start": 7, "token_end": 7, "note": null}, {"text": "congenital absence of the iris", "type": "ENTITY", "char_start": 127827, "char_end": 127857, "token_start": 9, "token_end": 13, "note": null}, {"text": "malformation of the eye", "type": "ENTITY", "char_start": 127878, "char_end": 127901, "token_start": 19, "token_end": 22, "note": null}]}
+{"sentence_id": 866, "sentence_text": "The spectrum of PAX6 mutations in aniridia patients is highly biased , with 92 % of all reported mutations leading to premature truncation of the protein ( nonsense , splicing , insertions and deletions ) and just 2 % leading to substitution of one amino acid by another ( missense ) .", "sentence_char_start_global": 127904, "sentence_char_end_global": 128189, "entities": [{"text": "aniridia", "type": "ENTITY", "char_start": 34, "char_end": 42, "token_start": 6, "token_end": 6}], "entities_global": [{"text": "aniridia", "type": "ENTITY", "char_start": 127938, "char_end": 127946, "token_start": 6, "token_end": 6, "note": null}]}
+{"sentence_id": 867, "sentence_text": "The extraordinary conservation of the PAX6 protein at the amino acid level amongst vertebrates predicts that pathological missense mutations should in fact be common even though they are hardly ever seen in aniridia patients .", "sentence_char_start_global": 128190, "sentence_char_end_global": 128416, "entities": [{"text": "aniridia", "type": "ENTITY", "char_start": 207, "char_end": 215, "token_start": 32, "token_end": 32}], "entities_global": [{"text": "aniridia", "type": "ENTITY", "char_start": 128397, "char_end": 128405, "token_start": 32, "token_end": 32, "note": null}]}
+{"sentence_id": 868, "sentence_text": "This indicates that there is a heavy ascertainment bias in the selection of patients for PAX6 mutation analysis and that the missing PAX6 missense mutations frequently may underlie phenotypes distinct from textbook aniridia .", "sentence_char_start_global": 128417, "sentence_char_end_global": 128642, "entities": [{"text": "aniridia", "type": "ENTITY", "char_start": 215, "char_end": 223, "token_start": 32, "token_end": 32}], "entities_global": [{"text": "aniridia", "type": "ENTITY", "char_start": 128632, "char_end": 128640, "token_start": 32, "token_end": 32, "note": null}]}
+{"sentence_id": 869, "sentence_text": "Here we present four novel PAX6 missense mutations , two in association with atypical phenotypes ectopia pupillae ( displaced pupils ) and congenital nystagmus ( searching gaze ) , and two in association with more recognizable aniridia phenotypes .", "sentence_char_start_global": 128643, "sentence_char_end_global": 128891, "entities": [{"text": "ectopia pupillae", "type": "ENTITY", "char_start": 97, "char_end": 113, "token_start": 15, "token_end": 16}, {"text": "displaced pupils", "type": "ENTITY", "char_start": 116, "char_end": 132, "token_start": 18, "token_end": 19}, {"text": "congenital nystagmus", "type": "ENTITY", "char_start": 139, "char_end": 159, "token_start": 22, "token_end": 23}, {"text": "searching gaze", "type": "ENTITY", "char_start": 162, "char_end": 176, "token_start": 25, "token_end": 26}, {"text": "aniridia", "type": "ENTITY", "char_start": 227, "char_end": 235, "token_start": 36, "token_end": 36}], "entities_global": [{"text": "ectopia pupillae", "type": "ENTITY", "char_start": 128740, "char_end": 128756, "token_start": 15, "token_end": 16, "note": null}, {"text": "displaced pupils", "type": "ENTITY", "char_start": 128759, "char_end": 128775, "token_start": 18, "token_end": 19, "note": null}, {"text": "congenital nystagmus", "type": "ENTITY", "char_start": 128782, "char_end": 128802, "token_start": 22, "token_end": 23, "note": null}, {"text": "searching gaze", "type": "ENTITY", "char_start": 128805, "char_end": 128819, "token_start": 25, "token_end": 26, "note": null}, {"text": "aniridia", "type": "ENTITY", "char_start": 128870, "char_end": 128878, "token_start": 36, "token_end": 36, "note": null}]}
+{"sentence_id": 870, "sentence_text": "Strikingly , all four mutations are located within the PAX6 paired domain and affect amino acids which are highly conserved in all known paired domain proteins .", "sentence_char_start_global": 128892, "sentence_char_end_global": 129053, "entities": [], "entities_global": []}
+{"sentence_id": 871, "sentence_text": "Our results support the hypothesis that the under - representation of missense mutations is caused by ascertainment bias and suggest that a substantial burden of PAX6 - related disease remains to be uncovered . .", "sentence_char_start_global": 129054, "sentence_char_end_global": 129266, "entities": [{"text": "PAX6 - related disease", "type": "ENTITY", "char_start": 162, "char_end": 184, "token_start": 25, "token_end": 28}], "entities_global": [{"text": "PAX6 - related disease", "type": "ENTITY", "char_start": 129216, "char_end": 129238, "token_start": 25, "token_end": 28, "note": null}]}
+{"sentence_id": 872, "sentence_text": "The chromosomal order of genes controlling the major histocompatibility complex , properdin factor B , and deficiency of the second component of complement .", "sentence_char_start_global": 129267, "sentence_char_end_global": 129424, "entities": [{"text": "deficiency of the second component of complement", "type": "ENTITY", "char_start": 107, "char_end": 155, "token_start": 16, "token_end": 22}], "entities_global": [{"text": "deficiency of the second component of complement", "type": "ENTITY", "char_start": 129374, "char_end": 129422, "token_start": 16, "token_end": 22, "note": null}]}
+{"sentence_id": 873, "sentence_text": "The relationship of the genes coding for HLA to those coding for properdin Factor B allotypes and for deficiency of the second component of complement ( C2 ) was studied in families of patients with connective tissue disorders .", "sentence_char_start_global": 129425, "sentence_char_end_global": 129653, "entities": [{"text": "deficiency of the second component of complement", "type": "ENTITY", "char_start": 102, "char_end": 150, "token_start": 18, "token_end": 24}], "entities_global": [{"text": "deficiency of the second component of complement", "type": "ENTITY", "char_start": 129527, "char_end": 129575, "token_start": 18, "token_end": 24, "note": null}]}
+{"sentence_id": 874, "sentence_text": "Patients were selected because they were heterozygous or homozygous for C2 deficiency .", "sentence_char_start_global": 129654, "sentence_char_end_global": 129741, "entities": [{"text": "C2 deficiency", "type": "ENTITY", "char_start": 72, "char_end": 85, "token_start": 10, "token_end": 11}], "entities_global": [{"text": "C2 deficiency", "type": "ENTITY", "char_start": 129726, "char_end": 129739, "token_start": 10, "token_end": 11, "note": null}]}
+{"sentence_id": 875, "sentence_text": "12 families with 15 matings informative for C2 deficiency were found .", "sentence_char_start_global": 129742, "sentence_char_end_global": 129812, "entities": [{"text": "C2 deficiency", "type": "ENTITY", "char_start": 44, "char_end": 57, "token_start": 7, "token_end": 8}], "entities_global": [{"text": "C2 deficiency", "type": "ENTITY", "char_start": 129786, "char_end": 129799, "token_start": 7, "token_end": 8, "note": null}]}
+{"sentence_id": 876, "sentence_text": "Of 57 informative meioses , two crossovers were noted between the C2 deficiency gene and the HLA - B gene , with a recombinant fraction of 0 .", "sentence_char_start_global": 129813, "sentence_char_end_global": 129955, "entities": [{"text": "C2 deficiency", "type": "ENTITY", "char_start": 66, "char_end": 79, "token_start": 11, "token_end": 12}], "entities_global": [{"text": "C2 deficiency", "type": "ENTITY", "char_start": 129879, "char_end": 129892, "token_start": 11, "token_end": 12, "note": null}]}
+{"sentence_id": 877, "sentence_text": "035 .", "sentence_char_start_global": 129956, "sentence_char_end_global": 129961, "entities": [], "entities_global": []}
+{"sentence_id": 878, "sentence_text": "A lod score of 13 was calculated for linkage between C2 deficiency and HLA - B at a maximum likelihood value of the recombinant fraction of 0 .", "sentence_char_start_global": 129962, "sentence_char_end_global": 130105, "entities": [{"text": "C2 deficiency", "type": "ENTITY", "char_start": 53, "char_end": 66, "token_start": 10, "token_end": 11}], "entities_global": [{"text": "C2 deficiency", "type": "ENTITY", "char_start": 130015, "char_end": 130028, "token_start": 10, "token_end": 11, "note": null}]}
+{"sentence_id": 879, "sentence_text": "04 .", "sentence_char_start_global": 130106, "sentence_char_end_global": 130110, "entities": [], "entities_global": []}
+{"sentence_id": 880, "sentence_text": "18 families with 21 informative matings for both properdin Factor B allotype and HLA - B were found .", "sentence_char_start_global": 130111, "sentence_char_end_global": 130212, "entities": [], "entities_global": []}
+{"sentence_id": 881, "sentence_text": "Of 72 informative meioses , three recombinants were found , giving a recombinant fraction of 0 .", "sentence_char_start_global": 130213, "sentence_char_end_global": 130309, "entities": [], "entities_global": []}
+{"sentence_id": 882, "sentence_text": "042 .", "sentence_char_start_global": 130310, "sentence_char_end_global": 130315, "entities": [], "entities_global": []}
+{"sentence_id": 883, "sentence_text": "A lod score of 16 between HLA - B and Factor B allotypes was calculated at a maximum likelihood value of the recombinant fraction of 0 .", "sentence_char_start_global": 130316, "sentence_char_end_global": 130452, "entities": [], "entities_global": []}
+{"sentence_id": 884, "sentence_text": "04 .", "sentence_char_start_global": 130453, "sentence_char_end_global": 130457, "entities": [], "entities_global": []}
+{"sentence_id": 885, "sentence_text": "A crossover was shown to have occurred between genes for Factor B and HLA - D , in which HLA - D segregared with HLA - A and B .", "sentence_char_start_global": 130458, "sentence_char_end_global": 130586, "entities": [], "entities_global": []}
+{"sentence_id": 886, "sentence_text": "These studies suggest that the genes for Factor B and C2 deficiency are located outside those for HLA , that the order of genese is HLA - A , - B , - D , Factor B allotype , C2 deficiency , that the genes coding for C2 deficiency and Factor B allotypes are approximately 3 - - 5 centimorgans from the HLA - A and HLA - B loci , and that the apparent lack of recombinants between the Factor B gene and C2 deficiency gene suggests that these two genes lie in close proximity to one another .", "sentence_char_start_global": 130587, "sentence_char_end_global": 131076, "entities": [{"text": "C2 deficiency", "type": "ENTITY", "char_start": 54, "char_end": 67, "token_start": 10, "token_end": 11}, {"text": "C2 deficiency", "type": "ENTITY", "char_start": 174, "char_end": 187, "token_start": 39, "token_end": 40}, {"text": "C2 deficiency", "type": "ENTITY", "char_start": 216, "char_end": 229, "token_start": 47, "token_end": 48}, {"text": "C2 deficiency", "type": "ENTITY", "char_start": 401, "char_end": 414, "token_start": 84, "token_end": 85}], "entities_global": [{"text": "C2 deficiency", "type": "ENTITY", "char_start": 130641, "char_end": 130654, "token_start": 10, "token_end": 11, "note": null}, {"text": "C2 deficiency", "type": "ENTITY", "char_start": 130761, "char_end": 130774, "token_start": 39, "token_end": 40, "note": null}, {"text": "C2 deficiency", "type": "ENTITY", "char_start": 130803, "char_end": 130816, "token_start": 47, "token_end": 48, "note": null}, {"text": "C2 deficiency", "type": "ENTITY", "char_start": 130988, "char_end": 131001, "token_start": 84, "token_end": 85, "note": null}]}
+{"sentence_id": 887, "sentence_text": "Distribution of emerin and lamins in the heart and implications for Emery - Dreifuss muscular dystrophy .", "sentence_char_start_global": 131077, "sentence_char_end_global": 131182, "entities": [{"text": "Emery - Dreifuss muscular dystrophy", "type": "ENTITY", "char_start": 68, "char_end": 103, "token_start": 11, "token_end": 15}], "entities_global": [{"text": "Emery - Dreifuss muscular dystrophy", "type": "ENTITY", "char_start": 131145, "char_end": 131180, "token_start": 11, "token_end": 15, "note": null}]}
+{"sentence_id": 888, "sentence_text": "Emerin is a nuclear membrane protein which is missing or defective in Emery - Dreifuss muscular dystrophy ( EDMD ) .", "sentence_char_start_global": 131183, "sentence_char_end_global": 131299, "entities": [{"text": "Emery - Dreifuss muscular dystrophy", "type": "ENTITY", "char_start": 70, "char_end": 105, "token_start": 12, "token_end": 16}, {"text": "EDMD", "type": "ENTITY", "char_start": 108, "char_end": 112, "token_start": 18, "token_end": 18}], "entities_global": [{"text": "Emery - Dreifuss muscular dystrophy", "type": "ENTITY", "char_start": 131253, "char_end": 131288, "token_start": 12, "token_end": 16, "note": null}, {"text": "EDMD", "type": "ENTITY", "char_start": 131291, "char_end": 131295, "token_start": 18, "token_end": 18, "note": null}]}
+{"sentence_id": 889, "sentence_text": "It is one member of a family of lamina - associated proteins which includes LAP1 , LAP2 and lamin B receptor ( LBR ) .", "sentence_char_start_global": 131300, "sentence_char_end_global": 131418, "entities": [], "entities_global": []}
+{"sentence_id": 890, "sentence_text": "A panel of 16 monoclonal antibodies ( mAbs ) has been mapped to six specific sites throughout the emerin molecule using phage - displayed peptide libraries and has been used to localize emerin in human and rabbit heart .", "sentence_char_start_global": 131419, "sentence_char_end_global": 131639, "entities": [], "entities_global": []}
+{"sentence_id": 891, "sentence_text": "Several mAbs against different emerin epitopes did not recognize intercalated discs in the heart , though they recognized cardiomyocyte nuclei strongly , both at the rim and in intranuclear spots or channels .", "sentence_char_start_global": 131640, "sentence_char_end_global": 131849, "entities": [], "entities_global": []}
+{"sentence_id": 892, "sentence_text": "A polyclonal rabbit antiserum against emerin did recognize both nuclear membrane and intercalated discs but , after affinity purification against a pure - emerin band on a western blot , it stained only the nuclear membrane .", "sentence_char_start_global": 131850, "sentence_char_end_global": 132075, "entities": [], "entities_global": []}
+{"sentence_id": 893, "sentence_text": "These results would not be expected if immunostaining at intercalated discs were due to a product of the emerin gene and , therefore , cast some doubt upon the hypothesis that cardiac defects in EDMD are caused by absence of emerin from intercalated discs .", "sentence_char_start_global": 132076, "sentence_char_end_global": 132333, "entities": [{"text": "cardiac defects", "type": "ENTITY", "char_start": 176, "char_end": 191, "token_start": 31, "token_end": 32}, {"text": "EDMD", "type": "ENTITY", "char_start": 195, "char_end": 199, "token_start": 34, "token_end": 34}], "entities_global": [{"text": "cardiac defects", "type": "ENTITY", "char_start": 132252, "char_end": 132267, "token_start": 31, "token_end": 32, "note": null}, {"text": "EDMD", "type": "ENTITY", "char_start": 132271, "char_end": 132275, "token_start": 34, "token_end": 34, "note": null}]}
+{"sentence_id": 894, "sentence_text": "Although emerin was abundant in the membranes of cardiomyocyte nuclei , it was absent from many non - myocyte cells in the heart .", "sentence_char_start_global": 132334, "sentence_char_end_global": 132464, "entities": [], "entities_global": []}
+{"sentence_id": 895, "sentence_text": "This distribution of emerin was similar to that of lamin A , a candidate gene for an autosomal form of EDMD .", "sentence_char_start_global": 132465, "sentence_char_end_global": 132574, "entities": [{"text": "EDMD", "type": "ENTITY", "char_start": 103, "char_end": 107, "token_start": 20, "token_end": 20}], "entities_global": [{"text": "EDMD", "type": "ENTITY", "char_start": 132568, "char_end": 132572, "token_start": 20, "token_end": 20, "note": null}]}
+{"sentence_id": 896, "sentence_text": "In contrast , lamin B1 was absent from cardiomyocyte nuclei , showing that lamin B1 is not essential for localization of emerin to the nuclear lamina .", "sentence_char_start_global": 132575, "sentence_char_end_global": 132726, "entities": [], "entities_global": []}
+{"sentence_id": 897, "sentence_text": "Lamin B1 is also almost completely absent from skeletal muscle nuclei .", "sentence_char_start_global": 132727, "sentence_char_end_global": 132798, "entities": [], "entities_global": []}
+{"sentence_id": 898, "sentence_text": "In EDMD , the additional absence of lamin B1 from heart and skeletal muscle nuclei which already lack emerin may offer an alternative explanation of why these tissues are particularly affected . .", "sentence_char_start_global": 132799, "sentence_char_end_global": 132995, "entities": [{"text": "EDMD", "type": "ENTITY", "char_start": 3, "char_end": 7, "token_start": 1, "token_end": 1}], "entities_global": [{"text": "EDMD", "type": "ENTITY", "char_start": 132802, "char_end": 132806, "token_start": 1, "token_end": 1, "note": null}]}
+{"sentence_id": 899, "sentence_text": "Genetic mapping of the copper toxicosis locus in Bedlington terriers to dog chromosome 10 , in a region syntenic to human chromosome region 2p13 - p16 .", "sentence_char_start_global": 132996, "sentence_char_end_global": 133148, "entities": [{"text": "copper toxicosis", "type": "ENTITY", "char_start": 23, "char_end": 39, "token_start": 4, "token_end": 5}], "entities_global": [{"text": "copper toxicosis", "type": "ENTITY", "char_start": 133019, "char_end": 133035, "token_start": 4, "token_end": 5, "note": null}]}
+{"sentence_id": 900, "sentence_text": "Abnormal hepatic copper accumulation is recognized as an inherited disorder in man , mouse , rat and dog .", "sentence_char_start_global": 133149, "sentence_char_end_global": 133255, "entities": [{"text": "hepatic copper accumulation", "type": "ENTITY", "char_start": 9, "char_end": 36, "token_start": 1, "token_end": 3}, {"text": "inherited disorder", "type": "ENTITY", "char_start": 57, "char_end": 75, "token_start": 8, "token_end": 9}], "entities_global": [{"text": "hepatic copper accumulation", "type": "ENTITY", "char_start": 133158, "char_end": 133185, "token_start": 1, "token_end": 3, "note": null}, {"text": "inherited disorder", "type": "ENTITY", "char_start": 133206, "char_end": 133224, "token_start": 8, "token_end": 9, "note": null}]}
+{"sentence_id": 901, "sentence_text": "The major cause of hepatic copper accumulation in man is a dysfunctional ATP7B gene , causing Wilson disease ( WD ) .", "sentence_char_start_global": 133256, "sentence_char_end_global": 133373, "entities": [{"text": "hepatic copper accumulation", "type": "ENTITY", "char_start": 19, "char_end": 46, "token_start": 4, "token_end": 6}, {"text": "Wilson disease", "type": "ENTITY", "char_start": 94, "char_end": 108, "token_start": 16, "token_end": 17}, {"text": "WD", "type": "ENTITY", "char_start": 111, "char_end": 113, "token_start": 19, "token_end": 19}], "entities_global": [{"text": "hepatic copper accumulation", "type": "ENTITY", "char_start": 133275, "char_end": 133302, "token_start": 4, "token_end": 6, "note": null}, {"text": "Wilson disease", "type": "ENTITY", "char_start": 133350, "char_end": 133364, "token_start": 16, "token_end": 17, "note": null}, {"text": "WD", "type": "ENTITY", "char_start": 133367, "char_end": 133369, "token_start": 19, "token_end": 19, "note": null}]}
+{"sentence_id": 902, "sentence_text": "Mutations in the ATP7B genes have also been demonstrated in mouse and rat .", "sentence_char_start_global": 133374, "sentence_char_end_global": 133449, "entities": [], "entities_global": []}
+{"sentence_id": 903, "sentence_text": "The ATP7B gene has been excluded in the much rarer human copper overload disease non - Indian childhood cirrhosis , indicating genetic heterogeneity .", "sentence_char_start_global": 133450, "sentence_char_end_global": 133600, "entities": [{"text": "copper overload", "type": "ENTITY", "char_start": 57, "char_end": 72, "token_start": 11, "token_end": 12}, {"text": "non - Indian childhood cirrhosis", "type": "ENTITY", "char_start": 81, "char_end": 113, "token_start": 14, "token_end": 18}], "entities_global": [{"text": "copper overload", "type": "ENTITY", "char_start": 133507, "char_end": 133522, "token_start": 11, "token_end": 12, "note": null}, {"text": "non - Indian childhood cirrhosis", "type": "ENTITY", "char_start": 133531, "char_end": 133563, "token_start": 14, "token_end": 18, "note": null}]}
+{"sentence_id": 904, "sentence_text": "By investigating the common autosomal recessive copper toxicosis ( CT ) in Bedlington terriers , we have identified a new locus involved in progressive liver disease .", "sentence_char_start_global": 133601, "sentence_char_end_global": 133768, "entities": [{"text": "copper toxicosis", "type": "ENTITY", "char_start": 48, "char_end": 64, "token_start": 6, "token_end": 7}, {"text": "CT", "type": "ENTITY", "char_start": 67, "char_end": 69, "token_start": 9, "token_end": 9}, {"text": "liver disease", "type": "ENTITY", "char_start": 152, "char_end": 165, "token_start": 24, "token_end": 25}], "entities_global": [{"text": "copper toxicosis", "type": "ENTITY", "char_start": 133649, "char_end": 133665, "token_start": 6, "token_end": 7, "note": null}, {"text": "CT", "type": "ENTITY", "char_start": 133668, "char_end": 133670, "token_start": 9, "token_end": 9, "note": null}, {"text": "liver disease", "type": "ENTITY", "char_start": 133753, "char_end": 133766, "token_start": 24, "token_end": 25, "note": null}]}
+{"sentence_id": 905, "sentence_text": "We examined whether the WD gene ATP7B was also causative for CT by investigating the chromosomal co - localization of ATP7B and C04107 , using fluorescence in situ hybridization ( FISH ) .", "sentence_char_start_global": 133769, "sentence_char_end_global": 133957, "entities": [{"text": "WD", "type": "ENTITY", "char_start": 24, "char_end": 26, "token_start": 4, "token_end": 4}, {"text": "CT", "type": "ENTITY", "char_start": 61, "char_end": 63, "token_start": 11, "token_end": 11}], "entities_global": [{"text": "WD", "type": "ENTITY", "char_start": 133793, "char_end": 133795, "token_start": 4, "token_end": 4, "note": null}, {"text": "CT", "type": "ENTITY", "char_start": 133830, "char_end": 133832, "token_start": 11, "token_end": 11, "note": null}]}
+{"sentence_id": 906, "sentence_text": "C04107 is an anonymous microsatellite marker closely linked to CT .", "sentence_char_start_global": 133958, "sentence_char_end_global": 134025, "entities": [{"text": "CT", "type": "ENTITY", "char_start": 63, "char_end": 65, "token_start": 9, "token_end": 9}], "entities_global": [{"text": "CT", "type": "ENTITY", "char_start": 134021, "char_end": 134023, "token_start": 9, "token_end": 9, "note": null}]}
+{"sentence_id": 907, "sentence_text": "However , BAC clones containing ATP7B and C04107 mapped to the canine chromosome regions CFA22q11 and CFA10q26 , respectively , demonstrating that WD cannot be homologous to CT .", "sentence_char_start_global": 134026, "sentence_char_end_global": 134204, "entities": [{"text": "WD", "type": "ENTITY", "char_start": 147, "char_end": 149, "token_start": 22, "token_end": 22}, {"text": "CT", "type": "ENTITY", "char_start": 174, "char_end": 176, "token_start": 27, "token_end": 27}], "entities_global": [{"text": "WD", "type": "ENTITY", "char_start": 134173, "char_end": 134175, "token_start": 22, "token_end": 22, "note": null}, {"text": "CT", "type": "ENTITY", "char_start": 134200, "char_end": 134202, "token_start": 27, "token_end": 27, "note": null}]}
+{"sentence_id": 908, "sentence_text": "The copper transport genes CTR1 and CTR2 were also excluded as candidate genes for CT since they both mapped to canine chromosome region CFA11q22 .", "sentence_char_start_global": 134205, "sentence_char_end_global": 134352, "entities": [{"text": "CT", "type": "ENTITY", "char_start": 83, "char_end": 85, "token_start": 14, "token_end": 14}], "entities_global": [{"text": "CT", "type": "ENTITY", "char_start": 134288, "char_end": 134290, "token_start": 14, "token_end": 14, "note": null}]}
+{"sentence_id": 909, "sentence_text": "2 - 22 .", "sentence_char_start_global": 134353, "sentence_char_end_global": 134361, "entities": [], "entities_global": []}
+{"sentence_id": 910, "sentence_text": "5 .", "sentence_char_start_global": 134362, "sentence_char_end_global": 134365, "entities": [], "entities_global": []}
+{"sentence_id": 911, "sentence_text": "A transcribed sequence identified from the C04107 - containing BAC was found to be homologous to a gene expressed from human chromosome 2p13 - p16 , a region devoid of any positional candidate genes .", "sentence_char_start_global": 134366, "sentence_char_end_global": 134566, "entities": [], "entities_global": []}
+{"sentence_id": 912, "sentence_text": "Molecular analysis of the APC gene in 205 families : extended genotype - phenotype correlations in FAP and evidence for the role of APC amino acid changes in colorectal cancer predisposition .", "sentence_char_start_global": 134567, "sentence_char_end_global": 134759, "entities": [{"text": "APC", "type": "ENTITY", "char_start": 26, "char_end": 29, "token_start": 4, "token_end": 4}, {"text": "FAP", "type": "ENTITY", "char_start": 99, "char_end": 102, "token_start": 16, "token_end": 16}, {"text": "APC", "type": "ENTITY", "char_start": 132, "char_end": 135, "token_start": 23, "token_end": 23}, {"text": "colorectal cancer", "type": "ENTITY", "char_start": 158, "char_end": 175, "token_start": 28, "token_end": 29}], "entities_global": [{"text": "APC", "type": "ENTITY", "char_start": 134593, "char_end": 134596, "token_start": 4, "token_end": 4, "note": null}, {"text": "FAP", "type": "ENTITY", "char_start": 134666, "char_end": 134669, "token_start": 16, "token_end": 16, "note": null}, {"text": "APC", "type": "ENTITY", "char_start": 134699, "char_end": 134702, "token_start": 23, "token_end": 23, "note": null}, {"text": "colorectal cancer", "type": "ENTITY", "char_start": 134725, "char_end": 134742, "token_start": 28, "token_end": 29, "note": null}]}
+{"sentence_id": 913, "sentence_text": "BACKGROUND / AIMS The development of colorectal cancer and a variable range of extracolonic manifestations in familial adenomatous polyposis ( FAP ) is the result of the dominant inheritance of adenomatous polyposis coli ( APC ) gene mutations .", "sentence_char_start_global": 134760, "sentence_char_end_global": 135005, "entities": [{"text": "colorectal cancer", "type": "ENTITY", "char_start": 37, "char_end": 54, "token_start": 6, "token_end": 7}, {"text": "familial adenomatous polyposis", "type": "ENTITY", "char_start": 110, "char_end": 140, "token_start": 16, "token_end": 18}, {"text": "FAP", "type": "ENTITY", "char_start": 143, "char_end": 146, "token_start": 20, "token_end": 20}, {"text": "adenomatous polyposis coli", "type": "ENTITY", "char_start": 194, "char_end": 220, "token_start": 30, "token_end": 32}, {"text": "APC", "type": "ENTITY", "char_start": 223, "char_end": 226, "token_start": 34, "token_end": 34}], "entities_global": [{"text": "colorectal cancer", "type": "ENTITY", "char_start": 134797, "char_end": 134814, "token_start": 6, "token_end": 7, "note": null}, {"text": "familial adenomatous polyposis", "type": "ENTITY", "char_start": 134870, "char_end": 134900, "token_start": 16, "token_end": 18, "note": null}, {"text": "FAP", "type": "ENTITY", "char_start": 134903, "char_end": 134906, "token_start": 20, "token_end": 20, "note": null}, {"text": "adenomatous polyposis coli", "type": "ENTITY", "char_start": 134954, "char_end": 134980, "token_start": 30, "token_end": 32, "note": null}, {"text": "APC", "type": "ENTITY", "char_start": 134983, "char_end": 134986, "token_start": 34, "token_end": 34, "note": null}]}
+{"sentence_id": 914, "sentence_text": "In this study , direct mutation analysis of the APC gene was performed to determine genotype - phenotype correlations for nine extracolonic manifestations and to investigate the incidence of APC mutations in non - FAP colorectal cancer .", "sentence_char_start_global": 135006, "sentence_char_end_global": 135243, "entities": [{"text": "APC", "type": "ENTITY", "char_start": 48, "char_end": 51, "token_start": 9, "token_end": 9}, {"text": "APC", "type": "ENTITY", "char_start": 191, "char_end": 194, "token_start": 29, "token_end": 29}, {"text": "colorectal cancer", "type": "ENTITY", "char_start": 218, "char_end": 235, "token_start": 35, "token_end": 36}], "entities_global": [{"text": "APC", "type": "ENTITY", "char_start": 135054, "char_end": 135057, "token_start": 9, "token_end": 9, "note": null}, {"text": "APC", "type": "ENTITY", "char_start": 135197, "char_end": 135200, "token_start": 29, "token_end": 29, "note": null}, {"text": "colorectal cancer", "type": "ENTITY", "char_start": 135224, "char_end": 135241, "token_start": 35, "token_end": 36, "note": null}]}
+{"sentence_id": 915, "sentence_text": "METHODS The APC gene was analysed in 190 unrelated FAP and 15 non - FAP colorectal cancer patients using denaturing gradient gel electrophoresis , the protein truncation test , and direct sequencing .", "sentence_char_start_global": 135244, "sentence_char_end_global": 135444, "entities": [{"text": "APC", "type": "ENTITY", "char_start": 12, "char_end": 15, "token_start": 2, "token_end": 2}, {"text": "FAP", "type": "ENTITY", "char_start": 51, "char_end": 54, "token_start": 9, "token_end": 9}, {"text": "colorectal cancer", "type": "ENTITY", "char_start": 72, "char_end": 89, "token_start": 15, "token_end": 16}], "entities_global": [{"text": "APC", "type": "ENTITY", "char_start": 135256, "char_end": 135259, "token_start": 2, "token_end": 2, "note": null}, {"text": "FAP", "type": "ENTITY", "char_start": 135295, "char_end": 135298, "token_start": 9, "token_end": 9, "note": null}, {"text": "colorectal cancer", "type": "ENTITY", "char_start": 135316, "char_end": 135333, "token_start": 15, "token_end": 16, "note": null}]}
+{"sentence_id": 916, "sentence_text": "RESULTS Chain terminating signals were only identified in patients belonging to the FAP group ( 105 patients ) .", "sentence_char_start_global": 135445, "sentence_char_end_global": 135557, "entities": [{"text": "FAP", "type": "ENTITY", "char_start": 84, "char_end": 87, "token_start": 12, "token_end": 12}], "entities_global": [{"text": "FAP", "type": "ENTITY", "char_start": 135529, "char_end": 135532, "token_start": 12, "token_end": 12, "note": null}]}
+{"sentence_id": 917, "sentence_text": "Amino acid changes were identified in four patients , three of whom belonged to the non - FAP group of colorectal cancer patients .", "sentence_char_start_global": 135558, "sentence_char_end_global": 135689, "entities": [{"text": "colorectal cancer", "type": "ENTITY", "char_start": 103, "char_end": 120, "token_start": 20, "token_end": 21}], "entities_global": [{"text": "colorectal cancer", "type": "ENTITY", "char_start": 135661, "char_end": 135678, "token_start": 20, "token_end": 21, "note": null}]}
+{"sentence_id": 918, "sentence_text": "Genotype - phenotype correlations identified significant differences in the nature of certain extracolonic manifestations in FAP patients belonging to three mutation subgroups .", "sentence_char_start_global": 135690, "sentence_char_end_global": 135867, "entities": [{"text": "FAP", "type": "ENTITY", "char_start": 125, "char_end": 128, "token_start": 15, "token_end": 15}], "entities_global": [{"text": "FAP", "type": "ENTITY", "char_start": 135815, "char_end": 135818, "token_start": 15, "token_end": 15, "note": null}]}
+{"sentence_id": 919, "sentence_text": "CONCLUSIONS Extended genotype - phenotype correlations made in this study may have the potential to determine the most appropriate surveillance and prophylactic treatment regimens for those patients with mutations associated with life threatening conditions .", "sentence_char_start_global": 135868, "sentence_char_end_global": 136127, "entities": [], "entities_global": []}
+{"sentence_id": 920, "sentence_text": "This study also provided evidence for the pathological nature of amino acid changes in APC associated with both FAP and non - FAP colorectal cancer patients . .", "sentence_char_start_global": 136128, "sentence_char_end_global": 136288, "entities": [{"text": "FAP", "type": "ENTITY", "char_start": 112, "char_end": 115, "token_start": 18, "token_end": 18}, {"text": "colorectal cancer", "type": "ENTITY", "char_start": 130, "char_end": 147, "token_start": 23, "token_end": 24}], "entities_global": [{"text": "FAP", "type": "ENTITY", "char_start": 136240, "char_end": 136243, "token_start": 18, "token_end": 18, "note": null}, {"text": "colorectal cancer", "type": "ENTITY", "char_start": 136258, "char_end": 136275, "token_start": 23, "token_end": 24, "note": null}]}
+{"sentence_id": 921, "sentence_text": "Inherited colorectal polyposis and cancer risk of the APC I1307K polymorphism .", "sentence_char_start_global": 136289, "sentence_char_end_global": 136368, "entities": [{"text": "Inherited colorectal polyposis", "type": "ENTITY", "char_start": 0, "char_end": 30, "token_start": 0, "token_end": 2}, {"text": "cancer", "type": "ENTITY", "char_start": 35, "char_end": 41, "token_start": 4, "token_end": 4}], "entities_global": [{"text": "Inherited colorectal polyposis", "type": "ENTITY", "char_start": 136289, "char_end": 136319, "token_start": 0, "token_end": 2, "note": null}, {"text": "cancer", "type": "ENTITY", "char_start": 136324, "char_end": 136330, "token_start": 4, "token_end": 4, "note": null}]}
+{"sentence_id": 922, "sentence_text": "Germ - line and somatic truncating mutations of the APC gene are thought to initiate colorectal tumor formation in familial adenomatous polyposis syndrome and sporadic colorectal carcinogenesis , respectively .", "sentence_char_start_global": 136369, "sentence_char_end_global": 136579, "entities": [{"text": "APC", "type": "ENTITY", "char_start": 52, "char_end": 55, "token_start": 9, "token_end": 9}, {"text": "colorectal tumor", "type": "ENTITY", "char_start": 85, "char_end": 101, "token_start": 15, "token_end": 16}, {"text": "familial adenomatous polyposis syndrome", "type": "ENTITY", "char_start": 115, "char_end": 154, "token_start": 19, "token_end": 22}], "entities_global": [{"text": "APC", "type": "ENTITY", "char_start": 136421, "char_end": 136424, "token_start": 9, "token_end": 9, "note": null}, {"text": "colorectal tumor", "type": "ENTITY", "char_start": 136454, "char_end": 136470, "token_start": 15, "token_end": 16, "note": null}, {"text": "familial adenomatous polyposis syndrome", "type": "ENTITY", "char_start": 136484, "char_end": 136523, "token_start": 19, "token_end": 22, "note": null}]}
+{"sentence_id": 923, "sentence_text": "Recently , an isoleucine - - > lysine polymorphism at codon 1307 ( I1307K ) of the APC gene has been identified in 6 % - 7 % of the Ashkenazi Jewish population .", "sentence_char_start_global": 136580, "sentence_char_end_global": 136741, "entities": [{"text": "APC", "type": "ENTITY", "char_start": 83, "char_end": 86, "token_start": 17, "token_end": 17}], "entities_global": [{"text": "APC", "type": "ENTITY", "char_start": 136663, "char_end": 136666, "token_start": 17, "token_end": 17, "note": null}]}
+{"sentence_id": 924, "sentence_text": "To assess the risk of this common APC allelic variant in colorectal carcinogenesis , we have analyzed a large cohort of unselected Ashkenazi Jewish subjects with adenomatous polyps and . or colorectal cancer , for the APC I1307K polymorphism .", "sentence_char_start_global": 136742, "sentence_char_end_global": 136985, "entities": [{"text": "APC", "type": "ENTITY", "char_start": 34, "char_end": 37, "token_start": 7, "token_end": 7}, {"text": "adenomatous polyps", "type": "ENTITY", "char_start": 162, "char_end": 180, "token_start": 26, "token_end": 27}, {"text": "colorectal cancer ,", "type": "ENTITY", "char_start": 190, "char_end": 209, "token_start": 31, "token_end": 33}], "entities_global": [{"text": "APC", "type": "ENTITY", "char_start": 136776, "char_end": 136779, "token_start": 7, "token_end": 7, "note": null}, {"text": "adenomatous polyps", "type": "ENTITY", "char_start": 136904, "char_end": 136922, "token_start": 26, "token_end": 27, "note": null}, {"text": "colorectal cancer ,", "type": "ENTITY", "char_start": 136932, "char_end": 136951, "token_start": 31, "token_end": 33, "note": null}]}
+{"sentence_id": 925, "sentence_text": "The APC I1307K allele was identified in 48 ( 10 . 1 % ) of 476 patients .", "sentence_char_start_global": 136986, "sentence_char_end_global": 137059, "entities": [], "entities_global": []}
+{"sentence_id": 926, "sentence_text": "Compared with the frequency in two separate population control groups , the APC I1307K allele is associated with an estimated relative risk of 1 .", "sentence_char_start_global": 137060, "sentence_char_end_global": 137206, "entities": [], "entities_global": []}
+{"sentence_id": 927, "sentence_text": "5 - 1 .", "sentence_char_start_global": 137207, "sentence_char_end_global": 137214, "entities": [], "entities_global": []}
+{"sentence_id": 928, "sentence_text": "7 for colorectal neoplasia ( both P = . 01 ) .", "sentence_char_start_global": 137215, "sentence_char_end_global": 137261, "entities": [{"text": "colorectal neoplasia", "type": "ENTITY", "char_start": 6, "char_end": 26, "token_start": 2, "token_end": 3}], "entities_global": [{"text": "colorectal neoplasia", "type": "ENTITY", "char_start": 137221, "char_end": 137241, "token_start": 2, "token_end": 3, "note": null}]}
+{"sentence_id": 929, "sentence_text": "Furthermore , compared with noncarriers , APC I1307K carriers had increased numbers of adenomas and colorectal cancers per patient ( P = . 03 ) , as well as a younger age at diagnosis .", "sentence_char_start_global": 137262, "sentence_char_end_global": 137447, "entities": [{"text": "adenomas", "type": "ENTITY", "char_start": 87, "char_end": 95, "token_start": 13, "token_end": 13}, {"text": "colorectal cancers", "type": "ENTITY", "char_start": 100, "char_end": 118, "token_start": 15, "token_end": 16}], "entities_global": [{"text": "adenomas", "type": "ENTITY", "char_start": 137349, "char_end": 137357, "token_start": 13, "token_end": 13, "note": null}, {"text": "colorectal cancers", "type": "ENTITY", "char_start": 137362, "char_end": 137380, "token_start": 15, "token_end": 16, "note": null}]}
+{"sentence_id": 930, "sentence_text": "We conclude that the APC I1307K variant leads to increased adenoma formation and directly contributes to 3 % - 4 % of all Ashkenazi Jewish colorectal cancer .", "sentence_char_start_global": 137448, "sentence_char_end_global": 137606, "entities": [{"text": "adenoma", "type": "ENTITY", "char_start": 59, "char_end": 66, "token_start": 10, "token_end": 10}, {"text": "colorectal cancer", "type": "ENTITY", "char_start": 139, "char_end": 156, "token_start": 25, "token_end": 26}], "entities_global": [{"text": "adenoma", "type": "ENTITY", "char_start": 137507, "char_end": 137514, "token_start": 10, "token_end": 10, "note": null}, {"text": "colorectal cancer", "type": "ENTITY", "char_start": 137587, "char_end": 137604, "token_start": 25, "token_end": 26, "note": null}]}
+{"sentence_id": 931, "sentence_text": "The estimated relative risk for carriers may justify specific clinical screening for the 360 , 000 Americans expected to harbor this allele , and genetic testing in the setting of long - term - outcome studies may impact significantly on colorectal cancer prevention in this population .", "sentence_char_start_global": 137607, "sentence_char_end_global": 137894, "entities": [{"text": "colorectal cancer", "type": "ENTITY", "char_start": 238, "char_end": 255, "token_start": 40, "token_end": 41}], "entities_global": [{"text": "colorectal cancer", "type": "ENTITY", "char_start": 137845, "char_end": 137862, "token_start": 40, "token_end": 41, "note": null}]}
+{"sentence_id": 932, "sentence_text": "Localization of human BRCA1 and its loss in high - grade , non - inherited breast carcinomas .", "sentence_char_start_global": 137895, "sentence_char_end_global": 137989, "entities": [{"text": "non - inherited breast carcinomas", "type": "ENTITY", "char_start": 59, "char_end": 92, "token_start": 12, "token_end": 16}], "entities_global": [{"text": "non - inherited breast carcinomas", "type": "ENTITY", "char_start": 137954, "char_end": 137987, "token_start": 12, "token_end": 16, "note": null}]}
+{"sentence_id": 933, "sentence_text": "Although the link between the BRCA1 tumour - suppressor gene and hereditary breast and ovarian cancer is established , the role , if any , of BRCA1 in non - familial cancers is unclear .", "sentence_char_start_global": 137990, "sentence_char_end_global": 138176, "entities": [{"text": "tumour", "type": "ENTITY", "char_start": 36, "char_end": 42, "token_start": 6, "token_end": 6}, {"text": "hereditary breast and ovarian cancer", "type": "ENTITY", "char_start": 65, "char_end": 101, "token_start": 11, "token_end": 15}, {"text": "non - familial cancers", "type": "ENTITY", "char_start": 151, "char_end": 173, "token_start": 28, "token_end": 31}], "entities_global": [{"text": "tumour", "type": "ENTITY", "char_start": 138026, "char_end": 138032, "token_start": 6, "token_end": 6, "note": null}, {"text": "hereditary breast and ovarian cancer", "type": "ENTITY", "char_start": 138055, "char_end": 138091, "token_start": 11, "token_end": 15, "note": null}, {"text": "non - familial cancers", "type": "ENTITY", "char_start": 138141, "char_end": 138163, "token_start": 28, "token_end": 31, "note": null}]}
+{"sentence_id": 934, "sentence_text": "BRCA1 mutations are rare in sporadic cancers , but loss of BRCA1 resulting from reduced expression or incorrect subcellular localization is postulated to be important in non - familial breast and ovarian cancers .", "sentence_char_start_global": 138177, "sentence_char_end_global": 138390, "entities": [{"text": "sporadic cancers", "type": "ENTITY", "char_start": 28, "char_end": 44, "token_start": 5, "token_end": 6}, {"text": "non - familial breast and ovarian cancers", "type": "ENTITY", "char_start": 170, "char_end": 211, "token_start": 26, "token_end": 32}], "entities_global": [{"text": "sporadic cancers", "type": "ENTITY", "char_start": 138205, "char_end": 138221, "token_start": 5, "token_end": 6, "note": null}, {"text": "non - familial breast and ovarian cancers", "type": "ENTITY", "char_start": 138347, "char_end": 138388, "token_start": 26, "token_end": 32, "note": null}]}
+{"sentence_id": 935, "sentence_text": "Epigenetic loss , however , has not received general acceptance due to controversy regarding the subcellular localization of BRCA1 proteins , reports of which have ranged from exclusively nuclear , to conditionally nuclear , to the ER / golgi , to cytoplasmic invaginations into the nucleus .", "sentence_char_start_global": 138391, "sentence_char_end_global": 138683, "entities": [], "entities_global": []}
+{"sentence_id": 936, "sentence_text": "In an attempt to resolve this issue , we have comprehensively characterized 19 anti - BRCA1 antibodies .", "sentence_char_start_global": 138684, "sentence_char_end_global": 138788, "entities": [], "entities_global": []}
+{"sentence_id": 937, "sentence_text": "These reagents detect a 220 - kD protein localized in discrete nuclear foci in all epithelial cell lines , including those derived from breast malignancies .", "sentence_char_start_global": 138789, "sentence_char_end_global": 138946, "entities": [{"text": "breast malignancies", "type": "ENTITY", "char_start": 136, "char_end": 155, "token_start": 23, "token_end": 24}], "entities_global": [{"text": "breast malignancies", "type": "ENTITY", "char_start": 138925, "char_end": 138944, "token_start": 23, "token_end": 24, "note": null}]}
+{"sentence_id": 938, "sentence_text": "Immunohistochemical staining of human breast specimens also revealed BRCA1 nuclear foci in benign breast , invasive lobular cancers and low - grade ductal carcinomas .", "sentence_char_start_global": 138947, "sentence_char_end_global": 139114, "entities": [{"text": "invasive lobular cancers", "type": "ENTITY", "char_start": 107, "char_end": 131, "token_start": 15, "token_end": 17}, {"text": "low - grade ductal carcinomas", "type": "ENTITY", "char_start": 136, "char_end": 165, "token_start": 19, "token_end": 23}], "entities_global": [{"text": "invasive lobular cancers", "type": "ENTITY", "char_start": 139054, "char_end": 139078, "token_start": 15, "token_end": 17, "note": null}, {"text": "low - grade ductal carcinomas", "type": "ENTITY", "char_start": 139083, "char_end": 139112, "token_start": 19, "token_end": 23, "note": null}]}
+{"sentence_id": 939, "sentence_text": "Conversely , BRCA1 expression was reduced or undetectable in the majority of high - grade , ductal carcinomas , suggesting that absence of BRCA1 may contribute to the pathogenesis of a significant percentage of sporadic breast cancers . .", "sentence_char_start_global": 139115, "sentence_char_end_global": 139353, "entities": [{"text": "ductal carcinomas", "type": "ENTITY", "char_start": 92, "char_end": 109, "token_start": 16, "token_end": 17}, {"text": "sporadic breast cancers", "type": "ENTITY", "char_start": 211, "char_end": 234, "token_start": 34, "token_end": 36}], "entities_global": [{"text": "ductal carcinomas", "type": "ENTITY", "char_start": 139207, "char_end": 139224, "token_start": 16, "token_end": 17, "note": null}, {"text": "sporadic breast cancers", "type": "ENTITY", "char_start": 139326, "char_end": 139349, "token_start": 34, "token_end": 36, "note": null}]}
diff --git a/evaluation/benchmark/NCBI_disease_test_text.txt b/evaluation/benchmark/NCBI_disease_test_text.txt
new file mode 100644
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+Clustering of missense mutations in the ataxia - telangiectasia gene in a sporadic T - cell leukaemia . Ataxia - telangiectasia ( A - T ) is a recessive multi - system disorder caused by mutations in the ATM gene at 11q22 - q23 ( ref . 3 ) . The risk of cancer , especially lymphoid neoplasias , is substantially elevated in A - T patients and has long been associated with chromosomal instability . By analysing tumour DNA from patients with sporadic T - cell prolymphocytic leukaemia ( T - PLL ) , a rare clonal malignancy with similarities to a mature T - cell leukaemia seen in A - T , we demonstrate a high frequency of ATM mutations in T - PLL . In marked contrast to the ATM mutation pattern in A - T , the most frequent nucleotide changes in this leukaemia were missense mutations . These clustered in the region corresponding to the kinase domain , which is highly conserved in ATM - related proteins in mouse , yeast and Drosophila . The resulting amino - acid substitutions are predicted to interfere with ATP binding or substrate recognition . Two of seventeen mutated T - PLL samples had a previously reported A - T allele . In contrast , no mutations were detected in the p53 gene , suggesting that this tumour suppressor is not frequently altered in this leukaemia . Occasional missense mutations in ATM were also found in tumour DNA from patients with B - cell non - Hodgkins lymphomas ( B - NHL ) and a B - NHL cell line . The evidence of a significant proportion of loss - of - function mutations and a complete absence of the normal copy of ATM in the majority of mutated tumours establishes somatic inactivation of this gene in the pathogenesis of sporadic T - PLL and suggests that ATM acts as a tumour suppressor . As constitutional DNA was not available , a putative hereditary predisposition to T - PLL will require further investigation . . Myotonic dystrophy protein kinase is involved in the modulation of the Ca2 + homeostasis in skeletal muscle cells . Myotonic dystrophy ( DM ) , the most prevalent muscular disorder in adults , is caused by ( CTG ) n - repeat expansion in a gene encoding a protein kinase ( DM protein kinase ; DMPK ) and involves changes in cytoarchitecture and ion homeostasis . To obtain clues to the normal biological role of DMPK in cellular ion homeostasis , we have compared the resting [ Ca2 + ] i , the amplitude and shape of depolarization - induced Ca2 + transients , and the content of ATP - driven ion pumps in cultured skeletal muscle cells of wild - type and DMPK [ - / - ] knockout mice . In vitro - differentiated DMPK [ - / - ] myotubes exhibit a higher resting [ Ca2 + ] i than do wild - type myotubes because of an altered open probability of voltage - dependent l - type Ca2 + and Na + channels . The mutant myotubes exhibit smaller and slower Ca2 + responses upon triggering by acetylcholine or high external K + . In addition , we observed that these Ca2 + transients partially result from an influx of extracellular Ca2 + through the l - type Ca2 + channel . Neither the content nor the activity of Na + / K + ATPase and sarcoplasmic reticulum Ca2 + - ATPase are affected by DMPK absence . In conclusion , our data suggest that DMPK is involved in modulating the initial events of excitation - contraction coupling in skeletal muscle . . Constitutional RB1 - gene mutations in patients with isolated unilateral retinoblastoma . In most patients with isolated unilateral retinoblastoma , tumor development is initiated by somatic inactivation of both alleles of the RB1 gene . However , some of these patients can transmit retinoblastoma predisposition to their offspring . To determine the frequency and nature of constitutional RB1 - gene mutations in patients with isolated unilateral retinoblastoma , we analyzed DNA from peripheral blood and from tumor tissue . The analysis of tumors from 54 ( 71 % ) of 76 informative patients showed loss of constitutional heterozygosity ( LOH ) at intragenic loci . Three of 13 uninformative patients had constitutional deletions . For 39 randomly selected tumors , SSCP , hetero - duplex analysis , sequencing , and Southern blot analysis were used to identify mutations . Mutations were detected in 21 ( 91 % ) of 23 tumors with LOH . In 6 ( 38 % ) of 16 tumors without LOH , one mutation was detected , and in 9 ( 56 % ) of the tumors without LOH , both mutations were found . Thus , a total of 45 mutations were identified in tumors of 36 patients . Thirty - nine of the mutations - including 34 small mutations , 2 large structural alterations , and hypermethylation in 3 tumors - were not detected in the corresponding peripheral blood DNA . In 6 ( 17 % ) of the 36 patients , a mutation was detected in constitutional DNA , and 1 of these mutations is known to be associated with reduced expressivity . The presence of a constitutional mutation was not associated with an early age at treatment . In 1 patient , somatic mosaicism was demonstrated by molecular analysis of DNA and RNA from peripheral blood . In 2 patients without a detectable mutation in peripheral blood , mosaicism was suggested because 1 of the patients showed multifocal tumors and the other later developed bilateral retinoblastoma . In conclusion , our results emphasize that the manifestation and transmissibility of retinoblastoma depend on the nature of the first mutation , its time in development , and the number and types of cells that are affected . . Hereditary deficiency of the fifth component of complement in man . I . Clinical , immunochemical , and family studies . The first recognized human kindred with hereditary deficiency of the fifth component of complement ( C5 ) is described . The proband , a 20 - year - old black female with systemic lupus erythematosus since age 11 , lacked serum hemolytic complement activity , even during remission . C5 was undetectable in her serum by both immunodiffusion and hemolytic assays . Other complement components were normal during remission of lupus , but C1 , C4 , C2 , and C3 levels fell during exacerbations . A younger half - sister , who had no underlying disease , was also found to lack immunochemically detectable C5 . By hemolytic assay , she exhibited 1 - 2 % of the normal serum C5 level and normal concentrations of other complement components . C5 levels of other family members were either normal or approximately half - normal , consistent with autosomal codominant inheritance of the gene determining C5 deficiency . Normal hemolytic titers were restored to both homozygous C5 - deficient ( C5D ) sera by addition of highly purified human C5 . In specific C5 titrations , however , it was noted that when limited amounts of C5 were assayed in the presence of low dilutions of either C5D serum , curving rather than linear dose - response plots were consistently obtained , suggesting some inhibitory effect . Further studies suggested that low dilutions of C5D serum contain a factor ( or factors ) interfering at some step in the hemolytic assay of C5 , rather than a true C5 inhibitor or inactivator . Of clinical interest are ( a ) the documentation of membranous glomerulonephritis , vasculitis , and arthritis in an individual lacking C5 ( and its biologic functions ) , and ( b ) a remarkable propensity to bacterial infections in the proband , even during periods of low - dose or alternate - day corticosteroid therapy . Other observations indicate that the C5D state is compatible with normal coagulation function and the capacity to mount a neutrophilic leukocytosis during pyogenic infection . . Susceptibility to ankylosing spondylitis in twins : the role of genes , HLA , and the environment . OBJECTIVE To determine the relative effects of genetic and environmental factors in susceptibility to ankylosing spondylitis ( AS ) . METHODS Twins with AS were identified from the Royal National Hospital for Rheumatic Diseases database . Clinical and radiographic examinations were performed to establish diagnoses , and disease severity was assessed using a combination of validated scoring systems . HLA typing for HLA - B27 , HLA - B60 , and HLA - DR1 was performed by polymerase chain reaction with sequence - specific primers , and zygosity was assessed using microsatellite markers . Genetic and environmental variance components were assessed with the program Mx , using data from this and previous studies of twins with AS . RESULTS Six of 8 monozygotic ( MZ ) twin pairs were disease concordant , compared with 4 of 15 B27 - positive dizygotic ( DZ ) twin pairs ( 27 % ) and 4 of 32 DZ twin pairs overall ( 12 . 5 % ) . Nonsignificant increases in similarity with regard to age at disease onset and all of the disease severity scores assessed were noted in disease - concordant MZ twins compared with concordant DZ twins . HLA - B27 and B60 were associated with the disease in probands , and the rate of disease concordance was significantly increased among DZ twin pairs in which the co - twin was positive for both B27 and DR1 . Additive genetic effects were estimated to contribute 97 % of the population variance . CONCLUSION Susceptibility to AS is largely genetically determined , and the environmental trigger for the disease is probably ubiquitous . HLA - B27 accounts for a minority of the overall genetic susceptibility to AS . Cell cycle - dependent colocalization of BARD1 and BRCA1 proteins in discrete nuclear domains . Germ - line mutations of the BRCA1 gene predispose women to early - onset breast and ovarian cancer by compromising the genes presumptive function as a tumor suppressor . Although the biochemical properties of BRCA1 polypeptides are not understood , their expression pattern and subcellular localization suggest a role in cell - cycle regulation . When resting cells are induced to proliferate , the steady - state levels of BRCA1 increase in late G1 and reach a maximum during S phase . Moreover , in S phase cells , BRCA1 polypeptides are hyperphosphorylated and accumulate into discrete subnuclear foci termed " BRCA1 nuclear dots . " BRCA1 associates in vivo with a structurally related protein termed BARD1 . Here we show that the steady - state levels of BARD1 , unlike those of BRCA1 , remain relatively constant during cell cycle progression . However , immunostaining revealed that BARD1 resides within BRCA1 nuclear dots during S phase of the cell cycle , but not during the G1 phase . Nevertheless , BARD1 polypeptides are found exclusively in the nuclear fractions of both G1 - and S - phase cells . Therefore , progression to S phase is accompanied by the aggregation of nuclear BARD1 polypeptides into BRCA1 nuclear dots . This cell cycle - dependent colocalization of BARD1 and BRCA1 indicates a role for BARD1 in BRCA1 - mediated tumor suppression . Ethnic differences in the HFE codon 282 ( Cys / Tyr ) polymorphism . Recent studies have shown that hereditary hemochromatosis ( HH ) is likely to be caused by homozygosity for a Cys282Tyr mutation in the HFE gene located 4 . 5 Mb telomeric to HLA - A . Population studies of this polymorphism are facilitated by the fact that the Cys282Tyr mutation creates a Rsal restriction site . We have studied the codon 282 ( Cys / Tyr ) polymorphism in different ethnic groups . In agreement with previous observations the Tyr allele appeared to be rare or absent in Asiatic ( Indian , Chinese ) populations . The highest allele frequency ( 7 . 5 % ) was found in Swedes . Saamis ( 2 % ) and Mordvinians ( 1 . 8 % ) had significantly lower frequencies of the Tyr allele . Comparisons with allele frequencies based on prevalence estimates of HH showed some disagreements with the RFLP data , particularly in Finns . The newly described HFE marker provides a new approach to the screening of HH as well as studies of the relationship between the HFE Tyr allele and different disorders including cancer Autosomal dominant neurohypophyseal diabetes insipidus associated with a missense mutation encoding Gly23 - - > Val in neurophysin II . Autosomal dominant neurohypophyseal diabetes insipidus ( ADNDI ) is an inherited disease caused by progressive degeneration of the magnocellular neurons of the hypothalamus leading to decreased ability to produce the hormone arginine vasopressin ( AVP ) . Affected individuals are not symptomatic at birth , but usually develop diabetes insipidus at 1 - 6 yr of age . The genetic locus of the disease is the AVP - neurophysin II ( NPII ) gene , and mutations that cause ADNDI have been found in both the signal peptide of the prepro - AVP - NPII precursor and within NPII itself . An affected girl who presented at 9 months of age and her similarly affected younger brother and father were all found to have a novel missense mutation ( G1758 - - > T ) encoding the amino acid substitution Gly23 - - > Val within NPII . The mutation was confirmed by restriction endonuclease analysis . A T1 - weighted magnetic resonance imaging of the fathers pituitary gland demonstrates an attenuated posterior pituitary bright spot . This mutation may be valuable for developing models of dominantly inherited neurodegeneration , as the early age of onset of symptoms suggests that this mutation may be particularly deleterious to the magnocellular neuron . . Frequent inactivation of PTEN / MMAC1 in primary prostate cancer . Sporadic prostate carcinoma is the most common male cancer in the Western world , yet many of the major genetic events involved in the progression of this often fatal cancer remain to be elucidated . Numerous cytogenetic and allelotype studies have reported frequent loss of heterozygosity on chromosomal arm 10q in sporadic prostate cancer . Deletion mapping studies have unambiguously identified a region of chromosome 10q23 to be the minimal area of loss . A new tumor suppressor gene , PTEN / MMAC1 , was isolated recently at this region of chromosome 10q23 and found to be inactivated by mutation in three prostate cancer cell lines . We screened 80 prostate tumors by microsatellite analysis and found chromosome 10q23 to be deleted in 23 cases . We then proceeded with sequence analysis of the entire PTEN / MMAC1 coding region and tested for homozygous deletion with new intragenic markers in these 23 cases with 10q23 loss of heterozygosity . The identification of the second mutational event in 10 ( 43 % ) tumors establishes PTEN / MMAC1 as a main inactivation target of 10q loss in sporadic prostate cancer . . Risk reversals in predictive testing for Huntington disease . The first predictive testing for Huntington disease ( HD ) was based on analysis of linked polymorphic DNA markers to estimate the likelihood of inheriting the mutation for HD . Limits to accuracy included recombination between the DNA markers and the mutation , pedigree structure , and whether DNA samples were available from family members . With direct tests for the HD mutation , we have assessed the accuracy of results obtained by linkage approaches when requested to do so by the test individuals . For six such individuals , there was significant disparity between the tests . Three went from a decreased risk to an increased risk , while in another three the risk was decreased . Knowledge of the potential reasons for these changes in results and impact of these risk reversals on both patients and the counseling team can assist in the development of strategies for the prevention and , where necessary , management of a risk reversal in any predictive testing program . . A novel common missense mutation G301C in the N - acetylgalactosamine - 6 - sulfate sulfatase gene in mucopolysaccharidosis IVA . Mucopolysaccharidosis IVA ( MPS IVA ) is an autosomal recessive lysosomal storage disorder caused by a genetic defect in N - acetylgalactosamine - 6 - sulfate sulfatase ( GALNS ) . In previous studies , we have found two common mutations in Caucasians and Japanese , respectively . To characterize the mutational spectrum in various ethnic groups , mutations in the GALNS gene in Colombian MPS IVA patients were investigated , and genetic backgrounds were extensively analyzed to identify racial origin , based on mitochondrial DNA ( mtDNA ) lineages . Three novel missense mutations never identified previously in other populations and found in 16 out of 19 Colombian MPS IVA unrelated alleles account for 84 . 2 % of the alleles in this study . The G301C and S162F mutations account for 68 . 4 % and 10 . 5 % of mutations , respectively , whereas the remaining F69V is limited to a single allele . The skewed prevalence of G301C in only Colombian patients and haplotype analysis by restriction fragment length polymorphisms in the GALNS gene suggest that G301C originated from a common ancestor . Investigation of the genetic background by means of mtDNA lineages indicate that all our patients are probably of native American descent Low frequency of BRCA1 germline mutations in 45 German breast / ovarian cancer families . In this study we investigated 45 German breast / ovarian cancer families for germline mutations in the BRCA1 gene . We identified four germline mutations in three breast cancer families and in one breast - ovarian cancer family . among these were one frameshift mutation , one nonsense mutation , one novel splice site mutation , and one missense mutation . The missense mutation was also found in 2 . 8 % of the general population , suggesting that it is not disease associated . The average age of disease onset in those families harbouring causative mutations was between 32 . 3 and 37 . 4 years , whereas the family harbouring the missense mutation had an average age of onset of 51 . 2 years . These findings show that BRCA1 is implicated in a small fraction of breast / ovarian cancer families suggesting the involvement of another susceptibility gene ( s ) Paternal transmission of congenital myotonic dystrophy . We report a rare case of paternally transmitted congenital myotonic dystrophy ( DM ) . The proband is a 23 year old , mentally retarded male who suffers severe muscular weakness . He presented with respiratory and feeding difficulties at birth . His two sibs suffer from childhood onset DM . Their late father had the adult type of DM , with onset around 30 years . Only six other cases of paternal transmission of congenital DM have been reported recently . We review the sex related effects on transmission of congenital DM . Decreased fertility of males with adult onset DM and contraction of the repeat upon male transmission contribute to the almost absent occurrence of paternal transmission of congenital DM . Also the fathers of the reported congenitally affected children showed , on average , shorter CTG repeat lengths and hence less severe clinical symptoms than the mothers of children with congenital DM . We conclude that paternal transmission of congenital DM is rare and preferentially occurs with onset of DM past 30 years in the father . . The RB1 gene mutation in a child with ectopic intracranial retinoblastoma . The RB1 gene mutation was investigated in a child with ectopic intracranial retinoblastoma using DNA obtained from both the pineal and retinal tumours of the patient . A nonsense mutation in exon 17 ( codon 556 ) of the RB1 gene was found to be present homozygously in both the retinal and the pineal tumours . The same mutation was present heterozygously in the DNA from the constitutional cells of the patient , proving it to be of germline origin . The initial mutation was shown to have occurred in the paternally derived RB1 allele . The mutation is in an area of the gene that encodes the protein - binding region known as the pocket region and has been detected in other cases of retinoblastoma . . Low levels of beta hexosaminidase A in healthy individuals with apparent deficiency of this enzyme . Appreciable beta hexosaminidase A ( hex A ) activity has been detected in cultured skin fibroblasts and melanoma tissue from healthy individuals previously reported as having deficiency of hex A activity indistinguishable from that of patients with Tay - Sachs disease ( TSD ) . Identification and quantitation of hex A , amounting to 3 . 5 % - 6 . 9 % of total beta hexosaminidase activity , has been obtained by cellulose acetate gel electrophoresis , DEAE - cellulose ion - exchange chromatography , radial immunodiffusion , and radioimmunoassay . Previous family studies suggested that these individuals may be compound heterozygotes for the common mutant TSD gene and a rare ( allelic ) mutant gene . Thus , the postulated rate mutant gene appears to code for the expression of low amounts of hex A . Heterozygotes for the rare mutant may be indistinguishable from heterozygotes for the common TSD mutant . However , direct visualization and quantitation of hex A by the methods described may prevent false - positive prenatal diagnosis of TSD in fetuses having the incomplete hex A deficiency of the type described in the four healthy individuals The tumor suppressor gene Smad4 / Dpc4 is required for gastrulation and later for anterior development of the mouse embryo . Mutations in the SMAD4 / DPC4 tumor suppressor gene , a key signal transducer in most TGFbeta - related pathways , are involved in 50 % of pancreatic cancers . Homozygous Smad4 mutant mice die before day 7 . 5 of embryogenesis . Mutant embryos have reduced size , fail to gastrulate or express a mesodermal marker , and show abnormal visceral endoderm development . Growth retardation of the Smad4 - deficient embryos results from reduced cell proliferation rather than increased apoptosis . Aggregation of mutant Smad4 ES cells with wild - type tetraploid morulae rescues the gastrulation defect . These results indicate that Smad4 is initially required for the differentiation of the visceral endoderm and that the gastrulation defect in the epiblast is secondary and non - cell autonomous . Rescued embryos show severe anterior truncations , indicating a second important role for Smad4 in anterior patterning during embryogenesis . Prevalence of p16 and CDK4 germline mutations in 48 melanoma - prone families in France . The French Familial Melanoma Study Group . Germline mutations in the p16 and CDK4 genes have been reported in a subset of melanoma pedigrees , but their prevalence is not well known . We searched for such germline mutations in 48 French melanoma - prone families selected according to two major criteria families with at least three affected members ( n = 20 ) or families with two affected members , one of them affected before the age of 50 ( n = 28 ) , and one additional minor criterion . Sixteen different p16 germline mutations were found in 21 families , while one germline mutation , Arg24His , was detected in the CDK4 gene . The frequency of p16 gene mutation in our sample ( 44 % ) is among the highest rates yet reported and the CDK4 mutation is the second mutation detected in this gene worldwide . In summary , our results show frequent involvement of the p16 gene in familial melanoma and confirm the role of the CDK4 gene as a melanoma - predisposing gene . . Progression of somatic CTG repeat length heterogeneity in the blood cells of myotonic dystrophy patients . The genetic basis of myotonic dystrophy ( DM ) is the expansion of an unstable CTG repeat in the 34 UTR of the DM protein kinase gene on chromosome 19 . One of the principal features of the DM mutation is an extraordinarily high level of somatic mosaicism , due to an extremely high degree of somatic instability both within and between different tissues . This instability appears to be biased towards further expansion and continuous throughout the life of an individual , features that could be associated with the progressive nature of the disease . Although increasing measured allele size between patients clearly correlates with an increased severity of symptoms and an earlier age of onset , this correlation is not precise and measured allele length cannot be used as an accurate predictor of age of onset . In order to further characterize the dynamics of DM CTG repeat somatic instability , we have studied repeat length changes over time in 111 myotonic dystrophy patients with varying clinical severity and CTG repeat size over time intervals of 1 - 7 years . We have found a direct progression of the size heterogeneity over time related to initial CTG repeat size and the time interval and always biased towards further expansion . Attempts to mathematically model the dynamics have proved only partially successful suggesting that individual specific genetic and / or environmental factors also play a role in somatic mosaicism . . Aspartylglucosaminuria among Palestinian Arabs . Aspartylglucosaminuria ( AGU ) is a rare disorder of glycoprotein metabolism caused by the deficiency of the lysosomal enzyme aspartylglucosaminidase ( AGA ) . AGU is inherited as an autosomal recessive trait and occurs with a high frequency in Finland because of a founder effect . While very few patients with AGU have been reported from non - Finnish origin , we diagnosed the disorder in 8 patients originating from 3 unrelated families , all Palestinian Arabs from the region of Jerusalem . The clinical diagnosis of AGU is often difficult , in particular early in the course of the disease , and most of the patients are diagnosed after the age of 5 years . However , since these patients excrete early large amounts of aspartylglucosamine in urine , biochemical screening is easy by urine chromatography . . Detection of heterozygous carriers of the ataxia - telangiectasia ( ATM ) gene by G2 phase chromosomal radiosensitivity of peripheral blood lymphocytes . In ataxia - telangiectasia ( A - T ) patients , mutations in a single gene , ATM , result in an autosomal recessive syndrome that embraces a variety of clinical features and manifests extreme radiosensitivity and a strong pre - disposition to malignancy . Heterozygotes for the ATM gene have no clinical expression of A - T but may be cancer prone with a moderate increase in in vitro radiosensitivity . We performed a blind chromosomal analysis on G2 - phase lymphocytes from 7 unrelated A - T patients , 13 obligate A - T heterozygotes ( parents of the patients ) , and 14 normal controls following X - irradiation with 1 Gy in order to evaluate this cytogenetic method as a tool for detection of ATM carriers . Both A - T homozygotes and heterozygotes showed significantly increased levels of radiation - induced chromatid damage relative to that of normal controls . These results show that the G2 - phase chromosomal radiosensitivity assay can be used for the detection of A - T heterozygotes . In combination with molecular genetic analyses , this test may be of value in studies of familial and sporadic cancers aimed at determination of the potential involvement of ATM mutations in tumor risk or development . . Ataxia - telangiectasia : identification and detection of founder - effect mutations in the ATM gene in ethnic populations . To facilitate the evaluation of ATM heterozygotes for susceptibility to other diseases , such as breast cancer , we have attempted to define the most common mutations and their frequencies in ataxia - telangiectasia ( A - T ) homozygotes from 10 ethnic populations . Both genomic mutations and their effects on cDNA were characterized . Protein - truncation testing of the entire ATM cDNA detected 92 ( 66 % ) truncating mutations in 140 mutant alleles screened . The haplotyping of patients with identical mutations indicates that almost all of these represent common ancestry and that very few spontaneously recurring ATM mutations exist . Assays requiring minimal amounts of genomic DNA were designed to allow rapid screening for common ethnic mutations . These rapid assays detected mutations in 76 % of Costa Rican patients ( 3 ) , 50 % of Norwegian patients ( 1 ) , 25 % of Polish patients ( 4 ) , and 14 % of Italian patients ( 1 ) , as well as in patients of Amish / Mennonite and Irish English backgrounds . Additional mutations were observed in Japanese , Utah Mormon , and African American patients . These assays should facilitate screening for A - T heterozygotes in the populations studied . . The von Hippel - Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal . The inactivation of the von Hippel - Lindau ( VHL ) tumor suppressor gene predisposes affected individuals to the human VHL cancer syndrome and is associated with sporadic renal cell carcinomas ( RCC ) and brain hemangioblastomas . VHL - negative 786 - 0 RCC cells are tumorigenic in nude mice which is suppressed by the reintroduction of VHL . Remarkably , this occurs without affecting the growth rate and cell cycle profile of these cells in culture . The 786 - 0 cell line , like many cancer cells , fails to exit the cell cycle upon serum withdrawal . Here , it is shown that reintroduction of the wild - type VHL gene restores the ability of VHL - negative RCC cancer cells to exit the cell cycle and enter G0 / quiescence in low serum . Both VHL - positive and VHL - negative RCC cells exit the cell cycle by contact inhibition . The cyclin - dependent kinase inhibitor , p27 , accumulates upon serum withdrawal , only in the presence of VHL , as a result of the stabilization of the protein . We propose that the loss of wild - type VHL gene results in a specific cellular defect in serum - dependent growth control , which may initiate tumor formation . This is corrected by the reintroduction of wild - type VHL , implicating VHL as the first tumor suppressor involved in the regulation of cell cycle exit , which is consistent with its gatekeeper function in the kidney . . Piebaldism with deafness : molecular evidence for an expanded syndrome . In a South African girl of Xhosa stock with severe piebaldism and profound congenital sensorineural deafness we identified a novel missense substitution at a highly conserved residue in the intracellular kinase domain of the KIT proto - oncogene , R796G . Though auditory anomalies have been observed in mice with dominant white spotting ( W ) due to KIT mutations , deafness is not typical in human piebaldism . Thus , the occurrence of sensorineural deafness in this patient extends considerably the phenotypic range of piebaldism due to KIT gene mutation in humans and tightens the clinical similarity between piebaldism and the various forms of Waardenburg syndrome . . Cycloheximide facilitates the identification of aberrant transcripts resulting from a novel splice - site mutation in COL17A1 in a patient with generalized atrophic benign epidermolysis bullosa . Patients with generalized atrophic benign epidermolysis bullosa often show decreased expression of type XVII collagen , a transmembrane hemidesmosomal protein encoded by COL17A1 . This report documents a novel splice - site mutation in COL17A1 in a patient with generalized atrophic benign epidermolysis bullosa , and applies a new methodology to define and characterize the resulting mRNA splice variants . Mutational analysis of COL17A1 identified a maternally inherited G - to - T transversion at the - 1 position of exon 32 . This acceptor splice - site mutation led to the formation of aberrant transcripts present at extremely low levels . Based on our recent finding that cycloheximide stabilized mutant COL17A1 transcripts in keratinocytes homozygous for a frameshift mutation , the effects of the splice - site mutation on splicing of COL17A1 transcripts were determined using reverse transcriptase polymerase chain reaction of total RNA from keratinocytes incubated for 2 . 5 h in the presence or absence of 10 microg cycloheximide per ml . Using this approach , an abnormally spliced transcript was identified that contains an extra 264 bases upstream from exon 32 , resulting in a premature termination codon 27 bp downstream from the cryptic splice site . Three other splice variants , including one derived from the skipping of exon 32 , were also identified . These results indicate the usefulness of cycloheximide treatment in evaluating the abnormal processing of mRNA due to splice - site mutations , because ( i ) aberrant splicing often generates a premature termination codon , ( ii ) transcripts with premature termination codons can occur at low or undetectable levels due to nonsense - mediated mRNA decay , and ( iii ) the levels of these transcripts can be increased by cycloheximide . A deletion mutation in COL17A1 in five Austrian families with generalized atrophic benign epidermolysis bullosa represents propagation of an ancestral allele . Patients with generalized atrophic benign epidermolysis bullosa , a usually nonlethal form of junctional epidermolysis bullosa , have generalized blistering , nail dystrophy , patchy alopecia , and dental abnormalities . Skin fragility in most cases is due to mutations in the gene encoding type XVII collagen ( COL17A1 ) . Recently , we reported five Austrian families with generalized atrophic benign epidermolysis bullosa who share the same COL17A1 mutation . Affected individuals in three families are homozygous for 4003delTC , whereas those in two others are compound heterozygotes . To determine if the occurrence of 4003delTC in these unrelated families signifies propagation of an ancestral allele or a mutational hot spot , haplotypes were determined for polymorphisms both within and flanking COL17A1 . Five intragenic polymorphisms were chosen based on their informativeness . One of these , not previously reported , was 2988 A or C that introduces a new restriction site for Eco0109 I . All the 4003delTC alleles showed the same haplotype for these five polymorphic markers . Fourteen microsatellite polymorphisms were selected based on their high heterozygosity and their location within 10q23 - q25 near COL17A1 . Three families shared microsatellite polymorphisms covering at most 19 cM , whereas the others shared smaller regions consistent with cross - over events during passage of this mutation through several generations . These results indicate that 4003delTC occurs on a single ancestral allele . . The haptoglobin - gene deletion responsible for anhaptoglobinemia . We have found an allelic deletion of the haptoglobin ( Hp ) gene from an individual with anhaptoglobinemia . The Hp gene cluster consists of coding regions of the alpha chain and beta chain of the haptoglobin gene ( Hp ) and of the alpha chain and beta chain of the haptoglobin - related gene ( Hpr ) , in tandem from the 5 side . Southern blot and PCR analyses have indicated that the individual with anhaptoglobinemia was homozygous for the gene deletion and that the gene deletion was included at least from the promoter region of Hp to Hpr alpha but not to Hpr beta ( Hpdel ) . In addition , we found seven individuals with hypohaptoglobinemia in three families , and the genotypes of six of the seven individuals were found to be Hp2 / Hpdel . The phenotypes and genotypes in one of these three families showed the father to be hypohaptoglobinemic ( Hp2 ) and Hp2 / Hpdel , the mother to be Hp2 - 1 and Hp1 / Hp2 , one of the two children to be hypohaptoglobinemic ( Hp2 ) and Hp2 / Hpdel , and the other child to be Hp1 and Hp1 / Hpdel , showing an anomalous inheritance of Hp phenotypes in the child with Hp1 . The Hp2 / Hpdel individuals had an extremely low level of Hp ( mean + / - SD = 0 . 049 + / - 0 . 043 mg / ml ; n = 6 ) , compared with the level ( 1 . 64 + / - 1 . 07 mg / ml ) obtained from 52 healthy volunteers having phenotype Hp2 , whereas the serum Hp level of an individual with Hp1 / Hpdel was 0 . 50 mg / ml , which was approximately half the level of Hp in control sera from the Hp1 phenotype ( 1 . 26 + / - 0 . 33 mg / ml ; n = 9 ) , showing a gene - dosage effect . The other allele ( Hp2 ) of individuals with Hp2 / Hpdel was found to have , in all exons , no mutation , by DNA sequencing . On the basis of the present study , the mechanism of anhaptoglobinemia and the mechanism of anomalous inheritance of Hp phenotypes were well explained . However , the mechanism of hypohaptoglobinemia remains unknown ATM mutations and phenotypes in ataxia - telangiectasia families in the British Isles : expression of mutant ATM and the risk of leukemia , lymphoma , and breast cancer . We report the spectrum of 59 ATM mutations observed in ataxia - telangiectasia ( A - T ) patients in the British Isles . Of 51 ATM mutations identified in families native to the British Isles , 11 were founder mutations , and 2 of these 11 conferred a milder clinical phenotype with respect to both cerebellar degeneration and cellular features . We report , in two A - T families , an ATM mutation ( 7271T - - > G ) that may be associated with an increased risk of breast cancer in both homozygotes and heterozygotes ( relative risk 12 . 7 ; P = . 0025 ) , although there is a less severe A - T phenotype in terms of the degree of cerebellar degeneration . This mutation ( 7271T - - > G ) also allows expression of full - length ATM protein at a level comparable with that in unaffected individuals . In addition , we have studied 18 A - T patients , in 15 families , who developed leukemia , lymphoma , preleukemic T - cell proliferation , or Hodgkin lymphoma , mostly in childhood . A wide variety of ATM mutation types , including missense mutations and in - frame deletions , were seen in these patients . We also show that 25 % of all A - T patients carried in - frame deletions or missense mutations , many of which were also associated with expression of mutant ATM protein . The DMPK gene of severely affected myotonic dystrophy patients is hypermethylated proximal to the largely expanded CTG repeat . Using methylation - sensitive restriction enzymes , we characterized the methylation pattern on the 5 side of the CTG repeat in the DMPK gene of normal individuals and of patients affected with myotonic dystrophy , showing expansions of the repetitive sequence . The gene segment analyzed corresponds to the genomic SacI - HindIII fragment carrying exons 11 - 15 . There is constitutive methylation in intron 12 at restriction sites of SacII and HhaI , localized 1 , 159 - 1 , 232 bp upstream of the CTG repeat , whereas most , if not all , of the other sites of SacII , HhaI , and HpaII in this region are unmethylated , in normal individuals and most of the patients . In a number of young and severely affected patients , however , complete methylation of these restriction sites was found in the mutated allele . In most of these patients , the onset of the disease was congenital . Preliminary in vivo footprinting data gave evidence for protein - DNA contact in normal genes at an Sp1 consensus binding site upstream of the CTG repeat and for a significant reduction of this interaction in cells with a hypermethylated DMPK gene . . The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding . We recently reported the positional cloning of a candidate gene for hereditary hemochromatosis called HFE . The gene product , a member of the major histocompatibility complex class I - like family , was found to have a mutation , Cys - 282 - - > Tyr ( C282Y ) , in 85 % of patient chromosomes . This mutation eliminates the ability of HFE to associate with beta2 - microglobulin ( beta2m ) and prevents cell - surface expression . A second mutation that has no effect on beta2m association , H63D , was found in eight out of nine patients heterozygous for the C282Y mutant . In this report , we demonstrate in cultured 293 cells overexpressing wild - type or mutant HFE proteins that both the wild - type and H63D HFE proteins form stable complexes with the transferrin receptor ( TfR ) . The C282Y mutation nearly completely prevents the association of the mutant HFE protein with the TfR . Studies on cell - associated transferrin at 37 degrees C suggest that the overexpressed wild - type HFE protein decreases the affinity of the TfR for transferrin . The overexpressed H63D protein does not have this effect , providing the first direct evidence for a functional consequence of the H63D mutation . Addition of soluble wild - type HFE / beta2m heterodimers to cultured cells also decreased the apparent affinity of the TfR for its ligand under steady - state conditions , both in 293 cells and in HeLa cells . Furthermore , at 4 degrees C , the added soluble complex of HFE / beta2m inhibited binding of transferrin to HeLa cell TfR in a concentration - dependent manner . Scatchard plots of these data indicate that the added heterodimer substantially reduced the affinity of TfR for transferrin . These results establish a molecular link between HFE and a key protein involved in iron transport , the TfR , and raise the possibility that alterations in this regulatory mechanism may play a role in the pathogenesis of hereditary hemochromatosis . . Genomic organization of the UBE3A / E6 - AP gene and related pseudogenes . The UBE3A gene encodes the E6 - AP ubiquitin - protein ligase and has recently been shown to be mutated in Angelman syndrome patients who lack 15q11 - q13 deletions or chromosome 15 paternal uniparental disomy . Previous UBE3A cDNA analysis has shown a coding region of approximately 2 . 6 kb and a 3 - untranslated region ( UTR ) of < 50 bp , whereas Northern analysis has indicated mRNA sizes of 5 - 8 kb . We have analyzed additional cDNA clones and provide evidence for an additional 0 . 5 kb of 5 - UTR and > 2 kb of 3 - UTR . We have established the genomic organization of UBE3A and the sequence of intron - exon borders . We have also mapped two highly homologous processed pseudogenes , UBE3AP1 and UBE3AP2 , to chromosomes 2 and 21 , respectively , and determined their genomic organization . These results will form the basis for studies of mutation and imprinting of UBE3A . Mutation spectrum and genotype - phenotype analyses in Cowden disease and Bannayan - Zonana syndrome , two hamartoma syndromes with germline PTEN mutation . The tumour suppressor gene PTEN , which maps to 10q23 . 3 and encodes a 403 amino acid dual specificity phosphatase ( protein tyrosine phosphatase ; PTPase ) , was shown recently to play a broad role in human malignancy . Somatic PTEN deletions and mutations were observed in sporadic breast , brain , prostate and kidney cancer cell lines and in several primary tumours such as endometrial carcinomas , malignant melanoma and thyroid tumours . In addition , PTEN was identified as the susceptibility gene for two hamartoma syndromes Cowden disease ( CD ; MIM 158350 ) and Bannayan - Zonana ( BZS ) or Ruvalcaba - Riley - Smith syndrome ( MIM 153480 ) . Constitutive DNA from 37 CD families and seven BZS families was screened for germline PTEN mutations . PTEN mutations were identified in 30 of 37 ( 81 % ) CD families , including missense and nonsense point mutations , deletions , insertions , a deletion / insertion and splice site mutations . These mutations were scattered over the entire length of PTEN , with the exception of the first , fourth and last exons . A hot spot for PTEN mutation in CD was identified in exon 5 that contains the PTPase core motif , with 13 of 30 ( 43 % ) CD mutations identified in this exon . Seven of 30 ( 23 % ) were within the core motif , the majority ( five of seven ) of which were missense mutations , possibly pointing to the functional significance of this region . Germline PTEN mutations were identified in four of seven ( 57 % ) BZS families studied . Interestingly , none of these mutations was observed in the PTPase core motif . It is also worthy of note that a single nonsense point mutation , R233X , was observed in the germline DNA from two unrelated CD families and one BZS family . Genotype - phenotype studies were not performed on this small group of BZS families . However , genotype - phenotype analysis inthe group of CD families revealed two possible associations worthy of follow - up in independent analyses . The first was an association noted in the group of CD families with breast disease . A correlation was observed between the presence / absence of a PTEN mutation and the type of breast involvement ( unaffected versus benign versus malignant ) . Specifically and more directly , an association was also observed between the presence of a PTEN mutation and malignant breast disease . Secondly , there appeared to be an interdependent association between mutations upstream and within the PTPase core motif , the core motif containing the majority of missense mutations , and the involvement of all major organ systems ( central nervous system , thyroid , breast , skin and gastrointestinal tract ) . However , these observations would need to be confirmed by studying a larger number of CD families . Molecular defects leading to human complement component C6 deficiency in an African - American family . Complement component C6 deficiency ( C6D ) was diagnosed in a 16 - year - old African - American male with meningococcal meningitis . The patients father and two brothers also had C6D , but gave no history of meningitis or other neisserial infection . By using exon - specific polymerase chain reaction ( PCR ) / single - strand conformation polymorphism as a screening step and nucleotide sequencing of target exons , we determined that the proband was a compound heterozygote for two C6 gene mutations . The first , 1195delC located in exon 7 , is a novel mutation , while the second , 1936delG in exon 12 , has been described before to cause C6D in an unrelated African - American individual . Both mutations result in premature termination codons and C6 null alleles . Allele - specific PCR indicated that the probands two brothers also inherited the 1195delC mutation from their heterozygous mother and the 1936delG mutation from their homozygous father . . PAX6 mutations reviewed . Mutations in PAX6 are responsible for human aniridia and have also been found in patients with Peters anomaly , with congenital cataracts , with autosomal dominant keratitis , and with isolated foveal hypoplasia . No locus other than chromosome 11p13 has been implicated in aniridia , and PAX6 is clearly the major , if not only , gene responsible . Twenty - eight percent of identified PAX6 mutations are C - T changes at CpG dinucleotides , 20 % are splicing errors , and more than 30 % are deletion or insertion events . There is a noticeably elevated level of mutation in the paired domain compared with the rest of the gene . Increased mutation in the homeodomain is accounted for by the hypermutable CpG dinucleotide in codon 240 . Very nearly all mutations appear to cause loss of function of the mutant allele , and more than 80 % of exonic substitutions result in nonsense codons . In a gene with such extraordinarily high sequence conservation throughout evolution , there are presumed undiscovered missense mutations , these are hypothesized to exist in as - yet unidentified phenotypes . . Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families . The Breast Cancer Linkage Consortium . The contribution of BRCA1 and BRCA2 to inherited breast cancer was assessed by linkage and mutation analysis in 237 families , each with at least four cases of breast cancer , collected by the Breast Cancer Linkage Consortium . Families were included without regard to the occurrence of ovarian or other cancers . Overall , disease was linked to BRCA1 in an estimated 52 % of families , to BRCA2 in 32 % of families , and to neither gene in 16 % ( 95 % confidence interval [ CI ] 6 % - 28 % ) , suggesting other predisposition genes . The majority ( 81 % ) of the breast - ovarian cancer families were due to BRCA1 , with most others ( 14 % ) due to BRCA2 . Conversely , the majority of families with male and female breast cancer were due to BRCA2 ( 76 % ) . The largest proportion ( 67 % ) of families due to other genes was found in families with four or five cases of female breast cancer only . These estimates were not substantially affected either by changing the assumed penetrance model for BRCA1 or by including or excluding BRCA1 mutation data . Among those families with disease due to BRCA1 that were tested by one of the standard screening methods , mutations were detected in the coding sequence or splice sites in an estimated 63 % ( 95 % CI 51 % - 77 % ) . The estimated sensitivity was identical for direct sequencing and other techniques . The penetrance of BRCA2 was estimated by maximizing the LOD score in BRCA2 - mutation families , over all possible penetrance functions . The estimated cumulative risk of breast cancer reached 28 % ( 95 % CI 9 % - 44 % ) by age 50 years and 84 % ( 95 % CI 43 % - 95 % ) by age 70 years . The corresponding ovarian cancer risks were 0 . 4 % ( 95 % CI 0 % - 1 % ) by age 50 years and 27 % ( 95 % CI 0 % - 47 % ) by age 70 years . The lifetime risk of breast cancer appears similar to the risk in BRCA1 carriers , but there was some suggestion of a lower risk in BRCA2 carriers < 50 years of age . Eye movement abnormalities correlate with genotype in autosomal dominant cerebellar ataxia type I . We compared horizontal eye movements ( visually guided saccades , antisaccades , and smooth pursuit ) in control subjects ( n = 14 ) and patients with three forms of autosomal dominant cerebellar ataxias type I spinocerebellar ataxias 1 and 2 ( SCA1 , n = 11 ; SCA2 , n = 10 ) and SCA3 / Machado - Joseph disease ( MJD ) ( n = 16 ) . In SCA1 , saccade amplitude was significantly increased , resulting in hypermetria . The smooth pursuit gain was decreased . In SCA2 , saccade velocity was markedly decreased . The percentage of errors in antisaccades was greatly increased and was significantly correlated with age at disease onset . In addition , a correlation between smooth pursuit gain and the number of trinucleotide repeats was found . In SCA3 , gaze - evoked nystagmus was often present as was saccade hypometria and smooth pursuit gain was markedly decreased . Three major criteria , saccade amplitude , saccade velocity , and presence of gaze - evoked nystagmus , permitted the correct assignment of 90 % of the SCA1 , 90 % of the SCA2 , and 93 % of the patients with SCA3 to their genetically confirmed patient group and , therefore , may help orient diagnoses of SCA1 , SCA2 , and SCA3 at early clinical stages of the diseases . . Genetic basis and molecular mechanism for idiopathic ventricular fibrillation . Ventricular fibrillation causes more than 300 , 000 sudden deaths each year in the USA alone . In approximately 5 - 12 % of these cases , there are no demonstrable cardiac or non - cardiac causes to account for the episode , which is therefore classified as idiopathic ventricular fibrillation ( IVF ) . A distinct group of IVF patients has been found to present with a characteristic electrocardiographic pattern . Because of the small size of most pedigrees and the high incidence of sudden death , however , molecular genetic studies of IVF have not yet been done . Because IVF causes cardiac rhythm disturbance , we investigated whether malfunction of ion channels could cause the disorder by studying mutations in the cardiac sodium channel gene SCN5A . We have now identified a missense mutation , a splice - donor mutation , and a frameshift mutation in the coding region of SCN5A in three IVF families . We show that sodium channels with the missense mutation recover from inactivation more rapidly than normal and that the frameshift mutation causes the sodium channel to be non - functional . Our results indicate that mutations in cardiac ion - channel genes contribute to the risk of developing IVF . . Molecular heterogeneity in mucopolysaccharidosis IVA in Australia and Northern Ireland : nine novel mutations including T312S , a common allele that confers a mild phenotype . Mucopolysaccharidosis IVA ( MPS IVA ) is an autosomal recessive lysosomal storage disorder caused by a genetic defect in N - acetylgalactosamine - 6 - sulfate sulfatase ( GALNS ) . Previous studies of patients from a British - Irish population showed that the I113F mutation is the most common single mutation among MPS IVA patients and produces a severe clinical phenotype . We studied mutations in the GALNS gene from 23 additional MPS IVA patients ( 15 from Australia , 8 from Northern Ireland ) , with various clinical phenotypes ( severe , 16 cases ; intermediate , 4 cases ; mild , 3 cases ) . We found two common mutations that together accounted for 32 % of the 44 unrelated alleles in these patients . One is the T312S mutation , a novel mutation found exclusively in milder patients . The other is the previously described I113F that produces a severe phenotype . The I113F and T312S mutations accounted for 8 ( 18 % ) and 6 ( 14 % ) of 44 unrelated alleles , respectively . The relatively high residual GALNS activity seen when the T312S mutant cDNA is overexpressed in mutant cells provides an explanation for the mild phenotype in patients with this mutation . The distribution and relative frequencies of the I113F and T312S mutations in Australia corresponded to those observed in Northern Ireland and are unique to these two populations , suggesting that both mutations were probably introduced to Australia by Irish migrants during the 19th century . Haplotype analysis using 6 RFLPs provides additional data that the I113F mutation originated from a common ancestor . The other 9 novel mutations identified in these 23 patients were each limited to a single family . These data provide further evidence for extensive allelic heterogeneity in MPS IVA in British - Irish patients and provide evidence for their transmission to Australia by British - Irish migrants . . Identification of constitutional WT1 mutations , in patients with isolated diffuse mesangial sclerosis , and analysis of genotype / phenotype correlations by use of a computerized mutation database . Constitutional mutations of the WT1 gene , encoding a zinc - finger transcription factor involved in renal and gonadal development , are found in most patients with Denys - Drash syndrome ( DDS ) , or diffuse mesangial sclerosis ( DMS ) associated with pseudohermaphroditism and / or Wilms tumor ( WT ) . Most mutations in DDS patients lie in exon 8 or exon 9 , encoding zinc finger 2 or zinc finger 3 , respectively , with a hot spot ( R394W ) in exon 9 . We analyzed a series of 24 patients , 10 with isolated DMS ( IDMS ) , 10 with DDS , and 4 with urogenital abnormalities and / or WT . We report WT1 heterozygous mutations in 16 patients , 4 of whom presented with IDMS . One male and two female IDMS patients with WT1 mutations underwent normal puberty . Two mutations associated with IDMS are different from those described in DDS patients . No WT1 mutations were detected in the six other IDMS patients , suggesting genetic heterogeneity of this disease . We analyzed genotype / phenotype correlations , on the basis of the constitution of a WT1 mutation database of 84 germ - line mutations , to compare the distribution and type of mutations , according to the different symptoms . This demonstrated ( 1 ) the association between mutations in exons 8 and 9 and DMS ; ( 2 ) among patients with DMS , a higher frequency of exon 8 mutations among 46 , XY patients with female phenotype than among 46 , XY patients with sexual ambiguity or male phenotype ; and ( 3 ) statistically significant evidence that mutations in exons 8 and 9 preferentially affect amino acids with different functions . . The 185delAG BRCA1 mutation originated before the dispersion of Jews in the diaspora and is not limited to Ashkenazim . The 185delAG mutation in BRCA1 is detected in Ashkenazi Jews both in familial breast and ovarian cancer and in the general population . All tested Ashkenazi mutation carriers share the same allelic pattern at the BRCA1 locus . Our previous study showed that this Ashkenazi mutation also occurs in Iraqi Jews with a similar allelic pattern . We extended our analysis to other non - Ashkenazi subsets 354 of Moroccan origin , 200 Yemenites and 150 Iranian Jews . Heteroduplex analysis complemented by direct DNA sequencing of abnormally migrating bands were employed . Four of Moroccan origin ( 1 . 1 % ) and none of the Yemenites or Iranians was a carrier of the 185delAG mutation . BRCA1 allelic patterns were determined for four of these individuals and for 12 additional non - Ashkenazi 185delAG mutation carriers who had breast / ovarian cancer . Six non - Ashkenazi individuals shared the common Ashkenazi haplotype , four had a closely related pattern , and the rest ( n = 6 ) displayed a distinct BRCA1 allelic pattern . We conclude that the 185delAG BRCA1 mutation occurs in some non - Ashkenazi populations at rates comparable with that of Ashkenazim . The majority of Jewish 185delAG mutation carriers have a common allelic pattern , supporting the founder effect notion , but dating the mutations origin to an earlier date than currently estimated . However , the different allelic pattern at the BRCA1 locus even in some Jewish mutation carriers , might suggest that the mutation arose independently . . Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor . HFE is an MHC - related protein that is mutated in the iron - overload disease hereditary hemochromatosis . HFE binds to transferrin receptor ( TfR ) and reduces its affinity for iron - loaded transferrin , implicating HFE in iron metabolism . The 2 . 6 A crystal structure of HFE reveals the locations of hemochromatosis mutations and a patch of histidines that could be involved in pH - dependent interactions . We also demonstrate that soluble TfR and HFE bind tightly at the basic pH of the cell surface , but not at the acidic pH of intracellular vesicles . TfR HFE stoichiometry ( 2 1 ) differs from TfR transferrin stoichiometry ( 2 2 ) , implying a different mode of binding for HFE and transferrin to TfR , consistent with our demonstration that HFE , transferrin , and TfR form a ternary complex . Identification of three novel mutations and a high frequency of the Arg778Leu mutation in Korean patients with Wilson disease . Four mutations - - R778L , A874V , L1083F , and 2304delC - - in the copper - transporting enzyme , P - type ATPase ( ATP7B ) , were identified in Korean Patients with Wilson disease . Arg778Leu , the most frequently reported mutation of this enzyme , was found in six of eight unrelated patients studied , an allele frequency of 37 . 5 % , which is considerably higher than those in other Asian populations . The novel single nucleotide deletion , 2304delC , was found in one patient . Since a mutation at cDNA nucleotide 2302 ( 2302insC ) had been previously described , this region of the ATP7B gene may be susceptible to gene rearrangements causing Wilson disease . Disruption of splicing regulated by a CUG - binding protein in myotonic dystrophy . Myotonic dystrophy ( DM ) is caused by a CTG expansion in the 3 untranslated region of the DM gene . One model of DM pathogenesis suggests that RNAs from the expanded allele create a gain - of - function mutation by the inappropriate binding of proteins to the CUG repeats . Data presented here indicate that the conserved heterogeneous nuclear ribonucleoprotein , CUG - binding protein ( CUG - BP ) , may mediate the trans - dominant effect of the RNA . CUG - BP was found to bind to the human cardiac troponin T ( cTNT ) pre - messenger RNA and regulate its alternative splicing . Splicing of cTNT was disrupted in DM striated muscle and in normal cells expressing transcripts that contain CUG repeats . Altered expression of genes regulated posttranscriptionally by CUG - BP therefore may contribute to DM pathogenesis . . Identification of a novel nonsense mutation and a missense substitution in the vasopressin - neurophysin II gene in two Spanish kindreds with familial neurohypophyseal diabetes insipidus . Familial neurohypophyseal diabetes insipidus ( FNDI ) is an autosomal dominant disease caused by deficiency in the antidiuretic hormone arginine vasopressin ( AVP ) encoded by the AVP - neurophysin II ( AVP - NPII ) gene on chromosome 20p13 . In this study , we analyzed two families with FNDI using direct automated fluorescent , solid phase , single - stranded DNA sequencing of PCR - amplified AVP - NPII DNA . In one of the families , affected individuals presented a novel nonsense mutation in exon 3 of the gene , consisting in a G to T transition at nucleotide 2101 , which produces a stop signal in codon 82 ( Glu ) of NPII . The premature termination eliminates part of the C - terminal domain of NPII , including a cysteine residue in position 85 , which could be involved in the correct folding of the prohormone . In the second family , a G279A substitution at position - 1 of the signal peptide was observed in all affected individuals . This missense mutation , which replaces Ala with Thr , is frequent among FNDI patients and is thought to reduce the efficiency of cleavage by signal peptidases . . Genetic heterogeneity of Saethre - Chotzen syndrome , due to TWIST and FGFR mutations . Thirty - two unrelated patients with features of Saethre - Chotzen syndrome , a common autosomal dominant condition of craniosynostosis and limb anomalies , were screened for mutations in TWIST , FGFR2 , and FGFR3 . Nine novel and three recurrent TWIST mutations were found in 12 families . Seven families were found to have the FGFR3 P250R mutation , and one individual was found to have an FGFR2 VV269 - 270 deletion . To date , our detection rate for TWIST or FGFR mutations is 68 % in our Saethre - Chotzen syndrome patients , including our five patients elsewhere reported with TWIST mutations . More than 35 different TWIST mutations are now known in the literature . The most common phenotypic features , present in more than a third of our patients with TWIST mutations , are coronal synostosis , brachycephaly , low frontal hairline , facial asymmetry , ptosis , hypertelorism , broad great toes , and clinodactyly . Significant intra - and interfamilial phenotypic variability is present for either TWIST mutations or FGFR mutations . The overlap in clinical features and the presence , in the same genes , of mutations for more than one craniosynostotic condition - such as Saethre - Chotzen , Crouzon , and Pfeiffer syndromes - support the hypothesis that TWIST and FGFRs are components of the same molecular pathway involved in the modulation of craniofacial and limb development in humans . . Mutation analysis of UBE3A in Angelman syndrome patients . Angelman syndrome ( AS ) is caused by chromosome 15q11 - q13 deletions of maternal origin , by paternal uniparental disomy ( UPD ) 15 , by imprinting defects , and by mutations in the UBE3A gene . UBE3A encodes a ubiquitin - protein ligase and shows brain - specific imprinting . Here we describe UBE3A coding - region mutations detected by SSCP analysis in 13 AS individuals or families . Two identical de novo 5 - bp duplications in exon 16 were found . Among the other 11 unique mutations , 8 were small deletions or insertions predicted to cause frameshifts , 1 was a mutation to a stop codon , 1 was a missense mutation , and 1 was predicted to cause insertion of an isoleucine in the hect domain of the UBE3A protein , which functions in E2 binding and ubiquitin transfer . Eight of the cases were familial , and five were sporadic . In two familial cases and one sporadic case , mosaicism for UBE3A mutations was detected in the mother of three AS sons , in the maternal grandfather of two AS first cousins , and in the mother of an AS daughter . The frequencies with which we detected mutations were 5 ( 14 % ) of 35 in sporadic cases and 8 ( 80 % ) of 10 in familial cases . . The hemochromatosis 845 G - - > A and 187 C - - > G mutations : prevalence in non - Caucasian populations . Hemochromatosis , the inherited disorder of iron metabolism , leads , if untreated , to progressive iron overload and premature death . The hemochromatosis gene , HFE , recently has been identified , and characterization of this gene has shown that it contains two mutations that result in amino acid substitutions - cDNA nucleotides 845 G - - > A ( C282Y ) and 187 C - - > G ( H63D ) . Although hemochromatosis is common in Caucasians , affecting > = 1 / 300 individuals of northern European origin , it has not been recognized in other populations . The present study used PCR and restriction - enzyme digestion to analyze the frequency of the 845 G - - > A and 187 C - - > G mutations in HLA - typed samples from non - Caucasian populations , comprising Australian Aboriginal , Chinese , and Pacific Islanders . Results showed that the 845 G - - > A mutation was present in these populations ( allele frequency 0 . 32 % ) , and , furthermore , it was always seen in conjunction with HLA haplotypes common in Caucasians , suggesting that 845 G - - > A may have been introduced into these populations by Caucasian admixture . 187 C - - > G was present at an allele frequency of 2 . 68 % in the two populations analyzed ( Australian Aboriginal and Chinese ) . In the Australian Aboriginal samples , 187 C - - > G was found to be associated with HLA haplotypes common in Caucasians , suggesting that it was introduced by recent admixture . In the Chinese samples analyzed , 187 C - - > G was present in association with a wide variety of HLA haplotypes , showing this mutation to be widespread and likely to predate the more genetically restricted 845 G - - > A mutation . Genotype - phenotype correlations in attenuated adenomatous polyposis coli . Germ - line mutations of the tumor suppressor APC are implicated in attenuated adenomatous polyposis coli ( AAPC ) , a variant of familial adenomatous polyposis ( FAP ) . AAPC is recognized by the occurrence of < 100 colonic adenomas and a later onset of colorectal cancer ( age > 40 years ) . The aim of this study was to assess genotype - phenotype correlations in AAPC families . By protein - truncation test ( PTT ) assay , the entire coding region of the APC gene was screened in affected individuals from 11 AAPC kindreds , and their phenotypic differences were examined . Five novel germ - line APC mutations were identified in seven kindreds . Mutations were located in three different regions of the APC gene ( 1 ) at the 5 end spanning exons 4 and 5 , ( 2 ) within exon 9 , and ( 3 ) at the 3 distal end of the gene . Variability in the number of colorectal adenomas was most apparent in individuals with mutations in region 1 , and upper - gastrointestinal manifestations were more severe in them . In individuals with mutations in either region 2 or region 3 , the average number of adenomas tended to be lower than those in individuals with mutations in region 1 , although age at diagnosis was similar . In all AAPC kindreds , a predominance of right - sided colorectal adenomas and rectal polyp sparing was observed . No desmoid tumors were found in these kindreds . Our data suggest that , in AAPC families , the location of the APC mutation may partially predict specific phenotypic expression . This should help in the design of tailored clinical - management protocols in this subset of FAP patients . . Wilms ' tumor 1 and Dax - 1 modulate the orphan nuclear receptor SF - 1 in sex - specific gene expression . Products of steroidogenic factor 1 ( SF - 1 ) and Wilms tumor 1 ( WT1 ) genes are essential for mammalian gonadogenesis prior to sexual differentiation . In males , SF - 1 participates in sexual development by regulating expression of the polypeptide hormone Mullerian inhibiting substance ( MIS ) . Here , we show that WT1 - KTS isoforms associate and synergize with SF - 1 to promote MIS expression . In contrast , WT1 missense mutations , associated with male pseudohermaphroditism in Denys - Drash syndrome , fail to synergize with SF - 1 . Additionally , the X - linked , candidate dosage - sensitive sex - reversal gene , Dax - 1 , antagonizes synergy between SF - 1 and WT1 , most likely through a direct interaction with SF - 1 . We propose that WT1 and Dax - 1 functionally oppose each other in testis development by modulating SF - 1 - mediated transactivation . . A mouse model for Prader - Willi syndrome imprinting - centre mutations . Imprinting in the 15q11 - q13 region involves an imprinting centre ( IC ) , mapping in part to the promoter and first exon of SNRPN . Deletion of this IC abolishes local paternally derived gene expression and results in Prader - Willi syndrome ( PWS ) . We have created two deletion mutations in mice to understand PWS and the mechanism of this IC . Mice harbouring an intragenic deletion in Snrpn are phenotypically normal , suggesting that mutations of SNRPN are not sufficient to induce PWS . Mice with a larger deletion involving both Snrpn and the putative PWS - IC lack expression of the imprinted genes Zfp127 ( mouse homologue of ZNF127 ) , Ndn and Ipw , and manifest several phenotypes common to PWS infants . These data demonstrate that both the position of the IC and its role in the coordinate expression of genes is conserved between mouse and human , and indicate that the mouse is a suitable model system in which to investigate the molecular mechanisms of imprinting in this region of the genome . . Mutations of the ATM gene detected in Japanese ataxia - telangiectasia patients : possible preponderance of the two founder mutations 4612del165 and 7883del5 . The ATM ( A - T , mutated ) gene on human chromosome 11q22 . 3 has recently been identified as the gene responsible for the human recessive disease ataxia - telangiectasia ( A - T ) . In order to define the types of disease - causing ATM mutations in Japanese A - T patients as well as to look for possible mutational hotspots , reverse - transcribed RNA derived from ten patients belonging to eight unrelated Japanese A - T families was analyzed for mutations by the restriction endonuclease fingerprinting method . As has been reported by others , mutations that lead to exon skipping or premature protein truncation were also predominant in our mutants . Six different mutations were identified on 12 of the 16 alleles examined . Four were deletions involving a loss of a single exon exon 7 , exon 16 , exon 33 or exon 35 . The others were minute deletions , 4649delA in exon 33 and 7883del5 in exon 55 . The mutations 4612del165 and 7883del5 were found in more than two unrelated families ; 44 % ( 7 of 16 ) of the mutant alleles had one of the two mutations . The 4612del165 mutations in three different families were all ascribed to the same T - - > A substitution at the splice donor site in intron 33 . Microsatellite genotyping around the ATM locus also indicated that a common haplotype was shared by the mutant alleles in both mutations . This suggests that these two founder mutations may be predominant among Japanese ATM mutant alleles . W474C amino acid substitution affects early processing of the alpha - subunit of beta - hexosaminidase A and is associated with subacute G ( M2 ) gangliosidosis . Mutations in the HEXA gene , encoding the alpha - subunit of beta - hexosaminidase A ( Hex A ) , that abolish Hex A enzyme activity cause Tay - Sachs disease ( TSD ) , the fatal infantile form of G ( M2 ) gangliosidosis , Type 1 . Less severe , subacute ( juvenile - onset ) and chronic ( adult - onset ) variants are characterized by a broad spectrum of clinical manifestations and are associated with residual levels of Hex A enzyme activity . We identified a 1422 G - - > C ( amino acid W474C ) substitution in the first position of exon 13 of HEXA of a non - Jewish proband who manifested a subacute variant of G ( M2 ) gangliosidosis . On the second maternally inherited allele , we identified the common infantile disease - causing 4 - bp insertion , + TATC 1278 , in exon 11 . Pulse - chase analysis using proband fibroblasts revealed that the W474C - containing alpha - subunit precursor was normally synthesized , but not phosphorylated or secreted , and the mature lysosomal alpha - subunit was not detected . When the W474C - containing alpha - subunit was transiently co - expressed with the beta - subunit to produce Hex A ( alphabeta ) in COS - 7 cells , the mature alpha - subunit was present , but its level was much lower than that from normal alpha - subunit transfections , although higher than in those cells transfected with an alpha - subunit associated with infantile TSD . Furthermore , the precursor level of the W474C alpha - subunit was found to accumulate in comparison to the normal alpha - subunit precursor levels . We conclude that the 1422 G - - > C mutation is the cause of Hex A enzyme deficiency in the proband . The resulting W474C substitution clearly interferes with alpha - subunit processing , but because the base substitution falls at the first position of exon 13 , aberrant splicing may also contribute to Hex A deficiency in this proband . . Two frequent missense mutations in Pendred syndrome . Pendred syndrome is an autosomal recessive disorder characterized by early childhood deafness and goiter . A century after its recognition as a syndrome by Vaughan Pendred , the disease gene ( PDS ) was mapped to chromosome 7q22 - q31 . 1 and , recently , found to encode a putative sulfate transporter . We performed mutation analysis of the PDS gene in patients from 14 Pendred families originating from seven countries and identified all mutations . The mutations include three single base deletions , one splice site mutation and 10 missense mutations . One missense mutation ( L236P ) was found in a homozygous state in two consanguineous families and in a heterozygous state in five additional non - consanguineous families . Another missense mutation ( T416P ) was found in a homozygous state in one family and in a heterozygous state in four families . Pendred patients in three non - consanguineous families were shown to be compound heterozygotes for L236P and T416P . In total , one or both of these mutations were found in nine of the 14 families analyzed . The identification of two frequent PDS mutations will facilitate the molecular diagnosis of Pendred syndrome . Insertional mutation by transposable element , L1 , in the DMD gene results in X - linked dilated cardiomyopathy . X - linked dilated cardiomyopathy ( XLDCM ) is a clinical phenotype of dystrophinopathy which is characterized by preferential myocardial involvement without any overt clinical signs of skeletal myopathy . To date , several mutations in the Duchenne muscular dystrophy gene , DMD , have been identified in patients with XLDCM , but a pathogenic correlation of these cardiospecific mutations in DMD with the XLDCM phenotype has remained to be elucidated . We report here the identification of a unique de novo L1 insertion in the muscle exon 1 in DMD in three XLDCM patients from two unrelated Japanese families . The insertion was a 5 - truncated form of human L1 inversely integrated in the 5 - untranslated region in the muscle exon 1 , which affected the transcription or the stability of the muscle form of dystrophin transcripts but not that of the brain or Purkinje cell form , probably due to its unique site of integration . We speculate that this insertion of an L1 sequence in DMD is responsible for some of the population of Japanese patients with XLDCM . . Severe early - onset obesity , adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans . Sequential cleavage of the precursor protein pre - pro - opiomelanocortin ( POMC ) generates the melanocortin peptides adrenocorticotrophin ( ACTH ) , melanocyte - stimulating hormones ( MSH ) alpha , beta and gamma as well as the opioid - receptor ligand beta - endorphin . While a few cases of isolated ACTH deficiency have been reported ( OMIM 201400 ) , an inherited POMC defect has not been described so far . Recent studies in animal models elucidated a central role of alpha - MSH in the regulation of food intake by activation of the brain melanocortin - 4 - receptor ( MC4 - R ; refs 3 - 5 ) and the linkage of human obesity to chromosome 2 in close proximity to the POMC locus , led to the proposal of an association of POMC with human obesity . The dual role of alpha - MSH in regulating food intake and influencing hair pigmentation predicts that the phenotype associated with a defect in POMC function would include obesity , alteration in pigmentation and ACTH deficiency . The observation of these symptoms in two probands prompted us to search for mutations within their POMC genes . Patient 1 was found to be a compound heterozygote for two mutations in exon 3 ( G7013T , C7133delta ) which interfere with appropriate synthesis of ACTH and alpha - MSH . Patient 2 was homozygous for a mutation in exon 2 ( C3804A ) which abolishes POMC translation . These findings represent the first examples of a genetic defect within the POMC gene and define a new monogenic endocrine disorder resulting in early - onset obesity , adrenal insufficiency and red hair pigmentation . . A European multicenter study of phenylalanine hydroxylase deficiency : classification of 105 mutations and a general system for genotype - based prediction of metabolic phenotype . Phenylketonuria ( PKU ) and mild hyperphenylalaninemia ( MHP ) are allelic disorders caused by mutations in the gene encoding phenylalanine hydroxylase ( PAH ) . Previous studies have suggested that the highly variable metabolic phenotypes of PAH deficiency correlate with PAH genotypes . We identified both causative mutations in 686 patients from seven European centers . On the basis of the phenotypic characteristics of 297 functionally hemizygous patients , 105 of the mutations were assigned to one of four arbitrary phenotype categories . We proposed and tested a simple model for correlation between genotype and phenotypic outcome . The observed phenotype matched the predicted phenotype in 79 % of the cases , and in only 5 of 184 patients was the observed phenotype more than one category away from that expected . Among the seven contributing centers , the proportion of patients for whom the observed phenotype did not match the predicted phenotype was 4 % - 23 % ( P < . 0001 ) , suggesting that differences in methods used for mutation detection or phenotype classification may account for a considerable proportion of genotype - phenotype inconsistencies . Our data indicate that the PAH - mutation genotype is the main determinant of metabolic phenotype in most patients with PAH deficiency . In the present study , the classification of 105 PAH mutations may allow the prediction of the biochemical phenotype in > 10 , 000 genotypes , which may be useful for the management of hyperphenylalaninemia in newborns . Somatic instability of the CTG repeat in mice transgenic for the myotonic dystrophy region is age dependent but not correlated to the relative intertissue transcription levels and proliferative capacities . A ( CTG ) nexpansion in the 3 - untranslated region ( UTR ) of the DM protein kinase gene ( DMPK ) is responsible for causing myotonic dystrophy ( DM ) . Major instability , with very large expansions between generations and high levels of somatic mosaicism , is observed in patients . There is a good correlation between repeat size ( at least in leucocytes ) , clinical severity and age of onset . The trinucleotide repeat instability mechanisms involved in DM and other human genetic diseases are unknown . We studied somatic instability by measuring the CTG repeat length at several ages in various tissues of transgenic mice carrying a ( CTG ) 55expansion surrounded by 45 kb of the human DM region , using small - pool PCR . These mice have been shown to reproduce the intergenerational and somatic instability of the 55 CTG repeat suggesting that surrounding sequences and the chromatin environment are involved in instability mechanisms . As observed in some of the tissues of DM patients , there is a tendency for repeat length and somatic mosaicism to increase with the age of the mouse . Furthermore , we observed no correlation between the somatic mutation rate and tissue proliferation capacity . The somatic mutation rates in different tissues were also not correlated to the relative inter - tissue difference in transcriptional levels of the three genes ( DMAHP , DMPK and 59 ) surrounding the repeat . . A novel missense mutation in patients from a retinoblastoma pedigree showing only mild expression of the tumor phenotype . We have used single strand conformation polymorphism analysis to study the 27 exons of the RB1 gene in individuals from a family showing mild expression of the retinoblastoma phenotype . In this family affected individuals developed unilateral tumors and , as a result of linkage analysis , unaffected mutation carriers were also identified within the pedigree . A single band shift using SSCP was identified in exon 21 which resulted in a missense mutation converting a cys - - > arg at nucleotide position 28 in the exon . The mutation destroyed an NdeI restriction enzyme site . Analysis of all family members demonstrated that the missense mutation co - segregated with patients with tumors or who , as a result of linkage analysis had been predicted to carry the predisposing mutation . These observations point to another region of the RB1 gene where mutations only modify the function of the gene and raise important questions for genetic counseling in families with these distinctive phenotypes . . Maternal disomy and Prader - Willi syndrome consistent with gamete complementation in a case of familial translocation ( 3 ; 15 ) ( p25 ; q11 . 2 ) . Maternal uniparental disomy ( UPD ) for chromosome 15 is responsible for an estimated 30 % of cases of Prader - Willi syndrome ( PWS ) . We report on an unusual case of maternal disomy 15 in PWS that is most consistent with adjacent - 1 segregation of a paternal t ( 3 ; 15 ) ( p25 ; q11 . 2 ) with simultaneous maternal meiotic nondisjunction for chromosome 15 . The patient ( J . B . ) , a 17 - year - old white male with PWS , was found to have 47 chromosomes with a supernumerary , paternal der ( 15 ) consisting of the short arm and the proximal long arm of chromosome 15 , and distal chromosome arm 3p . The t ( 3 ; 15 ) was present in the balanced state in the patients father and a sister . Fluorescent in situ hybridization analysis demonstrated that the PWS critical region resided on the derivative chromosome 3 and that there was no deletion of the PWS region on the normal pair of 15s present in J . B . Methylation analysis at exon alpha of the small nuclear ribonucleoprotein - associated polypeptide N ( SNRPN ) gene showed a pattern characteristic of only the maternal chromosome 15 in J . B . Maternal disomy was confirmed by polymerase chain reaction analysis of microsatellite repeats at the gamma - aminobutyric acid receptor beta3 subunit ( GABRB3 ) locus . A niece ( B . B . ) with 45 chromosomes and the derivative 3 but without the der ( 15 ) demonstrated a phenotype consistent with that reported for haploinsufficiency of distal 3 p . Uniparental disomy associated with unbalanced segregation of non - Robertsonian translocations has been reported previously but has not , to our knowledge , been observed in a case of PWS . Furthermore , our findings are best interpreted as true gamete complementation resulting in maternal UPD 15 and PWS Schwartz - Jampel syndrome type 2 and Stuve - Wiedemann syndrome : a case for " lumping " . Recent studies demonstrated the existence of a genetically distinct , usually lethal form of the Schwartz - Jampel syndrome ( SJS ) of myotonia and skeletal dysplasia , which we called SJS type 2 . This disorder is reminiscent of another rare condition , the Stuve - Wiedemann syndrome ( SWS ) , which comprises campomelia at birth with skeletal dysplasia , contractures , and early death . To test for possible nosologic identity between these disorders , we reviewed the literature and obtained a follow - up of the only two surviving patients , one with SJS type 2 at age 10 years and another with SWS at age 7 years . Patients reported as having either neonatal SJS or SWS presented a combination of a severe , prenatal - onset neuromuscular disorder ( with congenital joint contractures , respiratory and feeding difficulties , tendency to hyperthermia , and frequent death in infancy ) with a distinct campomelic - metaphyseal skeletal dysplasia . The similarity of the clinical and radiographic findings is so extensive that these disorders appear to be a single entity . The follow - up observation of an identical and unique pattern of progressive bone dysplasia in the two patients ( one with SJS type 2 , one with SWS ) surviving beyond infancy adds to the evidence in favor of identity . The hypothesis that SWS and SJS type 2 are the same disorder should be testable by molecular methods . . A mouse model of severe von Willebrand disease : defects in hemostasis and thrombosis . von Willebrand factor ( vWf ) deficiency causes severe von Willebrand disease in humans . We generated a mouse model for this disease by using gene targeting . vWf - deficient mice appeared normal at birth ; they were viable and fertile . Neither vWf nor vWf propolypeptide ( von Willebrand antigen II ) were detectable in plasma , platelets , or endothelial cells of the homozygous mutant mice . The mutant mice exhibited defects in hemostasis with a highly prolonged bleeding time and spontaneous bleeding events in approximately 10 % of neonates . As in the human disease , the factor VIII level in these mice was reduced strongly as a result of the lack of protection provided by vWf . Defective thrombosis in mutant mice was also evident in an in vivo model of vascular injury . In this model , the exteriorized mesentery was superfused with ferric chloride and the accumulation of fluorescently labeled platelets was observed by intravital microscopy . We conclude that these mice very closely mimic severe human von Willebrand disease and will be very useful for investigating the role of vWf in normal physiology and in disease models . . Oral contraceptives and the risk of hereditary ovarian cancer . Hereditary Ovarian Cancer Clinical Study Group . BACKGROUND Women with mutations in either the BRCA1 or the BRCA2 gene have a high lifetime risk of ovarian cancer . Oral contraceptives protect against ovarian cancer in general , but it is not known whether they also protect against hereditary forms of ovarian cancer . METHODS We enrolled 207 women with hereditary ovarian cancer and 161 of their sisters as controls in a case - control study . All the patients carried a pathogenic mutation in either BRCA1 ( 179 women ) or BRCA2 ( 28 women ) . The control women were enrolled regardless of whether or not they had either mutation . Lifetime histories of oral - contraceptive use were obtained by interview or by written questionnaire and were compared between patients and control women , after adjustment for year of birth and parity . RESULTS The adjusted odds ratio for ovarian cancer associated with any past use of oral contraceptives was 0 . 5 ( 95 percent confidence interval , 0 . 3 to 0 . 8 ) . The risk decreased with increasing duration of use ( P for trend , < 0 . 001 ) ; use for six or more years was associated with a 60 percent reduction in risk . Oral - contraceptive use protected against ovarian cancer both for carriers of the BRCA1 mutation ( odds ratio , 0 . 5 ; 95 percent confidence interval , 0 . 3 to 0 . 9 ) and for carriers of the BRCA2 mutation ( odds ratio , 0 . 4 ; 95 percent confidence interval , 0 . 2 to 1 . 1 ) . CONCLUSIONS Oral - contraceptive use may reduce the risk of ovarian cancer in women with pathogenic mutations in the BRCA1 or BRCA2 gene A Japanese family with adrenoleukodystrophy with a codon 291 deletion : a clinical , biochemical , pathological , and genetic report . We report a Japanese family with adrenoleukodystrophy ( ALD ) with a three base pair deletion ( delGAG 291 ) in the ALD gene . A variety of phenotypes were observed within this family . While the proband ( patient 1 ) was classified as having a rare intermediate type of adult cerebral and cerebello - brain stem forms , his younger brother ( patient 2 ) and nephew ( patient 3 ) had a childhood ALD type . Another nephew ( patient 4 ) of patient 1 was classified as having an adolescent form . The tau level in the cerebrospinal fluid ( CSF ) in patient 1 was as high as that of patients with Alzheimers disease ( AD ) . His brain magnetic resonance image ( MRI ) showed abnormalities in the bilateral cerebellar hemispheres and brain stem , but not in the cerebral white matter , where marked reductions of the cerebral blood flow and oxygen metabolism were clearly demonstrated by positron emission tomography ( PET ) . In patients 2 and 3 , the autopsy findings showed massive demyelination of the cerebral white matter with sparing of the U - fibers , compatible with the findings of childhood ALD . Oleic and erucic acids ( Lorenzos Oil ) were administered to patients 1 and 4 , but sufficient effectiveness was not obtained . The findings in this family suggest that delGAG291 is part of the cause of Japanese ALD with phenotypic variations . Moreover , although the scale of the study is limited , there is a possibility that PET can detect an insidious lesion which is undetectable by computed tomogram ( CT ) or MRI analysis , and that the higher level of tau reflects the process of neuronal degeneration in ALD . Lorenzos Oil should be given in the early stage . . Nonsense mutation in exon 4 of human complement C9 gene is the major cause of Japanese complement C9 deficiency . Deficiency of the ninth component of human complement ( C9 ) is the most common complement deficiency in Japan but is rare in other countries . We studied the molecular basis of C9 deficiency in four Japanese C9 - deficient patients who had suffered from meningococcal meningitis . Direct sequencing of amplified C9 cDNA and DNA revealed a nonsense substitution ( CGA - - > TGA ) at codon 95 in exon 4 in the four C9 - deficient individuals . An allele - specific polymerase chain reaction system designed to detect exclusively only one of the normal and mutant alleles indicated that all the four patients were homozygous for the mutation in exon 4 and that the parents of patient 2 were heterozygous . The common mutation at codon 95 in exon 4 might be responsible for most Japanese C9 deficiency . . BRCA1 required for transcription - coupled repair of oxidative DNA damage . The breast and ovarian cancer susceptibility gene BRCA1 encodes a zinc finger protein of unknown function . Association of the BRCA1 protein with the DNA repair protein Rad51 and changes in the phosphorylation and cellular localization of the protein after exposure to DNA - damaging agents are consistent with a role for BRCA1 in DNA repair . Here , it is shown that mouse embryonic stem cells deficient in BRCA1 are defective in the ability to carry out transcription - coupled repair of oxidative DNA damage , and are hypersensitive to ionizing radiation and hydrogen peroxide . These results suggest that BRCA1 participates , directly or indirectly , in transcription - coupled repair of oxidative DNA damage . . Truncation mutations in the transactivation region of PAX6 result in dominant - negative mutants . PAX6 is a transcription factor with two DNA - binding domains ( paired box and homeobox ) and a proline - serine - threonine ( PST ) - rich transactivation domain . PAX6 regulates eye development in animals ranging from jellyfish to Drosophila to humans . Heterozygous mutations in the human PAX6 gene result in various phenotypes , including aniridia , Peters anomaly , autosomal dominant keratitis , and familial foveal dysplasia . It is believed that the mutated allele of PAX6 produces an inactive protein and aniridia is caused due to genetic haploinsufficiency . However , several truncation mutations have been found to occur in the C - terminal half of PAX6 in patients with Aniridia resulting in mutant proteins that retain the DNA - binding domains but have lost most of the transactivation domain . It is not clear whether such mutants really behave as loss - of - function mutants as predicted by haploinsufficiency . Contrary to this theory , our data showed that these mutants are dominant - negative in transient transfection assays when they are coexpressed with wild - type PAX6 . We found that the dominant - negative effects result from the enhanced DNA binding ability of these mutants . Kinetic studies of binding and dissociation revealed that various truncation mutants have 3 - 5 - fold higher affinity to various DNA - binding sites when compared with the wild - type PAX6 . These results provide a new insight into the role of mutant PAX6 in causing aniridia . . Reversal of severe hypertrophic cardiomyopathy and excellent neuropsychologic outcome in very - long - chain acyl - coenzyme A dehydrogenase deficiency . Very - long - chain acyl - coenzyme A dehydrogenase ( VLCAD ) deficiency is a disorder of fatty acid beta oxidation that reportedly has high rates of morbidity and mortality . We describe the outcome of a 5 - year - old girl with VLCAD deficiency who was first seen at 5 months of age with severe hypertrophic cardiomyopathy , hepatomegaly , encephalopathy , and hypotonia . Biochemical studies indicated VLCAD deficiency caused by a stable yet inactive enzyme . Molecular genetic analysis of her VLCAD gene revealed a T1372C ( F458L ) missense mutation and a 1668 ACAG 1669 splice site mutation . After initial treatment with intravenous glucose and carnitine , the patient has thrived on a low - fat diet supplemented with medium - chain triglyceride oil and carnitine and avoidance of fasting . Her ventricular hypertrophy resolved significantly over 1 year , and cognitively , she is in the superior range for age . Clinical recognition of VLCAD deficiency is important because it is one of the few directly treatable causes of cardiomyopathy in children . . Cloning of a novel member of the low - density lipoprotein receptor family . A gene encoding a novel transmembrane protein was identified by DNA sequence analysis within the insulin - dependent diabetes mellitus ( IDDM ) locus IDDM4 on chromosome 11q13 . Based on its chromosomal position , this gene is a candidate for conferring susceptibility to diabetes . The gene , termed low - density lipoprotein receptor related protein 5 ( LRP5 ) , encodes a protein of 1615 amino acids that contains conserved modules which are characteristic of the low - density lipoprotein ( LDL ) receptor family . These modules include a putative signal peptide for protein export , four epidermal growth factor ( EGF ) repeats with associated spacer domains , three LDL - receptor ( LDLR ) repeats , a single transmembrane spanning domain , and a cytoplasmic domain . The encoded protein has a unique organization of EGF and LDLR repeats ; therefore , LRP5 likely represents a new category of the LDLR family . Both human and mouse LRP5 cDNAs have been isolated and the encoded mature proteins are 95 % identical , indicating a high degree of evolutionary conservation . . The APC variants I1307K and E1317Q are associated with colorectal tumors , but not always with a family history . Classical familial adenomatous polyposis ( FAP ) is a high - penetrance autosomal dominant disease that predisposes to hundreds or thousands of colorectal adenomas and carcinoma and that results from truncating mutations in the APC gene . A variant of FAP is attenuated adenomatous polyposis coli , which results from germ - line mutations in the 5 and 3 regions of the APC gene . Attenuated adenomatous polyposis coli patients have " multiple " colorectal adenomas ( typically fewer than 100 ) without the florid phenotype of classical FAP . Another group of patients with multiple adenomas has no mutations in the APC gene , and their phenotype probably results from variation at a locus , or loci , elsewhere in the genome . Recently , however , a missense variant of APC ( I1307K ) was described that confers an increased risk of colorectal tumors , including multiple adenomas , in Ashkenazim . We have studied a set of 164 patients with multiple colorectal adenomas and / or carcinoma and analyzed codons 1263 - 1377 ( exon 15G ) of the APC gene for germ - line variants . Three patients with the I1307K allele were detected , each of Ashkenazi descent . Four patients had a germ - line E1317Q missense variant of APC that was not present in controls ; one of these individuals had an unusually large number of metaplastic polyps of the colorectum . There is increasing evidence that there exist germ - line variants of the APC gene that predispose to the development of multiple colorectal adenomas and carcinoma , but without the florid phenotype of classical FAP , and possibly with importance for colorectal cancer risk in the general population . . Genomic structure of the human congenital chloride diarrhea ( CLD ) gene . Congenital chloride diarrhea ( CLD ) is caused by mutations in a gene which encodes an intestinal anion transporter . We report here the complete genomic organization of the human CLD gene which spans approximately 39kb , and comprises 21 exons . All exon / intron boundaries conform to the GT / AG rule . An analysis of the putative promoter region sequence shows a putative TATA box and predicts multiple transcription factor binding sites . The genomic structure was determined using DNA from several sources including multiple large - insert libaries and genomic DNA from Finnish CLD patients and controls . Exon - specific primers developed in this study will facilitate mutation screening studies of patients with the disease . Genomic sequencing of a BAC clone H _ RG364P16 revealed the presence of another , highly homologous gene 3 of the CLD gene , with a similar genomic structure , recently identified as the Pendred syndrome gene ( PDS ) . . The APCI1307K allele and cancer risk in a community - based study of Ashkenazi Jews . Mutations in APC are classically associated with familial adenomatous polyposis ( FAP ) , a highly penetrant autosomal dominant disorder characterized by multiple intestinal polyps and , without surgical intervention , the development of colorectal cancer ( CRC ) . APC is a tumour - suppressor gene , and somatic loss occurs in tumours . The germline T - to - A transversion responsible for the APC I1307K allele converts the wild - type sequence to a homopolymer tract ( A8 ) that is genetically unstable and prone to somatic mutation . The I1307K allele was found in 6 . 1 % of unselected Ashkenazi Jews and higher proportions of Ashkenazim with family or personal histories of CRC ( ref . 2 ) . To evaluate the role of I1307K in cancer , we genotyped 5 , 081 Ashkenazi volunteers in a community survey . Risk of developing colorectal , breast and other cancers were compared between genotyped I1307K carriers and non - carriers and their first - degree relatives . Sperm DNA analysis in a Friedreich ataxia premutation carrier suggests both meiotic and mitotic expansion in the FRDA gene . Friedreich ataxia is usually caused by an expansion of a GAA trinucleotide repeat in intron 1 of the FRDA gene . Occasionally , a fully expanded allele has been found to arise from a premutation of 100 or less triplet repeats . We have examined the sperm DNA of a premutation carrier . This mans leucocyte DNA showed one normal allele and one allele of approximately 100 repeats . His sperm showed an expanded allele in a tight range centering on a size of approximately 320 trinucleotide repeats . His affected son has repeat sizes of 1040 and 540 . These data suggest that expansion occurs in two stages , the first during meiosis followed by a second mitotic expansion . We also show that in all informative carrier father to affected child transmissions , with the notable exception of the premutation carrier , the expansion size decreases . . The R496H mutation of arylsulfatase A does not cause metachromatic leukodystrophy . Deficiency of arylsulfatase A ( ARSA ) enzyme activity causes metachromatic leukodystrophy ( MLD ) . A number of ARSA gene mutations responsible for MLD have been identified . Recently , the R496H mutation of ARSA was proposed to be a cause of MLD ( Draghia et al . , 1997 ) . We have investigated the R496H mutation and found this mutation at a relatively high frequency in an African American population ( f = 0 . 09 , n = 61 subjects ) . The ARSA enzyme activity in subjects with and without the R496H mutation was determined and found to be normal . It is therefore concluded that the R496H mutation of ARSA does not negatively influence the activity of ARSA and is not a cause of MLD Down - regulation of transmembrane carbonic anhydrases in renal cell carcinoma cell lines by wild - type von Hippel - Lindau transgenes . To discover genes involved in von Hippel - Lindau ( VHL ) - mediated carcinogenesis , we used renal cell carcinoma cell lines stably transfected with wild - type VHL - expressing transgenes . Large - scale RNA differential display technology applied to these cell lines identified several differentially expressed genes , including an alpha carbonic anhydrase gene , termed CA12 . The deduced protein sequence was classified as a one - pass transmembrane CA possessing an apparently intact catalytic domain in the extracellular CA module . Reintroduced wild - type VHL strongly inhibited the overexpression of the CA12 gene in the parental renal cell carcinoma cell lines . Similar results were obtained with CA9 , encoding another transmembrane CA with an intact catalytic domain . Although both domains of the VHL protein contribute to regulation of CA12 expression , the elongin binding domain alone could effectively regulate CA9 expression . We mapped CA12 and CA9 loci to chromosome bands 15q22 and 17q21 . 2 respectively , regions prone to amplification in some human cancers . Additional experiments are needed to define the role of CA IX and CA XII enzymes in the regulation of pH in the extracellular microenvironment and its potential impact on cancer cell growth . A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy ( Wolfram syndrome ) . Wolfram syndrome ( WFS ; OMIM 222300 ) is an autosomal recessive neurodegenerative disorder defined by young - onset non - immune insulin - dependent diabetes mellitus and progressive optic atrophy . Linkage to markers on chromosome 4p was confirmed in five families . On the basis of meiotic recombinants and disease - associated haplotypes , the WFS gene was localized to a BAC / P1 contig of less than 250 kb . Mutations in a novel gene ( WFS1 ) encoding a putative transmembrane protein were found in all affected individuals in six WFS families , and these mutations were associated with the disease phenotype . WFS1 appears to function in survival of islet beta - cells and neurons . . Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells . BRCA1 and BRCA2 account for most cases of familial , early onset breast and / or ovarian cancer and encode products that each interact with hRAD51 . Results presented here show that BRCA1 and BRCA2 coexist in a biochemical complex and colocalize in subnuclear foci in somatic cells and on the axial elements of developing synaptonemal complexes . Like BRCA1 and RAD51 , BRCA2 relocates to PCNA + replication sites following exposure of S phase cells to hydroxyurea or UV irradiation . Thus , BRCA1 and BRCA2 participate , together , in a pathway ( s ) associated with the activation of double - strand break repair and / or homologous recombination . Dysfunction of this pathway may be a general phenomenon in the majority of cases of hereditary breast and / or ovarian cancer . . A novel Arg362Ser mutation in the sterol 27 - hydroxylase gene ( CYP27 ) : its effects on pre - mRNA splicing and enzyme activity . A novel C to A mutation in the sterol 27 - hydroxylase gene ( CYP27 ) was identified by sequencing amplified CYP27 gene products from a patient with cerebrotendinous xanthomatosis ( CTX ) . The mutation changed the adrenodoxin cofactor binding residue 362Arg to 362Ser ( CGT 362Arg to AGT 362Ser ) , and was responsible for deficiency in the sterol 27 - hydroxylase activity , as confirmed by expression of mutant cDNA into COS - 1 cells . Quantitative analysis showed that the expression of CYP27 gene mRNA in the patient represented 52 . 5 % of the normal level . As the mutation occurred at the penultimate nucleotide of exon 6 ( - 2 position of exon 6 - intron 6 splice site ) of the gene , we hypothesized that the mutation may partially affect the normal splicing efficiency in exon 6 and cause alternative splicing elsewhere , which resulted in decreased transcript in the patient . Transfection of constructed minigenes , with or without the mutation , into COS - 1 cells confirmed that the mutant minigene was responsible for a mRNA species alternatively spliced at an activated cryptic 5 splice site 88 bp upstream from the 3 end of exon 6 . Our data suggest that the C to A mutation at the penultimate nucleotide of exon 6 of the CYP27 gene not only causes the deficiency in the sterol 27 - hydroxylase activity , but also partially leads to alternative pre - mRNA splicing of the gene . To our knowledge , this is the first report regarding effects on pre - mRNA splicing of a mutation at the - 2 position of a 5 splice site . ATM germline mutations in classical ataxia - telangiectasia patients in the Dutch population . Germline mutations in the ATM gene are responsible for the autosomal recessive disorder ataxia - telangiectasia ( A - T ) . In our study , we have determined the ATM mutation spectrum in 19 classical A - T patients , including some immigrant populations , as well as 12 of Dutch ethnic origin . Both the protein truncation test ( PTT ) and the restriction endonuclease fingerprinting ( REF ) method were used and compared for their detection efficiency , identifying 76 % and 60 % of the mutations , respectively . Most patients were found to be compound heterozygote . Seventeen mutations were distinct , of which 10 were not reported previously . Mutations are small deletions or point mutations frequently affecting splice sites . Moreover , a 16 . 7 - kb genomic deletion of the 3 end of the gene , most likely a result of recombination between two LINE elements , was identified . The most frequently found mutation , identified in three unrelated Turkish A - T individuals , was previously described to be a Turkish A - T founder mutation . The presence of a founder mutation among relatively small ethnic population groups in Western Europe could indicate a high carrier frequency in such communities . In patients of Dutch ethnic origin , however , no significant founder effect could be identified . The observed genetic heterogeneity including the relative high percentage of splice - site mutations had no reflection on the phenotype . All patients manifested classical A - T and increased cellular radioresistant DNA synthesis . Determination of the genomic structure of the COL4A4 gene and of novel mutations causing autosomal recessive Alport syndrome . Autosomal recessive Alport syndrome is a progressive hematuric glomerulonephritis characterized by glomerular basement membrane abnormalities and associated with mutations in either the COL4A3 or the COL4A4 gene , which encode the alpha3 and alpha4 type IV collagen chains , respectively . To date , mutation screening in the two genes has been hampered by the lack of genomic structure information . We report here the complete characterization of the 48 exons of the COL4A4 gene , a comprehensive gene screen , and the subsequent detection of 10 novel mutations in eight patients diagnosed with autosomal recessive Alport syndrome . Furthermore , we identified a glycine to alanine substitution in the collagenous domain that is apparently silent in the heterozygous carriers , in 11 . 5 % of all control individuals , and in one control individual homozygous for this glycine substitution . There has been no previous finding of a glycine substitution that is not associated with any obvious phenotype in homozygous individuals . Founder BRCA1 and BRCA2 mutations in French Canadian breast and ovarian cancer families . We have identified four mutations in each of the breast cancer - susceptibility genes , BRCA1 and BRCA2 , in French Canadian breast cancer and breast / ovarian cancer families from Quebec . To identify founder effects , we examined independently ascertained French Canadian cancer families for the distribution of these eight mutations . Mutations were found in 41 of 97 families . Six of eight mutations were observed at least twice . The BRCA1 C4446T mutation was the most common mutation found , followed by the BRCA2 8765delAG mutation . Together , these mutations were found in 28 of 41 families identified to have a mutation . The odds of detection of any of the four BRCA1 mutations was 18 . 7x greater if one or more cases of ovarian cancer were also present in the family . The odds of detection of any of the four BRCA2 mutations was 5 . 3x greater if there were at least five cases of breast cancer in the family . Interestingly , the presence of a breast cancer case < 36 years of age was strongly predictive of the presence of any of the eight mutations screened . Carriers of the same mutation , from different families , shared similar haplotypes , indicating that the mutant alleles were likely to be identical by descent for a mutation in the founder population . The identification of common BRCA1 and BRCA2 mutations will facilitate carrier detection in French Canadian breast cancer and breast / ovarian cancer families . Are Dp71 and Dp140 brain dystrophin isoforms related to cognitive impairment in Duchenne muscular dystrophy ? Molecular study and neuropsychological analysis were performed concurrently on 49 patients with Duchenne muscular dystrophy ( DMD ) in order to find a molecular explanation for the cognitive impairment observed in most DMD patients . Complete analysis of the dystrophin gene was performed to define the localization of deletions and duplications in relation to the different DMD promoters . Qualitative analysis of the Dp71 transcript and testing for the specific first exon of Dp140 were also carried out . Neuropsychological analysis assessed verbal and visuospatial intelligence , verbal memory , and reading skills . Comparison of molecular and psychometric findings demonstrated that deletions and duplications that were localized in the distal part of the gene seemed to be preferentially associated with cognitive impairment . Two altered Dp71 transcripts and two deleted Dp140 DNA sequences were found in four patients with severe cerebral dysfunction . These findings suggest that some sequences located in the distal part of the gene and , in particular , some DMD isoforms expressed in the brain may be related to the cognitive impairment associated with DMD . . I1307K APC and hMLH1 mutations in a non - Jewish family with hereditary non - polyposis colorectal cancer . We describe a French Canadian hereditary non - polyposis colorectal cancer ( HNPCC ) kindred which carries a novel truncating mutation in hMLH1 . Interestingly , the I1307K APC polymorphism , associated with an increased risk of colorectal cancer , is also present in this family . The I1307K polymorphism has previously only been identified in individuals of self - reported Ashkenazi Jewish origins . In addition , in this family , there appears to be no relationship between the I1307K polymorphism and the presence or absence of cancer . . Identification of a novel mutation of the CPO gene in a Japanese hereditary coproporphyria family . Hereditary coproporphyria ( HCP ) is an autosomal dominant disease characterized by a deficiency of coproporphyrinogen oxidase ( CPO ) caused by a mutation in the CPO gene . Only 11 mutations of the gene have been reported in HCP patients . We report another mutation in a Japanese family . Polymerase chain reaction - single strand conformational polymorphism and direct sequence analyses demonstrated a C to T substitution in exon 1 of the CPO gene at nucleotide position 85 , which lies in the putative presequence for targeting to mitochondria . This mutation changes the codon for glutamine to a termination codon at amino acid position 29 . MaeI restriction analysis showed two other carriers in the family . The C - T mutation is located within a recently proposed putative alternative translation initiation codon ( TIC - 1 ) , supporting that TIC - 1 is the real TIC rather than TIC - 2 . . Human complement factor H deficiency associated with hemolytic uremic syndrome . This study reports on six cases of deficiency in the human complement regulatory protein Factor H ( FH ) in the context of an acute renal disease . Five of the cases were observed in children presenting with idiopathic hemolytic uremic syndrome ( HUS ) . Two of the children exhibited a homozygous deficiency characterized by the absence of the 150 - kD form of Factor H and the presence , upon immunoblotting , of the 42 - kD Factor H - like protein 1 ( FHL - 1 ) and other FH - related protein ( FHR ) bands . Southern blot and PCR analysis of DNA of one patient with homozygous deficiency ruled out the presence of a large deletion of the FH gene as the underlying defect for the deficiency . The other four children presented with heterozygous deficiency and exhibited a normal immunoblotting pattern of proteins of the FH family . Factor H deficiency is the only complement deficiency associated with HUS . These observations suggest a role for FH and / or FH receptors in the pathogenesis of idiopathic HUS . . Further evidence for a major ancient mutation underlying myotonic dystrophy from linkage disequilibrium studies in the Japanese population . The myotonic dystrophy ( DM ) mutation is an unstable ( CTG ) n repeat , present at a copy number of 5 - 37 repeats on normal chromosomes but amplified to 50 - 3000 copies on DM chromosomes . Previous findings in Caucasian populations of a DM founder chromosome raise a question about the molecular events involved in the expansion mutation . To investigate whether a founder chromosome for the DM mutation exists in the Japanese population , we genotyped families using polymorphic markers near the ( CTG ) n repeat region and constructed haplotypes . Six different haplotypes were found and DM alleles were always haplotype A . To find an origin of the ( CTG ) n repeat mutation and to investigate the mechanism of the expansion mutation in the Japanese population we have studied 90 Japanese DM families comprising 190 affected and 130 unaffected members . The results suggest that a few common ancestral mutations in both Caucasian and Japanese populations have originated by expansion of an ancestral n = 5 repeat to n = 19 - 37 copies . These data support multistep models of triplet repeat expansion that have been proposed for both DM and Friedreichs ataxia . . The molecular basis of C6 deficiency in the western Cape , South Africa . Deficiency of the sixth component of human complement ( C6 ) has been reported in a number of families from the western Cape , South Africa . Meningococcal disease is endemic in the Cape and almost all pedigrees of total C6 deficiency ( C6Q0 ) have been ascertained because of recurrent disease . We have sequenced the expressed exons of the C6 gene from selected cases and have found three molecular defects leading to total deficiency 879delG , which is the common defect in the Cape and hitherto unreported , and 1195delC and 1936delG , which have been previously reported in African - Americans . We also show that the 879delG and 1195delC defects are associated with characteristic C6 / C7 region DNA marker haplotypes , although small variations were observed . The 1936delG defect was observed only once in the Cape , but its associated haplotype could be deduced . The data from the haplotypes indicate that these three molecular defects account for the defects in all the 38 unrelated C6Q0 individuals we have studied from the Cape . We have also observed the 879delG defect in two Dutch C6 - deficient kindreds , but the 879delG defect in the Cape probably did not come from The Netherlands . . Complement C7 deficiency : seven further molecular defects and their associated marker haplotypes . Seven further molecular bases of C7 deficiency are described . All these new molecular defects involve single - nucleotide events , deletions and substitutions , some of which alter splice sites , and others codons . They are distributed along the C7 gene , but predominantly towards the 3 end . All were found in compound heterozygous individuals . The C6 / C7 marker haplotypes associated with most C7 defects are tabulated . . A genome - wide search for chromosomal loci linked to mental health wellness in relatives at high risk for bipolar affective disorder among the Old Order Amish . Bipolar affective disorder ( BPAD ; manic - depressive illness ) is characterized by episodes of mania and / or hypomania interspersed with periods of depression . Compelling evidence supports a significant genetic component in the susceptibility to develop BPAD . To date , however , linkage studies have attempted only to identify chromosomal loci that cause or increase the risk of developing BPAD . To determine whether there could be protective alleles that prevent or reduce the risk of developing BPAD , similar to what is observed in other genetic disorders , we used mental health wellness ( absence of any psychiatric disorder ) as the phenotype in our genome - wide linkage scan of several large multigeneration Old Order Amish pedigrees exhibiting an extremely high incidence of BPAD . We have found strong evidence for a locus on chromosome 4p at D4S2949 ( maximum GENEHUNTER - PLUS nonparametric linkage score = 4 . 05 , P = 5 . 22 x 10 ( - 4 ) ; SIBPAL Pempirical value < 3 x 10 ( - 5 ) ) and suggestive evidence for a locus on chromosome 4q at D4S397 ( maximum GENEHUNTER - PLUS nonparametric linkage score = 3 . 29 , P = 2 . 57 x 10 ( - 3 ) ; SIBPAL Pempirical value < 1 x 10 ( - 3 ) ) that are linked to mental health wellness . These findings are consistent with the hypothesis that certain alleles could prevent or modify the clinical manifestations of BPAD and perhaps other related affective disorders . Segregation distortion in myotonic dystrophy . Myotonic dystrophy ( DM ) is an autosomal dominant disease which , in the typical pedigree , shows a three generation anticipation cascade . This results in infertility and congenital myotonic dystrophy ( CDM ) with the disappearance of DM in that pedigree . The concept of segregation distortion , where there is preferential transmission of the larger allele at the DM locus , has been put forward to explain partially the maintenance of DM in the population . In a survey of DM in Northern Ireland , 59 pedigrees were ascertained . Sibships where the status of all the members had been identified were examined to determine the transmission of the DM expansion from affected parents to their offspring . Where the transmitting parent was male , 58 . 3 % of the offspring were affected , and in the case of a female transmitting parent , 68 . 7 % were affected . Studies on meiotic drive in DM have shown increased transmission of the larger allele at the DM locus in non - DM heterozygotes for CTGn . This study provides further evidence that the DM expansion tends to be transmitted preferentially . Diagnosis of hemochromatosis . If untreated , hemochromatosis can cause serious illness and early death , but the disease is still substantially under - diagnosed . The cornerstone of screening and case detection is the measurement of serum transferrin saturation and the serum ferritin level . Once the diagnosis is suspected , physicians must use serum ferritin levels and hepatic iron stores on liver biopsy specimens to assess patients for the presence of iron overload . Liver biopsy is also used to establish the presence or absence of cirrhosis , which can affect prognosis and management . A DNA - based test for the HFE gene is commercially available , but its place in the diagnosis of hemochromatosis is still being evaluated . Currently , the most useful role for this test is in the detection of hemochromatosis in the family members of patients with a proven case of the disease . It is crucial to diagnose hemochromatosis before hepatic cirrhosis develops because phlebotomy therapy can avert serious chronic disease and can even lead to normal life expectancy . . Prevalence of the I1307K APC gene variant in Israeli Jews of differing ethnic origin and risk for colorectal cancer . BACKGROUND & AIMS Israeli Jews of European birth , i . e . , Ashkenazim , have the highest colorectal cancer incidence of any Israeli ethnic group . The I1307K APC gene variant was found in 6 . 1 % of American Jews , 28 % of their familial colorectal cancer cases , but not in non - Jews . We assessed the I1307K prevalence in Israeli Jews of differing ethnic origin and risk for colorectal cancer . METHODS DNA samples from 500 unrelated Jews of European or non - European origin , with or without a personal and / or family history of neoplasia , were examined for the I1307K variant by the allele - specific oligonucleotide ( ASO ) method . RESULTS In persons at average risk for colorectal cancer , I1307K was found in 5 . 0 % of 120 European and 1 . 6 % of 188 non - European Jews ( P = 0 . 08 ) . It occurred in 15 . 4 % of 52 Ashkenazi Israelis with familial cancer ( P = 0 . 02 ) and was not detected in 51 non - European Jews at increased cancer risk . Colorectal neoplasia occurred personally or in the families of 13 of 20 Ashkenazi I1307K carriers , 8 of whom also had a personal or family history of noncolonic neoplasia . CONCLUSIONS The I1307K APC variant may represent a susceptibility gene for colorectal , or other , cancers in Ashkenazi Jews , and partially explains the higher incidence of colorectal cancer in European Israelis . Systematic analysis of coproporphyrinogen oxidase gene defects in hereditary coproporphyria and mutation update . Hereditary coproporphyria ( HC ) is an acute hepatic porphyria with autosomal dominant inheritance caused by deficient activity of coproporphyrinogen III oxidase ( CPO ) . Clinical manifestations of the disease are characterized by acute attacks of neurological dysfunction often precipitated by drugs , fasting , cyclical hormonal changes , or infectious diseases . Skin photosensitivity may also be present . The seven exons , the exon / intron boundaries and part of 3 noncoding sequence of the CPO gene were systematically analyzed by an exon - by - exon denaturing gradient gel electrophoresis ( DGGE ) strategy followed by direct sequencing in seven unrelated heterozygous HC patients from France , Holland , and Czech Republic . Seven novel mutations and two new polymorphisms were detected . Among these mutations two are missense ( G197W , W427R ) , two are nonsense ( Q306X , Q385X ) , two are small deletions ( 662de14bp ; 1168del3bp removing a glycine at position 390 ) , and one is a splicing mutation ( IVS1 - 15c - - > g ) which creates a new acceptor splice site . The pathological significance of the point mutations G197W , W427R , and the in - frame deletion 390delGly were assessed by their respective expression in a prokaryotic system using site - directed mutagenesis . These mutations resulted in the absence or a dramatic decrease of CPO activity . The two polymorphisms were localized in noncoding part of the gene 1 ) a C / G polymorphism in the promotor region , 142 bp upstream from the transcriptional initiation site ( - 142C / G ) , and 2 ) a 6 bp deletion polymorphism in the 3 noncoding part of the CPO gene , 574 bp downstream of the last base of the normal termination codon ( + 574 delATTCTT ) . Five intragenic dimorphisms are now well characterized and the high degree of allelic heterogeneity in HC is demonstrated with seven new different mutations making a total of nineteen CPO gene defects reported so far . . Coincidence of two novel arylsulfatase A alleles and mutation 459 + 1G > A within a family with metachromatic leukodystrophy : molecular basis of phenotypic heterogeneity . In a family with three siblings , one developed classical late infantile metachromatic leukodystrophy ( MLD ) , fatal at age 5 years , with deficient arylsulfatase A ( ARSA ) activity and increased galactosylsulfatide ( GS ) excretion . The two other siblings , apparently healthy at 12 ( 1 / 2 ) and 15 years , respectively , and their father , apparently healthy as well , presented ARSA and GS values within the range of MLD patients . Mutation screening and sequence analysis disclosed the involvement of three different ARSA mutations being the molecular basis of intrafamilial phenotypic heterogeneity . The late infantile patient inherited from his mother the frequent 0 - type mutation 459 + 1G > A , and from his father a novel , single basepair microdeletion of guanine at nucleotide 7 in exon 1 ( 7delG ) . The two clinically unaffected siblings carried the maternal mutation 459 + 1G > A and , on their paternal allele , a novel cytosine to thymidine transition at nucleotide 2435 in exon 8 , resulting in substitution of alanine 464 by valine ( A464V ) . The fathers genotype thus was 7delG / A464V . Mutation A464V was not found in 18 unrelated MLD patients and 50 controls . A464V , although clearly modifying ARSA and GS levels , apparently bears little significance for clinical manifestation of MLD , mimicking the frequent ARSA pseudodeficiency allele . Our results demonstrate that in certain genetic conditions MLD - like ARSA and GS values need not be paralleled by clinical disease , a finding with serious diagnostic and prognostic implications . Moreover , further ARSA alleles functionally similar to A464V might exist which , together with 0 - type mutations , may cause pathological ARSA and GS levels , but not clinical outbreak of the disease . . Human MLH1 deficiency predisposes to hematological malignancy and neurofibromatosis type 1 . Heterozygous germ - line mutations in the DNA mismatch repair genes lead to hereditary nonpolyposis colorectal cancer . The disease susceptibility of individuals who constitutionally lack both wild - type alleles is unknown . We have identified three offspring in a hereditary nonpolyposis colorectal cancer family who developed hematological malignancy at a very early age , and at least two of them displayed signs of neurofibromatosis type 1 ( NF1 ) . DNA sequence analysis and allele - specific amplification in two siblings revealed a homozygous MLH1 mutation ( C676T - - > Arg226Stop ) . Thus , a homozygous germ - line MLH1 mutation and consequent mismatch repair deficiency results in a mutator phenotype characterized by leukemia and / or lymphoma associated with neurofibromatosis type 1 . . Missense mutations in the most ancient residues of the PAX6 paired domain underlie a spectrum of human congenital eye malformations . Mutations of the human PAX6 gene underlie aniridia ( congenital absence of the iris ) , a rare dominant malformation of the eye . The spectrum of PAX6 mutations in aniridia patients is highly biased , with 92 % of all reported mutations leading to premature truncation of the protein ( nonsense , splicing , insertions and deletions ) and just 2 % leading to substitution of one amino acid by another ( missense ) . The extraordinary conservation of the PAX6 protein at the amino acid level amongst vertebrates predicts that pathological missense mutations should in fact be common even though they are hardly ever seen in aniridia patients . This indicates that there is a heavy ascertainment bias in the selection of patients for PAX6 mutation analysis and that the missing PAX6 missense mutations frequently may underlie phenotypes distinct from textbook aniridia . Here we present four novel PAX6 missense mutations , two in association with atypical phenotypes ectopia pupillae ( displaced pupils ) and congenital nystagmus ( searching gaze ) , and two in association with more recognizable aniridia phenotypes . Strikingly , all four mutations are located within the PAX6 paired domain and affect amino acids which are highly conserved in all known paired domain proteins . Our results support the hypothesis that the under - representation of missense mutations is caused by ascertainment bias and suggest that a substantial burden of PAX6 - related disease remains to be uncovered . . The chromosomal order of genes controlling the major histocompatibility complex , properdin factor B , and deficiency of the second component of complement . The relationship of the genes coding for HLA to those coding for properdin Factor B allotypes and for deficiency of the second component of complement ( C2 ) was studied in families of patients with connective tissue disorders . Patients were selected because they were heterozygous or homozygous for C2 deficiency . 12 families with 15 matings informative for C2 deficiency were found . Of 57 informative meioses , two crossovers were noted between the C2 deficiency gene and the HLA - B gene , with a recombinant fraction of 0 . 035 . A lod score of 13 was calculated for linkage between C2 deficiency and HLA - B at a maximum likelihood value of the recombinant fraction of 0 . 04 . 18 families with 21 informative matings for both properdin Factor B allotype and HLA - B were found . Of 72 informative meioses , three recombinants were found , giving a recombinant fraction of 0 . 042 . A lod score of 16 between HLA - B and Factor B allotypes was calculated at a maximum likelihood value of the recombinant fraction of 0 . 04 . A crossover was shown to have occurred between genes for Factor B and HLA - D , in which HLA - D segregared with HLA - A and B . These studies suggest that the genes for Factor B and C2 deficiency are located outside those for HLA , that the order of genese is HLA - A , - B , - D , Factor B allotype , C2 deficiency , that the genes coding for C2 deficiency and Factor B allotypes are approximately 3 - - 5 centimorgans from the HLA - A and HLA - B loci , and that the apparent lack of recombinants between the Factor B gene and C2 deficiency gene suggests that these two genes lie in close proximity to one another . Distribution of emerin and lamins in the heart and implications for Emery - Dreifuss muscular dystrophy . Emerin is a nuclear membrane protein which is missing or defective in Emery - Dreifuss muscular dystrophy ( EDMD ) . It is one member of a family of lamina - associated proteins which includes LAP1 , LAP2 and lamin B receptor ( LBR ) . A panel of 16 monoclonal antibodies ( mAbs ) has been mapped to six specific sites throughout the emerin molecule using phage - displayed peptide libraries and has been used to localize emerin in human and rabbit heart . Several mAbs against different emerin epitopes did not recognize intercalated discs in the heart , though they recognized cardiomyocyte nuclei strongly , both at the rim and in intranuclear spots or channels . A polyclonal rabbit antiserum against emerin did recognize both nuclear membrane and intercalated discs but , after affinity purification against a pure - emerin band on a western blot , it stained only the nuclear membrane . These results would not be expected if immunostaining at intercalated discs were due to a product of the emerin gene and , therefore , cast some doubt upon the hypothesis that cardiac defects in EDMD are caused by absence of emerin from intercalated discs . Although emerin was abundant in the membranes of cardiomyocyte nuclei , it was absent from many non - myocyte cells in the heart . This distribution of emerin was similar to that of lamin A , a candidate gene for an autosomal form of EDMD . In contrast , lamin B1 was absent from cardiomyocyte nuclei , showing that lamin B1 is not essential for localization of emerin to the nuclear lamina . Lamin B1 is also almost completely absent from skeletal muscle nuclei . In EDMD , the additional absence of lamin B1 from heart and skeletal muscle nuclei which already lack emerin may offer an alternative explanation of why these tissues are particularly affected . . Genetic mapping of the copper toxicosis locus in Bedlington terriers to dog chromosome 10 , in a region syntenic to human chromosome region 2p13 - p16 . Abnormal hepatic copper accumulation is recognized as an inherited disorder in man , mouse , rat and dog . The major cause of hepatic copper accumulation in man is a dysfunctional ATP7B gene , causing Wilson disease ( WD ) . Mutations in the ATP7B genes have also been demonstrated in mouse and rat . The ATP7B gene has been excluded in the much rarer human copper overload disease non - Indian childhood cirrhosis , indicating genetic heterogeneity . By investigating the common autosomal recessive copper toxicosis ( CT ) in Bedlington terriers , we have identified a new locus involved in progressive liver disease . We examined whether the WD gene ATP7B was also causative for CT by investigating the chromosomal co - localization of ATP7B and C04107 , using fluorescence in situ hybridization ( FISH ) . C04107 is an anonymous microsatellite marker closely linked to CT . However , BAC clones containing ATP7B and C04107 mapped to the canine chromosome regions CFA22q11 and CFA10q26 , respectively , demonstrating that WD cannot be homologous to CT . The copper transport genes CTR1 and CTR2 were also excluded as candidate genes for CT since they both mapped to canine chromosome region CFA11q22 . 2 - 22 . 5 . A transcribed sequence identified from the C04107 - containing BAC was found to be homologous to a gene expressed from human chromosome 2p13 - p16 , a region devoid of any positional candidate genes . Molecular analysis of the APC gene in 205 families : extended genotype - phenotype correlations in FAP and evidence for the role of APC amino acid changes in colorectal cancer predisposition . BACKGROUND / AIMS The development of colorectal cancer and a variable range of extracolonic manifestations in familial adenomatous polyposis ( FAP ) is the result of the dominant inheritance of adenomatous polyposis coli ( APC ) gene mutations . In this study , direct mutation analysis of the APC gene was performed to determine genotype - phenotype correlations for nine extracolonic manifestations and to investigate the incidence of APC mutations in non - FAP colorectal cancer . METHODS The APC gene was analysed in 190 unrelated FAP and 15 non - FAP colorectal cancer patients using denaturing gradient gel electrophoresis , the protein truncation test , and direct sequencing . RESULTS Chain terminating signals were only identified in patients belonging to the FAP group ( 105 patients ) . Amino acid changes were identified in four patients , three of whom belonged to the non - FAP group of colorectal cancer patients . Genotype - phenotype correlations identified significant differences in the nature of certain extracolonic manifestations in FAP patients belonging to three mutation subgroups . CONCLUSIONS Extended genotype - phenotype correlations made in this study may have the potential to determine the most appropriate surveillance and prophylactic treatment regimens for those patients with mutations associated with life threatening conditions . This study also provided evidence for the pathological nature of amino acid changes in APC associated with both FAP and non - FAP colorectal cancer patients . . Inherited colorectal polyposis and cancer risk of the APC I1307K polymorphism . Germ - line and somatic truncating mutations of the APC gene are thought to initiate colorectal tumor formation in familial adenomatous polyposis syndrome and sporadic colorectal carcinogenesis , respectively . Recently , an isoleucine - - > lysine polymorphism at codon 1307 ( I1307K ) of the APC gene has been identified in 6 % - 7 % of the Ashkenazi Jewish population . To assess the risk of this common APC allelic variant in colorectal carcinogenesis , we have analyzed a large cohort of unselected Ashkenazi Jewish subjects with adenomatous polyps and . or colorectal cancer , for the APC I1307K polymorphism . The APC I1307K allele was identified in 48 ( 10 . 1 % ) of 476 patients . Compared with the frequency in two separate population control groups , the APC I1307K allele is associated with an estimated relative risk of 1 . 5 - 1 . 7 for colorectal neoplasia ( both P = . 01 ) . Furthermore , compared with noncarriers , APC I1307K carriers had increased numbers of adenomas and colorectal cancers per patient ( P = . 03 ) , as well as a younger age at diagnosis . We conclude that the APC I1307K variant leads to increased adenoma formation and directly contributes to 3 % - 4 % of all Ashkenazi Jewish colorectal cancer . The estimated relative risk for carriers may justify specific clinical screening for the 360 , 000 Americans expected to harbor this allele , and genetic testing in the setting of long - term - outcome studies may impact significantly on colorectal cancer prevention in this population . Localization of human BRCA1 and its loss in high - grade , non - inherited breast carcinomas . Although the link between the BRCA1 tumour - suppressor gene and hereditary breast and ovarian cancer is established , the role , if any , of BRCA1 in non - familial cancers is unclear . BRCA1 mutations are rare in sporadic cancers , but loss of BRCA1 resulting from reduced expression or incorrect subcellular localization is postulated to be important in non - familial breast and ovarian cancers . Epigenetic loss , however , has not received general acceptance due to controversy regarding the subcellular localization of BRCA1 proteins , reports of which have ranged from exclusively nuclear , to conditionally nuclear , to the ER / golgi , to cytoplasmic invaginations into the nucleus . In an attempt to resolve this issue , we have comprehensively characterized 19 anti - BRCA1 antibodies . These reagents detect a 220 - kD protein localized in discrete nuclear foci in all epithelial cell lines , including those derived from breast malignancies . Immunohistochemical staining of human breast specimens also revealed BRCA1 nuclear foci in benign breast , invasive lobular cancers and low - grade ductal carcinomas . Conversely , BRCA1 expression was reduced or undetectable in the majority of high - grade , ductal carcinomas , suggesting that absence of BRCA1 may contribute to the pathogenesis of a significant percentage of sporadic breast cancers . .
\ No newline at end of file
diff --git a/evaluation/benchmark/readme.md b/evaluation/benchmark/readme.md
new file mode 100644
index 0000000..5f4d4e0
--- /dev/null
+++ b/evaluation/benchmark/readme.md
@@ -0,0 +1,13 @@
+# Benchmarking Dataset
+
+This repository provides a benchmarking dataset for evaluating **StructSense**.
+
+The dataset includes named entity recognition (NER) annotations (test set) from two widely used biomedical corpora:
+- **NCBI Disease** dataset (disease entities)
+- **JNLPBA** dataset (gene and protein entities)
+
+## Repository Structure
+
+- `*.txt` — Plain text files used as input to StructSense.
+- `*.jsonl` — Ground-truth annotations in JSON Lines format, containing sentence-level entity information.
+- `script/bio_txt.py` — Utility script for converting BIO-tagged data into the corresponding `*.txt` and `*.jsonl` formats.
diff --git a/evaluation/benchmark/script/bio_txt.py b/evaluation/benchmark/script/bio_txt.py
new file mode 100644
index 0000000..b865c7a
--- /dev/null
+++ b/evaluation/benchmark/script/bio_txt.py
@@ -0,0 +1,272 @@
+#!/usr/bin/env python3
+"""
+Convert a (T)SV with BIO tags into:
+  1) one continuous text file (all sentences concatenated into one text block)
+  2) one entities/mapping file (JSONL)
+
+Supports:
+- Delimiter auto-detect per line: TAB or COMMA (token<TAB>tag OR token,tag)
+- Tags can be either:
+    * O / B / I   (no type)  -> entity type will be "ENTITY"
+    * O / B-XXX / I-XXX      -> entity type will be XXX
+- Sentence boundaries:
+    * blank line
+    * a line that is just "," (common in some corpora exports)
+
+Outputs:
+- OUT_TEXT: single continuous text block (sentences separated by one space)
+- OUT_ENTS_JSONL: JSONL (one record per sentence) with entities and global offsets
+"""
+
+import json
+from pathlib import Path
+from typing import Any, Dict, List, Tuple, Optional
+
+
+
+IN_FILE = Path("JNLPBA_gene_protein_test.tsv")
+OUT_TEXT = Path("JNLPBA_gene_protein_test_text.txt")
+OUT_ENTS_JSONL = Path("JNLPBA_gene_protein_test_entities_mapping.jsonl")
+
+# Column indices after splitting line into fields
+TOKEN_COL = 0
+TAG_COL = 1
+
+
+def split_fields(line: str) -> List[str]:
+    """
+    Auto-detect delimiter: prefer TAB if present, else comma.
+    """
+    if "\t" in line:
+        return line.split("\t")
+    return line.split(",")
+
+
+def is_sentence_break(parts: List[str], raw_line: str) -> bool:
+    """
+    Decide if this line indicates sentence boundary.
+    """
+    if not raw_line.strip():
+        return True
+    stripped = raw_line.strip()
+    if stripped == ",":
+        return True
+    # If only one column and it's just a comma, treat as break
+    if len(parts) == 1 and parts[0].strip() == ",":
+        return True
+    return False
+
+
+def parse_tag(tag: str) -> Tuple[str, str]:
+    """
+    Returns (bio, etype)
+      - bio in {"B","I","O"}
+      - etype is "" if unknown
+    Handles:
+      O
+      B / I
+      B-XXX / I-XXX
+    Note: we just mark every entity as Entity
+    """
+    tag = tag.strip()
+    if not tag or tag == "O":
+        return "O", ""
+
+    if tag == "B":
+        return "B", "ENTITY"
+    if tag == "I":
+        return "I", "ENTITY"
+
+    if tag.startswith("B-"):
+        return "B", tag.split("-", 1)[1] or "ENTITY"
+    if tag.startswith("I-"):
+        return "I", tag.split("-", 1)[1] or "ENTITY"
+
+    # Unknown format -> treat as O
+    return "O", ""
+
+
+def read_bio_file(path: Path) -> Tuple[List[List[str]], List[List[Tuple[str, str]]]]:
+    """
+    Returns:
+      sentences_tokens: List[List[token]]
+      sentences_tags:   List[List[(bio, etype)]]
+    """
+    sentences_tokens: List[List[str]] = []
+    sentences_tags: List[List[Tuple[str, str]]] = []
+
+    cur_tokens: List[str] = []
+    cur_tags: List[Tuple[str, str]] = []
+
+    def flush():
+        nonlocal cur_tokens, cur_tags
+        if cur_tokens:
+            sentences_tokens.append(cur_tokens)
+            sentences_tags.append(cur_tags)
+            cur_tokens = []
+            cur_tags = []
+
+    with path.open("r", encoding="utf-8") as f:
+        for lineno, raw in enumerate(f, start=1):
+            raw = raw.rstrip("\n")
+            parts = split_fields(raw)
+
+            if is_sentence_break(parts, raw):
+                flush()
+                continue
+
+            # Need at least token + tag
+            if len(parts) <= max(TOKEN_COL, TAG_COL):
+                # If the line is just punctuation delimiter in its own column,
+                # you can decide to flush. Otherwise it is malformed.
+                only = parts[0].strip() if parts else ""
+                if only == ",":
+                    flush()
+                    continue
+                raise ValueError(
+                    f"Line {lineno}: not enough columns for TOKEN_COL={TOKEN_COL}, TAG_COL={TAG_COL}: {raw!r}"
+                )
+
+            token = parts[TOKEN_COL].strip()
+            tag_raw = parts[TAG_COL].strip()
+
+            bio, etype = parse_tag(tag_raw)
+
+            cur_tokens.append(token)
+            cur_tags.append((bio, etype))
+
+    flush()
+    return sentences_tokens, sentences_tags
+
+
+def token_starts_in_joined(tokens: List[str]) -> List[int]:
+    """
+    For sentence_text = " ".join(tokens), compute start char for each token.
+    """
+    starts: List[int] = []
+    pos = 0
+    for i, t in enumerate(tokens):
+        starts.append(pos)
+        pos += len(t)
+        if i != len(tokens) - 1:
+            pos += 1  # space
+    return starts
+
+
+def bio_to_entities(tokens: List[str], tags: List[Tuple[str, str]]) -> List[Dict[str, Any]]:
+    """
+    Build entity spans (relative to sentence text).
+    """
+    sentence = " ".join(tokens)
+    starts = token_starts_in_joined(tokens)
+    entities: List[Dict[str, Any]] = []
+
+    i = 0
+    while i < len(tokens):
+        bio, etype = tags[i]
+        if bio == "O":
+            i += 1
+            continue
+
+        # Start entity on B, or treat stray I as B
+        if bio in ("B", "I"):
+            start_tok = i
+            end_tok = i
+            cur_type = etype or "ENTITY"
+
+            j = i + 1
+            while j < len(tokens):
+                bio_j, etype_j = tags[j]
+                if bio_j != "I":
+                    break
+                # If types exist and mismatch, stop; if no types, keep going
+                next_type = etype_j or cur_type
+                if etype and etype_j and next_type != cur_type:
+                    break
+                end_tok = j
+                j += 1
+
+            char_start = starts[start_tok]
+            char_end = starts[end_tok] + len(tokens[end_tok])
+            text = sentence[char_start:char_end]
+
+            ent: Dict[str, Any] = {
+                "text": text,
+                "type": cur_type,
+                "char_start": char_start,
+                "char_end": char_end,
+                "token_start": start_tok,
+                "token_end": end_tok,
+            }
+            if bio == "I":
+                ent["note"] = "started_with_I"
+            entities.append(ent)
+
+            i = j
+            continue
+
+        i += 1
+
+    return entities
+
+
+def main() -> None:
+    if not IN_FILE.exists():
+        raise FileNotFoundError(f"Input file not found: {IN_FILE}")
+
+    OUT_TEXT.parent.mkdir(parents=True, exist_ok=True)
+    OUT_ENTS_JSONL.parent.mkdir(parents=True, exist_ok=True)
+
+    sentences_tokens, sentences_tags = read_bio_file(IN_FILE)
+
+    sentence_texts: List[str] = [" ".join(toks).replace("\n", " ").strip() for toks in sentences_tokens]
+    sentence_texts = [s for s in sentence_texts if s]
+
+    # One continuous text block
+    global_text = " ".join(sentence_texts)
+    OUT_TEXT.write_text(global_text, encoding="utf-8")
+
+    # Mapping with global offsets
+    global_cursor = 0
+    with OUT_ENTS_JSONL.open("w", encoding="utf-8") as f:
+        for sid, (toks, tags, sent_text) in enumerate(zip(sentences_tokens, sentences_tags, sentence_texts)):
+            ents = bio_to_entities(toks, tags)
+
+            sent_start_global = global_cursor
+            sent_end_global = sent_start_global + len(sent_text)
+
+            ents_global = []
+            for e in ents:
+                ents_global.append(
+                    {
+                        "text": e["text"],
+                        "type": e["type"],
+                        "char_start": sent_start_global + int(e["char_start"]),
+                        "char_end": sent_start_global + int(e["char_end"]),
+                        "token_start": e.get("token_start"),
+                        "token_end": e.get("token_end"),
+                        "note": e.get("note"),
+                    }
+                )
+
+            rec = {
+                "sentence_id": sid,
+                "sentence_text": sent_text,
+                "sentence_char_start_global": sent_start_global,
+                "sentence_char_end_global": sent_end_global,
+                "entities": ents,
+                "entities_global": ents_global,
+            }
+            f.write(json.dumps(rec, ensure_ascii=False) + "\n")
+
+            # move cursor by sentence length + 1 space (except last; harmless if +1)
+            global_cursor = sent_end_global + 1
+
+    print("Done.")
+    print(f"- Wrote continuous text: {OUT_TEXT}")
+    print(f"- Wrote entities mapping: {OUT_ENTS_JSONL}")
+    print(f"- Sentences: {len(sentence_texts)}")
+
+
+if __name__ == "__main__":
+    main()
diff --git a/evaluation/combined_all_token_cost_data/old/combined_all.numbers b/evaluation/combined_all_token_cost_data/old/combined_all.numbers
new file mode 100755
index 0000000..b934727
Binary files /dev/null and b/evaluation/combined_all_token_cost_data/old/combined_all.numbers differ
diff --git a/evaluation/combined_all_token_cost_data/old/combined_all_csv.csv b/evaluation/combined_all_token_cost_data/old/combined_all_csv.csv
new file mode 100644
index 0000000..e10bb69
--- /dev/null
+++ b/evaluation/combined_all_token_cost_data/old/combined_all_csv.csv
@@ -0,0 +1,289 @@
+Timestamp,Provider,Model,App,Input Tokens,Output Tokens,Cost ($),Speed (tps),Finish,Paper,Task,Human loop
+"Jun 28, 10:03 AM",Favicon for InferenceNet,DeepSeek V3 0324,liteLLM,840,720,0.00142,7.7,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 10:01 AM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,4251,316,0.00147,22.4,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 10:01 AM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,72343,834,0.0212,23.2,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:57 AM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,443,415,0.000489,19.7,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:57 AM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,2777,289,0.00111,25.8,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:57 AM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,24235,416,0.00726,15.6,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:56 AM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,310,291,0.000343,20.5,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:55 AM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,6364,252,0.00207,20.0,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:55 AM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,31851,282,0.00924,24.3,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:54 AM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,5155,5131,0.00596,24.0,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:50 AM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,42568,465,0.0125,18.7,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:49 AM",Favicon for Nebius,DeepSeek V3 0324,liteLLM,79864,5149,0.0477,15.0,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:15 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,4469,4421,0.003,61.1,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:14 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,21489,1335,0.00402,58.9,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:14 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,70022,4432,0.0132,64.5,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:11 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,4440,4409,0.00331,56.6,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:10 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,15378,612,0.00267,78.3,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:10 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,0,0,0.0,0.0,--,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:08 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,5399,5351,0.00402,76.9,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:07 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,11508,1701,0.00275,60.4,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:06 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,17158,5363,0.00579,65.8,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:05 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,5399,5352,0.00402,58.0,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:03 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,43032,1984,0.00765,63.0,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:03 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,80322,5361,0.0153,56.1,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 08:41 AM",Favicon for Novita,DeepSeek V3 0324,liteLLM,1343,1315,0.00215,21.8,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:40 AM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,3656,688,0.00185,28.1,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:39 AM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,12182,1315,0.0053,26.9,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:38 AM",Favicon for BaseTen,DeepSeek V3 0324,liteLLM,918,281,0.000923,104.3,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:38 AM",Favicon for Together,DeepSeek V3 0324,liteLLM,4977,461,0.0068,77.7,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:38 AM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,27871,885,0.0103,34.8,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:38 AM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,2830,2805,0.00326,23.7,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:36 AM",Favicon for Phala,DeepSeek V3 0324,liteLLM,2830,1644,0.00408,29.8,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:35 AM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,40240,1022,0.0146,28.3,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:34 AM",Favicon for InferenceNet,DeepSeek V3 0324,liteLLM,79877,2822,0.04,16.1,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:31 AM",Favicon for Nebius,DeepSeek V3 0324,liteLLM,3313,780,0.00283,21.6,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:30 AM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,3310,3274,0.00381,21.3,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:27 AM",Favicon for Nebius,DeepSeek V3 0324,liteLLM,3313,1217,0.00348,19.9,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:26 AM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,40699,1293,0.0125,12.1,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:24 AM",Favicon for Novita,DeepSeek V3 0324,liteLLM,79819,3281,0.0306,92.8,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:23 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,8257,7507,0.137,79.1,tool_calls,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:21 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,22867,578,0.0773,59.1,tool_calls,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:21 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,38038,7854,0.232,84.0,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:19 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,6971,6592,0.12,86.1,tool_calls,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:18 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,29017,485,0.0943,65.6,tool_calls,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:18 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,49699,6574,0.248,81.2,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:16 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,22691,22315,0.403,91.2,tool_calls,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:12 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,67573,1223,0.221,66.8,tool_calls,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:11 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,95310,22350,0.621,92.4,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:07 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,95204,44862,0.959,90.9,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 07:53 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,6240,6354,0.00475,65.3,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 07:51 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,17692,1659,0.00365,55.7,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 07:51 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,30469,6202,0.00829,60.4,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 07:49 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,5539,5491,0.00413,72.6,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 07:48 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,11611,492,0.00204,60.3,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 07:47 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,17086,5502,0.00586,66.4,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 07:46 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,5552,5505,0.00414,56.5,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 07:44 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,43185,624,0.00685,77.7,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 07:44 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,80010,5514,0.0153,68.2,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 27, 11:49 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,2965,2938,0.0048,72.1,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:49 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,14138,803,0.00467,20.8,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:48 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,58760,2935,0.019,10.6,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:42 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,2730,2706,0.00315,24.9,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:40 PM",Favicon for GMICloud,DeepSeek V3 0324,liteLLM,8566,889,0.00714,120.5,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:40 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,45999,2700,0.0187,128.3,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:40 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,2285,2261,0.00263,26.2,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:38 PM",Favicon for Nebius,DeepSeek V3 0324,liteLLM,2288,2459,0.00483,23.8,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:37 PM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,5871,721,0.00247,27.2,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:36 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,16254,2256,0.00654,22.1,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:34 PM",Favicon for BaseTen,DeepSeek V3 0324,liteLLM,2248,2221,0.00344,156.2,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:34 PM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,38090,807,0.0137,27.6,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:34 PM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,71866,2218,0.0227,18.3,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:30 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,19203,18822,0.34,75.0,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:25 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,84710,677,0.264,58.4,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:25 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,133687,18817,0.683,81.8,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:20 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,17648,17270,0.312,82.3,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:16 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,44622,705,0.144,119.6,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:16 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,43731,717,0.142,61.4,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:16 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,54832,17328,0.424,82.0,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:12 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,12626,12250,0.222,80.2,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:09 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,24951,882,0.0881,59.8,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:09 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,44255,12293,0.317,79.0,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:06 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,11739,11063,0.201,75.1,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:04 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,53924,1105,0.178,64.9,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:03 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,84326,11344,0.423,81.3,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:01 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,84220,8159,0.375,81.7,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 10:59 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,84114,9869,0.4,80.5,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 10:38 PM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,2360,2336,0.00286,26.5,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:36 PM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,7636,782,0.00304,28.0,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:36 PM",Favicon for Phala,DeepSeek V3 0324,liteLLM,9049,2333,0.00972,24.7,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:34 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,2006,1982,0.00231,23.3,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:33 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,5318,572,0.0025,20.0,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:32 PM",Favicon for Nebius,DeepSeek V3 0324,liteLLM,10328,1979,0.00813,20.1,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:31 PM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,1879,1855,0.00227,32.3,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:30 PM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,37726,749,0.0114,25.7,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:28 PM",Favicon for GMICloud,DeepSeek V3 0324,liteLLM,71917,1852,0.0549,110.8,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:15 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,10772,10394,0.188,78.1,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:12 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,28469,602,0.0944,59.5,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:12 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,34828,10372,0.26,78.0,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:10 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,8910,8534,0.155,77.5,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:08 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,17693,950,0.0673,61.0,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:07 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,19703,8568,0.188,76.1,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:06 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,7728,7082,0.129,76.8,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:04 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,51376,1294,0.174,89.0,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:04 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,49910,1291,0.169,61.6,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:03 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,83918,7330,0.362,77.9,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:27 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,2026,1988,0.0015,68.2,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:26 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,7043,620,0.00143,69.8,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:26 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,27039,1989,0.00525,70.7,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:25 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1915,1867,0.00141,80.9,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:25 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,4924,572,0.00108,81.2,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:25 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,23024,1920,0.00461,62.2,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:24 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1607,1560,0.00118,64.9,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:24 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,37545,165,0.00573,84.2,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:24 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,72143,1571,0.00637,72.9,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 02:41 PM",Favicon for Nebius,DeepSeek V3 0324,liteLLM,4045,385,0.0026,19.2,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:41 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,2871,1254,0.00191,21.3,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:39 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,1322,1278,0.0021,102.9,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:39 PM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,6527,347,0.00223,13.2,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:39 PM",Favicon for GMICloud,DeepSeek V3 0324,liteLLM,5334,1295,0.00511,69.5,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:38 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,10035,303,0.00371,19.7,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:38 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,4947,5191,0.00595,21.9,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:34 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,6167,502,0.00217,21.1,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:34 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,1777,4748,0.00676,86.5,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:31 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,19104,501,0.0648,63.0,tool_calls,Sample-data,Reproschema,YES
+"Jun 27, 02:31 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,12359,6237,0.131,93.2,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:29 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,13080,398,0.0452,70.9,tool_calls,Sample-data,Reproschema,YES
+"Jun 27, 02:29 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,6349,6236,0.113,93.0,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:28 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,11766,387,0.0411,61.3,tool_calls,Sample-data,Reproschema,YES
+"Jun 27, 02:28 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,5075,6197,0.108,95.8,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:27 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,6778,482,0.0276,64.4,tool_calls,Sample-data,Reproschema,YES
+"Jun 27, 02:27 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,1986,4622,0.0753,95.7,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:24 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,16406,289,0.00263,51.3,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:24 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,9914,6578,0.00543,60.9,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:21 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,6559,6512,0.00489,66.6,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:19 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,11636,284,0.00192,48.3,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:19 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,5215,6521,0.00469,60.3,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:17 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,10376,215,0.00169,48.3,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:17 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,4089,6391,0.00445,56.3,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:15 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,5408,286,0.000983,71.0,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:15 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1808,3999,0.00267,60.6,stop,Sample-data,Reproschema,YES
+"Jun 26, 05:07 PM",Favicon for InferenceNet,DeepSeek V3 0324,liteLLM,2925,409,0.00191,28.3,tps,Sample-data,Reproschema,NO
+"Jun 26, 05:06 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,1932,1076,0.00149,17.9,tps,Sample-data,Reproschema,NO
+"Jun 26, 05:03 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,614,665,0.000757,20.2,tps,Sample-data,Reproschema,NO
+"Jun 26, 05:03 PM",Favicon for Nebius,DeepSeek V3 0324,liteLLM,617,87,0.000439,27.3,tps,Sample-data,Reproschema,NO
+"Jun 26, 05:03 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,6848,313,0.00219,16.4,tps,Sample-data,Reproschema,NO
+"Jun 26, 05:02 PM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,6361,587,0.00268,29.6,tps,Sample-data,Reproschema,NO
+"Jun 26, 05:02 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,6276,7397,0.00827,17.5,tps,Sample-data,Reproschema,NO
+"Jun 26, 04:47 PM",Favicon for InferenceNet,DeepSeek V3 0324,liteLLM,11140,353,0.00552,28.9,tps,Sample-data,Reproschema,NO
+"Jun 26, 04:47 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,4994,6248,0.0069,27.9,tps,Sample-data,Reproschema,NO
+"Jun 26, 04:43 PM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,6218,376,0.00217,23.7,tps,Sample-data,Reproschema,NO
+"Jun 26, 04:43 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,1766,4797,0.00472,22.9,tps,Sample-data,Reproschema,NO
+"Jun 26, 04:35 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,7385,6995,0.127,95.2,tps,Sample-data,Reproschema,NO
+"Jun 26, 04:33 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,14726,415,0.0504,59.6,tps,Sample-data,Reproschema,NO
+"Jun 26, 04:33 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,7244,6987,0.127,95.5,tps,Sample-data,Reproschema,NO
+"Jun 26, 04:32 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,12851,489,0.0459,66.8,tps,Sample-data,Reproschema,NO
+"Jun 26, 04:32 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,5074,7283,0.124,97.2,tps,Sample-data,Reproschema,NO
+"Jun 26, 04:31 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,6777,565,0.0288,67.0,tps,Sample-data,Reproschema,NO
+"Jun 26, 04:30 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,1781,4621,0.0747,95.2,tps,Sample-data,Reproschema,NO
+"Jun 26, 02:32 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,11202,243,0.00183,42.4,tps,Sample-data,Reproschema,NO
+"Jun 26, 02:32 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,4997,6305,0.00453,83.7,tps,Sample-data,Reproschema,NO
+"Jun 26, 02:30 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,9936,345,0.000958,59.5,tps,Sample-data,Reproschema,NO
+"Jun 26, 02:30 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,9936,297,0.00167,78.5,tps,Sample-data,Reproschema,NO
+"Jun 26, 02:30 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,3871,6169,0.00428,62.2,tps,Sample-data,Reproschema,NO
+"Jun 27, 12:19 PM",Favicon for Phala,DeepSeek V3 0324,liteLLM,3503,334,0.00311,31.6,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:18 PM",Favicon for Phala,DeepSeek V3 0324,liteLLM,4017,780,0.00402,29.6,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:17 PM",Favicon for GMICloud,DeepSeek V3 0324,liteLLM,2037,373,0.00184,99.5,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:17 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,2352,361,0.00125,20.5,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:17 PM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,1429,281,0.000733,30.9,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:17 PM",Favicon for Nebius,DeepSeek V3 0324,liteLLM,1249,350,0.00115,31.5,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:17 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,15137,617,0.00478,25.6,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:16 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,15544,264,0.00458,22.2,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:15 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,7004,499,0.0285,69.2,tool_calls,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:15 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,8476,873,0.0385,58.2,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:14 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,4086,481,0.0195,63.2,tool_calls,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:14 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,3851,798,0.0235,64.8,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:14 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,2842,543,0.0167,27.2,tool_calls,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:13 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,1747,668,0.0153,63.7,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:13 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,754,518,0.01,109.9,tool_calls,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:13 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,18461,475,0.0625,64.7,tool_calls,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:13 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,18225,359,0.0601,61.1,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 11:42 AM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,2125,446,0.000987,20.3,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:42 AM",Favicon for Together,DeepSeek V3 0324,liteLLM,2478,376,0.00357,157.7,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:42 AM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,1466,292,0.000755,28.1,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:41 AM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,1267,365,0.000676,21.9,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:41 AM",Favicon for Novita,DeepSeek V3 0324,liteLLM,15154,310,0.0054,25.4,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:41 AM",Favicon for Atoma,DeepSeek V3 0324,liteLLM,15574,281,0.00549,16.4,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:39 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,3512,399,0.0165,70.1,tool_calls,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:39 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,3161,638,0.0191,63.6,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:39 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,2495,454,0.0143,75.1,tool_calls,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:38 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,1621,447,0.0116,58.5,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:38 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,706,330,0.00707,136.6,tool_calls,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:38 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,18433,509,0.0629,71.2,tool_calls,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:38 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,18241,331,0.0597,52.8,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:36 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1769,269,0.000427,56.4,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:36 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,2068,271,0.000473,63.3,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:36 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1261,471,0.000472,36.7,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:36 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1159,264,0.000332,44.1,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:36 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,15118,197,0.00239,55.4,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:36 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,15560,193,0.00245,77.1,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 01:40 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,2569,405,0.00137,106.7 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:40 PM",Favicon for GMICloud,DeepSeek V3 0324,liteLLM,2984,518,0.00267,102.1 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:40 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,1577,475,0.00114,101.9 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:40 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,1226,517,0.000798,17.2 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:39 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,64551,745,0.0187,13.4 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:38 PM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,64954,245,0.0185,20.7 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:37 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,4358,451,0.0198,69.6 tps,tool_calls,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:37 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,4245,834,0.0252,64.2 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:37 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,2795,652,0.0182,73.7 tps,tool_calls,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:36 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,1672,696,0.0155,63.9 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:36 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,744,368,0.00775,128.3 tps,tool_calls,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:36 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,75638,595,0.236,64.2 tps,tool_calls,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:36 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,75333,347,0.231,57.0 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:35 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,2434,398,0.000604,52.6 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:35 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,2863,459,0.000705,70.6 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:35 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1512,362,0.000444,73.7 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:35 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1200,474,0.000464,54.2 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:35 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,263,225,0.000174,57.6 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:35 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,64160,564,0.00996,75.1 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:34 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,64420,225,0.0098,71.4 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:40 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,2569,405,0.00137,106.7 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:40 PM",Favicon for GMICloud,DeepSeek V3 0324,liteLLM,2984,518,0.00267,102.1 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:40 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,1577,475,0.00114,101.9 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:40 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,1226,517,0.000798,17.2 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:39 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,64551,745,0.0187,13.4 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:38 PM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,64954,245,0.0185,20.7 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:37 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,4358,451,0.0198,69.6 tps,tool_calls,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:37 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,4245,834,0.0252,64.2 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:37 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,2795,652,0.0182,73.7 tps,tool_calls,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:36 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,1672,696,0.0155,63.9 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:36 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,744,368,0.00775,128.3 tps,tool_calls,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:36 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,75638,595,0.236,64.2 tps,tool_calls,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:36 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,75333,347,0.231,57.0 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:35 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,2434,398,0.000604,52.6 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:35 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,2863,459,0.000705,70.6 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:35 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1512,362,0.000444,73.7 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:35 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1200,474,0.000464,54.2 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:35 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,263,225,0.000174,57.6 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:35 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,64160,564,0.00996,75.1 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:34 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,64420,225,0.0098,71.4 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:24 PM",Nebius,DeepSeek V3 0324,liteLLM,4009,424,0.00264,18.2,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:24 PM",Lambda,DeepSeek V3 0324,liteLLM,5181,583,0.00227,20.3,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:22 PM",DeepInfra,DeepSeek V3 0324,liteLLM,2522,392,0.00105,21.9,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:22 PM",DeepInfra,DeepSeek V3 0324,liteLLM,2922,506,0.00126,24.8,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:22 PM",Novita,DeepSeek V3 0324,liteLLM,1570,538,0.00122,83.4,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:22 PM",Lambda,DeepSeek V3 0324,liteLLM,1242,495,0.000858,32.3,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:21 PM",Crusoe,DeepSeek V3 0324,liteLLM,59280,289,0.0169,20.9,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:20 PM",Phala,DeepSeek V3 0324,liteLLM,59644,268,0.0468,22.4,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:19 PM",Google,Claude 3.7 Sonnet,liteLLM,8200,586,0.0334,73.0,tool_calls,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:19 PM",Google,Claude 3.7 Sonnet,liteLLM,10200,1037,0.0462,62.2,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:18 PM",Google,Claude 3.7 Sonnet,liteLLM,4732,454,0.021,61.7,tool_calls,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:18 PM",Google,Claude 3.7 Sonnet,liteLLM,4615,986,0.0286,65.9,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:17 PM",Google,Claude 3.7 Sonnet,liteLLM,3053,447,0.0159,63.8,tool_calls,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:17 PM",Google,Claude 3.7 Sonnet,liteLLM,1740,886,0.0185,64.4,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:17 PM",Google,Claude 3.7 Sonnet,liteLLM,837,443,0.00916,106.4,tool_calls,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:17 PM",Google,Claude 3.7 Sonnet,liteLLM,68694,562,0.215,76.2,tool_calls,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:17 PM",Google,Claude 3.7 Sonnet,liteLLM,68374,440,0.212,56.5,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:16 PM",OpenAI,GPT-4o-mini,liteLLM,1042,1004,0.000759,68.4,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:15 PM",OpenAI,GPT-4o-mini,liteLLM,4580,389,0.00092,77.3,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:15 PM",OpenAI,GPT-4o-mini,liteLLM,5538,1006,0.00143,42.7,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:15 PM",OpenAI,GPT-4o-mini,liteLLM,5441,517,0.00113,35.0,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:14 PM",OpenAI,GPT-4o-mini,liteLLM,2584,447,0.000656,72.3,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:14 PM",OpenAI,GPT-4o-mini,liteLLM,3042,502,0.000758,66.9,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:14 PM",OpenAI,GPT-4o-mini,liteLLM,1582,561,0.000574,69.0,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:13 PM",OpenAI,GPT-4o-mini,liteLLM,1234,510,0.000491,47.1,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:13 PM",OpenAI,GPT-4o-mini,liteLLM,59037,435,0.00912,34.6,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:13 PM",OpenAI,GPT-4o-mini,liteLLM,59381,283,0.00908,66.8,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:00 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,2665,432,0.00144,100.3 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:59 PM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,3093,547,0.00153,17.1 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:59 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,1615,333,0.000745,22.5 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:59 PM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,1248,536,0.000966,22.8 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:58 PM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,59272,416,0.0171,18.0 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:58 PM",Favicon for Phala,DeepSeek V3 0324,liteLLM,59270,801,0.0471,31.1 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:57 PM",Favicon for Atoma,DeepSeek V3 0324,liteLLM,59270,741,0.0205,16.9 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:56 PM",Favicon for Atoma,DeepSeek V3 0324,liteLLM,59624,260,0.02,8.2 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:55 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,4349,657,0.0229,76.7 tps,tool_calls,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:55 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,4161,875,0.0256,65.6 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:55 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,2727,633,0.0177,70.2 tps,tool_calls,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:55 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,1645,655,0.0148,73.0 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:55 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,727,344,0.00734,126.3 tps,tool_calls,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:54 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,68584,465,0.213,65.8 tps,tool_calls,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:54 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,68282,330,0.21,54.9 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:53 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,2583,399,0.000627,98.1 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:53 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,3043,500,0.000756,61.5 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:53 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1569,362,0.000453,94.3 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:53 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1236,495,0.000482,47.0 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:53 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,300,262,0.000202,69.8 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:53 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,59016,634,0.00923,67.6 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:53 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,59239,262,0.00904,80.6 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
\ No newline at end of file
diff --git a/evaluation/ner/old/evaluation/Integrating-brainstem/with_hil/Integrating-brainstem-token-usage-with-hl.csv b/evaluation/ner/old/evaluation/Integrating-brainstem/with_hil/Integrating-brainstem-token-usage-with-hl.csv
new file mode 100644
index 0000000..ff0c6dd
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Integrating-brainstem/with_hil/Integrating-brainstem-token-usage-with-hl.csv
@@ -0,0 +1,25 @@
+Timestamp,Provider,Model,App,Input Tokens,Output Tokens,Cost ($),Speed (tps),Finish
+"Jun 28, 10:03 AM",Favicon for InferenceNet,DeepSeek V3 0324,liteLLM,840,720,0.00142,7.7,stop
+"Jun 28, 10:01 AM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,4251,316,0.00147,22.4,stop
+"Jun 28, 10:01 AM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,72343,834,0.0212,23.2,stop
+"Jun 28, 09:57 AM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,443,415,0.000489,19.7,stop
+"Jun 28, 09:57 AM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,2777,289,0.00111,25.8,stop
+"Jun 28, 09:57 AM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,24235,416,0.00726,15.6,stop
+"Jun 28, 09:56 AM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,310,291,0.000343,20.5,stop
+"Jun 28, 09:55 AM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,6364,252,0.00207,20.0,stop
+"Jun 28, 09:55 AM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,31851,282,0.00924,24.3,stop
+"Jun 28, 09:54 AM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,5155,5131,0.00596,24.0,stop
+"Jun 28, 09:50 AM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,42568,465,0.0125,18.7,stop
+"Jun 28, 09:49 AM",Favicon for Nebius,DeepSeek V3 0324,liteLLM,79864,5149,0.0477,15.0,stop
+"Jun 28, 09:15 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,4469,4421,0.003,61.1,stop
+"Jun 28, 09:14 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,21489,1335,0.00402,58.9,stop
+"Jun 28, 09:14 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,70022,4432,0.0132,64.5,stop
+"Jun 28, 09:11 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,4440,4409,0.00331,56.6,stop
+"Jun 28, 09:10 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,15378,612,0.00267,78.3,stop
+"Jun 28, 09:10 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,0,0,0.0,0.0,--
+"Jun 28, 09:08 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,5399,5351,0.00402,76.9,stop
+"Jun 28, 09:07 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,11508,1701,0.00275,60.4,stop
+"Jun 28, 09:06 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,17158,5363,0.00579,65.8,stop
+"Jun 28, 09:05 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,5399,5352,0.00402,58.0,stop
+"Jun 28, 09:03 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,43032,1984,0.00765,63.0,stop
+"Jun 28, 09:03 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,80322,5361,0.0153,56.1,stop
diff --git a/evaluation/ner/old/evaluation/Integrating-brainstem/with_hil/ner_config_claudesonet_s41593-024-01787-0_with_hil.json b/evaluation/ner/old/evaluation/Integrating-brainstem/with_hil/ner_config_claudesonet_s41593-024-01787-0_with_hil.json
new file mode 100644
index 0000000..3770caf
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Integrating-brainstem/with_hil/ner_config_claudesonet_s41593-024-01787-0_with_hil.json
@@ -0,0 +1,951 @@
+{
+  "judged_structured_information": {
+    "judge_ner_terms": {
+      "1": [
+        {
+          "entity": "brainstem",
+          "label": "ANATOMICAL_REGION",
+          "ontology_id": "UBERON:0000955",
+          "ontology_label": "brainstem",
+          "sentence": [
+            "The brainstem is a fundamental component of the central nervous system, yet it is typically excluded from in vivo human brain mapping efforts, precluding a complete understanding of how the brainstem influences cortical function."
+          ],
+          "start": [
+            4
+          ],
+          "end": [
+            13
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "remarks": [
+            "Core anatomical structure that is the focus of the paper",
+            "Alignment made using ontology matching to UBERON",
+            "Perfect alignment with UBERON ontology term",
+            "Accurate extraction of a primary anatomical structure studied in the paper"
+          ],
+          "paper_location": [
+            "abstract"
+          ],
+          "paper_title": [
+            "Integrating brainstem and cortical functional architectures"
+          ],
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "2": [
+        {
+          "entity": "central nervous system",
+          "label": "ANATOMICAL_REGION",
+          "ontology_id": "UBERON:0001017",
+          "ontology_label": "central nervous system",
+          "sentence": [
+            "The brainstem is a fundamental component of the central nervous system, yet it is typically excluded from in vivo human brain mapping efforts, precluding a complete understanding of how the brainstem influences cortical function."
+          ],
+          "start": [
+            45
+          ],
+          "end": [
+            67
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "remarks": [
+            "Major anatomical system containing the brainstem and other structures",
+            "Alignment made using ontology matching to UBERON",
+            "Excellent match with precise UBERON term",
+            "Appropriate extraction of the broader neural system context"
+          ],
+          "paper_location": [
+            "abstract"
+          ],
+          "paper_title": [
+            "Integrating brainstem and cortical functional architectures"
+          ],
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "3": [
+        {
+          "entity": "cortex",
+          "label": "ANATOMICAL_REGION",
+          "ontology_id": "UBERON:0000956",
+          "ontology_label": "cortex",
+          "sentence": [
+            "The brainstem is a fundamental component of the central nervous system, yet it is typically excluded from in vivo human brain mapping efforts, precluding a complete understanding of how the brainstem influences cortical function."
+          ],
+          "start": [
+            159
+          ],
+          "end": [
+            167
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "remarks": [
+            "Major anatomical region interacting with the brainstem",
+            "Alignment made using ontology matching to UBERON",
+            "Perfect match with UBERON term for cortex",
+            "Number of extractions is appropriate as cortex is a key structure studied alongside brainstem"
+          ],
+          "paper_location": [
+            "abstract"
+          ],
+          "paper_title": [
+            "Integrating brainstem and cortical functional architectures"
+          ],
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "4": [
+        {
+          "entity": "7-Tesla functional magnetic resonance imaging",
+          "label": "METHOD",
+          "ontology_id": "NCIT:C16809",
+          "ontology_label": "Functional Magnetic Resonance Imaging",
+          "sentence": [
+            "In this study, we used high-resolution 7-Tesla functional magnetic resonance imaging to derive a functional connectome encompassing cortex and 58 brainstem nuclei spanning the midbrain, pons and medulla."
+          ],
+          "start": [
+            43
+          ],
+          "end": [
+            88
+          ],
+          "judge_score": [
+            0.9
+          ],
+          "remarks": [
+            "Advanced imaging technique used in the study",
+            "Partial alignment to NCIT ontology (for fMRI component)",
+            "Strong match although the specific 7-Tesla component isn't reflected in the ontology term",
+            "Correctly identified method with appropriate ontology alignment despite lack of field strength specification in ontology"
+          ],
+          "paper_location": [
+            "abstract"
+          ],
+          "paper_title": [
+            "Integrating brainstem and cortical functional architectures"
+          ],
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "5": [
+        {
+          "entity": "functional connectome",
+          "label": "METHOD",
+          "ontology_id": "NCIT:C94604",
+          "ontology_label": "Connectome",
+          "sentence": [
+            "In this study, we used high-resolution 7-Tesla functional magnetic resonance imaging to derive a functional connectome encompassing cortex and 58 brainstem nuclei spanning the midbrain, pons and medulla."
+          ],
+          "start": [
+            101
+          ],
+          "end": [
+            122
+          ],
+          "judge_score": [
+            0.95
+          ],
+          "remarks": [
+            "Analytical approach to map brain connectivity",
+            "Aligned to NCIT ontology term for connectome",
+            "Very good match with standard term in neuroscience",
+            "Appropriate extraction as it represents the key methodological output of the study"
+          ],
+          "paper_location": [
+            "abstract"
+          ],
+          "paper_title": [
+            "Integrating brainstem and cortical functional architectures"
+          ],
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "6": [
+        {
+          "entity": "brainstem nuclei",
+          "label": "ANATOMICAL_REGION",
+          "ontology_id": "UBERON:0002698",
+          "ontology_label": "brainstem nucleus",
+          "sentence": [
+            "In this study, we used high-resolution 7-Tesla functional magnetic resonance imaging to derive a functional connectome encompassing cortex and 58 brainstem nuclei spanning the midbrain, pons and medulla."
+          ],
+          "start": [
+            154
+          ],
+          "end": [
+            170
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "remarks": [
+            "Specific anatomical structures within the brainstem that are the focus of the study",
+            "Alignment made using ontology matching to UBERON",
+            "Perfect match with UBERON term (singular vs plural form only difference)",
+            "Extraction count is appropriate given the importance of these structures to the study"
+          ],
+          "paper_location": [
+            "abstract"
+          ],
+          "paper_title": [
+            "Integrating brainstem and cortical functional architectures"
+          ],
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "7": [
+        {
+          "entity": "midbrain",
+          "label": "ANATOMICAL_REGION",
+          "ontology_id": "UBERON:0001891",
+          "ontology_label": "midbrain",
+          "sentence": [
+            "In this study, we used high-resolution 7-Tesla functional magnetic resonance imaging to derive a functional connectome encompassing cortex and 58 brainstem nuclei spanning the midbrain, pons and medulla."
+          ],
+          "start": [
+            180
+          ],
+          "end": [
+            188
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "remarks": [
+            "Specific region of the brainstem studied",
+            "Alignment made using ontology matching to UBERON",
+            "Perfect match with UBERON ontology term",
+            "Accurate extraction of one of the three major brainstem divisions mentioned in the paper"
+          ],
+          "paper_location": [
+            "abstract"
+          ],
+          "paper_title": [
+            "Integrating brainstem and cortical functional architectures"
+          ],
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "8": [
+        {
+          "entity": "pons",
+          "label": "ANATOMICAL_REGION",
+          "ontology_id": "UBERON:0000988",
+          "ontology_label": "pons",
+          "sentence": [
+            "In this study, we used high-resolution 7-Tesla functional magnetic resonance imaging to derive a functional connectome encompassing cortex and 58 brainstem nuclei spanning the midbrain, pons and medulla."
+          ],
+          "start": [
+            190
+          ],
+          "end": [
+            194
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "remarks": [
+            "Specific region of the brainstem studied",
+            "Alignment made using ontology matching to UBERON",
+            "Perfect match with UBERON ontology term",
+            "Accurate extraction of the second major brainstem division mentioned in the paper"
+          ],
+          "paper_location": [
+            "abstract"
+          ],
+          "paper_title": [
+            "Integrating brainstem and cortical functional architectures"
+          ],
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "9": [
+        {
+          "entity": "medulla",
+          "label": "ANATOMICAL_REGION",
+          "ontology_id": "UBERON:0001896",
+          "ontology_label": "medulla oblongata",
+          "sentence": [
+            "In this study, we used high-resolution 7-Tesla functional magnetic resonance imaging to derive a functional connectome encompassing cortex and 58 brainstem nuclei spanning the midbrain, pons and medulla."
+          ],
+          "start": [
+            199
+          ],
+          "end": [
+            206
+          ],
+          "judge_score": [
+            0.95
+          ],
+          "remarks": [
+            "Specific region of the brainstem studied",
+            "Alignment made using ontology matching to UBERON",
+            "Very good match, though extracted term is shortened version of full anatomical name",
+            "Accurate extraction of the third major brainstem division mentioned in the paper"
+          ],
+          "paper_location": [
+            "abstract"
+          ],
+          "paper_title": [
+            "Integrating brainstem and cortical functional architectures"
+          ],
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "10": [
+        {
+          "entity": "integrative hubs",
+          "label": "CONCEPT",
+          "ontology_id": "NCIT:C94659",
+          "ontology_label": "Brain Hub",
+          "sentence": [
+            "We identified a compact set of integrative hubs in the brainstem with widespread connectivity with cerebral cortex."
+          ],
+          "start": [
+            36
+          ],
+          "end": [
+            52
+          ],
+          "judge_score": [
+            0.9
+          ],
+          "remarks": [
+            "Key organizational feature identified in the study",
+            "Aligned to NCIT concept of brain hub",
+            "Good conceptual match although terminology varies slightly",
+            "Appropriate extraction as it represents a core finding of the research"
+          ],
+          "paper_location": [
+            "abstract"
+          ],
+          "paper_title": [
+            "Integrating brainstem and cortical functional architectures"
+          ],
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "11": [
+        {
+          "entity": "cerebral cortex",
+          "label": "ANATOMICAL_REGION",
+          "ontology_id": "UBERON:0000956",
+          "ontology_label": "cortex",
+          "sentence": [
+            "We identified a compact set of integrative hubs in the brainstem with widespread connectivity with cerebral cortex."
+          ],
+          "start": [
+            96
+          ],
+          "end": [
+            110
+          ],
+          "judge_score": [
+            0.95
+          ],
+          "remarks": [
+            "Major brain region studied in relation to the brainstem",
+            "Alignment made using ontology matching to UBERON",
+            "Strong match, though 'cerebral' qualifier is not in the ontology label",
+            "Number of extractions is appropriate as both 'cortex' and 'cerebral cortex' are used in the paper"
+          ],
+          "paper_location": [
+            "abstract"
+          ],
+          "paper_title": [
+            "Integrating brainstem and cortical functional architectures"
+          ],
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "12": [
+        {
+          "entity": "neurophysiological oscillatory rhythms",
+          "label": "CONCEPT",
+          "ontology_id": "NCIT:C94601",
+          "ontology_label": "Neural Oscillation",
+          "sentence": [
+            "Patterns of connectivity between brainstem and cerebral cortex manifest as neurophysiological oscillatory rhythms, patterns of cognitive functional specialization and the unimodal\u2013transmodal functional hierarchy."
+          ],
+          "start": [
+            71
+          ],
+          "end": [
+            108
+          ],
+          "judge_score": [
+            0.9
+          ],
+          "remarks": [
+            "Neural activity patterns observed in the study",
+            "Aligned to NCIT concept of neural oscillation",
+            "Good conceptual match with more detailed description in extracted term",
+            "Appropriate extraction as it represents a key neurophysiological phenomenon studied"
+          ],
+          "paper_location": [
+            "abstract"
+          ],
+          "paper_title": [
+            "Integrating brainstem and cortical functional architectures"
+          ],
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "13": [
+        {
+          "entity": "cognitive functional specialization",
+          "label": "CONCEPT",
+          "ontology_id": "NCIT:C94089",
+          "ontology_label": "Functional Specialization",
+          "sentence": [
+            "Patterns of connectivity between brainstem and cerebral cortex manifest as neurophysiological oscillatory rhythms, patterns of cognitive functional specialization and the unimodal\u2013transmodal functional hierarchy."
+          ],
+          "start": [
+            120
+          ],
+          "end": [
+            155
+          ],
+          "judge_score": [
+            0.95
+          ],
+          "remarks": [
+            "Organization principle of brain function studied",
+            "Aligned to NCIT concept of functional specialization",
+            "Strong match with 'cognitive' qualifier providing additional specificity",
+            "Appropriate extraction as it represents a key organizational principle examined in the study"
+          ],
+          "paper_location": [
+            "abstract"
+          ],
+          "paper_title": [
+            "Integrating brainstem and cortical functional architectures"
+          ],
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "14": [
+        {
+          "entity": "unimodal\u2013transmodal functional hierarchy",
+          "label": "CONCEPT",
+          "ontology_id": "NCIT:C94088",
+          "ontology_label": "Functional Hierarchy",
+          "sentence": [
+            "Patterns of connectivity between brainstem and cerebral cortex manifest as neurophysiological oscillatory rhythms, patterns of cognitive functional specialization and the unimodal\u2013transmodal functional hierarchy."
+          ],
+          "start": [
+            164
+          ],
+          "end": [
+            205
+          ],
+          "judge_score": [
+            0.85
+          ],
+          "remarks": [
+            "Key organizational principle of cortical function",
+            "Partial alignment to NCIT concept of functional hierarchy",
+            "Good match for core concept, but extracted term contains specific type not reflected in ontology",
+            "Appropriate extraction as it identifies another important brain organizational principle studied"
+          ],
+          "paper_location": [
+            "abstract"
+          ],
+          "paper_title": [
+            "Integrating brainstem and cortical functional architectures"
+          ],
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "15": [
+        {
+          "entity": "cortical functional topographies",
+          "label": "CONCEPT",
+          "ontology_id": "NCIT:C94091",
+          "ontology_label": "Cortical Map",
+          "sentence": [
+            "This persistent alignment between cortical functional topographies and brainstem nuclei is shaped by the spatial arrangement of multiple neurotransmitter receptors and transporters."
+          ],
+          "start": [
+            39
+          ],
+          "end": [
+            71
+          ],
+          "judge_score": [
+            0.9
+          ],
+          "remarks": [
+            "Spatial patterns of brain function studied",
+            "Aligned to NCIT concept of cortical map",
+            "Good semantic match despite different terminology",
+            "Appropriate extraction as it represents a key functional organization pattern investigated"
+          ],
+          "paper_location": [
+            "abstract"
+          ],
+          "paper_title": [
+            "Integrating brainstem and cortical functional architectures"
+          ],
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "16": [
+        {
+          "entity": "neurotransmitter receptors",
+          "label": "CELLULAR_COMPONENT",
+          "ontology_id": "GO:0099602",
+          "ontology_label": "neurotransmitter receptor complex",
+          "sentence": [
+            "This persistent alignment between cortical functional topographies and brainstem nuclei is shaped by the spatial arrangement of multiple neurotransmitter receptors and transporters."
+          ],
+          "start": [
+            137
+          ],
+          "end": [
+            163
+          ],
+          "judge_score": [
+            0.95
+          ],
+          "remarks": [
+            "Molecular components involved in neural signaling",
+            "Aligned to GO cellular component term",
+            "Very good match with GO term, only differing in 'complex' specification",
+            "Appropriate extraction as it identifies key molecular components discussed in the paper"
+          ],
+          "paper_location": [
+            "abstract"
+          ],
+          "paper_title": [
+            "Integrating brainstem and cortical functional architectures"
+          ],
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "17": [
+        {
+          "entity": "transporters",
+          "label": "CELLULAR_COMPONENT",
+          "ontology_id": "GO:0005215",
+          "ontology_label": "transporter activity",
+          "sentence": [
+            "This persistent alignment between cortical functional topographies and brainstem nuclei is shaped by the spatial arrangement of multiple neurotransmitter receptors and transporters."
+          ],
+          "start": [
+            168
+          ],
+          "end": [
+            180
+          ],
+          "judge_score": [
+            0.85
+          ],
+          "remarks": [
+            "Molecular components involved in neural signaling",
+            "Aligned to GO molecular function term for transporter activity",
+            "Good match though entity refers to the protein while ontology refers to activity",
+            "Appropriate extraction as it identifies another molecular component discussed alongside receptors"
+          ],
+          "paper_location": [
+            "abstract"
+          ],
+          "paper_title": [
+            "Integrating brainstem and cortical functional architectures"
+          ],
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "18": [
+        {
+          "entity": "3-Tesla data",
+          "label": "DATA_TYPE",
+          "ontology_id": "NCIT:C161396",
+          "ontology_label": "Magnetic Resonance Imaging Data",
+          "sentence": [
+            "We replicated all findings using 3-Tesla data from the same participants."
+          ],
+          "start": [
+            33
+          ],
+          "end": [
+            45
+          ],
+          "judge_score": [
+            0.8
+          ],
+          "remarks": [
+            "Data type used for replication",
+            "Partially aligned to NCIT term for MRI data",
+            "Reasonable match though specific field strength not captured in ontology term",
+            "Appropriate extraction as it identifies a distinct data type used for validation"
+          ],
+          "paper_location": [
+            "abstract"
+          ],
+          "paper_title": [
+            "Integrating brainstem and cortical functional architectures"
+          ],
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "19": [
+        {
+          "entity": "functional interacting neural populations",
+          "label": "CONCEPT",
+          "ontology_id": "NCIT:C94600",
+          "ontology_label": "Neural Population",
+          "sentence": [
+            "The brain is a network of functionally interacting neural populations."
+          ],
+          "start": [
+            19
+          ],
+          "end": [
+            60
+          ],
+          "judge_score": [
+            0.85
+          ],
+          "remarks": [
+            "Conceptualization of brain organization",
+            "Partially aligned to NCIT concept of neural population",
+            "Good match for base concept, though functional interaction aspect not captured in ontology",
+            "Appropriate extraction as it identifies a fundamental conceptual framework for the study"
+          ],
+          "paper_location": [
+            "introduction"
+          ],
+          "paper_title": [
+            "Integrating brainstem and cortical functional architectures"
+          ],
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "20": [
+        {
+          "entity": "functionally specialized brain regions",
+          "label": "CONCEPT",
+          "ontology_id": "NCIT:C94089",
+          "ontology_label": "Functional Specialization",
+          "sentence": [
+            "As a result, key findings about functional activity in the brain\u2014including the presence of functionally specialized brain regions, networks of regions with synchronized neural activity and mechanisms behind higher-order cognitive processes\u2014are primarily limited to the cerebral cortex."
+          ],
+          "start": [
+            78
+          ],
+          "end": [
+            115
+          ],
+          "judge_score": [
+            0.95
+          ],
+          "remarks": [
+            "Important concept in neuroscience research",
+            "Aligned to NCIT concept of functional specialization",
+            "Strong match with entity specifying the regions exhibiting the specialization",
+            "Extraction count is appropriate given that this is a distinct form of the specialization concept"
+          ],
+          "paper_location": [
+            "introduction"
+          ],
+          "paper_title": [
+            "Integrating brainstem and cortical functional architectures"
+          ],
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "21": [
+        {
+          "entity": "networks of regions",
+          "label": "CONCEPT",
+          "ontology_id": "NCIT:C94598",
+          "ontology_label": "Brain Network",
+          "sentence": [
+            "As a result, key findings about functional activity in the brain\u2014including the presence of functionally specialized brain regions, networks of regions with synchronized neural activity and mechanisms behind higher-order cognitive processes\u2014are primarily limited to the cerebral cortex."
+          ],
+          "start": [
+            117
+          ],
+          "end": [
+            135
+          ],
+          "judge_score": [
+            0.9
+          ],
+          "remarks": [
+            "Important concept in systems neuroscience",
+            "Aligned to NCIT concept of Brain Network",
+            "Good match with standard terminology in the field",
+            "New extraction added to address concern about number of extractions"
+          ],
+          "paper_location": [
+            "introduction"
+          ],
+          "paper_title": [
+            "Integrating brainstem and cortical functional architectures"
+          ],
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "22": [
+        {
+          "entity": "synchronized neural activity",
+          "label": "CONCEPT",
+          "ontology_id": "NCIT:C94601",
+          "ontology_label": "Neural Oscillation",
+          "sentence": [
+            "As a result, key findings about functional activity in the brain\u2014including the presence of functionally specialized brain regions, networks of regions with synchronized neural activity and mechanisms behind higher-order cognitive processes\u2014are primarily limited to the cerebral cortex."
+          ],
+          "start": [
+            147
+          ],
+          "end": [
+            175
+          ],
+          "judge_score": [
+            0.85
+          ],
+          "remarks": [
+            "Neural activity pattern discussed in the paper",
+            "Aligned to NCIT concept of neural oscillation",
+            "Good conceptual match though terminology differs slightly",
+            "New extraction added to address concern about number of extractions"
+          ],
+          "paper_location": [
+            "introduction"
+          ],
+          "paper_title": [
+            "Integrating brainstem and cortical functional architectures"
+          ],
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "23": [
+        {
+          "entity": "higher-order cognitive processes",
+          "label": "CONCEPT",
+          "ontology_id": "NCIT:C17809",
+          "ontology_label": "Cognition",
+          "sentence": [
+            "As a result, key findings about functional activity in the brain\u2014including the presence of functionally specialized brain regions, networks of regions with synchronized neural activity and mechanisms behind higher-order cognitive processes\u2014are primarily limited to the cerebral cortex."
+          ],
+          "start": [
+            197
+          ],
+          "end": [
+            230
+          ],
+          "judge_score": [
+            0.9
+          ],
+          "remarks": [
+            "Cognitive processes mentioned in the paper",
+            "Aligned to NCIT concept of Cognition",
+            "Good match with the qualifier 'higher-order' providing additional specificity",
+            "New extraction added to address concern about number of extractions"
+          ],
+          "paper_location": [
+            "introduction"
+          ],
+          "paper_title": [
+            "Integrating brainstem and cortical functional architectures"
+          ],
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
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+          ],
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+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "26": [
+        {
+          "entity": "cortical functional architectures",
+          "label": "CONCEPT",
+          "ontology_id": "NCIT:C94091",
+          "ontology_label": "Cortical Map",
+          "sentence": [
+            "The title 'Integrating brainstem and cortical functional architectures' indicates a focus on connecting brain region organizations."
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+            61
+          ],
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+            0.9
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+            "Key concept from the paper title",
+            "Aligned to NCIT concept of cortical map",
+            "Good match though architecture concept is broader than just mapping",
+            "New extraction added to address concern about number of extractions"
+          ],
+          "paper_location": [
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+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "27": [
+        {
+          "entity": "persistent alignment",
+          "label": "CONCEPT",
+          "ontology_id": "NCIT:C25747",
+          "ontology_label": "Relationship",
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+            0.8
+          ],
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+            "Relational concept discussed in the paper",
+            "Aligned to NCIT concept of Relationship",
+            "Reasonable match though the specific nature of persistence isn't captured",
+            "New extraction added to address concern about number of extractions"
+          ],
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+          ],
+          "paper_title": [
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+          ],
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ]
+    }
+  }
+}
\ No newline at end of file
diff --git a/evaluation/ner/old/evaluation/Integrating-brainstem/with_hil/ner_config_deepseek_s41593-024-01787-0_with_hil.json b/evaluation/ner/old/evaluation/Integrating-brainstem/with_hil/ner_config_deepseek_s41593-024-01787-0_with_hil.json
new file mode 100644
index 0000000..3a7eabc
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Integrating-brainstem/with_hil/ner_config_deepseek_s41593-024-01787-0_with_hil.json
@@ -0,0 +1,117 @@
+{
+  "judged_structured_information": {
+    "judge_ner_terms": {
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+          "ontology_label": "brainstem",
+          "sentence": [
+            "The brainstem is a fundamental component of the central nervous system",
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+            1.0
+          ],
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+          ],
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+          ],
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+          "doi": [
+            "10.1038/s41593-024-01787-0",
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "2": [
+        {
+          "entity": "cerebral cortex",
+          "label": "ANATOMICAL_REGION",
+          "ontology_id": "UBERON:0000956",
+          "ontology_label": "cerebral cortex",
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+            "The study focuses on interactions between brainstem and cerebral cortex",
+            "Cerebral cortex connectivity patterns were analyzed alongside brainstem networks"
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+          ],
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+            "10.1038/s41593-024-01787-0"
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+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ]
+    }
+  }
+}
\ No newline at end of file
diff --git a/evaluation/ner/old/evaluation/Integrating-brainstem/with_hil/ner_config_gpt_s41593-024-01787-0_with_hil.json b/evaluation/ner/old/evaluation/Integrating-brainstem/with_hil/ner_config_gpt_s41593-024-01787-0_with_hil.json
new file mode 100644
index 0000000..f03272b
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Integrating-brainstem/with_hil/ner_config_gpt_s41593-024-01787-0_with_hil.json
@@ -0,0 +1,820 @@
+{
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+          "s41593-024-01787-0.pdf"
+        ],
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+          "10.1038/s41593-024-01787-0"
+        ]
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+          85
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+        "judge_score": [
+          1.0
+        ],
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+        "paper_location": [
+          "results"
+        ],
+        "paper_title": [
+          "s41593-024-01787-0.pdf"
+        ],
+        "doi": [
+          "10.1038/s41593-024-01787-0"
+        ]
+      }
+    ],
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+        "ontology_id": null,
+        "ontology_label": null,
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+          139
+        ],
+        "judge_score": [
+          0.85
+        ],
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+        ],
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+        ]
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+    ],
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+        ],
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+          "10.1038/s41593-024-01787-0"
+        ]
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+          "s41593-024-01787-0.pdf"
+        ],
+        "doi": [
+          "10.1038/s41593-024-01787-0"
+        ]
+      }
+    ],
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+          "s41593-024-01787-0.pdf"
+        ],
+        "doi": [
+          "10.1038/s41593-024-01787-0"
+        ]
+      }
+    ],
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+        ],
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+        ],
+        "paper_location": [
+          "results"
+        ],
+        "paper_title": [
+          "s41593-024-01787-0.pdf"
+        ],
+        "doi": [
+          "10.1038/s41593-024-01787-0"
+        ]
+      }
+    ],
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+        "ontology_label": null,
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+          82
+        ],
+        "judge_score": [
+          0.8
+        ],
+        "remarks": [
+          "Specific imaging technique used in the study.",
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+        ],
+        "paper_location": [
+          "methods"
+        ],
+        "paper_title": [
+          "s41593-024-01787-0.pdf"
+        ],
+        "doi": [
+          "10.1038/s41593-024-01787-0"
+        ]
+      }
+    ],
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+        "entity": "3-Tesla data",
+        "label": "IMAGING_TECHNIQUE",
+        "ontology_id": null,
+        "ontology_label": null,
+        "sentence": [
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+          57
+        ],
+        "end": [
+          69
+        ],
+        "judge_score": [
+          0.8
+        ],
+        "remarks": [
+          "Mention of an alternative imaging technique.",
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+        ],
+        "paper_location": [
+          "results"
+        ],
+        "paper_title": [
+          "s41593-024-01787-0.pdf"
+        ],
+        "doi": [
+          "10.1038/s41593-024-01787-0"
+        ]
+      }
+    ],
+    "10": [
+      {
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+        "ontology_id": null,
+        "ontology_label": null,
+        "sentence": [
+          "This persistent alignment between cortical functional topographies and brainstem nuclei is shaped by the spatial arrangement of multiple neurotransmitter receptors and transporters."
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+          88
+        ],
+        "end": [
+          116
+        ],
+        "judge_score": [
+          0.75
+        ],
+        "remarks": [
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+        ],
+        "paper_location": [
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+        ],
+        "paper_title": [
+          "s41593-024-01787-0.pdf"
+        ],
+        "doi": [
+          "10.1038/s41593-024-01787-0"
+        ]
+      }
+    ],
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+      {
+        "entity": "transporters",
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+        "ontology_id": null,
+        "ontology_label": null,
+        "sentence": [
+          "This persistent alignment between cortical functional topographies and brainstem nuclei is shaped by the spatial arrangement of multiple neurotransmitter receptors and transporters."
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+          0.75
+        ],
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+        "paper_location": [
+          "results"
+        ],
+        "paper_title": [
+          "s41593-024-01787-0.pdf"
+        ],
+        "doi": [
+          "10.1038/s41593-024-01787-0"
+        ]
+      }
+    ],
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+        "ontology_id": null,
+        "ontology_label": null,
+        "sentence": [
+          "We validated the brainstem atlas by parcellating PET images of neurotransmitter receptor densities to the brainstem and confirmed that receptors show high density in their associated brainstem nuclei."
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+        ],
+        "end": [
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+        ],
+        "judge_score": [
+          0.85
+        ],
+        "remarks": [
+          "Mention of a specific type of neurotransmitter receptor.",
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+        ],
+        "paper_location": [
+          "methods"
+        ],
+        "paper_title": [
+          "s41593-024-01787-0.pdf"
+        ],
+        "doi": [
+          "10.1038/s41593-024-01787-0"
+        ]
+      }
+    ],
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+      {
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+        "label": "MOLECULE",
+        "ontology_id": null,
+        "ontology_label": null,
+        "sentence": [
+          "We validated the brainstem atlas by parcellating PET images of neurotransmitter receptor densities to the brainstem and confirmed that receptors show high density in their associated brainstem nuclei."
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+        ],
+        "end": [
+          79
+        ],
+        "judge_score": [
+          0.85
+        ],
+        "remarks": [
+          "A specific neurotransmitter receptor type involved in the study.",
+          "No ontological mapping available."
+        ],
+        "paper_location": [
+          "methods"
+        ],
+        "paper_title": [
+          "s41593-024-01787-0.pdf"
+        ],
+        "doi": [
+          "10.1038/s41593-024-01787-0"
+        ]
+      }
+    ],
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+        "entity": "noradrenergic norepinephrine transporter",
+        "label": "MOLECULE",
+        "ontology_id": null,
+        "ontology_label": null,
+        "sentence": [
+          "We replicated all findings using 3-Tesla data from the same participants."
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+        ],
+        "end": [
+          95
+        ],
+        "judge_score": [
+          0.75
+        ],
+        "remarks": [
+          "Specific transporter associated with norepinephrine signaling.",
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+        ],
+        "paper_location": [
+          "results"
+        ],
+        "paper_title": [
+          "s41593-024-01787-0.pdf"
+        ],
+        "doi": [
+          "10.1038/s41593-024-01787-0"
+        ]
+      }
+    ],
+    "15": [
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+        "entity": "Humans",
+        "label": "SPECIES",
+        "ontology_id": "NCBITaxon:9606",
+        "ontology_label": "Homo sapiens",
+        "sentence": [
+          "Studying the functional architecture of the brain in awake humans is possible with multiple imaging technologies."
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+        ],
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+          32
+        ],
+        "judge_score": [
+          1.0
+        ],
+        "remarks": [
+          "Species involved in the study.",
+          "Mapped to NCBI taxonomy."
+        ],
+        "paper_location": [
+          "introduction"
+        ],
+        "paper_title": [
+          "s41593-024-01787-0.pdf"
+        ],
+        "doi": [
+          "10.1038/s41593-024-01787-0"
+        ]
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+        "ontology_id": null,
+        "ontology_label": null,
+        "sentence": [
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+        ],
+        "end": [
+          144
+        ],
+        "judge_score": [
+          0.85
+        ],
+        "remarks": [
+          "Major research initiative related to human brain mapping.",
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+        ],
+        "paper_location": [
+          "results"
+        ],
+        "paper_title": [
+          "s41593-024-01787-0.pdf"
+        ],
+        "doi": [
+          "10.1038/s41593-024-01787-0"
+        ]
+      }
+    ],
+    "17": [
+      {
+        "entity": "Locus coeruleus",
+        "label": "ANATOMICAL_REGION",
+        "ontology_id": "UBERON:0000527",
+        "ontology_label": "locus coeruleus",
+        "sentence": [
+          "Surprisingly, the locus coeruleus is not identified as a hub, despite its known widespread projections throughout the cortex."
+        ],
+        "start": [
+          119
+        ],
+        "end": [
+          137
+        ],
+        "judge_score": [
+          1.0
+        ],
+        "remarks": [
+          "A specific area in the brainstem associated with various functions.",
+          "Mapped to UBERON ontology."
+        ],
+        "paper_location": [
+          "discussion"
+        ],
+        "paper_title": [
+          "s41593-024-01787-0.pdf"
+        ],
+        "doi": [
+          "10.1038/s41593-024-01787-0"
+        ]
+      }
+    ],
+    "18": [
+      {
+        "entity": "inferior olivary nucleus",
+        "label": "ANATOMICAL_REGION",
+        "ontology_id": "UBERON:0000569",
+        "ontology_label": "inferior olivary nucleus",
+        "sentence": [
+          "Brainstem hubs in the medulla include the inferior olivary nucleus and inferior medullary reticular formation."
+        ],
+        "start": [
+          104
+        ],
+        "end": [
+          129
+        ],
+        "judge_score": [
+          1.0
+        ],
+        "remarks": [
+          "Important hub in brainstem discussed in the study.",
+          "Mapped to UBERON ontology."
+        ],
+        "paper_location": [
+          "results"
+        ],
+        "paper_title": [
+          "s41593-024-01787-0.pdf"
+        ],
+        "doi": [
+          "10.1038/s41593-024-01787-0"
+        ]
+      }
+    ],
+    "19": [
+      {
+        "entity": "dorsal raphe",
+        "label": "ANATOMICAL_REGION",
+        "ontology_id": "UBERON:0000570",
+        "ontology_label": "dorsal raphe nucleus",
+        "sentence": [
+          "Brainstem-to-cortex hubs include the dorsal raphe."
+        ],
+        "start": [
+          77
+        ],
+        "end": [
+          94
+        ],
+        "judge_score": [
+          1.0
+        ],
+        "remarks": [
+          "Key region connected to various cognitive functions.",
+          "Mapped to UBERON ontology."
+        ],
+        "paper_location": [
+          "results"
+        ],
+        "paper_title": [
+          "s41593-024-01787-0.pdf"
+        ],
+        "doi": [
+          "10.1038/s41593-024-01787-0"
+        ]
+      }
+    ],
+    "20": [
+      {
+        "entity": "ventral tegmental area",
+        "label": "ANATOMICAL_REGION",
+        "ontology_id": "UBERON:0000568",
+        "ontology_label": "ventral tegmental area",
+        "sentence": [
+          "Brainstem hubs in the pons include the ventral tegmental area."
+        ],
+        "start": [
+          86
+        ],
+        "end": [
+          107
+        ],
+        "judge_score": [
+          1.0
+        ],
+        "remarks": [
+          "Region of interest in dopamine signaling.",
+          "Mapped to UBERON ontology."
+        ],
+        "paper_location": [
+          "results"
+        ],
+        "paper_title": [
+          "s41593-024-01787-0.pdf"
+        ],
+        "doi": [
+          "10.1038/s41593-024-01787-0"
+        ]
+      }
+    ],
+    "21": [
+      {
+        "entity": "insular cortex",
+        "label": "ANATOMICAL_REGION",
+        "ontology_id": "UBERON:0000464",
+        "ontology_label": "insula",
+        "sentence": [
+          "We found that the insular regions with greatest brainstem FC are the ventral anterior insular cortex."
+        ],
+        "start": [
+          215
+        ],
+        "end": [
+          243
+        ],
+        "judge_score": [
+          1.0
+        ],
+        "remarks": [
+          "Notable brain region discussed in relation to brainstem connectivity.",
+          "Mapped to UBERON ontology."
+        ],
+        "paper_location": [
+          "results"
+        ],
+        "paper_title": [
+          "s41593-024-01787-0.pdf"
+        ],
+        "doi": [
+          "10.1038/s41593-024-01787-0"
+        ]
+      }
+    ],
+    "22": [
+      {
+        "entity": "anterior cingulate cortex",
+        "label": "ANATOMICAL_REGION",
+        "ontology_id": "UBERON:0000283",
+        "ontology_label": "anterior cingulate cortex",
+        "sentence": [
+          "we found that the anterior insula and anterior cingulate cortex demonstrate the greatest cortex-to-brainstem FC."
+        ],
+        "start": [
+          130
+        ],
+        "end": [
+          159
+        ],
+        "judge_score": [
+          1.0
+        ],
+        "remarks": [
+          "Higher-order brain region related to emotion and cognition.",
+          "Mapped to UBERON ontology."
+        ],
+        "paper_location": [
+          "results"
+        ],
+        "paper_title": [
+          "s41593-024-01787-0.pdf"
+        ],
+        "doi": [
+          "10.1038/s41593-024-01787-0"
+        ]
+      }
+    ],
+    "23": [
+      {
+        "entity": "spinal cord",
+        "label": "ANATOMICAL_REGION",
+        "ontology_id": "UBERON:0002104",
+        "ontology_label": "spinal cord",
+        "sentence": [
+          "including cortex, subcortex and spinal cord"
+        ],
+        "start": [
+          134
+        ],
+        "end": [
+          145
+        ],
+        "judge_score": [
+          1.0
+        ],
+        "remarks": [
+          "A critical structure in the central nervous system for transmitting signals.",
+          "Mapped to UBERON ontology."
+        ],
+        "paper_location": [
+          "results"
+        ],
+        "paper_title": [
+          "s41593-024-01787-0.pdf"
+        ],
+        "doi": [
+          "10.1038/s41593-024-01787-0"
+        ]
+      }
+    ],
+    "24": [
+      {
+        "entity": "subcortex",
+        "label": "ANATOMICAL_REGION",
+        "ontology_id": "UBERON:0000458",
+        "ontology_label": "subcortex",
+        "sentence": [
+          "including cortex, subcortex and spinal cord"
+        ],
+        "start": [
+          148
+        ],
+        "end": [
+          155
+        ],
+        "judge_score": [
+          1.0
+        ],
+        "remarks": [
+          "Refers to regions beneath the cortex involved in various functions.",
+          "Mapped to UBERON ontology."
+        ],
+        "paper_location": [
+          "results"
+        ],
+        "paper_title": [
+          "s41593-024-01787-0.pdf"
+        ],
+        "doi": [
+          "10.1038/s41593-024-01787-0"
+        ]
+      }
+    ],
+    "25": [
+      {
+        "entity": "emotional stimuli",
+        "label": "STIMULUS_TYPE",
+        "ontology_id": null,
+        "ontology_label": null,
+        "sentence": [
+          "The connections are likely involved in autonomic responses to emotional stimuli."
+        ],
+        "start": [
+          114
+        ],
+        "end": [
+          136
+        ],
+        "judge_score": [
+          0.8
+        ],
+        "remarks": [],
+        "paper_location": [],
+        "paper_title": [],
+        "doi": []
+      }
+    ]
+  }
+}
\ No newline at end of file
diff --git a/evaluation/ner/old/evaluation/Integrating-brainstem/without_hil/Integrating-brainstem-token-usage-without-hl.csv b/evaluation/ner/old/evaluation/Integrating-brainstem/without_hil/Integrating-brainstem-token-usage-without-hl.csv
new file mode 100644
index 0000000..835c766
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Integrating-brainstem/without_hil/Integrating-brainstem-token-usage-without-hl.csv
@@ -0,0 +1,35 @@
+Timestamp,Provider,Model,App,Input Tokens,Output Tokens,Cost ($),Speed (tps),Finish
+"Jun 28, 08:41 AM",Favicon for Novita,DeepSeek V3 0324,liteLLM,1343,1315,0.00215,21.8,stop
+"Jun 28, 08:40 AM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,3656,688,0.00185,28.1,stop
+"Jun 28, 08:39 AM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,12182,1315,0.0053,26.9,stop
+"Jun 28, 08:38 AM",Favicon for BaseTen,DeepSeek V3 0324,liteLLM,918,281,0.000923,104.3,stop
+"Jun 28, 08:38 AM",Favicon for Together,DeepSeek V3 0324,liteLLM,4977,461,0.0068,77.7,stop
+"Jun 28, 08:38 AM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,27871,885,0.0103,34.8,stop
+"Jun 28, 08:38 AM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,2830,2805,0.00326,23.7,stop
+"Jun 28, 08:36 AM",Favicon for Phala,DeepSeek V3 0324,liteLLM,2830,1644,0.00408,29.8,stop
+"Jun 28, 08:35 AM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,40240,1022,0.0146,28.3,stop
+"Jun 28, 08:34 AM",Favicon for InferenceNet,DeepSeek V3 0324,liteLLM,79877,2822,0.04,16.1,stop
+"Jun 28, 08:31 AM",Favicon for Nebius,DeepSeek V3 0324,liteLLM,3313,780,0.00283,21.6,stop
+"Jun 28, 08:30 AM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,3310,3274,0.00381,21.3,stop
+"Jun 28, 08:27 AM",Favicon for Nebius,DeepSeek V3 0324,liteLLM,3313,1217,0.00348,19.9,stop
+"Jun 28, 08:26 AM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,40699,1293,0.0125,12.1,stop
+"Jun 28, 08:24 AM",Favicon for Novita,DeepSeek V3 0324,liteLLM,79819,3281,0.0306,92.8,stop
+"Jun 28, 08:23 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,8257,7507,0.137,79.1,tool_calls
+"Jun 28, 08:21 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,22867,578,0.0773,59.1,tool_calls
+"Jun 28, 08:21 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,38038,7854,0.232,84.0,stop
+"Jun 28, 08:19 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,6971,6592,0.12,86.1,tool_calls
+"Jun 28, 08:18 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,29017,485,0.0943,65.6,tool_calls
+"Jun 28, 08:18 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,49699,6574,0.248,81.2,stop
+"Jun 28, 08:16 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,22691,22315,0.403,91.2,tool_calls
+"Jun 28, 08:12 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,67573,1223,0.221,66.8,tool_calls
+"Jun 28, 08:11 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,95310,22350,0.621,92.4,stop
+"Jun 28, 08:07 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,95204,44862,0.959,90.9,stop
+"Jun 28, 07:53 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,6240,6354,0.00475,65.3,stop
+"Jun 28, 07:51 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,17692,1659,0.00365,55.7,stop
+"Jun 28, 07:51 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,30469,6202,0.00829,60.4,stop
+"Jun 28, 07:49 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,5539,5491,0.00413,72.6,stop
+"Jun 28, 07:48 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,11611,492,0.00204,60.3,stop
+"Jun 28, 07:47 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,17086,5502,0.00586,66.4,stop
+"Jun 28, 07:46 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,5552,5505,0.00414,56.5,stop
+"Jun 28, 07:44 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,43185,624,0.00685,77.7,stop
+"Jun 28, 07:44 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,80010,5514,0.0153,68.2,stop
diff --git a/evaluation/ner/old/evaluation/Integrating-brainstem/without_hil/ner_config_claudesonet_s41593-024-01787-0_without_hil.json b/evaluation/ner/old/evaluation/Integrating-brainstem/without_hil/ner_config_claudesonet_s41593-024-01787-0_without_hil.json
new file mode 100644
index 0000000..c7c6587
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Integrating-brainstem/without_hil/ner_config_claudesonet_s41593-024-01787-0_without_hil.json
@@ -0,0 +1,544 @@
+{
+  "judge_ner_terms": {
+    "1": {
+      "entity": "brainstem",
+      "label": "ANATOMICAL_REGION",
+      "ontology_id": "UBERON:0000126",
+      "ontology_label": "brainstem",
+      "sentence": "The brainstem is a fundamental component of the central nervous system, yet it is typically excluded from in vivo human brain mapping efforts, precluding a complete understanding of how the brainstem influences cortical function.",
+      "start": 4,
+      "end": 13,
+      "judge_score": 1.0,
+      "remarks": [
+        "Major anatomical region that is the focus of the paper",
+        "Aligned with UBERON ontology for brain stem structure",
+        "Perfect alignment with the correct ontology ID and label"
+      ],
+      "paper_location": "abstract",
+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
+    },
+    "2": {
+      "entity": "cortex",
+      "label": "ANATOMICAL_REGION",
+      "ontology_id": "UBERON:0000956",
+      "ontology_label": "cerebral cortex",
+      "sentence": "The brainstem is a fundamental component of the central nervous system, yet it is typically excluded from in vivo human brain mapping efforts, precluding a complete understanding of how the brainstem influences cortical function.",
+      "start": 139,
+      "end": 145,
+      "judge_score": 0.95,
+      "remarks": [
+        "Major anatomical region studied in relation to brainstem",
+        "Aligned with UBERON ontology for cerebral cortex",
+        "Very good alignment despite slight terminology difference (cortex vs cerebral cortex)"
+      ],
+      "paper_location": "abstract",
+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
+    },
+    "3": {
+      "entity": "central nervous system",
+      "label": "ANATOMICAL_REGION",
+      "ontology_id": "UBERON:0001017",
+      "ontology_label": "central nervous system",
+      "sentence": "The brainstem is a fundamental component of the central nervous system, yet it is typically excluded from in vivo human brain mapping efforts, precluding a complete understanding of how the brainstem influences cortical function.",
+      "start": 46,
+      "end": 68,
+      "judge_score": 1.0,
+      "remarks": [
+        "Major anatomical system that includes the brainstem",
+        "Aligned with UBERON ontology for central nervous system",
+        "Perfect alignment with exact ontology ID and label match"
+      ],
+      "paper_location": "abstract",
+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
+    },
+    "4": {
+      "entity": "7-Tesla functional magnetic resonance imaging",
+      "label": "METHOD",
+      "ontology_id": "NCIT:C16312",
+      "ontology_label": "Functional Magnetic Resonance Imaging",
+      "sentence": "In this study, we used high-resolution 7-Tesla functional magnetic resonance imaging to derive a functional connectome encompassing cortex and 58 brainstem nuclei spanning the midbrain, pons and medulla.",
+      "start": 38,
+      "end": 85,
+      "judge_score": 0.9,
+      "remarks": [
+        "Imaging method used in the study",
+        "Aligned with NCI Thesaurus for fMRI, with specification of 7-Tesla strength",
+        "Good alignment but the specific field strength (7-Tesla) not reflected in the ontology label"
+      ],
+      "paper_location": "abstract",
+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
+    },
+    "5": {
+      "entity": "midbrain",
+      "label": "ANATOMICAL_REGION",
+      "ontology_id": "UBERON:0001891",
+      "ontology_label": "midbrain",
+      "sentence": "In this study, we used high-resolution 7-Tesla functional magnetic resonance imaging to derive a functional connectome encompassing cortex and 58 brainstem nuclei spanning the midbrain, pons and medulla.",
+      "start": 177,
+      "end": 185,
+      "judge_score": 1.0,
+      "remarks": [
+        "Subdivision of the brainstem studied",
+        "Aligned with UBERON ontology for midbrain structure",
+        "Perfect alignment with exact ontology ID and label match"
+      ],
+      "paper_location": "abstract",
+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
+    },
+    "6": {
+      "entity": "pons",
+      "label": "ANATOMICAL_REGION",
+      "ontology_id": "UBERON:0000988",
+      "ontology_label": "pons",
+      "sentence": "In this study, we used high-resolution 7-Tesla functional magnetic resonance imaging to derive a functional connectome encompassing cortex and 58 brainstem nuclei spanning the midbrain, pons and medulla.",
+      "start": 187,
+      "end": 191,
+      "judge_score": 1.0,
+      "remarks": [
+        "Subdivision of the brainstem studied",
+        "Aligned with UBERON ontology for pons structure",
+        "Perfect alignment with exact ontology ID and label match"
+      ],
+      "paper_location": "abstract",
+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
+    },
+    "7": {
+      "entity": "medulla",
+      "label": "ANATOMICAL_REGION",
+      "ontology_id": "UBERON:0001896",
+      "ontology_label": "medulla oblongata",
+      "sentence": "In this study, we used high-resolution 7-Tesla functional magnetic resonance imaging to derive a functional connectome encompassing cortex and 58 brainstem nuclei spanning the midbrain, pons and medulla.",
+      "start": 196,
+      "end": 203,
+      "judge_score": 0.95,
+      "remarks": [
+        "Subdivision of the brainstem studied",
+        "Aligned with UBERON ontology for medulla oblongata",
+        "Very good alignment despite abbreviated term in text (medulla vs. medulla oblongata)"
+      ],
+      "paper_location": "abstract",
+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
+    },
+    "8": {
+      "entity": "integrative hubs",
+      "label": "CONCEPT",
+      "ontology_id": "NCIT:C172271",
+      "ontology_label": "Brain Network Hub",
+      "sentence": "We identified a compact set of integrative hubs in the brainstem with widespread connectivity with cerebral cortex.",
+      "start": 36,
+      "end": 51,
+      "judge_score": 0.85,
+      "remarks": [
+        "Neural connectivity concept identified in the study",
+        "Aligned with NCI Thesaurus concept for brain network hubs",
+        "Good alignment though the ontology term is more general than the specific concept mentioned"
+      ],
+      "paper_location": "abstract",
+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
+    },
+    "9": {
+      "entity": "cerebral cortex",
+      "label": "ANATOMICAL_REGION",
+      "ontology_id": "UBERON:0000956",
+      "ontology_label": "cerebral cortex",
+      "sentence": "We identified a compact set of integrative hubs in the brainstem with widespread connectivity with cerebral cortex.",
+      "start": 98,
+      "end": 112,
+      "judge_score": 1.0,
+      "remarks": [
+        "Major brain region studied in relation to brainstem",
+        "Aligned with UBERON ontology for cerebral cortex",
+        "Perfect alignment with exact ontology ID and label match"
+      ],
+      "paper_location": "abstract",
+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
+    },
+    "10": {
+      "entity": "neurophysiological oscillatory rhythms",
+      "label": "NEUROLOGICAL_PHENOMENON",
+      "ontology_id": "OMIT:0005639",
+      "ontology_label": "neural oscillation",
+      "sentence": "Patterns of connectivity between brainstem and cerebral cortex manifest as neurophysiological oscillatory rhythms, patterns of cognitive functional specialization and the unimodal\u2013transmodal functional hierarchy.",
+      "start": 65,
+      "end": 104,
+      "judge_score": 0.9,
+      "remarks": [
+        "Neural activity pattern studied in relation to brainstem-cortex connectivity",
+        "Aligned with OMIT ontology for neural oscillation",
+        "Strong alignment with appropriate ontology term, slightly different wording"
+      ],
+      "paper_location": "abstract",
+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
+    },
+    "11": {
+      "entity": "cognitive functional specialization",
+      "label": "NEUROLOGICAL_PHENOMENON",
+      "ontology_id": "NCIT:C94625",
+      "ontology_label": "Functional Specialization",
+      "sentence": "Patterns of connectivity between brainstem and cerebral cortex manifest as neurophysiological oscillatory rhythms, patterns of cognitive functional specialization and the unimodal\u2013transmodal functional hierarchy.",
+      "start": 116,
+      "end": 151,
+      "judge_score": 0.9,
+      "remarks": [
+        "Neural organization pattern studied in relation to brainstem-cortex connectivity",
+        "Aligned with NCI Thesaurus term for functional specialization in neural systems",
+        "Strong alignment with the concept, though the 'cognitive' qualifier is not in the ontology label"
+      ],
+      "paper_location": "abstract",
+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
+    },
+    "12": {
+      "entity": "unimodal\u2013transmodal functional hierarchy",
+      "label": "NEUROLOGICAL_PHENOMENON",
+      "ontology_id": "NCIT:C172270",
+      "ontology_label": "Cortical Hierarchy",
+      "sentence": "Patterns of connectivity between brainstem and cerebral cortex manifest as neurophysiological oscillatory rhythms, patterns of cognitive functional specialization and the unimodal\u2013transmodal functional hierarchy.",
+      "start": 160,
+      "end": 200,
+      "judge_score": 0.85,
+      "remarks": [
+        "Neural organizational hierarchy studied in relation to brainstem-cortex connectivity",
+        "Aligned with NCI Thesaurus concept for cortical hierarchy",
+        "Good alignment though the specific unimodal-transmodal aspect is not reflected in the ontology label"
+      ],
+      "paper_location": "abstract",
+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
+    },
+    "13": {
+      "entity": "neurotransmitter receptors",
+      "label": "BIOLOGICAL_COMPONENT",
+      "ontology_id": "GO:0030594",
+      "ontology_label": "neurotransmitter receptor activity",
+      "sentence": "This persistent alignment between cortical functional topographies and brainstem nuclei is shaped by the spatial arrangement of multiple neurotransmitter receptors and transporters.",
+      "start": 126,
+      "end": 150,
+      "judge_score": 0.95,
+      "remarks": [
+        "Molecular components shaping brainstem-cortex connectivity",
+        "Aligned with Gene Ontology term for neurotransmitter receptor activity",
+        "Very good alignment though GO term refers to activity rather than the physical receptor"
+      ],
+      "paper_location": "abstract",
+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
+    },
+    "14": {
+      "entity": "neurotransmitter transporters",
+      "label": "BIOLOGICAL_COMPONENT",
+      "ontology_id": "GO:0005326",
+      "ontology_label": "neurotransmitter transporter activity",
+      "sentence": "This persistent alignment between cortical functional topographies and brainstem nuclei is shaped by the spatial arrangement of multiple neurotransmitter receptors and transporters.",
+      "start": 155,
+      "end": 166,
+      "judge_score": 0.95,
+      "remarks": [
+        "Molecular components shaping brainstem-cortex connectivity",
+        "Aligned with Gene Ontology term for neurotransmitter transporter activity",
+        "Very good alignment though GO term refers to activity rather than the physical transporter"
+      ],
+      "paper_location": "abstract",
+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
+    },
+    "15": {
+      "entity": "3-Tesla",
+      "label": "METHOD",
+      "ontology_id": "NCIT:C16312",
+      "ontology_label": "Functional Magnetic Resonance Imaging",
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+      "start": 32,
+      "end": 39,
+      "judge_score": 0.8,
+      "remarks": [
+        "Alternative imaging method used for validation",
+        "Aligned with NCI Thesaurus for MRI, with specification of 3-Tesla strength",
+        "Acceptable alignment but the specific field strength (3-Tesla) not reflected in the ontology label"
+      ],
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+      "doi": "10.1038/s41593-024-01787-0"
+    },
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+      "end": 64,
+      "judge_score": 1.0,
+      "remarks": [
+        "Cellular components making up brain network",
+        "Aligned with NCI Thesaurus concept for neuronal populations",
+        "Perfect alignment with the appropriate ontology term"
+      ],
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+        "Neural organization pattern primarily studied in cortex",
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+      "judge_score": 1.0,
+      "remarks": [
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+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
+    },
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+      "entity": "extracortical structures",
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+      "start": 48,
+      "end": 72,
+      "judge_score": 0.85,
+      "remarks": [
+        "Brain regions outside cortex, including brainstem",
+        "Aligned with UBERON ontology for subcortical regions",
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+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
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+      "ontology_id": "NCIT:C25578",
+      "ontology_label": "Consciousness",
+      "sentence": "This early evolutionary structure is crucial for survival and consciousness and integrates signals from across the nervous system.",
+      "start": 55,
+      "end": 68,
+      "judge_score": 1.0,
+      "remarks": [
+        "Neural state supported by brainstem function",
+        "Aligned with NCI Thesaurus concept for consciousness",
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+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
+    },
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+      "entity": "neurotransmitter systems",
+      "label": "BIOLOGICAL_COMPONENT",
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+      "ontology_label": "Neurotransmitter System",
+      "sentence": "In addition, multiple neurotransmitter systems originate in brainstem nuclei and project throughout the cortex, shaping cortical activity.",
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+      "end": 45,
+      "judge_score": 1.0,
+      "remarks": [
+        "Chemical signaling pathways originating in brainstem",
+        "Aligned with NCI Thesaurus concept for neurotransmitter systems",
+        "Perfect alignment with exact ontology term"
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+      "paper_location": "introduction",
+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
+    },
+    "23": {
+      "entity": "brainstem nuclei",
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+      "ontology_label": "brainstem nucleus",
+      "sentence": "In addition, multiple neurotransmitter systems originate in brainstem nuclei and project throughout the cortex, shaping cortical activity.",
+      "start": 57,
+      "end": 72,
+      "judge_score": 1.0,
+      "remarks": [
+        "Collection of discrete neural structures in brainstem",
+        "Aligned with UBERON ontology for brainstem nuclei",
+        "Perfect alignment with exact ontology term (plural vs singular form)"
+      ],
+      "paper_location": "introduction",
+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
+    },
+    "24": {
+      "entity": "lesion studies",
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+      "ontology_id": "NCIT:C16410",
+      "ontology_label": "Lesion Study",
+      "sentence": "In stark contrast to research on cortical function, knowledge about brainstem function comes predominantly from lesion studies or studies in model organisms, and these studies are often limited to specific brainstem nuclei or pathways.",
+      "start": 107,
+      "end": 120,
+      "judge_score": 1.0,
+      "remarks": [
+        "Experimental approach used to study brainstem function",
+        "Aligned with NCI Thesaurus concept for lesion studies",
+        "Perfect alignment with exact ontology term (plural vs singular form)"
+      ],
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+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
+    },
+    "25": {
+      "entity": "model organisms",
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+      "ontology_label": "Model Organism",
+      "sentence": "In stark contrast to research on cortical function, knowledge about brainstem function comes predominantly from lesion studies or studies in model organisms, and these studies are often limited to specific brainstem nuclei or pathways.",
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+      "end": 157,
+      "judge_score": 1.0,
+      "remarks": [
+        "Animal subjects used to study brainstem function",
+        "Aligned with NCI Thesaurus concept for model organisms",
+        "Perfect alignment with exact ontology term (plural vs singular form)"
+      ],
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+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
+    },
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+      "entity": "brainstem pathways",
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+      "ontology_label": "central nervous system",
+      "sentence": "In stark contrast to research on cortical function, knowledge about brainstem function comes predominantly from lesion studies or studies in model organisms, and these studies are often limited to specific brainstem nuclei or pathways.",
+      "start": 211,
+      "end": 229,
+      "judge_score": 0.7,
+      "remarks": [
+        "Neural tracts connecting brainstem structures",
+        "Aligned with UBERON ontology as part of central nervous system",
+        "Suboptimal alignment - the ontology term is much broader than the specific entity"
+      ],
+      "paper_location": "introduction",
+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
+    },
+    "27": {
+      "entity": "ultra-high-field magnetic resonance imaging",
+      "label": "METHOD",
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+      "ontology_label": "Functional Magnetic Resonance Imaging",
+      "sentence": "Exciting recent imaging advances have improved the feasibility of functional imaging in the whole brainstem, including ultra-high-field magnetic resonance imaging (MRI) scanners and extensive brainstem-specific physiological noise reduction pipelines.",
+      "start": 108,
+      "end": 150,
+      "judge_score": 0.8,
+      "remarks": [
+        "Advanced imaging technology for studying brainstem",
+        "Aligned with NCI Thesaurus concept for MRI with ultra-high-field specification",
+        "Good alignment but the 'ultra-high-field' specification is not reflected in the ontology term"
+      ],
+      "paper_location": "introduction",
+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
+    },
+    "28": {
+      "entity": "brainstem-specific physiological noise reduction pipelines",
+      "label": "METHOD",
+      "ontology_id": "NCIT:C47846",
+      "ontology_label": "Data Processing",
+      "sentence": "Exciting recent imaging advances have improved the feasibility of functional imaging in the whole brainstem, including ultra-high-field magnetic resonance imaging (MRI) scanners and extensive brainstem-specific physiological noise reduction pipelines.",
+      "start": 169,
+      "end": 227,
+      "judge_score": 0.75,
+      "remarks": [
+        "Data processing method for brainstem imaging",
+        "Aligned with NCI Thesaurus concept for data processing with specialized application",
+        "Satisfactory but general alignment - the ontology term is much broader than the specific technique"
+      ],
+      "paper_location": "introduction",
+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
+    },
+    "29": {
+      "entity": "brainstem atlases",
+      "label": "RESEARCH_TOOL",
+      "ontology_id": "NCIT:C43597",
+      "ontology_label": "Brain Atlas",
+      "sentence": "Furthermore, recent development of brainstem atlases encompassing multiple nuclei has made it possible to augment the cortical functional connectome with an anatomically comprehensive representation of the brainstem.",
+      "start": 34,
+      "end": 50,
+      "judge_score": 0.9,
+      "remarks": [
+        "Anatomical reference tools for brainstem research",
+        "Aligned with NCI Thesaurus concept for brain atlases with brainstem specialization",
+        "Very good alignment though the brainstem-specific aspect is not reflected in the ontology label"
+      ],
+      "paper_location": "introduction",
+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
+    },
+    "30": {
+      "entity": "functional connectome",
+      "label": "CONCEPT",
+      "ontology_id": "NCIT:C172267",
+      "ontology_label": "Functional Connectome",
+      "sentence": "Furthermore, recent development of brainstem atlases encompassing multiple nuclei has made it possible to augment the cortical functional connectome with an anatomically comprehensive representation of the brainstem.",
+      "start": 97,
+      "end": 117,
+      "judge_score": 1.0,
+      "remarks": [
+        "Network representation of functional neural connections",
+        "Aligned with NCI Thesaurus concept for functional connectome",
+        "Perfect alignment with exact ontology term"
+      ],
+      "paper_location": "introduction",
+      "paper_title": "Integrating brainstem and cortical functional architectures",
+      "doi": "10.1038/s41593-024-01787-0"
+    }
+  }
+}
\ No newline at end of file
diff --git a/evaluation/ner/old/evaluation/Integrating-brainstem/without_hil/ner_config_deepseek_s41593-024-01787-0_without_hil.json b/evaluation/ner/old/evaluation/Integrating-brainstem/without_hil/ner_config_deepseek_s41593-024-01787-0_without_hil.json
new file mode 100644
index 0000000..43e211a
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Integrating-brainstem/without_hil/ner_config_deepseek_s41593-024-01787-0_without_hil.json
@@ -0,0 +1,336 @@
+{
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+          "ontology_label": null,
+          "sentence": [
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+          "judge_score": [
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+          "remarks": [
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+            "Quality standard extracted correctly.",
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+            "quality_assurance"
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+            "LB15-47PP linear bearing specifications"
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+          "judge_score": [
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+          ],
+          "remarks": [
+            "Contact information extracted correctly.",
+            "No ontological mapping available."
+          ],
+          "paper_location": [
+            "contact"
+          ],
+          "paper_title": [
+            "LB15-47PP linear bearing specifications"
+          ],
+          "doi": [
+            null
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+        }
+      ]
+    }
+  }
+}
\ No newline at end of file
diff --git a/evaluation/ner/old/evaluation/Integrating-brainstem/without_hil/ner_config_gpt_s41593-024-01787-0_without_hil.json b/evaluation/ner/old/evaluation/Integrating-brainstem/without_hil/ner_config_gpt_s41593-024-01787-0_without_hil.json
new file mode 100644
index 0000000..4207418
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Integrating-brainstem/without_hil/ner_config_gpt_s41593-024-01787-0_without_hil.json
@@ -0,0 +1,1184 @@
+{
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+        {
+          "entity": "University of Padova",
+          "label": "INSTITUTION",
+          "ontology_id": null,
+          "ontology_label": null,
+          "sentence": [
+            "Parkinson\u2019s Disease and Movement Disorders Unit, Center for Rare Neurological Diseases (ERN-RND), University of Padova"
+          ],
+          "start": [
+            88
+          ],
+          "end": [
+            141
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "remarks": [
+            "Institution involved with the research",
+            "No ontological mapping available"
+          ],
+          "paper_location": [
+            "institution"
+          ],
+          "paper_title": "Integrating brainstem and cortical functional architectures",
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "33": [
+        {
+          "entity": "National Institute on Aging",
+          "label": "INSTITUTION",
+          "ontology_id": null,
+          "ontology_label": null,
+          "sentence": [
+            "Multiscale Imaging and Integrative Biophysics Unit, National Institute on Aging"
+          ],
+          "start": [
+            0
+          ],
+          "end": [
+            64
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "remarks": [
+            "Institution involved with the research",
+            "No ontological mapping available"
+          ],
+          "paper_location": [
+            "institution"
+          ],
+          "paper_title": "Integrating brainstem and cortical functional architectures",
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "34": [
+        {
+          "entity": "Universidad Nacional Aut\u00f3noma de M\u00e9xico",
+          "label": "INSTITUTION",
+          "ontology_id": null,
+          "ontology_label": null,
+          "sentence": [
+            "Escuela Nacional de Estudios Superiores, Unidad Juriquilla, Universidad Nacional Aut\u00f3noma de M\u00e9xico"
+          ],
+          "start": [
+            0
+          ],
+          "end": [
+            79
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "remarks": [
+            "Institution involved with the research",
+            "No ontological mapping available"
+          ],
+          "paper_location": [
+            "institution"
+          ],
+          "paper_title": "Integrating brainstem and cortical functional architectures",
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "35": [
+        {
+          "entity": "The University of Sydney",
+          "label": "INSTITUTION",
+          "ontology_id": null,
+          "ontology_label": null,
+          "sentence": [
+            "Brain and Mind Centre, The University of Sydney"
+          ],
+          "start": [
+            0
+          ],
+          "end": [
+            29
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "remarks": [
+            "Institution involved with the research",
+            "No ontological mapping available"
+          ],
+          "paper_location": [
+            "institution"
+          ],
+          "paper_title": "Integrating brainstem and cortical functional architectures",
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "36": [
+        {
+          "entity": "Harvard University",
+          "label": "INSTITUTION",
+          "ontology_id": null,
+          "ontology_label": null,
+          "sentence": [
+            "Division of Sleep Medicine, Harvard University"
+          ],
+          "start": [
+            0
+          ],
+          "end": [
+            29
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "remarks": [
+            "Institution involved with the research",
+            "No ontological mapping available"
+          ],
+          "paper_location": [
+            "institution"
+          ],
+          "paper_title": "Integrating brainstem and cortical functional architectures",
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "37": [
+        {
+          "entity": "functional magnetic resonance imaging",
+          "label": "METHOD",
+          "ontology_id": null,
+          "ontology_label": null,
+          "sentence": [
+            "high-resolution 7-Tesla functional magnetic resonance imaging"
+          ],
+          "start": [
+            6
+          ],
+          "end": [
+            42
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "remarks": [
+            "Imaging method utilized in the study",
+            "No ontological mapping available"
+          ],
+          "paper_location": [
+            "methods"
+          ],
+          "paper_title": "Integrating brainstem and cortical functional architectures",
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ],
+      "38": [
+        {
+          "entity": "positron emission tomography",
+          "label": "METHOD",
+          "ontology_id": null,
+          "ontology_label": null,
+          "sentence": [
+            "Using positron emission tomography (PET)-estimated brain maps for 18 neurotransmitter receptors and transporters."
+          ],
+          "start": [
+            0
+          ],
+          "end": [
+            44
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "remarks": [
+            "Additional imaging method mentioned",
+            "No ontological mapping available"
+          ],
+          "paper_location": [
+            "methods"
+          ],
+          "paper_title": "Integrating brainstem and cortical functional architectures",
+          "doi": [
+            "10.1038/s41593-024-01787-0"
+          ]
+        }
+      ]
+    }
+  }
+}
\ No newline at end of file
diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/comprehensive_analysis_report.txt b/evaluation/ner/old/evaluation/Latent-circuit/results/comprehensive_analysis_report.txt
new file mode 100644
index 0000000..789a4ee
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Latent-circuit/results/comprehensive_analysis_report.txt
@@ -0,0 +1,97 @@
+NER EVALUATION COMPREHENSIVE SUMMARY REPORT
+==================================================
+
+EXECUTIVE SUMMARY
+--------------------
+
+WITH_HIL GROUP:
+- Total unique entities in pool: 59
+- Best entity detection: Claude 3.7 Sonnet (84.7%)
+- Best ontology mapping: Claude 3.7 Sonnet (100.0%)
+- Highest judge scores: GPT-4o-mini (0.978)
+
+WITHOUT_HIL GROUP:
+- Total unique entities in pool: 38
+- Best entity detection: Claude 3.7 Sonnet (78.9%)
+- Best ontology mapping: Claude 3.7 Sonnet (96.7%)
+- Highest judge scores: GPT-4o-mini (0.995)
+
+
+DETAILED MODEL ANALYSIS
+-------------------------
+
+WITH_HIL GROUP DETAILED METRICS:
+
+GPT-4o-mini:
+  Entity Detection: 9/59 (15.3%)
+  Ontology Mapping: 5/9 complete (55.6%)
+  Judge Score: 0.978 ± 0.067
+  High Confidence: 100.0%
+  Label Diversity: 7 types (Shannon: 1.89)
+
+DeepSeek V3 0324:
+  Entity Detection: 15/59 (25.4%)
+  Ontology Mapping: 13/15 complete (86.7%)
+  Judge Score: 0.967 ± 0.049
+  High Confidence: 100.0%
+  Label Diversity: 11 types (Shannon: 2.34)
+
+Claude 3.7 Sonnet:
+  Entity Detection: 50/59 (84.7%)
+  Ontology Mapping: 50/50 complete (100.0%)
+  Judge Score: 0.857 ± 0.102
+  High Confidence: 85.3%
+  Label Diversity: 21 types (Shannon: 2.88)
+
+
+WITHOUT_HIL GROUP DETAILED METRICS:
+
+DeepSeek V3 0324:
+  Entity Detection: 10/38 (26.3%)
+  Ontology Mapping: 4/10 complete (40.0%)
+  Judge Score: 0.853 ± 0.083
+  High Confidence: 87.5%
+  Label Diversity: 7 types (Shannon: 1.89)
+
+Claude 3.7 Sonnet:
+  Entity Detection: 30/38 (78.9%)
+  Ontology Mapping: 29/30 complete (96.7%)
+  Judge Score: 0.885 ± 0.301
+  High Confidence: 88.5%
+  Label Diversity: 12 types (Shannon: 2.37)
+
+GPT-4o-mini:
+  Entity Detection: 11/38 (28.9%)
+  Ontology Mapping: 5/11 complete (45.5%)
+  Judge Score: 0.995 ± 0.015
+  High Confidence: 100.0%
+  Label Diversity: 9 types (Shannon: 2.15)
+
+
+CROSS-GROUP COMPARISON
+----------------------
+
+Common models performance comparison:
+
+DeepSeek V3 0324:
+  Detection Rate: 25.4% (with HIL) vs 26.3% (without HIL) [Δ-0.9%]
+  Ontology Mapping: 86.7% (with HIL) vs 40.0% (without HIL) [Δ+46.7%]
+  Judge Score: 0.967 (with HIL) vs 0.853 (without HIL) [Δ+0.114]
+
+Claude 3.7 Sonnet:
+  Detection Rate: 84.7% (with HIL) vs 78.9% (without HIL) [Δ+5.8%]
+  Ontology Mapping: 100.0% (with HIL) vs 96.7% (without HIL) [Δ+3.3%]
+  Judge Score: 0.857 (with HIL) vs 0.885 (without HIL) [Δ-0.028]
+
+GPT-4o-mini:
+  Detection Rate: 15.3% (with HIL) vs 28.9% (without HIL) [Δ-13.7%]
+  Ontology Mapping: 55.6% (with HIL) vs 45.5% (without HIL) [Δ+10.1%]
+  Judge Score: 0.978 (with HIL) vs 0.995 (without HIL) [Δ-0.018]
+
+
+KEY INSIGHTS
+------------
+
+1. Overall best performer: Claude 3.7 Sonnet (with_hil) (composite score: 90.7)
+2. Human-in-the-loop (HIL) appears to degrade performance in some cases
+3. Model ranking by average detection rate: Claude (81.8%) > DeepSeek (25.9%) > GPT (22.1%)
\ No newline at end of file
diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/comprehensive_summary_table.csv b/evaluation/ner/old/evaluation/Latent-circuit/results/comprehensive_summary_table.csv
new file mode 100644
index 0000000..e0098b3
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Latent-circuit/results/comprehensive_summary_table.csv
@@ -0,0 +1,7 @@
+Group,Model,Entities_Detected,Detection_Rate_%,Miss_Rate_%,Ontology_Complete_%,Judge_Score_Mean,High_Confidence_%,Label_Diversity,Unique_Labels,Unique_Locations
+with_hil,GPT-4o-mini,9,15.3%,84.7%,55.6%,0.978,100.0%,1.89,7,5
+with_hil,DeepSeek V3 0324,15,25.4%,74.6%,86.7%,0.967,100.0%,2.34,11,5
+with_hil,Claude 3.7 Sonnet,50,84.7%,15.3%,100.0%,0.857,85.3%,2.88,21,6
+without_hil,DeepSeek V3 0324,10,26.3%,73.7%,40.0%,0.853,87.5%,1.89,7,4
+without_hil,Claude 3.7 Sonnet,30,78.9%,21.1%,96.7%,0.885,88.5%,2.37,12,5
+without_hil,GPT-4o-mini,11,28.9%,71.1%,45.5%,0.995,100.0%,2.15,9,6
diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/entities_missing_ontology.csv b/evaluation/ner/old/evaluation/Latent-circuit/results/entities_missing_ontology.csv
new file mode 100644
index 0000000..c0d88e7
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Latent-circuit/results/entities_missing_ontology.csv
@@ -0,0 +1,20 @@
+Group,Model,Entity
+with_hil,GPT-4o-mini,Christopher Langdon
+with_hil,GPT-4o-mini,Nature Neuroscience
+with_hil,GPT-4o-mini,Tatiana A. Engel
+with_hil,GPT-4o-mini,task variables
+with_hil,DeepSeek V3 0324,Christopher Langdon
+with_hil,DeepSeek V3 0324,Tatiana A. Engel
+without_hil,DeepSeek V3 0324,Adam optimizer
+without_hil,DeepSeek V3 0324,PyTorch
+without_hil,DeepSeek V3 0324,RNN
+without_hil,DeepSeek V3 0324,ReLU
+without_hil,DeepSeek V3 0324,context-dependent decision-making task
+without_hil,DeepSeek V3 0324,latent circuit model
+without_hil,Claude 3.7 Sonnet,latent circuit model
+without_hil,GPT-4o-mini,Christopher Langdon
+without_hil,GPT-4o-mini,Nature Neuroscience
+without_hil,GPT-4o-mini,Tatiana A. Engel
+without_hil,GPT-4o-mini,cognitive functions
+without_hil,GPT-4o-mini,latent circuit model
+without_hil,GPT-4o-mini,s41593-025-01869-7
diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/entity_overlap_matrix_with_hil.pdf b/evaluation/ner/old/evaluation/Latent-circuit/results/entity_overlap_matrix_with_hil.pdf
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index 0000000..985e548
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diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/entity_pool_analysis_with_hil.pdf b/evaluation/ner/old/evaluation/Latent-circuit/results/entity_pool_analysis_with_hil.pdf
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index 0000000..e818f3b
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diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/entity_pool_analysis_without_hil.pdf b/evaluation/ner/old/evaluation/Latent-circuit/results/entity_pool_analysis_without_hil.pdf
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index 0000000..6df0256
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diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/entity_pool_summary_with_hil.csv b/evaluation/ner/old/evaluation/Latent-circuit/results/entity_pool_summary_with_hil.csv
new file mode 100644
index 0000000..e16b05f
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Latent-circuit/results/entity_pool_summary_with_hil.csv
@@ -0,0 +1,9 @@
+Metric,Value
+Total Pool Size,59
+All Models Shared,1
+GPT-4o-mini - Detected,9
+GPT-4o-mini - Missed,50
+DeepSeek V3 0324 - Detected,15
+DeepSeek V3 0324 - Missed,44
+Claude 3.7 Sonnet - Detected,50
+Claude 3.7 Sonnet - Missed,9
diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/entity_pool_summary_without_hil.csv b/evaluation/ner/old/evaluation/Latent-circuit/results/entity_pool_summary_without_hil.csv
new file mode 100644
index 0000000..7477844
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Latent-circuit/results/entity_pool_summary_without_hil.csv
@@ -0,0 +1,9 @@
+Metric,Value
+Total Pool Size,38
+All Models Shared,2
+DeepSeek V3 0324 - Detected,10
+DeepSeek V3 0324 - Missed,28
+Claude 3.7 Sonnet - Detected,30
+Claude 3.7 Sonnet - Missed,8
+GPT-4o-mini - Detected,11
+GPT-4o-mini - Missed,27
diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/entity_sharing_patterns_with_hil.pdf b/evaluation/ner/old/evaluation/Latent-circuit/results/entity_sharing_patterns_with_hil.pdf
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index 0000000..901a5dc
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diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/judge_score_detailed_statistics.csv b/evaluation/ner/old/evaluation/Latent-circuit/results/judge_score_detailed_statistics.csv
new file mode 100644
index 0000000..8233d3a
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Latent-circuit/results/judge_score_detailed_statistics.csv
@@ -0,0 +1,7 @@
+Group,Model,Count,Mean,Median,Std,Min,Max,High_Confidence_Pct,Low_Confidence_Pct
+with_hil,GPT-4o-mini,9,0.9777777777777779,1.0,0.06666666666666665,0.8,1.0,100.0,0.0
+with_hil,DeepSeek V3 0324,15,0.9666666666666667,1.0,0.04879500364742665,0.9,1.0,100.0,0.0
+with_hil,Claude 3.7 Sonnet,95,0.8568421052631576,0.8,0.10174292968163226,0.7,1.0,85.26315789473684,0.0
+without_hil,DeepSeek V3 0324,16,0.853125,0.85,0.08260094833999586,0.7,0.95,87.5,0.0
+without_hil,Claude 3.7 Sonnet,52,0.8846153846153846,1.0,0.3009036165042543,0.0,1.0,88.46153846153845,9.615384615384617
+without_hil,GPT-4o-mini,11,0.9954545454545454,1.0,0.015075567228888193,0.95,1.0,100.0,0.0
diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/judge_score_distributions_with_hil.pdf b/evaluation/ner/old/evaluation/Latent-circuit/results/judge_score_distributions_with_hil.pdf
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index 0000000..10fa999
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diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/judge_score_statistics_with_hil.csv b/evaluation/ner/old/evaluation/Latent-circuit/results/judge_score_statistics_with_hil.csv
new file mode 100644
index 0000000..1fb184d
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Latent-circuit/results/judge_score_statistics_with_hil.csv
@@ -0,0 +1,4 @@
+Model,Count,Mean,Median,Std,Min,Max,Q25,Q75,High_Confidence,Low_Confidence
+GPT-4o-mini,9,0.978,1.0,0.063,0.8,1.0,1.0,1.0,100.0,0.0
+Claude 3.7 Sonnet,95,0.857,0.8,0.101,0.7,1.0,0.8,0.9,85.263,0.0
+DeepSeek V3 0324,15,0.967,1.0,0.047,0.9,1.0,0.9,1.0,100.0,0.0
diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/judge_score_statistics_without_hil.csv b/evaluation/ner/old/evaluation/Latent-circuit/results/judge_score_statistics_without_hil.csv
new file mode 100644
index 0000000..98fdd98
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Latent-circuit/results/judge_score_statistics_without_hil.csv
@@ -0,0 +1,4 @@
+Model,Count,Mean,Median,Std,Min,Max,Q25,Q75,High_Confidence,Low_Confidence
+GPT-4o-mini,11,0.995,1.0,0.014,0.95,1.0,1.0,1.0,100.0,0.0
+Claude 3.7 Sonnet,52,0.885,1.0,0.298,0.0,1.0,1.0,1.0,88.462,9.615
+DeepSeek V3 0324,16,0.853,0.85,0.08,0.7,0.95,0.8,0.912,87.5,0.0
diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/judge_score_table_with_hil.pdf b/evaluation/ner/old/evaluation/Latent-circuit/results/judge_score_table_with_hil.pdf
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diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/label_distribution_group_comparison.pdf b/evaluation/ner/old/evaluation/Latent-circuit/results/label_distribution_group_comparison.pdf
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index 0000000..1bb0902
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diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/label_distribution_statistics.csv b/evaluation/ner/old/evaluation/Latent-circuit/results/label_distribution_statistics.csv
new file mode 100644
index 0000000..868c53e
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Latent-circuit/results/label_distribution_statistics.csv
@@ -0,0 +1,68 @@
+Group,Model,Label,Count,Percentage
+with_hil,GPT-4o-mini,AUTHOR,2,22.2%
+with_hil,GPT-4o-mini,ANATOMICAL_REGION,2,22.2%
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+with_hil,Claude 3.7 Sonnet,COMPUTATIONAL_COMPONENT,7,14.0%
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+with_hil,Claude 3.7 Sonnet,ORGANIZATION,2,4.0%
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+with_hil,Claude 3.7 Sonnet,STIMULUS_TYPE,2,4.0%
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+with_hil,Claude 3.7 Sonnet,NEURAL_ACTIVITY_MEASURE,1,2.0%
+with_hil,Claude 3.7 Sonnet,COGNITIVE_PROCESS,1,2.0%
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+with_hil,Claude 3.7 Sonnet,BIOLOGICAL_CONSTRAINT,1,2.0%
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+without_hil,DeepSeek V3 0324,COMPUTATIONAL_TOOL,2,20.0%
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+without_hil,DeepSeek V3 0324,ACTIVATION_FUNCTION,1,10.0%
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+without_hil,DeepSeek V3 0324,ANIMAL_SPECIES,1,10.0%
+without_hil,Claude 3.7 Sonnet,NEURAL_MECHANISM,5,16.7%
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+without_hil,Claude 3.7 Sonnet,CELL_TYPE,3,10.0%
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+without_hil,Claude 3.7 Sonnet,ANIMAL_SPECIES,2,6.7%
+without_hil,Claude 3.7 Sonnet,BIOLOGICAL_PRINCIPLE,1,3.3%
+without_hil,Claude 3.7 Sonnet,NEURAL_CIRCUIT,1,3.3%
+without_hil,Claude 3.7 Sonnet,MATHEMATICAL_ENTITY,1,3.3%
+without_hil,GPT-4o-mini,AUTHOR,2,18.2%
+without_hil,GPT-4o-mini,ANATOMICAL_REGION,2,18.2%
+without_hil,GPT-4o-mini,JOURNAL,1,9.1%
+without_hil,GPT-4o-mini,FUNCTIONAL_CONCEPT,1,9.1%
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+without_hil,GPT-4o-mini,CELL_TYPE,1,9.1%
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diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/label_distribution_with_hil.pdf b/evaluation/ner/old/evaluation/Latent-circuit/results/label_distribution_with_hil.pdf
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index 0000000..6cc9ae4
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diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/label_diversity_with_hil.pdf b/evaluation/ner/old/evaluation/Latent-circuit/results/label_diversity_with_hil.pdf
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index 0000000..ead860b
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diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/label_diversity_without_hil.pdf b/evaluation/ner/old/evaluation/Latent-circuit/results/label_diversity_without_hil.pdf
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index 0000000..af7e945
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diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/location_distribution_with_hil.pdf b/evaluation/ner/old/evaluation/Latent-circuit/results/location_distribution_with_hil.pdf
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diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/location_distribution_without_hil.pdf b/evaluation/ner/old/evaluation/Latent-circuit/results/location_distribution_without_hil.pdf
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index 0000000..8055091
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diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/location_heatmap_with_hil.pdf b/evaluation/ner/old/evaluation/Latent-circuit/results/location_heatmap_with_hil.pdf
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index 0000000..5631a73
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diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/location_heatmap_without_hil.pdf b/evaluation/ner/old/evaluation/Latent-circuit/results/location_heatmap_without_hil.pdf
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index 0000000..a5910ee
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diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/location_statistics.csv b/evaluation/ner/old/evaluation/Latent-circuit/results/location_statistics.csv
new file mode 100644
index 0000000..9950e1e
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Latent-circuit/results/location_statistics.csv
@@ -0,0 +1,27 @@
+Group,Model,Location,Count,Percentage
+with_hil,GPT-4o-mini,introduction,4,44.4%
+with_hil,GPT-4o-mini,results,2,22.2%
+with_hil,GPT-4o-mini,other,1,11.1%
+with_hil,GPT-4o-mini,discussion,1,11.1%
+with_hil,GPT-4o-mini,methods,1,11.1%
+with_hil,DeepSeek V3 0324,other,14,93.3%
+with_hil,DeepSeek V3 0324,methods,1,6.7%
+with_hil,Claude 3.7 Sonnet,results,51,53.7%
+with_hil,Claude 3.7 Sonnet,methods,16,16.8%
+with_hil,Claude 3.7 Sonnet,introduction,12,12.6%
+with_hil,Claude 3.7 Sonnet,abstract,8,8.4%
+with_hil,Claude 3.7 Sonnet,discussion,6,6.3%
+with_hil,Claude 3.7 Sonnet,other,2,2.1%
+without_hil,DeepSeek V3 0324,methods,6,37.5%
+without_hil,DeepSeek V3 0324,introduction,4,25.0%
+without_hil,DeepSeek V3 0324,results,3,18.8%
+without_hil,DeepSeek V3 0324,abstract,3,18.8%
+without_hil,Claude 3.7 Sonnet,results,25,48.1%
+without_hil,Claude 3.7 Sonnet,introduction,10,19.2%
+without_hil,Claude 3.7 Sonnet,abstract,8,15.4%
+without_hil,Claude 3.7 Sonnet,methods,8,15.4%
+without_hil,Claude 3.7 Sonnet,discussion,1,1.9%
+without_hil,GPT-4o-mini,introduction,7,63.6%
+without_hil,GPT-4o-mini,results,2,18.2%
+without_hil,GPT-4o-mini,methods,1,9.1%
+without_hil,GPT-4o-mini,discussion,1,9.1%
diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/missed_entities_details_with_hil.csv b/evaluation/ner/old/evaluation/Latent-circuit/results/missed_entities_details_with_hil.csv
new file mode 100644
index 0000000..91a3b23
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Latent-circuit/results/missed_entities_details_with_hil.csv
@@ -0,0 +1,104 @@
+Model,Missed Entity
+GPT-4o-mini,rnn
+GPT-4o-mini,choice axis
+GPT-4o-mini,context-dependent decision-making
+GPT-4o-mini,context axis
+GPT-4o-mini,sensory color nodes
+GPT-4o-mini,motion axis
+GPT-4o-mini,correct trials
+GPT-4o-mini,choice nodes
+GPT-4o-mini,monkey a
+GPT-4o-mini,linear decoder
+GPT-4o-mini,color context
+GPT-4o-mini,recurrent neural network
+GPT-4o-mini,motion coherence
+GPT-4o-mini,context cue
+GPT-4o-mini,rectified linear (relu) activation function
+GPT-4o-mini,input connectivity win
+GPT-4o-mini,monkey f
+GPT-4o-mini,single neurons
+GPT-4o-mini,incongruent trials
+GPT-4o-mini,cold spring harbor laboratory
+GPT-4o-mini,inhibitory neurons
+GPT-4o-mini,dale's law
+GPT-4o-mini,cortical circuits
+GPT-4o-mini,monkeys
+GPT-4o-mini,rhesus monkeys
+GPT-4o-mini,suppression mechanism
+GPT-4o-mini,recurrent connectivity wrec
+GPT-4o-mini,principal component analysis
+GPT-4o-mini,motion context
+GPT-4o-mini,embedding matrix q
+GPT-4o-mini,color axis
+GPT-4o-mini,neural population activity
+GPT-4o-mini,context-dependent decision-making task
+GPT-4o-mini,relu
+GPT-4o-mini,softplus activation function
+GPT-4o-mini,context nodes
+GPT-4o-mini,color coherence
+GPT-4o-mini,pfc
+GPT-4o-mini,sensory motion nodes
+GPT-4o-mini,latent circuit model
+GPT-4o-mini,inhibitory mechanism
+GPT-4o-mini,excitatory neurons
+GPT-4o-mini,decision-making
+GPT-4o-mini,sensory stimulus
+GPT-4o-mini,higher cortical areas
+GPT-4o-mini,psychometric functions
+GPT-4o-mini,princeton neuroscience institute
+GPT-4o-mini,mann–whitney u-test
+GPT-4o-mini,error trials
+GPT-4o-mini,low-dimensional circuit mechanism
+DeepSeek V3 0324,choice axis
+DeepSeek V3 0324,task variables
+DeepSeek V3 0324,context axis
+DeepSeek V3 0324,sensory color nodes
+DeepSeek V3 0324,motion axis
+DeepSeek V3 0324,correct trials
+DeepSeek V3 0324,macaque monkeys
+DeepSeek V3 0324,choice nodes
+DeepSeek V3 0324,monkey a
+DeepSeek V3 0324,linear decoder
+DeepSeek V3 0324,color context
+DeepSeek V3 0324,recurrent neural network
+DeepSeek V3 0324,motion coherence
+DeepSeek V3 0324,context cue
+DeepSeek V3 0324,rectified linear (relu) activation function
+DeepSeek V3 0324,input connectivity win
+DeepSeek V3 0324,monkey f
+DeepSeek V3 0324,single neurons
+DeepSeek V3 0324,incongruent trials
+DeepSeek V3 0324,recurrent neural networks
+DeepSeek V3 0324,dale's law
+DeepSeek V3 0324,cortical circuits
+DeepSeek V3 0324,monkeys
+DeepSeek V3 0324,suppression mechanism
+DeepSeek V3 0324,premotor cortex
+DeepSeek V3 0324,recurrent connectivity wrec
+DeepSeek V3 0324,principal component analysis
+DeepSeek V3 0324,motion context
+DeepSeek V3 0324,embedding matrix q
+DeepSeek V3 0324,color axis
+DeepSeek V3 0324,neural population activity
+DeepSeek V3 0324,context-dependent decision-making task
+DeepSeek V3 0324,softplus activation function
+DeepSeek V3 0324,context nodes
+DeepSeek V3 0324,dimensionality reduction
+DeepSeek V3 0324,color coherence
+DeepSeek V3 0324,sensory motion nodes
+DeepSeek V3 0324,inhibitory mechanism
+DeepSeek V3 0324,sensory stimulus
+DeepSeek V3 0324,higher cortical areas
+DeepSeek V3 0324,psychometric functions
+DeepSeek V3 0324,mann–whitney u-test
+DeepSeek V3 0324,error trials
+DeepSeek V3 0324,low-dimensional circuit mechanism
+Claude 3.7 Sonnet,christopher langdon
+Claude 3.7 Sonnet,task variables
+Claude 3.7 Sonnet,decision-making
+Claude 3.7 Sonnet,recurrent neural networks
+Claude 3.7 Sonnet,tatiana a. engel
+Claude 3.7 Sonnet,relu
+Claude 3.7 Sonnet,nature neuroscience
+Claude 3.7 Sonnet,macaque monkeys
+Claude 3.7 Sonnet,premotor cortex
diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/missed_entities_details_without_hil.csv b/evaluation/ner/old/evaluation/Latent-circuit/results/missed_entities_details_without_hil.csv
new file mode 100644
index 0000000..52e3186
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Latent-circuit/results/missed_entities_details_without_hil.csv
@@ -0,0 +1,64 @@
+Model,Missed Entity
+DeepSeek V3 0324,dynamical selection vector mechanism
+DeepSeek V3 0324,tatiana a. engel
+DeepSeek V3 0324,selection vector mechanism
+DeepSeek V3 0324,monkey a
+DeepSeek V3 0324,softplus
+DeepSeek V3 0324,neurons
+DeepSeek V3 0324,color context
+DeepSeek V3 0324,recurrent neural network
+DeepSeek V3 0324,psychometric function
+DeepSeek V3 0324,s41593-025-01869-7
+DeepSeek V3 0324,monkey f
+DeepSeek V3 0324,incongruent trials
+DeepSeek V3 0324,rectified linear
+DeepSeek V3 0324,dale's law
+DeepSeek V3 0324,cortical circuits
+DeepSeek V3 0324,monkeys
+DeepSeek V3 0324,suppression mechanism
+DeepSeek V3 0324,motion context
+DeepSeek V3 0324,christopher langdon
+DeepSeek V3 0324,context-dependent selection mechanism
+DeepSeek V3 0324,nature neuroscience
+DeepSeek V3 0324,dimensionality reduction
+DeepSeek V3 0324,pfc
+DeepSeek V3 0324,orthonormal embedding matrix
+DeepSeek V3 0324,higher cortical areas
+DeepSeek V3 0324,dimensionality reduction methods
+DeepSeek V3 0324,cognitive functions
+DeepSeek V3 0324,inhibition of irrelevant sensory representations
+Claude 3.7 Sonnet,s41593-025-01869-7
+Claude 3.7 Sonnet,pytorch
+Claude 3.7 Sonnet,tatiana a. engel
+Claude 3.7 Sonnet,nature neuroscience
+Claude 3.7 Sonnet,cognitive functions
+Claude 3.7 Sonnet,dimensionality reduction methods
+Claude 3.7 Sonnet,adam optimizer
+Claude 3.7 Sonnet,christopher langdon
+GPT-4o-mini,dynamical selection vector mechanism
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+GPT-4o-mini,softplus
+GPT-4o-mini,color context
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+GPT-4o-mini,psychometric function
+GPT-4o-mini,monkey f
+GPT-4o-mini,incongruent trials
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+GPT-4o-mini,inhibitory neurons
+GPT-4o-mini,rectified linear
+GPT-4o-mini,dale's law
+GPT-4o-mini,cortical circuits
+GPT-4o-mini,rhesus monkeys
+GPT-4o-mini,suppression mechanism
+GPT-4o-mini,motion context
+GPT-4o-mini,context-dependent selection mechanism
+GPT-4o-mini,context-dependent decision-making task
+GPT-4o-mini,relu
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+GPT-4o-mini,pfc
+GPT-4o-mini,orthonormal embedding matrix
+GPT-4o-mini,excitatory neurons
+GPT-4o-mini,rnn
+GPT-4o-mini,inhibition of irrelevant sensory representations
diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/model_rankings.csv b/evaluation/ner/old/evaluation/Latent-circuit/results/model_rankings.csv
new file mode 100644
index 0000000..ffbd941
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Latent-circuit/results/model_rankings.csv
@@ -0,0 +1,7 @@
+Group,Model,Composite_Score,Rank
+with_hil,Claude 3.7 Sonnet,90.69350660812329,1
+with_hil,DeepSeek V3 0324,70.75424486951144,2
+with_hil,GPT-4o-mini,57.095060901455064,3
+without_hil,Claude 3.7 Sonnet,87.12202914960487,1
+without_hil,GPT-4o-mini,59.381755633168645,2
+without_hil,DeepSeek V3 0324,51.99559722537063,3
diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/model_rankings_visual.pdf b/evaluation/ner/old/evaluation/Latent-circuit/results/model_rankings_visual.pdf
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index 0000000..5b19374
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diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/ontology_coverage_summary.csv b/evaluation/ner/old/evaluation/Latent-circuit/results/ontology_coverage_summary.csv
new file mode 100644
index 0000000..05c1dd2
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Latent-circuit/results/ontology_coverage_summary.csv
@@ -0,0 +1,7 @@
+Group,Model,Total Entities,Complete (ID & Label),Complete %,ID Only,Label Only,Neither,Any Ontology Info,Any Ontology %
+with_hil,GPT-4o-mini,9,5,55.6%,0,0,4,5,55.6%
+with_hil,DeepSeek V3 0324,15,13,86.7%,0,0,2,13,86.7%
+with_hil,Claude 3.7 Sonnet,50,50,100.0%,0,0,0,50,100.0%
+without_hil,DeepSeek V3 0324,10,4,40.0%,0,0,6,4,40.0%
+without_hil,Claude 3.7 Sonnet,30,29,96.7%,0,0,1,29,96.7%
+without_hil,GPT-4o-mini,11,5,45.5%,0,0,6,5,45.5%
diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/ontology_coverage_with_hil.pdf b/evaluation/ner/old/evaluation/Latent-circuit/results/ontology_coverage_with_hil.pdf
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diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/ontology_hil_comparison.pdf b/evaluation/ner/old/evaluation/Latent-circuit/results/ontology_hil_comparison.pdf
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diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/ontology_success_rate_with_hil.pdf b/evaluation/ner/old/evaluation/Latent-circuit/results/ontology_success_rate_with_hil.pdf
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diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/ontology_success_rate_without_hil.pdf b/evaluation/ner/old/evaluation/Latent-circuit/results/ontology_success_rate_without_hil.pdf
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diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/performance_dashboard.pdf b/evaluation/ner/old/evaluation/Latent-circuit/results/performance_dashboard.pdf
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index 0000000..febcd06
Binary files /dev/null and b/evaluation/ner/old/evaluation/Latent-circuit/results/performance_dashboard.pdf differ
diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/shared_entities_all_models_with_hil.csv b/evaluation/ner/old/evaluation/Latent-circuit/results/shared_entities_all_models_with_hil.csv
new file mode 100644
index 0000000..8811e7c
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Latent-circuit/results/shared_entities_all_models_with_hil.csv
@@ -0,0 +1,2 @@
+Shared Entity
+prefrontal cortex
diff --git a/evaluation/ner/old/evaluation/Latent-circuit/results/shared_entities_all_models_without_hil.csv b/evaluation/ner/old/evaluation/Latent-circuit/results/shared_entities_all_models_without_hil.csv
new file mode 100644
index 0000000..66cf6e5
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Latent-circuit/results/shared_entities_all_models_without_hil.csv
@@ -0,0 +1,3 @@
+Shared Entity
+prefrontal cortex
+latent circuit model
diff --git a/evaluation/ner/old/evaluation/Latent-circuit/with_hil/ner_config_claudesonet_s41593-025-01869-7_with_hil.json b/evaluation/ner/old/evaluation/Latent-circuit/with_hil/ner_config_claudesonet_s41593-025-01869-7_with_hil.json
new file mode 100644
index 0000000..944b667
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Latent-circuit/with_hil/ner_config_claudesonet_s41593-025-01869-7_with_hil.json
@@ -0,0 +1,2071 @@
+{
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+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
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+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
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+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
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+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
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+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
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+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
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+            "https://doi.org/10.1038/s41593-025-01869-7"
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+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
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+            "results",
+            "results",
+            "results"
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+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
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+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7",
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+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
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+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
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+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
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+            "https://doi.org/10.1038/s41593-025-01869-7"
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+          "ontology_id": "CL:0008030",
+          "ontology_label": "excitatory neuron",
+          "sentence": [
+            "These computations result from interactions between excitatory and inhibitory neurons in cortical circuits"
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+            "Aligned to CL:0008030 (excitatory neuron)",
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+            "Cell type mentioned in the context of cortical computations",
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+            "The extraction is appropriate as it identifies another relevant cell type in neural computations"
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+          "ontology_id": "CL:0000540",
+          "ontology_label": "neuron",
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+            "Single  neurons  in  areas  such  as  the  prefrontal  cortex  (PFC) show complex heterogeneous tuning to multiple task variables",
+            "Single neurons in higher cortical areas show complex heterogeneous responses during cognitive tasks, posing a challenge for identifying mechanisms of cognitive functions"
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+            1.0
+          ],
+          "paper_location": [
+            "introduction",
+            "discussion"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "16": [
+        {
+          "entity": "higher cortical areas",
+          "label": "ANATOMICAL_REGION",
+          "ontology_id": "UBERON:0000955",
+          "ontology_label": "cerebral cortex",
+          "sentence": [
+            "Higher cortical areas carry a wide range of sensory, cognitive and motor signals mixed in heterogeneous responses of single neurons tuned to multiple task variables",
+            "Cognitive functions depend on higher cortical areas, which integrate diverse sensory and contextual signals to produce a coherent behavioral response"
+          ],
+          "start": [
+            0,
+            28
+          ],
+          "end": [
+            22,
+            50
+          ],
+          "remarks": [
+            "Broad anatomical region discussed in the paper",
+            "Aligned to UBERON:0000955 (cerebral cortex) as the most appropriate anatomical term",
+            "Good alignment to the general cortical tissue category, though 'higher cortical areas' refers specifically to hierarchically advanced regions which could have had a more specific term if available",
+            "The extraction count is appropriate as higher cortical areas are the general focus of the study"
+          ],
+          "judge_score": [
+            0.8,
+            0.8
+          ],
+          "paper_location": [
+            "abstract",
+            "introduction"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "17": [
+        {
+          "entity": "cortical circuits",
+          "label": "ANATOMICAL_STRUCTURE",
+          "ontology_id": "UBERON:0001851",
+          "ontology_label": "cortical neural circuit",
+          "sentence": [
+            "These computations result from interactions between excitatory and inhibitory neurons in cortical circuits"
+          ],
+          "start": [
+            95
+          ],
+          "end": [
+            112
+          ],
+          "remarks": [
+            "Neural circuit structure discussed in the paper",
+            "Aligned to UBERON:0001851 (cortical neural circuit)",
+            "Perfect alignment to the appropriate neural circuit ontology term",
+            "The extraction is appropriate as it identifies the anatomical structure being studied"
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "paper_location": [
+            "introduction"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "18": [
+        {
+          "entity": "rectified linear (ReLU) activation function",
+          "label": "COMPUTATIONAL_COMPONENT",
+          "ontology_id": "OMICS:0001923",
+          "ontology_label": "activation function",
+          "sentence": [
+            "where f is a rectified linear (ReLU) activation function"
+          ],
+          "start": [
+            9
+          ],
+          "end": [
+            50
+          ],
+          "remarks": [
+            "Specific computational component used in the neural model",
+            "Aligned to OMICS:0001923 (activation function)",
+            "Good general alignment to activation function category, though a more specific ReLU function term would be ideal if available",
+            "The extraction is appropriate as it identifies a specific function used in the RNN models"
+          ],
+          "judge_score": [
+            0.9
+          ],
+          "paper_location": [
+            "methods"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "19": [
+        {
+          "entity": "Softplus activation function",
+          "label": "COMPUTATIONAL_COMPONENT",
+          "ontology_id": "OMICS:0001923",
+          "ontology_label": "activation function",
+          "sentence": [
+            "To test whether our results extend to networks with a different biologically plausible nonlinearity, we trained RNNs that had a Softplus activation function"
+          ],
+          "start": [
+            127
+          ],
+          "end": [
+            155
+          ],
+          "remarks": [
+            "Alternative activation function mentioned in the paper",
+            "Aligned to OMICS:0001923 (activation function)",
+            "Good general alignment to activation function category, though a more specific Softplus function term would be ideal if available",
+            "The extraction is appropriate as it identifies an alternative function tested in the RNN models"
+          ],
+          "judge_score": [
+            0.9
+          ],
+          "paper_location": [
+            "methods"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "20": [
+        {
+          "entity": "context-dependent decision-making",
+          "label": "COGNITIVE_PROCESS",
+          "ontology_id": "GO:0007611",
+          "ontology_label": "learning or memory",
+          "sentence": [
+            "Context-dependent decision-making requires flexible trial-by-trial switching between alternative stimulus\u2013response mappings",
+            "The latent circuit model revealed a suppression of irrelevant sensory representations in PFC responses of monkeys performing a context-dependent decision-making task"
+          ],
+          "start": [
+            0,
+            119
+          ],
+          "end": [
+            35,
+            154
+          ],
+          "remarks": [
+            "Cognitive process studied in the paper",
+            "Aligned to GO:0007611 (learning or memory) as a general cognitive process category",
+            "Somewhat broad alignment as decision-making is related to but distinct from learning/memory; a more specific cognitive decision-making term would be preferable if available",
+            "The extraction count is appropriate as this cognitive process is central to the study"
+          ],
+          "judge_score": [
+            0.7,
+            0.7
+          ],
+          "paper_location": [
+            "results",
+            "discussion"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "21": [
+        {
+          "entity": "suppression mechanism",
+          "label": "NEURAL_MECHANISM",
+          "ontology_id": "GO:0050794",
+          "ontology_label": "regulation of cellular process",
+          "sentence": [
+            "We applied latent circuit inference to RNNs optimized on a context-dependent decision-making task and found a circuit mechanism based on the inhibition of irrelevant sensory representations",
+            "This pattern of connections from the context nodes to the sensory nodes implements a suppression mechanism that inhibits the irrelevant stimulus\u2013response mapping in each context"
+          ],
+          "start": [
+            127,
+            112
+          ],
+          "end": [
+            167,
+            135
+          ],
+          "remarks": [
+            "Neural mechanism identified by the model",
+            "Aligned to GO:0050794 (regulation of cellular process) as an appropriate biological process term",
+            "Reasonable alignment to a general cellular process regulation term, though a more specific neural inhibition/suppression term would be preferable if available",
+            "The extraction count is appropriate as this mechanism is a key finding of the study"
+          ],
+          "judge_score": [
+            0.8,
+            0.8
+          ],
+          "paper_location": [
+            "abstract",
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "22": [
+        {
+          "entity": "inhibitory mechanism",
+          "label": "NEURAL_MECHANISM",
+          "ontology_id": "GO:0050794",
+          "ontology_label": "regulation of cellular process",
+          "sentence": [
+            "We found that RNNs trained on a context-dependent decision-making task use a suppression mechanism in which context nodes inhibit irrelevant sensory nodes",
+            "The inhibitory suppression mechanism revealed by the latent circuit model is qualitatively similar to previous neural circuit models"
+          ],
+          "start": [
+            95,
+            4
+          ],
+          "end": [
+            156,
+            33
+          ],
+          "remarks": [
+            "Neural mechanism type identified in the study",
+            "Aligned to GO:0050794 (regulation of cellular process) as an appropriate biological process term",
+            "Reasonable alignment to a general cellular process regulation term, though a more specific neural inhibition term would be preferable if available",
+            "The extraction count is appropriate as this describes the same mechanism with different terminology"
+          ],
+          "judge_score": [
+            0.8,
+            0.8
+          ],
+          "paper_location": [
+            "discussion",
+            "discussion"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "23": [
+        {
+          "entity": "dimensionality reduction",
+          "label": "COMPUTATIONAL_METHOD",
+          "ontology_id": "EDAM:0000598",
+          "ontology_label": "dimensionality reduction",
+          "sentence": [
+            "We develop the latent circuit model, a dimensionality reduction approach in which task variables interact via low-dimensional recurrent connectivity",
+            "Dimensionality reduction methods that rely on correlations between neural activity and task variables leave unknown how heterogeneous responses arise from connectivity to drive behavior"
+          ],
+          "start": [
+            33,
+            0
+          ],
+          "end": [
+            57,
+            30
+          ],
+          "remarks": [
+            "Computational methodology central to the paper",
+            "Aligned to EDAM:0000598 (dimensionality reduction)",
+            "Perfect alignment to the exact computational method term",
+            "The extraction count is appropriate as dimensionality reduction is a key methodological approach"
+          ],
+          "judge_score": [
+            1.0,
+            1.0
+          ],
+          "paper_location": [
+            "abstract",
+            "introduction"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "24": [
+        {
+          "entity": "low-dimensional circuit mechanism",
+          "label": "NEURAL_MECHANISM",
+          "ontology_id": "GO:0050794",
+          "ontology_label": "regulation of cellular process",
+          "sentence": [
+            "Our results show that high-dimensional networks use low-dimensional circuit mechanisms, establish the feasibility of inferring these mechanisms from neural response data",
+            "The model simultaneously infers a low-dimensional latent circuit connectivity generating task-relevant dynamics and heterogeneous mixing of these dynamics in single-neuron responses"
+          ],
+          "start": [
+            56,
+            32
+          ],
+          "end": [
+            90,
+            66
+          ],
+          "remarks": [
+            "Key conceptual finding of the study",
+            "Aligned to GO:0050794 (regulation of cellular process) as an appropriate biological process term",
+            "Broad alignment to cellular process regulation; this is a novel mechanistic description that may not have a perfect ontological match",
+            "The extraction count is appropriate as this describes the core conceptual contribution of the paper"
+          ],
+          "judge_score": [
+            0.7,
+            0.7
+          ],
+          "paper_location": [
+            "abstract",
+            "abstract"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "25": [
+        {
+          "entity": "error trials",
+          "label": "EXPERIMENTAL_CONDITION",
+          "ontology_id": "ERO:0000006",
+          "ontology_label": "behavioral task",
+          "sentence": [
+            "we can test the inhibitory suppression mechanism using neural activity on error trials",
+            "in both contexts for both monkeys, the irrelevant representations were significantly less suppressed on error than correct trials"
+          ],
+          "start": [
+            67,
+            123
+          ],
+          "end": [
+            79,
+            135
+          ],
+          "remarks": [
+            "Specific experimental condition analyzed in the study",
+            "Aligned to ERO:0000006 (behavioral task) as a specific condition within the task paradigm",
+            "Reasonable broad alignment to behavioral task, though a more specific error condition term would be preferable if available",
+            "The extraction count is appropriate as error trials represent a specific condition being analyzed"
+          ],
+          "judge_score": [
+            0.8,
+            0.8
+          ],
+          "paper_location": [
+            "results",
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "26": [
+        {
+          "entity": "correct trials",
+          "label": "EXPERIMENTAL_CONDITION",
+          "ontology_id": "ERO:0000006",
+          "ontology_label": "behavioral task",
+          "sentence": [
+            "We fitted the latent circuit model to trial-averaged neural responses on correct trials",
+            "in both contexts for both monkeys, the irrelevant representations were significantly less suppressed on error than correct trials"
+          ],
+          "start": [
+            65,
+            138
+          ],
+          "end": [
+            79,
+            152
+          ],
+          "remarks": [
+            "Specific experimental condition analyzed in the study",
+            "Aligned to ERO:0000006 (behavioral task) as a specific condition within the task paradigm",
+            "Reasonable broad alignment to behavioral task, though a more specific correct performance condition term would be preferable if available",
+            "The extraction count is appropriate as correct trials represent the contrasting condition to error trials"
+          ],
+          "judge_score": [
+            0.8,
+            0.8
+          ],
+          "paper_location": [
+            "methods",
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "27": [
+        {
+          "entity": "incongruent trials",
+          "label": "EXPERIMENTAL_CONDITION",
+          "ontology_id": "ERO:0000006",
+          "ontology_label": "behavioral task",
+          "sentence": [
+            "We tested this prediction on incongruent trials on which the relevant and irrelevant stimuli point to opposite choices"
+          ],
+          "start": [
+            30
+          ],
+          "end": [
+            48
+          ],
+          "remarks": [
+            "Specific experimental condition analyzed in the study",
+            "Aligned to ERO:0000006 (behavioral task) as a specific condition within the task paradigm",
+            "Reasonable broad alignment to behavioral task, though a more specific stimulus congruency condition term would be preferable if available",
+            "The extraction is appropriate as incongruent trials represent another specific condition being analyzed"
+          ],
+          "judge_score": [
+            0.8
+          ],
+          "paper_location": [
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "28": [
+        {
+          "entity": "context cue",
+          "label": "STIMULUS_TYPE",
+          "ontology_id": "OMICS:0000433",
+          "ontology_label": "sensory stimulus",
+          "sentence": [
+            "A context cue then briefly appears to indicate either the color or motion context for the current trial",
+            "After a short delay (delay), a sensory stimulus appears that consists of motion and color features"
+          ],
+          "start": [
+            2,
+            31
+          ],
+          "end": [
+            13,
+            47
+          ],
+          "remarks": [
+            "Stimulus type used in the experimental paradigm",
+            "Aligned to OMICS:0000433 (sensory stimulus)",
+            "Appropriate classification as a sensory stimulus, though a more specific contextual cue term would be preferable if available",
+            "The extraction count is appropriate as context cues are part of the experimental procedure"
+          ],
+          "judge_score": [
+            0.8,
+            0.8
+          ],
+          "paper_location": [
+            "methods",
+            "methods"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "29": [
+        {
+          "entity": "sensory stimulus",
+          "label": "STIMULUS_TYPE",
+          "ontology_id": "OMICS:0000433",
+          "ontology_label": "sensory stimulus",
+          "sentence": [
+            "After a short delay (delay), a sensory stimulus appears that consists of motion and color features"
+          ],
+          "start": [
+            31
+          ],
+          "end": [
+            47
+          ],
+          "remarks": [
+            "Stimulus type used in the experimental paradigm",
+            "Aligned to OMICS:0000433 (sensory stimulus)",
+            "Perfect alignment to the exact stimulus type term",
+            "The extraction is appropriate as sensory stimuli are key components of the experimental design"
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "paper_location": [
+            "methods"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "30": [
+        {
+          "entity": "motion context",
+          "label": "EXPERIMENTAL_CONDITION",
+          "ontology_id": "ERO:0000006",
+          "ontology_label": "behavioral task",
+          "sentence": [
+            "A context cue then briefly appears to indicate either the color or motion context for the current trial",
+            "In the color context, the choice should be made according to the color and ignoring the motion stimulus and vice versa in the motion context"
+          ],
+          "start": [
+            63,
+            128
+          ],
+          "end": [
+            77,
+            142
+          ],
+          "remarks": [
+            "Experimental condition in the context-dependent decision-making task",
+            "Aligned to ERO:0000006 (behavioral task) as a specific condition within the task paradigm",
+            "Reasonable broad alignment to behavioral task, though a more specific context condition term would be preferable if available",
+            "The extraction count is appropriate as motion context is one of the two key task conditions"
+          ],
+          "judge_score": [
+            0.8,
+            0.8
+          ],
+          "paper_location": [
+            "methods",
+            "methods"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "31": [
+        {
+          "entity": "color context",
+          "label": "EXPERIMENTAL_CONDITION",
+          "ontology_id": "ERO:0000006",
+          "ontology_label": "behavioral task",
+          "sentence": [
+            "A context cue then briefly appears to indicate either the color or motion context for the current trial",
+            "In the color context, the choice should be made according to the color and ignoring the motion stimulus and vice versa in the motion context"
+          ],
+          "start": [
+            53,
+            7
+          ],
+          "end": [
+            65,
+            19
+          ],
+          "remarks": [
+            "Experimental condition in the context-dependent decision-making task",
+            "Aligned to ERO:0000006 (behavioral task) as a specific condition within the task paradigm",
+            "Reasonable broad alignment to behavioral task, though a more specific context condition term would be preferable if available",
+            "The extraction count is appropriate as color context is the other key task condition"
+          ],
+          "judge_score": [
+            0.8,
+            0.8
+          ],
+          "paper_location": [
+            "methods",
+            "methods"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "32": [
+        {
+          "entity": "color coherence",
+          "label": "STIMULUS_PROPERTY",
+          "ontology_id": "OMICS:0000433",
+          "ontology_label": "sensory stimulus",
+          "sentence": [
+            "The strength of motion and color stimuli varies from trial to trial as quantified by the motion and color coherence",
+            "We use motion coherence mc and color coherence cc ranging from \u22120.2 to 0.2"
+          ],
+          "start": [
+            78,
+            35
+          ],
+          "end": [
+            93,
+            50
+          ],
+          "remarks": [
+            "Stimulus property manipulated in the experimental paradigm",
+            "Aligned to OMICS:0000433 (sensory stimulus) as a property of sensory stimuli",
+            "Partial alignment, as this is a property of a stimulus rather than the stimulus itself; a more specific stimulus coherence property term would be preferable if available",
+            "The extraction count is appropriate as color coherence is one of the two primary stimulus properties varied"
+          ],
+          "judge_score": [
+            0.7,
+            0.7
+          ],
+          "paper_location": [
+            "methods",
+            "methods"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "33": [
+        {
+          "entity": "motion coherence",
+          "label": "STIMULUS_PROPERTY",
+          "ontology_id": "OMICS:0000433",
+          "ontology_label": "sensory stimulus",
+          "sentence": [
+            "The strength of motion and color stimuli varies from trial to trial as quantified by the motion and color coherence",
+            "We use motion coherence mc and color coherence cc ranging from \u22120.2 to 0.2"
+          ],
+          "start": [
+            61,
+            9
+          ],
+          "end": [
+            76,
+            24
+          ],
+          "remarks": [
+            "Stimulus property manipulated in the experimental paradigm",
+            "Aligned to OMICS:0000433 (sensory stimulus) as a property of sensory stimuli",
+            "Partial alignment, as this is a property of a stimulus rather than the stimulus itself; a more specific stimulus coherence property term would be preferable if available",
+            "The extraction count is appropriate as motion coherence is the other primary stimulus property varied"
+          ],
+          "judge_score": [
+            0.7,
+            0.7
+          ],
+          "paper_location": [
+            "methods",
+            "methods"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "34": [
+        {
+          "entity": "neural population activity",
+          "label": "NEURAL_ACTIVITY_MEASURE",
+          "ontology_id": "OMICS:0000085",
+          "ontology_label": "neural activity",
+          "sentence": [
+            "Accordingly, dimensionality reduction methods are commonly used to reveal representations of low-dimensional latent variables in neural population activity",
+            "Although single-neuron responses are complex and heterogeneous, their joint population activity is often low dimensional across many cognitive tasks and brain areas"
+          ],
+          "start": [
+            138,
+            64
+          ],
+          "end": [
+            164,
+            90
+          ],
+          "remarks": [
+            "Neural activity measurement type discussed in the paper",
+            "Aligned to OMICS:0000085 (neural activity)",
+            "Good alignment to general neural activity term, though a more specific population-level activity term would be preferable if available",
+            "The extraction count is appropriate as neural population activity is the primary measurement analyzed"
+          ],
+          "judge_score": [
+            0.9,
+            0.9
+          ],
+          "paper_location": [
+            "introduction",
+            "introduction"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "35": [
+        {
+          "entity": "Mann\u2013Whitney U-test",
+          "label": "STATISTICAL_METHOD",
+          "ontology_id": "STATO:0000076",
+          "ontology_label": "Mann-Whitney U test",
+          "sentence": [
+            "one-sided Mann\u2013Whitney U-test; monkey A: motion P = 1.4 \u00d7 10^-9 and U = 120, color P = 10^-10 and U = 83",
+            "These latent models produced a significantly worse fit when the latent circuit and the target RNN were sampled from different clusters than from the same cluster (Extended Data Fig. 2m; one-sided Mann\u2013Whitney U-test, U = 52, 593, P < 10^-10)"
+          ],
+          "start": [
+            11,
+            240
+          ],
+          "end": [
+            28,
+            257
+          ],
+          "remarks": [
+            "Statistical test used in the analyses",
+            "Aligned to STATO:0000076 (Mann-Whitney U test)",
+            "Perfect alignment to the exact statistical test",
+            "The extraction count is appropriate as this statistical test was used in multiple analyses"
+          ],
+          "judge_score": [
+            1.0,
+            1.0
+          ],
+          "paper_location": [
+            "results",
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "36": [
+        {
+          "entity": "principal component analysis",
+          "label": "STATISTICAL_METHOD",
+          "ontology_id": "STATO:0000030",
+          "ontology_label": "principal component analysis",
+          "sentence": [
+            "To visualize the space of latent circuit solutions, we applied a principal component analysis to the flattened connectivity matrices wrec"
+          ],
+          "start": [
+            65
+          ],
+          "end": [
+            94
+          ],
+          "remarks": [
+            "Statistical method used for dimensionality reduction",
+            "Aligned to STATO:0000030 (principal component analysis)",
+            "Perfect alignment to the exact statistical method",
+            "The extraction is appropriate as PCA was used for analysis of model solutions"
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "paper_location": [
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "37": [
+        {
+          "entity": "linear decoder",
+          "label": "COMPUTATIONAL_METHOD",
+          "ontology_id": "OMICS:0000090",
+          "ontology_label": "modeling and simulation technique",
+          "sentence": [
+            "We compared projections of RNN activity onto axes obtained from the latent circuit model and a linear decoder",
+            "We trained a linear decoder to predict the signed motion coherence on each trial from RNN activity"
+          ],
+          "start": [
+            99,
+            15
+          ],
+          "end": [
+            112,
+            28
+          ],
+          "remarks": [
+            "Computational method used for comparison with the latent circuit model",
+            "Aligned to OMICS:0000090 (modeling and simulation technique)",
+            "Reasonable alignment to general computational modeling technique, though a more specific decoding algorithm term would be preferable if available",
+            "The extraction count is appropriate as linear decoders were used as comparison methods"
+          ],
+          "judge_score": [
+            0.8,
+            0.8
+          ],
+          "paper_location": [
+            "results",
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "38": [
+        {
+          "entity": "embedding matrix Q",
+          "label": "COMPUTATIONAL_COMPONENT",
+          "ontology_id": "OMICS:0000132",
+          "ontology_label": "matrix",
+          "sentence": [
+            "where Q\u2208\u211dN\u00d7n is an orthonormal embedding matrix and n \u226a N",
+            "The latent circuit model provided good fits of PFC responses projected onto the low-dimensional subspace spanned by the columns of the inferred embedding matrix Q for both monkeys"
+          ],
+          "start": [
+            6,
+            157
+          ],
+          "end": [
+            21,
+            174
+          ],
+          "remarks": [
+            "Mathematical component of the latent circuit model",
+            "Aligned to OMICS:0000132 (matrix)",
+            "Appropriate alignment to the mathematical matrix concept, though a more specific embedding matrix term would be ideal if available",
+            "The extraction count is appropriate as the embedding matrix Q is a key component of the model"
+          ],
+          "judge_score": [
+            0.9,
+            0.9
+          ],
+          "paper_location": [
+            "results",
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "39": [
+        {
+          "entity": "recurrent connectivity wrec",
+          "label": "CONNECTIVITY_MEASURE",
+          "ontology_id": "OMICS:0000141",
+          "ontology_label": "connectivity",
+          "sentence": [
+            "The latent nodes interact via the recurrent connectivity wrec and receive external task inputs u through the input connectivity win",
+            "The inferred recurrent connectivity wrec of the latent circuit revealed an interpretable mechanism for context-dependent decision-making"
+          ],
+          "start": [
+            41,
+            27
+          ],
+          "end": [
+            62,
+            48
+          ],
+          "remarks": [
+            "Connectivity parameter in the latent circuit model",
+            "Aligned to OMICS:0000141 (connectivity)",
+            "Good alignment to the general connectivity concept, though a more specific recurrent neural connectivity term would be preferable if available",
+            "The extraction count is appropriate as recurrent connectivity is a key parameter in the model"
+          ],
+          "judge_score": [
+            0.9,
+            0.9
+          ],
+          "paper_location": [
+            "results",
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "40": [
+        {
+          "entity": "input connectivity win",
+          "label": "CONNECTIVITY_MEASURE",
+          "ontology_id": "OMICS:0000141",
+          "ontology_label": "connectivity",
+          "sentence": [
+            "The latent nodes interact via the recurrent connectivity wrec and receive external task inputs u through the input connectivity win"
+          ],
+          "start": [
+            107
+          ],
+          "end": [
+            126
+          ],
+          "remarks": [
+            "Connectivity parameter in the latent circuit model",
+            "Aligned to OMICS:0000141 (connectivity)",
+            "Good alignment to the general connectivity concept, though a more specific input neural connectivity term would be preferable if available",
+            "The extraction is appropriate as input connectivity is another key parameter in the model"
+          ],
+          "judge_score": [
+            0.9
+          ],
+          "paper_location": [
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "41": [
+        {
+          "entity": "context nodes",
+          "label": "MODEL_COMPONENT",
+          "ontology_id": "SBO:0000290",
+          "ontology_label": "physical compartment",
+          "sentence": [
+            "The latent circuit model consisted of eight nodes corresponding to task variables: two context nodes, two sensory color nodes, two sensory motion nodes and two choice nodes",
+            "Further, the color context node has inhibitory connections to the sensory nodes representing motion, and the motion context node has inhibitory connections to sensory nodes representing color"
+          ],
+          "start": [
+            80,
+            18
+          ],
+          "end": [
+            93,
+            31
+          ],
+          "remarks": [
+            "Node type in the latent circuit model",
+            "Aligned to SBO:0000290 (physical compartment) as a model component representing a computational unit",
+            "Somewhat broad alignment to a general model compartment, though the node is a computational unit rather than a physical one; a more specific neural network node term would be preferable if available",
+            "The extraction count is appropriate as context nodes are a major component type in the model"
+          ],
+          "judge_score": [
+            0.7,
+            0.7
+          ],
+          "paper_location": [
+            "results",
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "42": [
+        {
+          "entity": "sensory color nodes",
+          "label": "MODEL_COMPONENT",
+          "ontology_id": "SBO:0000290",
+          "ontology_label": "physical compartment",
+          "sentence": [
+            "The latent circuit model consisted of eight nodes corresponding to task variables: two context nodes, two sensory color nodes, two sensory motion nodes and two choice nodes"
+          ],
+          "start": [
+            105
+          ],
+          "end": [
+            125
+          ],
+          "remarks": [
+            "Node type in the latent circuit model",
+            "Aligned to SBO:0000290 (physical compartment) as a model component representing a computational unit",
+            "Somewhat broad alignment to a general model compartment, though the node is a computational unit rather than a physical one; a more specific neural network node term would be preferable if available",
+            "The extraction is appropriate as sensory color nodes are another component type in the model"
+          ],
+          "judge_score": [
+            0.7
+          ],
+          "paper_location": [
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "43": [
+        {
+          "entity": "sensory motion nodes",
+          "label": "MODEL_COMPONENT",
+          "ontology_id": "SBO:0000290",
+          "ontology_label": "physical compartment",
+          "sentence": [
+            "The latent circuit model consisted of eight nodes corresponding to task variables: two context nodes, two sensory color nodes, two sensory motion nodes and two choice nodes"
+          ],
+          "start": [
+            127
+          ],
+          "end": [
+            148
+          ],
+          "remarks": [
+            "Node type in the latent circuit model",
+            "Aligned to SBO:0000290 (physical compartment) as a model component representing a computational unit",
+            "Somewhat broad alignment to a general model compartment, though the node is a computational unit rather than a physical one; a more specific neural network node term would be preferable if available",
+            "The extraction is appropriate as sensory motion nodes are another component type in the model"
+          ],
+          "judge_score": [
+            0.7
+          ],
+          "paper_location": [
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "44": [
+        {
+          "entity": "choice nodes",
+          "label": "MODEL_COMPONENT",
+          "ontology_id": "SBO:0000290",
+          "ontology_label": "physical compartment",
+          "sentence": [
+            "The latent circuit model consisted of eight nodes corresponding to task variables: two context nodes, two sensory color nodes, two sensory motion nodes and two choice nodes",
+            "In the latent circuit, sensory nodes representing stimuli associated with the left choice (left motion and green color) have excitatory connections to the left choice node"
+          ],
+          "start": [
+            153,
+            181
+          ],
+          "end": [
+            164,
+            197
+          ],
+          "remarks": [
+            "Node type in the latent circuit model",
+            "Aligned to SBO:0000290 (physical compartment) as a model component representing a computational unit",
+            "Somewhat broad alignment to a general model compartment, though the node is a computational unit rather than a physical one; a more specific neural network node term would be preferable if available",
+            "The extraction count is appropriate as choice nodes are the final component type in the model"
+          ],
+          "judge_score": [
+            0.7,
+            0.7
+          ],
+          "paper_location": [
+            "results",
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "45": [
+        {
+          "entity": "motion axis",
+          "label": "COMPUTATIONAL_COMPONENT",
+          "ontology_id": "OMICS:0000090",
+          "ontology_label": "modeling and simulation technique",
+          "sentence": [
+            "Further, the motion axis is the difference of columns of Q corresponding to the left and right motion nodes",
+            "Projections of RNN activity onto the motion and color axes reveal representations of relevant sensory stimuli, whereas representations of irrelevant stimuli are suppressed"
+          ],
+          "start": [
+            13,
+            25
+          ],
+          "end": [
+            24,
+            36
+          ],
+          "remarks": [
+            "Axis defined in the latent circuit model analysis",
+            "Aligned to OMICS:0000090 (modeling and simulation technique)",
+            "Somewhat broad alignment to general modeling technique; this is a specific dimensional component of the model analysis that could have a more specific term if available",
+            "The extraction count is appropriate as the motion axis is one of the principal analysis dimensions"
+          ],
+          "judge_score": [
+            0.8,
+            0.8
+          ],
+          "paper_location": [
+            "results",
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "46": [
+        {
+          "entity": "color axis",
+          "label": "COMPUTATIONAL_COMPONENT",
+          "ontology_id": "OMICS:0000090",
+          "ontology_label": "modeling and simulation technique",
+          "sentence": [
+            "and the color axis is the difference of columns of Q corresponding to the red and green color nodes",
+            "Projections of RNN activity onto the motion and color axes reveal representations of relevant sensory stimuli, whereas representations of irrelevant stimuli are suppressed"
+          ],
+          "start": [
+            9,
+            41
+          ],
+          "end": [
+            19,
+            51
+          ],
+          "remarks": [
+            "Axis defined in the latent circuit model analysis",
+            "Aligned to OMICS:0000090 (modeling and simulation technique)",
+            "Somewhat broad alignment to general modeling technique; this is a specific dimensional component of the model analysis that could have a more specific term if available",
+            "The extraction count is appropriate as the color axis is another principal analysis dimension"
+          ],
+          "judge_score": [
+            0.8,
+            0.8
+          ],
+          "paper_location": [
+            "results",
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "47": [
+        {
+          "entity": "choice axis",
+          "label": "COMPUTATIONAL_COMPONENT",
+          "ontology_id": "OMICS:0000090",
+          "ontology_label": "modeling and simulation technique",
+          "sentence": [
+            "Next, the choice axis is the difference of two columns of Q corresponding to the left and right choice nodes in the latent circuit",
+            "Projecting RNN activity onto the choice axis reveals trajectories separating according to choice regardless of context"
+          ],
+          "start": [
+            10,
+            28
+          ],
+          "end": [
+            21,
+            39
+          ],
+          "remarks": [
+            "Axis defined in the latent circuit model analysis",
+            "Aligned to OMICS:0000090 (modeling and simulation technique)",
+            "Somewhat broad alignment to general modeling technique; this is a specific dimensional component of the model analysis that could have a more specific term if available",
+            "The extraction count is appropriate as the choice axis is the third principal analysis dimension"
+          ],
+          "judge_score": [
+            0.8,
+            0.8
+          ],
+          "paper_location": [
+            "results",
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "48": [
+        {
+          "entity": "context axis",
+          "label": "COMPUTATIONAL_COMPONENT",
+          "ontology_id": "OMICS:0000090",
+          "ontology_label": "modeling and simulation technique",
+          "sentence": [
+            "By projecting RNN responses onto the difference of two columns of Q corresponding to the context nodes, we obtain a one-dimensional latent variable correlated with the activity difference of the motion context and color context nodes in the latent circuit"
+          ],
+          "start": [
+            72
+          ],
+          "end": [
+            84
+          ],
+          "remarks": [
+            "Axis defined in the latent circuit model analysis",
+            "Aligned to OMICS:0000090 (modeling and simulation technique)",
+            "Somewhat broad alignment to general modeling technique; this is a specific dimensional component of the model analysis that could have a more specific term if available",
+            "The extraction is appropriate as the context axis is the fourth principal analysis dimension"
+          ],
+          "judge_score": [
+            0.8
+          ],
+          "paper_location": [
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "49": [
+        {
+          "entity": "psychometric functions",
+          "label": "ANALYSIS_METHOD",
+          "ontology_id": "STATO:0000464",
+          "ontology_label": "statistical method",
+          "sentence": [
+            "Psychometric functions were then computed as the percentage of choices to the right for each combination of context, motion coherence and color coherence",
+            "Psychometric functions show that the RNN successfully learns the task; it responds to relevant stimuli and ignores irrelevant stimuli in each context"
+          ],
+          "start": [
+            0,
+            0
+          ],
+          "end": [
+            22,
+            22
+          ],
+          "remarks": [
+            "Analysis method used to evaluate behavioral performance",
+            "Aligned to STATO:0000464 (statistical method)",
+            "Reasonable alignment to general statistical method, though a more specific psychometric analysis term would be preferable if available",
+            "The extraction count is appropriate as psychometric functions were used to analyze behavioral performance"
+          ],
+          "judge_score": [
+            0.8,
+            0.8
+          ],
+          "paper_location": [
+            "methods",
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7",
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "50": [
+        {
+          "entity": "Dale's law",
+          "label": "BIOLOGICAL_CONSTRAINT",
+          "ontology_id": "GO:0007268",
+          "ontology_label": "chemical synaptic transmission",
+          "sentence": [
+            "The recurrent matrix is constrained to satisfy Dale's law with 80% excitatory units and 20% inhibitory units"
+          ],
+          "start": [
+            46
+          ],
+          "end": [
+            56
+          ],
+          "remarks": [
+            "Biological constraint imposed on the computational model",
+            "Aligned to GO:0007268 (chemical synaptic transmission) as it relates to principles of synaptic transmission",
+            "Reasonable alignment to the general process of synaptic transmission, though a more specific neuronal signaling constraint term would be preferable if available",
+            "The extraction is appropriate as it identifies a key biological constraint in the computational model"
+          ],
+          "judge_score": [
+            0.8
+          ],
+          "paper_location": [
+            "methods"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "https://doi.org/10.1038/s41593-025-01869-7"
+          ]
+        }
+      ]
+    }
+  }
+}
\ No newline at end of file
diff --git a/evaluation/ner/old/evaluation/Latent-circuit/with_hil/ner_config_deepseek_s41593-025-01869-7_with_hil.json b/evaluation/ner/old/evaluation/Latent-circuit/with_hil/ner_config_deepseek_s41593-025-01869-7_with_hil.json
new file mode 100644
index 0000000..d17acec
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Latent-circuit/with_hil/ner_config_deepseek_s41593-025-01869-7_with_hil.json
@@ -0,0 +1,531 @@
+{
+  "judged_structured_information": {
+    "judge_ner_terms": {
+      "1": [
+        {
+          "entity": "Nature Neuroscience",
+          "label": "JOURNAL",
+          "ontology_id": "ISSN:1097-6256",
+          "ontology_label": "Nature Neuroscience",
+          "sentence": [
+            "Nature Neuroscience | Volume 28 | March 2025 | 665\u2013675"
+          ],
+          "start": [
+            0
+          ],
+          "end": [
+            18
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "remarks": [
+            "Journal of publication",
+            "Alignment matches existing ontology ID",
+            "Perfect alignment to journal ISSN",
+            "Verified correct journal identification with ISSN"
+          ],
+          "paper_location": [
+            "header"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
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+}
\ No newline at end of file
diff --git a/evaluation/ner/old/evaluation/Latent-circuit/with_hil/ner_config_gpt_s41593-025-01869-7_with_hil.json b/evaluation/ner/old/evaluation/Latent-circuit/with_hil/ner_config_gpt_s41593-025-01869-7_with_hil.json
new file mode 100644
index 0000000..d438b2f
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Latent-circuit/with_hil/ner_config_gpt_s41593-025-01869-7_with_hil.json
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\ No newline at end of file
diff --git a/evaluation/ner/old/evaluation/Latent-circuit/with_hil/ner_token_usage_with_hil_latent.csv b/evaluation/ner/old/evaluation/Latent-circuit/with_hil/ner_token_usage_with_hil_latent.csv
new file mode 100644
index 0000000..0361ec2
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Latent-circuit/with_hil/ner_token_usage_with_hil_latent.csv
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diff --git a/evaluation/ner/old/evaluation/Latent-circuit/without_hil/ner_config_claudesonet_s41593-025-01869-7_without_hil.json b/evaluation/ner/old/evaluation/Latent-circuit/without_hil/ner_config_claudesonet_s41593-025-01869-7_without_hil.json
new file mode 100644
index 0000000..36daabf
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Latent-circuit/without_hil/ner_config_claudesonet_s41593-025-01869-7_without_hil.json
@@ -0,0 +1,1217 @@
+{
+  "judge_ner_terms": {
+    "judge_ner_terms": {
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+        {
+          "entity": "prefrontal cortex",
+          "label": "ANATOMICAL_REGION",
+          "ontology_id": "UBERON:0000451",
+          "ontology_label": "prefrontal cortex",
+          "sentence": [
+            "Single neurons in areas such as the prefrontal cortex (PFC) show complex heterogeneous tuning to multiple task variables.",
+            "We fitted the latent circuit model to the same dataset of PFC recordings during context-dependent decision-making as in the previous studies.",
+            "The latent circuit model revealed a suppression of irrelevant sensory representations in PFC responses of monkeys performing a context-dependent decision-making task."
+          ],
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+            66
+          ],
+          "judge_score": [
+            1.0,
+            0.95,
+            0.95
+          ],
+          "remarks": [
+            "Consistently referred to as PFC throughout the paper",
+            "Key brain region studied in the research",
+            "Successfully aligned to UBERON:0000451",
+            "Perfect alignment with clear ontology match and correct labeling as anatomical region"
+          ],
+          "paper_location": [
+            "introduction",
+            "results",
+            "discussion"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7",
+            "10.1038/s41593-025-01869-7",
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
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+        {
+          "entity": "PFC",
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+          "ontology_label": "prefrontal cortex",
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+          "judge_score": [
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+          ],
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+            "Abbreviation for prefrontal cortex",
+            "Used interchangeably with the full term",
+            "Same ontology ID as prefrontal cortex (UBERON:0000451)",
+            "First sentence doesn't contain 'PFC' at the indicated position, so scored 0.0",
+            "Second sentence correctly identifies PFC with proper ontology alignment"
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+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
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+            "10.1038/s41593-025-01869-7",
+            "10.1038/s41593-025-01869-7"
+          ]
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+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
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+            "10.1038/s41593-025-01869-7",
+            "10.1038/s41593-025-01869-7"
+          ]
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+            "First sentence correctly shows RNN as abbreviation",
+            "Second sentence uses plural form (RNNs), slight position mismatch but semantically correct"
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+            "We develop the latent circuit model, a dimensionality reduction approach in which task variables interact via low-dimensional recurrent connectivity to produce behavioral output.",
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+            "Both instances correctly identified with appropriate label assignment",
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+          ]
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+          "entity": "rhesus monkeys",
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+          "ontology_id": "NCBITaxon:9544",
+          "ontology_label": "Macaca mulatta",
+          "sentence": [
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+          "judge_score": [
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+            "Specific species of experimental animal used in the study",
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+            "Successfully aligned to CL:0000540",
+            "All three instances correctly identified with perfect alignment to the ontology"
+          ],
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+          ]
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+            "Second sentence uses 'excitatory' as an adjective for RNN units, not explicitly 'excitatory neurons'"
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+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
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+          "ontology_label": "inhibitory neuron",
+          "sentence": [
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+            "Type of neuron in biological neural circuits",
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+            "Successfully aligned to CL:0008031",
+            "First sentence correctly identifies 'inhibitory neurons'",
+            "Second sentence uses 'inhibitory' as an adjective for RNN units, not explicitly 'inhibitory neurons'"
+          ],
+          "paper_location": [
+            "introduction",
+            "methods"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7",
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "15": [
+        {
+          "entity": "cortical circuits",
+          "label": "NEURAL_CIRCUIT",
+          "ontology_id": "UBERON:0001851",
+          "ontology_label": "cortical neural circuit",
+          "sentence": [
+            "These computations result from interactions between excitatory and inhibitory neurons in cortical circuits."
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+          ],
+          "judge_score": [
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+          ],
+          "remarks": [
+            "Neural network structures in the cerebral cortex",
+            "Biological basis for the computational models",
+            "Aligned to UBERON:0001851 as the appropriate neural circuit term",
+            "Perfect alignment to the ontology with appropriate label"
+          ],
+          "paper_location": [
+            "introduction"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "16": [
+        {
+          "entity": "higher cortical areas",
+          "label": "ANATOMICAL_REGION",
+          "ontology_id": "UBERON:0000955",
+          "ontology_label": "cerebral cortex",
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+            "Higher cortical areas carry a wide range of sensory, cognitive and motor signals mixed in heterogeneous responses of single neurons tuned to multiple task variables.",
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+            "General term for advanced processing regions of the cerebral cortex",
+            "Aligned to UBERON:0000955 (cerebral cortex) as the most appropriate anatomical term",
+            "Both instances correctly identified with good ontology alignment"
+          ],
+          "paper_location": [
+            "abstract",
+            "introduction"
+          ],
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+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7",
+            "10.1038/s41593-025-01869-7"
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+        }
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+        {
+          "entity": "color context",
+          "label": "EXPERIMENTAL_CONDITION",
+          "ontology_id": "ERO:0000006",
+          "ontology_label": "behavioral task",
+          "sentence": [
+            "In the color context, the choice should be made according to the color, ignoring the motion stimulus, and vice versa in the motion context.",
+            "Further, the color context node has inhibitory connections to the sensory nodes representing motion, and the motion context node has inhibitory connections to sensory nodes representing color."
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+            "Aligned to ERO:0000006 (behavioral task) as a specific condition within the task paradigm",
+            "Both instances correctly identified and appropriately labeled"
+          ],
+          "paper_location": [
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+            "results"
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+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7",
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "18": [
+        {
+          "entity": "motion context",
+          "label": "EXPERIMENTAL_CONDITION",
+          "ontology_id": "ERO:0000006",
+          "ontology_label": "behavioral task",
+          "sentence": [
+            "In the color context, the choice should be made according to the color, ignoring the motion stimulus, and vice versa in the motion context.",
+            "Further, the color context node has inhibitory connections to the sensory nodes representing motion, and the motion context node has inhibitory connections to sensory nodes representing color."
+          ],
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+            "One of the two experimental conditions in the context-dependent task",
+            "Refers to trials where decisions should be based on motion stimuli",
+            "Aligned to ERO:0000006 (behavioral task) as a specific condition within the task paradigm",
+            "Both instances correctly identified and appropriately labeled"
+          ],
+          "paper_location": [
+            "methods",
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7",
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "19": [
+        {
+          "entity": "ReLU",
+          "label": "MATHEMATICAL_FUNCTION",
+          "ontology_id": "OMICS:0001923",
+          "ontology_label": "activation function",
+          "sentence": [
+            "The latent variables x are constrained to be nodes in a neural circuit with dynamics \u1e8b=\u2212x+f(wrecx+winu), where f is a rectified linear (ReLU) activation function."
+          ],
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+          ],
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+            155
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "remarks": [
+            "Rectified Linear Unit activation function used in the neural network model",
+            "Mathematical function important for the computational models",
+            "Aligned to OMICS:0001923 (activation function) as the appropriate functional category",
+            "Correctly identified with appropriate ontology alignment"
+          ],
+          "paper_location": [
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "20": [
+        {
+          "entity": "rectified linear",
+          "label": "MATHEMATICAL_FUNCTION",
+          "ontology_id": "OMICS:0001923",
+          "ontology_label": "activation function",
+          "sentence": [
+            "The latent variables x are constrained to be nodes in a neural circuit with dynamics \u1e8b=\u2212x+f(wrecx+winu), where f is a rectified linear (ReLU) activation function."
+          ],
+          "start": [
+            134
+          ],
+          "end": [
+            149
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "remarks": [
+            "Full name of ReLU activation function used in neural networks",
+            "Same ontology ID as ReLU (OMICS:0001923)",
+            "Correctly identified with appropriate ontology alignment"
+          ],
+          "paper_location": [
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "21": [
+        {
+          "entity": "Softplus",
+          "label": "MATHEMATICAL_FUNCTION",
+          "ontology_id": "OMICS:0001923",
+          "ontology_label": "activation function",
+          "sentence": [
+            "To test whether our results extend to networks with a different biologically plausible nonlinearity, we trained RNNs that had a Softplus activation function f(x)=g\u03b2log(1+e\u03b2x) for a range of parameter \u03b2 and also with varying gain g across units."
+          ],
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+            117
+          ],
+          "end": [
+            125
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "remarks": [
+            "Alternative activation function tested in the neural networks",
+            "A smoother approximation of the ReLU function",
+            "Aligned to OMICS:0001923 (activation function) like other activation functions",
+            "Correctly identified with appropriate ontology alignment"
+          ],
+          "paper_location": [
+            "methods"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "22": [
+        {
+          "entity": "orthonormal embedding matrix",
+          "label": "MATHEMATICAL_ENTITY",
+          "ontology_id": "OMICS:0000132",
+          "ontology_label": "matrix",
+          "sentence": [
+            "Similar to other dimensionality reduction methods, we model high-dimensional neural responses y\u2208\u211dN (N is the number of neurons) during a cognitive task using low-dimensional latent variables x\u2208\u211dn as y=Qx,(1) where Q\u2208\u211dN\u00d7n is an orthonormal embedding matrix and n \u226a N."
+          ],
+          "start": [
+            208
+          ],
+          "end": [
+            233
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "remarks": [
+            "Mathematical construct used in the latent circuit model",
+            "Key component of the dimensionality reduction approach",
+            "Aligned to OMICS:0000132 (matrix) as the general mathematical category",
+            "Correctly identified with appropriate ontology alignment"
+          ],
+          "paper_location": [
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "23": [
+        {
+          "entity": "monkey A",
+          "label": "EXPERIMENTAL_SUBJECT",
+          "ontology_id": "NCBITaxon:9544",
+          "ontology_label": "Macaca mulatta",
+          "sentence": [
+            "The dataset consists of several hundred PFC neurons (n = 727 and 574 for monkeys A and F, respectively) recorded from two rhesus monkeys performing a context-dependent decision-making task.",
+            "The latent circuit model provided good fits of PFC responses projected onto the low-dimensional subspace spanned by the columns of the inferred embedding matrix Q for both monkeys (r2 = 0.88 and 0.76 on test data for monkeys A and F, respectively)."
+          ],
+          "start": [
+            85,
+            220
+          ],
+          "end": [
+            93,
+            228
+          ],
+          "judge_score": [
+            1.0,
+            1.0
+          ],
+          "remarks": [
+            "Identifier for one of the two rhesus monkeys used in the experiments",
+            "Aligned to NCBITaxon:9544 (Macaca mulatta) based on species identification in the text",
+            "Both instances correctly identified with appropriate taxonomic alignment"
+          ],
+          "paper_location": [
+            "results",
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7",
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "24": [
+        {
+          "entity": "monkey F",
+          "label": "EXPERIMENTAL_SUBJECT",
+          "ontology_id": "NCBITaxon:9544",
+          "ontology_label": "Macaca mulatta",
+          "sentence": [
+            "The dataset consists of several hundred PFC neurons (n = 727 and 574 for monkeys A and F, respectively) recorded from two rhesus monkeys performing a context-dependent decision-making task.",
+            "The latent circuit model provided good fits of PFC responses projected onto the low-dimensional subspace spanned by the columns of the inferred embedding matrix Q for both monkeys (r2 = 0.88 and 0.76 on test data for monkeys A and F, respectively)."
+          ],
+          "start": [
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+          ],
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+            106,
+            241
+          ],
+          "judge_score": [
+            1.0,
+            1.0
+          ],
+          "remarks": [
+            "Identifier for one of the two rhesus monkeys used in the experiments",
+            "Aligned to NCBITaxon:9544 (Macaca mulatta) based on species identification in the text",
+            "Both instances correctly identified with appropriate taxonomic alignment"
+          ],
+          "paper_location": [
+            "results",
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7",
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "25": [
+        {
+          "entity": "Dale's law",
+          "label": "BIOLOGICAL_PRINCIPLE",
+          "ontology_id": "GO:0007268",
+          "ontology_label": "chemical synaptic transmission",
+          "sentence": [
+            "The recurrent matrix is constrained to satisfy Dale's law with 80% excitatory units and 20% inhibitory units."
+          ],
+          "start": [
+            49
+          ],
+          "end": [
+            59
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "remarks": [
+            "Neuroscience principle stating that neurons release the same neurotransmitters at all their synapses",
+            "Applied as a constraint in the neural network models",
+            "Aligned to GO:0007268 as it relates to principles of synaptic transmission",
+            "Correctly identified with appropriate ontology alignment"
+          ],
+          "paper_location": [
+            "methods"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "26": [
+        {
+          "entity": "psychometric function",
+          "label": "ANALYSIS_METHOD",
+          "ontology_id": "STATO:0000464",
+          "ontology_label": "statistical method",
+          "sentence": [
+            "To assess performance, a choice for the RNN was defined as the sign of the difference between output units at the end of the trial. Psychometric functions were then computed as the percentage of choices to the right for each combination of context, motion coherence and color coherence."
+          ],
+          "start": [
+            97
+          ],
+          "end": [
+            118
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "remarks": [
+            "Statistical function relating stimulus properties to performance",
+            "Used to evaluate model behavior",
+            "Aligned to STATO:0000464 as an appropriate statistical method category",
+            "Correctly identified with appropriate ontology alignment"
+          ],
+          "paper_location": [
+            "methods"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "27": [
+        {
+          "entity": "context-dependent selection mechanism",
+          "label": "NEURAL_MECHANISM",
+          "ontology_id": "GO:0050794",
+          "ontology_label": "regulation of cellular process",
+          "sentence": [
+            "Context-dependent selection arises because in each context, the relevant sensory input (IRel) aligns with the selection vector and the irrelevant sensory input (IIrrel) does not."
+          ],
+          "start": [
+            0
+          ],
+          "end": [
+            35
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "remarks": [
+            "Neural mechanism described in terms of vector alignments",
+            "Describes how context influences sensory processing",
+            "Aligned to GO:0050794 as the most appropriate general biological process term",
+            "Correctly identified with appropriate ontology alignment, though the term in the text is 'Context-dependent selection' rather than the full 'context-dependent selection mechanism'"
+          ],
+          "paper_location": [
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "28": [
+        {
+          "entity": "selection vector mechanism",
+          "label": "NEURAL_MECHANISM",
+          "ontology_id": "GO:0050794",
+          "ontology_label": "regulation of cellular process",
+          "sentence": [
+            "The inhibitory suppression mechanism that we consistently found across RNNs may seem distinct from a dynamical selection vector mechanism previously identified in RNNs trained on a similar task, which apparently does not require suppression of irrelevant sensory responses.",
+            "We analyzed dynamics in our RNNs and found the same selection vector mechanism, indicating that the dynamical selection vector mechanism is a local linear description of the inhibitory circuit mechanism."
+          ],
+          "start": [
+            110,
+            57
+          ],
+          "end": [
+            137,
+            84
+          ],
+          "judge_score": [
+            1.0,
+            1.0
+          ],
+          "remarks": [
+            "Previously identified neural mechanism in RNNs",
+            "Found to be compatible with the inhibitory suppression mechanism",
+            "Aligned to GO:0050794 as the most appropriate general biological process term",
+            "Both instances correctly identified with appropriate ontology alignment"
+          ],
+          "paper_location": [
+            "results",
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7",
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "29": [
+        {
+          "entity": "dynamical selection vector mechanism",
+          "label": "NEURAL_MECHANISM",
+          "ontology_id": "GO:0050794",
+          "ontology_label": "regulation of cellular process",
+          "sentence": [
+            "We analyzed dynamics in our RNNs and found the same selection vector mechanism, indicating that the dynamical selection vector mechanism is a local linear description of the inhibitory circuit mechanism."
+          ],
+          "start": [
+            92
+          ],
+          "end": [
+            128
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "remarks": [
+            "Full name of the selection vector mechanism",
+            "Described as a local linear description of the inhibitory circuit mechanism",
+            "Aligned to GO:0050794 as the most appropriate general biological process term",
+            "Correctly identified with appropriate ontology alignment"
+          ],
+          "paper_location": [
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "30": [
+        {
+          "entity": "incongruent trials",
+          "label": "EXPERIMENTAL_CONDITION",
+          "ontology_id": "ERO:0000006",
+          "ontology_label": "behavioral task",
+          "sentence": [
+            "We tested this prediction on incongruent trials on which the relevant and irrelevant stimuli point to opposite choices (Methods) because the errors on incongruent trials are more likely to result from a failure of the contextual mechanism than other factors (for example, attention lapse)."
+          ],
+          "start": [
+            29,
+            109
+          ],
+          "end": [
+            47,
+            127
+          ],
+          "judge_score": [
+            1.0,
+            1.0
+          ],
+          "remarks": [
+            "Trial condition where relevant and irrelevant stimuli suggest different choices",
+            "Important condition for testing the contextual mechanism",
+            "Aligned to ERO:0000006 (behavioral task) as a specific condition within the task paradigm",
+            "Both instances correctly identified with appropriate ontology alignment"
+          ],
+          "paper_location": [
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ]
+    }
+  }
+}
\ No newline at end of file
diff --git a/evaluation/ner/old/evaluation/Latent-circuit/without_hil/ner_config_deepseek_s41593-025-01869-7_without_hil.json b/evaluation/ner/old/evaluation/Latent-circuit/without_hil/ner_config_deepseek_s41593-025-01869-7_without_hil.json
new file mode 100644
index 0000000..156f4de
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Latent-circuit/without_hil/ner_config_deepseek_s41593-025-01869-7_without_hil.json
@@ -0,0 +1,362 @@
+{
+  "judge_ner_terms": {
+    "judge_ner_terms": {
+      "1": [
+        {
+          "entity": "prefrontal cortex",
+          "label": "ANATOMICAL_REGION",
+          "ontology_id": "UBERON:0001870",
+          "ontology_label": "prefrontal cortex",
+          "sentence": [
+            "Single neurons in areas such as the prefrontal cortex (PFC) show complex heterogeneous tuning to multiple task variables",
+            "We find similar suppression of irrelevant sensory responses in the prefrontal cortex of monkeys performing the same task"
+          ],
+          "start": [
+            683,
+            4532
+          ],
+          "end": [
+            700,
+            4550
+          ],
+          "judge_score": [
+            0.95,
+            0.95
+          ],
+          "remarks": [
+            "Key brain region studied in context-dependent decision-making",
+            "Alignment confirmed via UBERON ontology",
+            "Perfect match with ontology label and context"
+          ],
+          "paper_location": [
+            "introduction",
+            "results"
+          ],
+          "paper_title": "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+          "doi": [
+            "10.1038/s41593-025-01869-7",
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "2": [
+        {
+          "entity": "rhesus monkeys",
+          "label": "ANIMAL_SPECIES",
+          "ontology_id": "NCBITaxon:9544",
+          "ontology_label": "Macaca mulatta",
+          "sentence": [
+            "The dataset consists of several hundred PFC neurons (n = 727 and 574 for monkeys A and F, respectively) recorded from two rhesus monkeys performing a context-dependent decision-making task"
+          ],
+          "start": [
+            5095
+          ],
+          "end": [
+            5108
+          ],
+          "judge_score": [
+            0.9
+          ],
+          "remarks": [
+            "Experimental subjects in the study",
+            "Alignment confirmed via NCBI Taxonomy",
+            "High confidence alignment, though common name differs from scientific name"
+          ],
+          "paper_location": [
+            "results"
+          ],
+          "paper_title": "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "3": [
+        {
+          "entity": "excitatory neurons",
+          "label": "CELL_TYPE",
+          "ontology_id": "CL:0008031",
+          "ontology_label": "excitatory neuron",
+          "sentence": [
+            "These computations result from interactions between excitatory and inhibitory neurons in cortical circuits",
+            "The RNN consists of 50 recurrently connected units, 40 excitatory and 10 inhibitory"
+          ],
+          "start": [
+            429,
+            2585
+          ],
+          "end": [
+            446,
+            2597
+          ],
+          "judge_score": [
+            0.85,
+            0.8
+          ],
+          "remarks": [
+            "Key neural population in cortical circuits",
+            "Alignment confirmed via Cell Ontology",
+            "Good match, though second instance refers to model units rather than biological neurons"
+          ],
+          "paper_location": [
+            "introduction",
+            "methods"
+          ],
+          "paper_title": "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+          "doi": [
+            "10.1038/s41593-025-01869-7",
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "4": [
+        {
+          "entity": "inhibitory neurons",
+          "label": "CELL_TYPE",
+          "ontology_id": "CL:0008033",
+          "ontology_label": "inhibitory neuron",
+          "sentence": [
+            "These computations result from interactions between excitatory and inhibitory neurons in cortical circuits",
+            "The RNN consists of 50 recurrently connected units, 40 excitatory and 10 inhibitory"
+          ],
+          "start": [
+            451,
+            2605
+          ],
+          "end": [
+            468,
+            2618
+          ],
+          "judge_score": [
+            0.85,
+            0.8
+          ],
+          "remarks": [
+            "Key neural population in cortical circuits that implements suppression mechanisms",
+            "Alignment confirmed via Cell Ontology",
+            "Good match, though second instance refers to model units rather than biological neurons"
+          ],
+          "paper_location": [
+            "introduction",
+            "methods"
+          ],
+          "paper_title": "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+          "doi": [
+            "10.1038/s41593-025-01869-7",
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "5": [
+        {
+          "entity": "context-dependent decision-making task",
+          "label": "EXPERIMENTAL_PARADIGM",
+          "ontology_id": null,
+          "ontology_label": null,
+          "sentence": [
+            "We apply the latent circuit inference to recurrent neural networks trained to perform a context-dependent decision-making task",
+            "We analyzed a publicly available dataset of neural activity recordings from the PFC of two monkeys performing a context-dependent decision-making task"
+          ],
+          "start": [
+            292,
+            5049
+          ],
+          "end": [
+            328,
+            5092
+          ],
+          "judge_score": [
+            0.7,
+            0.7
+          ],
+          "remarks": [
+            "Core cognitive task studied in the paper",
+            "No direct ontology term available",
+            "Good contextual description despite lack of formal ontology alignment"
+          ],
+          "paper_location": [
+            "abstract",
+            "methods"
+          ],
+          "paper_title": "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+          "doi": [
+            "10.1038/s41593-025-01869-7",
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "6": [
+        {
+          "entity": "RNN",
+          "label": "COMPUTATIONAL_MODEL",
+          "ontology_id": null,
+          "ontology_label": null,
+          "sentence": [
+            "Similar heterogeneous responses emerge in high-dimensional recurrent neural network (RNN) models trained to perform cognitive tasks",
+            "We apply the latent circuit inference to recurrent neural networks (RNNs) optimized on a context-dependent decision-making task"
+          ],
+          "start": [
+            804,
+            274
+          ],
+          "end": [
+            807,
+            313
+          ],
+          "judge_score": [
+            0.8,
+            0.8
+          ],
+          "remarks": [
+            "Primary computational model used in the study",
+            "No direct ontology term available",
+            "Clear description of model type in context"
+          ],
+          "paper_location": [
+            "introduction",
+            "abstract"
+          ],
+          "paper_title": "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+          "doi": [
+            "10.1038/s41593-025-01869-7",
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "7": [
+        {
+          "entity": "latent circuit model",
+          "label": "COMPUTATIONAL_MODEL",
+          "ontology_id": null,
+          "ontology_label": null,
+          "sentence": [
+            "We develop the latent circuit model, a dimensionality reduction approach in which task variables interact via low-dimensional recurrent connectivity to produce behavioral output",
+            "The latent circuit model captures task-related neural activity in the low-dimensional subspace spanned by the columns of Q"
+          ],
+          "start": [
+            141,
+            2178
+          ],
+          "end": [
+            159,
+            2214
+          ],
+          "judge_score": [
+            0.9,
+            0.9
+          ],
+          "remarks": [
+            "Novel computational approach developed in this study",
+            "No direct ontology term available",
+            "Excellent description of model purpose and function"
+          ],
+          "paper_location": [
+            "abstract",
+            "results"
+          ],
+          "paper_title": "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+          "doi": [
+            "10.1038/s41593-025-01869-7",
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "8": [
+        {
+          "entity": "ReLU",
+          "label": "ACTIVATION_FUNCTION",
+          "ontology_id": null,
+          "ontology_label": null,
+          "sentence": [
+            "The latent nodes interact via the recurrent connectivity wrec and receive external task inputs u through the input connectivity win: \u0307x = \u2212x + f(wrecx + winu), where f is a rectified linear (ReLU) activation function"
+          ],
+          "start": [
+            2297
+          ],
+          "end": [
+            2301
+          ],
+          "judge_score": [
+            0.85
+          ],
+          "remarks": [
+            "Nonlinear activation function used in the latent circuit model",
+            "No direct ontology term available",
+            "Clear technical description with mathematical context"
+          ],
+          "paper_location": [
+            "methods"
+          ],
+          "paper_title": "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "9": [
+        {
+          "entity": "PyTorch",
+          "label": "COMPUTATIONAL_TOOL",
+          "ontology_id": null,
+          "ontology_label": null,
+          "sentence": [
+            "We perform this minimization using PyTorch and the Adam optimizer with default values 0.9 and 0.999 for the decay rate of the first and second moment estimates"
+          ],
+          "start": [
+            3321
+          ],
+          "end": [
+            3328
+          ],
+          "judge_score": [
+            0.95
+          ],
+          "remarks": [
+            "Deep learning framework used for model optimization",
+            "No direct ontology term available",
+            "Well-known tool in computational neuroscience"
+          ],
+          "paper_location": [
+            "methods"
+          ],
+          "paper_title": "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "10": [
+        {
+          "entity": "Adam optimizer",
+          "label": "COMPUTATIONAL_TOOL",
+          "ontology_id": null,
+          "ontology_label": null,
+          "sentence": [
+            "We perform this minimization using PyTorch and the Adam optimizer with default values 0.9 and 0.999 for the decay rate of the first and second moment estimates"
+          ],
+          "start": [
+            3333
+          ],
+          "end": [
+            3346
+          ],
+          "judge_score": [
+            0.95
+          ],
+          "remarks": [
+            "Optimization algorithm used for training models",
+            "No direct ontology term available",
+            "Standard optimization method with clear technical details"
+          ],
+          "paper_location": [
+            "methods"
+          ],
+          "paper_title": "Latent circuit inference from heterogeneous neural responses during cognitive tasks",
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ]
+    }
+  }
+}
\ No newline at end of file
diff --git a/evaluation/ner/old/evaluation/Latent-circuit/without_hil/ner_config_gpt_s41593-025-01869-7_without_hil.json b/evaluation/ner/old/evaluation/Latent-circuit/without_hil/ner_config_gpt_s41593-025-01869-7_without_hil.json
new file mode 100644
index 0000000..94a5736
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Latent-circuit/without_hil/ner_config_gpt_s41593-025-01869-7_without_hil.json
@@ -0,0 +1,369 @@
+{
+  "judge_ner_terms": {
+    "judge_ner_terms": {
+      "1": [
+        {
+          "entity": "Nature Neuroscience",
+          "label": "JOURNAL",
+          "ontology_id": null,
+          "ontology_label": null,
+          "sentence": [
+            "Nature Neuroscience | Volume 28 | March 2025 | 665\u2013675"
+          ],
+          "start": [
+            0
+          ],
+          "end": [
+            28
+          ],
+          "remarks": [
+            "Entry represents the name of the journal publishing the research.",
+            "No direct ontological mapping available."
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "paper_location": [
+            "introductory information"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "2": [
+        {
+          "entity": "Christopher Langdon",
+          "label": "AUTHOR",
+          "ontology_id": null,
+          "ontology_label": null,
+          "sentence": [
+            "Christopher Langdon 1,2 & Tatiana A. Engel 1,2"
+          ],
+          "start": [
+            0
+          ],
+          "end": [
+            20
+          ],
+          "remarks": [
+            "Entry represents the first author of the paper.",
+            "No direct ontological mapping available."
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "paper_location": [
+            "author information"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "3": [
+        {
+          "entity": "Tatiana A. Engel",
+          "label": "AUTHOR",
+          "ontology_id": null,
+          "ontology_label": null,
+          "sentence": [
+            "Christopher Langdon 1,2 & Tatiana A. Engel 1,2"
+          ],
+          "start": [
+            24
+          ],
+          "end": [
+            42
+          ],
+          "remarks": [
+            "Entry represents the second author of the paper.",
+            "No direct ontological mapping available."
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "paper_location": [
+            "author information"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "4": [
+        {
+          "entity": "Higher cortical areas",
+          "label": "ANATOMICAL_REGION",
+          "ontology_id": "UBERON:0000955",
+          "ontology_label": "cerebral cortex",
+          "sentence": [
+            "Higher cortical areas carry a wide range of sensory, cognitive and motor signals mixed in heterogeneous responses of single neurons tuned to multiple task variables."
+          ],
+          "start": [
+            0
+          ],
+          "end": [
+            21
+          ],
+          "remarks": [
+            "Anatomical region involved in higher-level brain functions.",
+            "Successfully aligned to UBERON:0000955."
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "paper_location": [
+            "introduction"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "5": [
+        {
+          "entity": "dimensionality reduction methods",
+          "label": "EXPERIMENTAL_CONDITION",
+          "ontology_id": "EDAM:0000598",
+          "ontology_label": "dimensionality reduction",
+          "sentence": [
+            "Dimensionality reduction methods that rely on correlations between neural activity and task variables leave unknown how heterogeneous responses arise from connectivity to drive behavior."
+          ],
+          "start": [
+            0
+          ],
+          "end": [
+            85
+          ],
+          "remarks": [
+            "Method used to analyze neural data.",
+            "Successfully aligned to EDAM:0000598."
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "paper_location": [
+            "introduction"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "6": [
+        {
+          "entity": "latent circuit model",
+          "label": "MODEL",
+          "ontology_id": null,
+          "ontology_label": null,
+          "sentence": [
+            "We develop the latent circuit model, a dimensionality reduction approach in which task variables interact via low-dimensional recurrent connectivity to produce behavioral output."
+          ],
+          "start": [
+            30
+          ],
+          "end": [
+            61
+          ],
+          "remarks": [
+            "New computational model proposed in the study.",
+            "No specific ontology ID available."
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "paper_location": [
+            "methods"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "7": [
+        {
+          "entity": "prefrontal cortex",
+          "label": "ANATOMICAL_REGION",
+          "ontology_id": "UBERON:0000451",
+          "ontology_label": "prefrontal cortex",
+          "sentence": [
+            "We find similar suppression of irrelevant sensory responses in the prefrontal cortex of monkeys performing the same task."
+          ],
+          "start": [
+            11
+          ],
+          "end": [
+            34
+          ],
+          "remarks": [
+            "Specific brain region focused on in the study.",
+            "Successfully aligned to UBERON:0000451."
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "paper_location": [
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "8": [
+        {
+          "entity": "monkeys",
+          "label": "ANIMAL_SPECIES",
+          "ontology_id": "NCBITaxon:9539",
+          "ontology_label": "Macaca",
+          "sentence": [
+            "We find similar suppression of irrelevant sensory responses in the prefrontal cortex of monkeys performing the same task."
+          ],
+          "start": [
+            38
+          ],
+          "end": [
+            45
+          ],
+          "remarks": [
+            "Refers to the animal subjects of the study.",
+            "Successfully aligned to NCBITaxon:9539."
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "paper_location": [
+            "results"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "9": [
+        {
+          "entity": "neurons",
+          "label": "CELL_TYPE",
+          "ontology_id": "CL:0000540",
+          "ontology_label": "neuron",
+          "sentence": [
+            "We show that incorporating causal interactions among task variables is critical for identifying behaviorally relevant computations from neural response data."
+          ],
+          "start": [
+            92
+          ],
+          "end": [
+            99
+          ],
+          "remarks": [
+            "Key cellular unit of the nervous system being studied.",
+            "Successfully aligned to CL:0000540."
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "paper_location": [
+            "discussion"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "10": [
+        {
+          "entity": "cognitive functions",
+          "label": "FUNCTIONAL_CONCEPT",
+          "ontology_id": null,
+          "ontology_label": null,
+          "sentence": [
+            "Cognitive functions depend on higher cortical areas, which integrate diverse sensory and contextual signals to produce a coherent behavioral response."
+          ],
+          "start": [
+            0
+          ],
+          "end": [
+            47
+          ],
+          "remarks": [
+            "Describes the functional outcomes supported by specific brain areas.",
+            "No direct ontological mapping available."
+          ],
+          "judge_score": [
+            0.95
+          ],
+          "paper_location": [
+            "introduction"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ],
+      "11": [
+        {
+          "entity": "s41593-025-01869-7",
+          "label": "DOI",
+          "ontology_id": null,
+          "ontology_label": null,
+          "sentence": [
+            "Nature Neuroscience | Volume 28 | March 2025 | 665\u2013675."
+          ],
+          "start": [
+            39
+          ],
+          "end": [
+            61
+          ],
+          "remarks": [
+            "Digital Object Identifier for the paper.",
+            "No direct ontological mapping available."
+          ],
+          "judge_score": [
+            1.0
+          ],
+          "paper_location": [
+            "introductory information"
+          ],
+          "paper_title": [
+            "Latent circuit inference from heterogeneous neural responses during cognitive tasks"
+          ],
+          "doi": [
+            "10.1038/s41593-025-01869-7"
+          ]
+        }
+      ]
+    }
+  }
+}
\ No newline at end of file
diff --git a/evaluation/ner/old/evaluation/Latent-circuit/without_hil/ner_token_usage_without_hil_latent.csv b/evaluation/ner/old/evaluation/Latent-circuit/without_hil/ner_token_usage_without_hil_latent.csv
new file mode 100644
index 0000000..b208e42
--- /dev/null
+++ b/evaluation/ner/old/evaluation/Latent-circuit/without_hil/ner_token_usage_without_hil_latent.csv
@@ -0,0 +1,29 @@
+Timestamp,Provider,Model,App,Input Tokens,Output Tokens,Cost ($),Speed (tps),Finish
+"Jun 27, 10:38 PM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,2360,2336,0.00286,26.5,stop
+"Jun 27, 10:36 PM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,7636,782,0.00304,28.0,stop
+"Jun 27, 10:36 PM",Favicon for Phala,DeepSeek V3 0324,liteLLM,9049,2333,0.00972,24.7,stop
+"Jun 27, 10:34 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,2006,1982,0.00231,23.3,stop
+"Jun 27, 10:33 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,5318,572,0.0025,20.0,stop
+"Jun 27, 10:32 PM",Favicon for Nebius,DeepSeek V3 0324,liteLLM,10328,1979,0.00813,20.1,stop
+"Jun 27, 10:31 PM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,1879,1855,0.00227,32.3,stop
+"Jun 27, 10:30 PM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,37726,749,0.0114,25.7,stop
+"Jun 27, 10:28 PM",Favicon for GMICloud,DeepSeek V3 0324,liteLLM,71917,1852,0.0549,110.8,stop
+"Jun 27, 10:15 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,10772,10394,0.188,78.1,tool_calls
+"Jun 27, 10:12 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,28469,602,0.0944,59.5,tool_calls
+"Jun 27, 10:12 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,34828,10372,0.26,78.0,stop
+"Jun 27, 10:10 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,8910,8534,0.155,77.5,tool_calls
+"Jun 27, 10:08 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,17693,950,0.0673,61.0,tool_calls
+"Jun 27, 10:07 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,19703,8568,0.188,76.1,stop
+"Jun 27, 10:06 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,7728,7082,0.129,76.8,tool_calls
+"Jun 27, 10:04 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,51376,1294,0.174,89.0,tool_calls
+"Jun 27, 10:04 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,49910,1291,0.169,61.6,tool_calls
+"Jun 27, 10:03 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,83918,7330,0.362,77.9,stop
+"Jun 27, 10:27 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,2026,1988,0.0015,68.2,stop
+"Jun 27, 10:26 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,7043,620,0.00143,69.8,stop
+"Jun 27, 10:26 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,27039,1989,0.00525,70.7,stop
+"Jun 27, 10:25 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1915,1867,0.00141,80.9,stop
+"Jun 27, 10:25 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,4924,572,0.00108,81.2,stop
+"Jun 27, 10:25 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,23024,1920,0.00461,62.2,stop
+"Jun 27, 10:24 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1607,1560,0.00118,64.9,stop
+"Jun 27, 10:24 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,37545,165,0.00573,84.2,stop
+"Jun 27, 10:24 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,72143,1571,0.00637,72.9,stop
diff --git a/evaluation/ner/old/ner_config_claudesonet.yaml b/evaluation/ner/old/ner_config_claudesonet.yaml
new file mode 100644
index 0000000..efe6959
--- /dev/null
+++ b/evaluation/ner/old/ner_config_claudesonet.yaml
@@ -0,0 +1,735 @@
+#agent config
+agent_config:
+  extractor_agent:
+    role: >
+      Neuroscience Named Entity Recognition (NER) Extractor Agent
+    goal: >
+      Perform Named Entity Recognition (NER) on neuroscience {literature} process it by paragraph, chunk as necessary and return structured JSON output.
+    backstory: >
+      You are an AI assistant specialized in processing neuroscience and who do not hallucinate. 
+      Your expertise includes recognizing and categorizing named entities such as anatomical regions, experimental conditions, and cell types. 
+      Your responses strictly adhere to JSON format, ensuring accurate and structured data extraction for downstream applications.
+    llm:
+      model: openrouter/anthropic/claude-3.7-sonnet
+      base_url: https://openrouter.ai/api/v1
+
+  alignment_agent:
+    role: >
+      Neuroscience Named Entity Recognition (NER) Concept Alignment Agent
+    goal: >
+      Perform concept alignment to the extracted Named Entity Recognition (NER) by extractor_agent {extracted_structured_information} and return structured JSON output.
+    backstory: >
+      You are an AI assistant specialized in processing neuroscience concept alignment with structured models, i.e., ontologies or schemas and who do not hallucinate. 
+      Your expertise includes recognizing and categorizing extracted named entities such as anatomical regions, experimental conditions, and cell types and aligning the recognized named entities such as cell types with corresponding ontological terms. 
+      Your responses strictly adhere to JSON format, ensuring accurate and structured data extraction for downstream applications.
+    llm:
+      model: openrouter/anthropic/claude-3.7-sonnet
+      base_url: https://openrouter.ai/api/v1
+
+  judge_agent:
+    role: >
+      Neuroscience Named Entity Recognition (NER) Judge Agent
+    goal: >
+      Evaluate the {aligned_structured_information} based on predefined criteria and generate a structured JSON output reflecting the assessment results.
+    backstory: >
+      You are an AI assistant with expert knowledge in neuroscience and structured models, i.e., ontologies or schemas, and someone who does not hallucinate.  
+      Your task is to evaluate the {aligned_structured_information} based on the accuracy and quality of the alignment. 
+      Assign the score between 0-1 with 1 being the highest score of your evaluation.
+      Your responses strictly adhere to JSON format, ensuring accurate and structured data extraction for downstream applications.
+    llm:
+      model: openrouter/anthropic/claude-3.7-sonnet
+      base_url: https://openrouter.ai/api/v1
+
+  humanfeedback_agent:
+    role: >
+      Neuroscience Named Entity Recognition (NER) Human feedback processor Agent
+    goal: >
+      Evaluate the {judged_structured_information_with_human_feedback} and review if everything is correct as human domain expert.
+    backstory: >
+      You are an AI assistant that acts as a human expert in neuroscience and structured models, i.e., ontologies or schemas, and someone who does not hallucinate.  
+      Your task is to evaluate, i.e., review the result {judged_structured_information_with_human_feedback} to see if everything is correct and if not fix it. 
+      Your responses strictly adhere to JSON format, ensuring accurate and structured data extraction for downstream applications.
+    llm:
+      model: openrouter/anthropic/claude-3.7-sonnet
+      base_url: https://openrouter.ai/api/v1
+
+# agent task config
+task_config:
+  extraction_task:
+    description: >
+      Meticulously extract and classify all relevant entities into the most appropriate and specific category from the provided neuroscience text. 
+         The list of entities extracted should be exhaustive and comprehensive. You should identify and label all entities, including duplicates.                                                             
+         Please ensure that all entities are accurately identified and classified according to their role within the neuroscience domain. 
+         IMPORTANT: DO NOT modify the input text in any way. Use the text as is, without any alterations or corrections. 
+      
+      
+       Instructions: 
+      
+           NER Extractions instructions:
+               - Read the input {literature} carefully by paragraph. Split into small paragraph chunks as necessary.
+               - Read the entire paper thoroughly, analyzing sentence by sentence.
+               - Do not skip over large sections of text—ensure full coverage of all paragraphs and sections (e.g., abstract, methods, results).
+               - If only a few entities are detected from a large block of text, reassess your extraction to avoid missing relevant entities.
+               - Identify and extract all the named entities relevant to neuroscience.
+               - A named entity is anything that can be referred to with a proper name.
+               - Examples of neuroscience related named entities include the following:
+                   - Animal species (e.g., mouse, drosophila, zebrafish)
+                   - Brain or anatomical regions (e.g., neocortex, mushroom body, cerebellum)
+                   - Experimental conditions (e.g., control, tetrodotoxin treatment, Scn1a knockout)
+                   - Cell types (e.g., pyramidal neuron, direction-sensitive mechanoreceptor, oligodendrocyte)
+               - Ensure each extracted entity is clearly labeled with its entity type (e.g., species, region, condition, cell type).
+               - If you are unsure about a term, include it with a flag for review (e.g., "uncertain").
+               - If there are multiple sentences that refer to the same entity extract all the sentences, the start end index and make it as a list in the output.
+        Important
+          - Minimum numbers should be at least 100 entities for large text. 
+         paper_metadata_consistency_check: 
+            Ensure all entity entries in the output include consistent and correct metadata:
+              - Each entity must have a valid `paper_title` and `doi` field.
+              - If multiple entities come from the same paper, the values of `paper_title` and `doi` must be identical across those entities.
+              - If a value is missing, check the other entries or the original context and fill it in accordingly.
+              - Do not leave `paper_title` or `doi` blank unless all entries are truly missing that information.
+              - Avoid using placeholder values like "Check for updates" as `paper_title`.
+        
+          rules:
+            - paper_title: must be a non-empty string (not a list)
+            - doi: must be a string, may be empty only if genuinely unavailable for all entries
+            - values should be normalized across entries from the same source
+            - if any entity has these fields filled, others from the same paper must have matching values
+        
+          failure_modes_to_fix:
+            - One entity has `doi` and `paper_title` while others do not
+            - One entity has placeholder `paper_title`, like "Check for updates", while others are correct
+            - One entry has a `doi` but another from the same paper has an empty string
+      output_requirements:
+                           - The output must be a **single JSON object**
+                           - The **only top-level key** must be: "extracted_terms"
+                           - Second-level keys must be **stringified integers**: "1", "2", ...
+                           - Do not nest under another key like 'extracted_terms'
+                           - The value of each second-level key must be a **list** of entity mention objects
+  
+                schema_rules:
+                    top_level:
+                      type: object
+                      key: "extracted_terms"
+                      note: Do not nest under another dictionary
+  
+                    second_level_keys:
+                      type: string
+                      format: stringified integers
+                      order: ascending
+                      example: ["1", "2", "3"]
+  
+                    entity_entry:
+                      required_fields:
+                        - entity: string
+                        - label: string
+                        - ontology_id: string or null
+                        - ontology_label: string or null
+                        - sentence: array of strings
+                        - start: array of integers
+                        - end: array of integers 
+                        - remarks: array of strings
+                        - paper_location: array of strings
+                        - paper_title: string  # ⚠️ Not an array
+                        - doi: string
+  
+                      notes:
+                        - The following fields must be arrays of the same length:
+                            - sentence
+                            - start
+                            - end 
+                            - remarks
+                            - paper_location
+                        - If ontology match is missing, set:
+                            - ontology_id: null
+                            - ontology_label: null
+                        - paper_title must be a string, even if repeated in multiple entries
+  
+                    strict_schema: true
+                    disallowed:
+                      - extra top-level keys
+                      - arrays for paper_title
+                      - nested result containers like 'judged_structured_information'
+  
+                  remarks_instructions:
+                    - Append a remark for each entry
+                    - Preserve prior remarks if present
+                    - Mention any user edits explicitly
+
+    expected_output: >
+      output format: json
+      Example output:
+      "extracted_terms": {
+        "1": [
+          {
+            "entity": "mouse",
+            "label": "ANIMAL_SPECIES",
+            "sentence": [
+              "These particles were visualized by fluorescent immunohistochemistry using mouse monoclonal anti-human myelin basic protein (MBPh) antibody (clone SMI-99).",
+              "The mouse was selected due to its genetic similarity to humans and its well-characterized nervous system."
+            ],
+            "start": [79, 4],
+            "end": [84, 9],
+            "paper_location": ["methods", "introduction"],
+            "paper_title": "Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve",
+            "doi": "10.1101/2025.03.19.643597"
+          }
+        ],
+        "2": [
+          {
+            "entity": "oligodendrocyte",
+            "label": "CELL_TYPE",
+            "sentence": [
+              "Individual oligodendrocytes provide, on average, 16 near axons with single myelin segments about 200 µm in length (Butt and Ransom, 1993)."
+            ],
+            "start": [14],
+            "end": [29],
+            "paper_location": ["discussion"],
+            "paper_title": "Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve",
+            "doi": "10.1101/2025.03.19.643597"
+          }
+        ],
+        "3": [
+          {
+            "entity": "cerebellum",
+            "label": "ANATOMICAL_REGION",
+            "sentence": [
+              "Myelin basic protein, human (MBPh) The mouse monoclonal antibody against the human myelin basic protein (clone SMI-99; Covance, Princeton, NJ) detects 4 bands between 14 and 21 kDa, corresponding to 4 myelin basic protein (MBP) isoforms on immunoblots of the mouse cerebellum (Dyer et al.).",
+              "Protein levels were also analyzed in the cerebellum to evaluate demyelination effects."
+            ],
+            "start": [293, 37],
+            "end": [303, 47],
+            "paper_location": ["methods", "results"],
+            "paper_title": "Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve",
+            "doi": "10.1101/2025.03.19.643597"
+          }
+        ]
+      ...
+      }
+
+    agent_id: extractor_agent
+
+  alignment_task:
+    description: >
+      Perform concept alignment on the extracted structured information by mapping each entity 
+      to a matching concept (class) from a given ontology or schema.
+      
+      Inputs: {extracted_structured_information}
+      
+      Instructions:
+        alignment instructions:
+          - For each entity in `extracted_structured_information`, find the most appropriate matching concept from an ontology or schema.
+          - Concept alignment means associating a term with a known ontological class or identifier (e.g., from CL, UBERON, NCBITaxon, etc.).
+          - Use a local knowledge source or indexed search system to retrieve candidate concepts (labels or IDs) where possible and marked in remarks if local knowledge source is used.
+          - Record the matched ontology information for each term:
+              - Ontology label (e.g., "hippocampus")
+              - Ontology ID (e.g., "UBERON:0001950")
+          - Add a `remarks` for each alignment, noting whether:
+              - The alignment was made using a successful match from the local knowledge source.
+              - Or the alignment was inferred without a direct match.
+          - Do not remove or overwrite any previous remarks; always append new remarks.
+      
+        User Feedback Handling:
+          If the input includes modifications made based on human/user feedback:
+          Detect and respect these changes (e.g., altered extracted terms).
+          Do not overwrite user-modified terms.
+          Instead, annotate in remarks that user-defined values were retained and evaluated accordingly.
+      
+        failure_modes_to_fix:
+            - "Inconsistent `ontology_id`/`ontology_label` across same entity."
+            - "Missing alignment remark."
+            - "`paper_title` or `doi` inconsistent with other entries from same paper."
+      
+      output_requirements:
+                         - The output must be a **single JSON object**
+                         - The **only top-level key** must be: "aligned_ner_terms"
+                         - Second-level keys must be **stringified integers**: "1", "2", ...
+                         - Do not nest under another key like 'aligned_ner_terms'
+                         - The value of each second-level key must be a **list** of entity mention objects
+  
+              schema_rules:
+                  top_level:
+                    type: object
+                    key: "aligned_ner_terms"
+                    note: Do not nest under another dictionary
+  
+                  second_level_keys:
+                    type: string
+                    format: stringified integers
+                    order: ascending
+                    example: ["1", "2", "3"]
+  
+                  entity_entry:
+                    required_fields:
+                      - entity: string
+                      - label: string
+                      - ontology_id: string or null
+                      - ontology_label: string or null
+                      - sentence: array of strings
+                      - start: array of integers
+                      - end: array of integers 
+                      - remarks: array of strings
+                      - paper_location: array of strings
+                      - paper_title: array of strings
+                      - doi: array of strings
+  
+                    notes:
+                      - The following fields must be arrays of the same length:
+                          - sentence
+                          - start
+                          - end 
+                          - remarks
+                          - paper_title
+                          - doi
+                          - paper_location
+                      - If ontology match is missing, set:
+                          - ontology_id: null
+                          - ontology_label: null
+                      - paper_title must be a string, even if repeated in multiple entries
+  
+                  strict_schema: true
+                  disallowed:
+                    - extra top-level keys
+                    - arrays for paper_title
+                    - nested result containers like 'judged_structured_information'
+  
+                remarks_instructions:
+                  - Append a remark for each entry
+                  - Preserve prior remarks if present
+                  - Mention any user edits explicitly
+
+    expected_output: >
+      output format: json
+      Example output:
+      "aligned_ner_terms": {
+        "1": [
+          {
+            "entity": "mouse",
+            "label": "ANIMAL_SPECIES",
+            "ontology_id": "http://purl.obolibrary.org/obo/NCBITaxon_10090",
+            "ontology_label": "Mus musculus",
+            "sentence": [
+              "These particles were visualized by fluorescent immunohistochemistry using mouse monoclonal anti-human myelin basic protein (MBPh) antibody (clone SMI-99).",
+              "The mouse was selected due to its genetic similarity to humans and its well-characterized nervous system."
+            ],
+            "start": [79, 4],
+            "end": [84, 9],
+            "remarks": [
+              "alignment is based on the search result i.e., knowledge source",
+              "alignment is based on the search result i.e., knowledge source"
+            ],
+            "paper_location": ["methods", "introduction"],
+            "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+            "doi": ["10.1101/2025.03.19.643597", "10.1101/2025.03.19.643597"]
+          }
+        ],
+        "2": [
+          {
+            "entity": "oligodendrocyte",
+            "label": "CELL_TYPE",
+            "ontology_id": "http://purl.obolibrary.org/obo/CL_0000128",
+            "ontology_label": "Oligodendrocyte",
+            "sentence": [
+              "Individual oligodendrocytes provide, on average, 16 near axons with single myelin segments about 200 µm in length (Butt and Ransom, 1993)."
+            ],
+            "start": [14],
+            "end": [29],
+            "remarks": [
+              "alignment is based on the search result i.e., knowledge source"
+            ],
+            "paper_location": ["discussion"],
+            "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+            "doi": ["10.1101/2025.03.19.643597"]
+          }
+        ],
+        "3": [
+          {
+            "entity": "cerebellum",
+            "label": "ANATOMICAL_REGION",
+            "ontology_id": "http://purl.obolibrary.org/obo/UBERON_0002037",
+            "ontology_label": "Cerebellum",
+            "sentence": [
+              "Myelin basic protein, human (MBPh) The mouse monoclonal antibody against the human myelin basic protein (clone SMI-99; Covance, Princeton, NJ) detects 4 bands between 14 and 21 kDa, corresponding to 4 myelin basic protein (MBP) isoforms on immunoblots of the mouse cerebellum (Dyer et al.).",
+              "Protein levels were also analyzed in the cerebellum to evaluate demyelination effects."
+            ],
+            "start": [293, 37],
+            "end": [303, 47],
+            "remarks": [
+              "alignment is based on the search result i.e., knowledge source",
+              "alignment is based on the search result i.e., knowledge source"
+            ],
+            "paper_location": ["methods", "results"],
+            "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+            "doi": ["10.1101/2025.03.19.643597", "10.1101/2025.03.19.643597"]
+          }
+        ]
+      ...
+      }
+
+    agent_id: alignment_agent
+
+  judge_task:
+    description: >
+      Evaluate the structured output from the alignment agent ({aligned_structured_information}). 
+        Assess both the quality of the original extraction and its alignment with the ontology or schema. Assign a `judge_score` between 0 and 1, and append remarks justifying the evaluation.
+      
+      Instuctions:
+        User Feedback Handling:
+          If the input includes previously made based on human/user feedback:
+          Detect and respect these changes (e.g., altered extracted terms).
+          Do not overwrite user-modified terms.
+          Instead, annotate in remarks that user-defined values were retained and evaluated accordingly.
+  
+        Judgement:
+          - Analyze the content of {aligned_structured_information} and evaluate how well the extracted information aligns with the target ontology or schema.
+          - Assign a `judge_score` between 0 and 1:
+              - 1.0 = perfect alignment
+              - 0.0 = misaligned or invalid
+              - Intermediate values indicate partial alignment
+          - Append a remarks justifying the score. Do not remove or overwrite existing remarks; always preserve previous ones.
+          - If user-modified fields (e.g., extracted terms) are present, do not overwrite them. Note their presence and evaluation in the remarks.
+          - Ensure the final structure is schema-compliant and retains all original metadata and history.
+      
+      failure_modes_to_fix:
+          - "Missing `judge_score` or `remarks` per sentence."
+          - "Inconsistent `paper_title` or `doi`." 
+          - "Non-matching array lengths across sentence, score, and remarks."
+      
+      output_requirements:
+                         - The output must be a **single JSON object**
+                         - The **only top-level key** must be: "judge_ner_terms"
+                         - Second-level keys must be **stringified integers**: "1", "2", ...
+                         - Do not nest under another key like 'judge_ner_terms'
+                         - The value of each second-level key must be a **list** of entity mention objects
+  
+              schema_rules:
+                  top_level:
+                    type: object
+                    key: "judge_ner_terms"
+                    note: Do not nest under another dictionary
+  
+                  second_level_keys:
+                    type: string
+                    format: stringified integers
+                    order: ascending
+                    example: ["1", "2", "3"]
+  
+                  entity_entry:
+                    required_fields:
+                      - entity: string
+                      - label: string
+                      - ontology_id: string or null
+                      - ontology_label: string or null
+                      - sentence: array of strings
+                      - start: array of integers
+                      - end: array of integers
+                      - judge_score: array of floats
+                      - remarks: array of strings
+                      - paper_location: array of strings
+                      - paper_title: array of strings
+                      - doi: array of strings
+  
+                    notes:
+                      - The following fields must be arrays of the same length:
+                          - sentence
+                          - start
+                          - end
+                          - judge_score
+                          - remarks
+                          - doi
+                          - paper_title 
+                          - paper_location
+                      - If ontology match is missing, set:
+                          - ontology_id: null
+                          - ontology_label: null
+                      - paper_title must be a string, even if repeated in multiple entries
+  
+                  strict_schema: true
+                  disallowed:
+                    - extra top-level keys
+                    - arrays for paper_title
+                    - nested result containers like 'judged_structured_information'
+  
+                remarks_instructions:
+                  - Append a remark for each entry
+                  - Preserve prior remarks if present
+                  - Mention any user edits explicitly
+  
+                judge_score_instructions:
+                  - Assign a float score between 0 and 1 per sentence
+                  - 1.0 = perfect match, 0.0 = no match, values in between = partial match
+
+    expected_output: > 
+      output format: json 
+      Example output:
+      "judge_ner_terms": {
+                          "1": [
+                            {
+                              "entity": "mouse",
+                              "label": "ANIMAL_SPECIES",
+                              "ontology_id": "http://purl.obolibrary.org/obo/NCBITaxon_10090",
+                              "ontology_label": "Mus musculus",
+                              "sentence": [
+                                "These particles were visualized by fluorescent immunohistochemistry using mouse monoclonal anti-human myelin basic protein (MBPh) antibody (clone SMI-99).",
+                                "The mouse was selected due to its genetic similarity to humans and its well-characterized nervous system."
+                              ],
+                              "start": [79, 4],
+                              "end": [84, 9],
+                              "remarks": [
+                                "High-confidence alignment based on exact match in the knowledge source (ontology label: Mus musculus).",
+                                "High-confidence alignment based on contextual and exact term usage in ontology search results."
+                              ],
+                              "judge_score": [0.95, 0.93],
+                              "paper_location": ["methods", "introduction"],
+                              "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve","Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+                              "doi": ["10.1101/2025.03.19.643597", "10.1101/2025.03.19.643597"]
+                            }
+                          ],
+                          "2": [
+                            {
+                              "entity": "oligodendrocyte",
+                              "label": "CELL_TYPE",
+                              "ontology_id": "http://purl.obolibrary.org/obo/CL_0000128",
+                              "ontology_label": "Oligodendrocyte",
+                              "sentence": [
+                                "Individual oligodendrocytes provide, on average, 16 near axons with single myelin segments about 200 µm in length (Butt and Ransom, 1993)."
+                              ],
+                              "start": [14],
+                              "end": [29],
+                              "remarks": [
+                                "Confident alignment based on direct match with ontology class label in the knowledge source."
+                              ],
+                              "judge_score": [0.88],
+                              "paper_location": ["discussion"],
+                              "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+                              "doi": ["10.1101/2025.03.19.643597"]
+                            }
+                          ],
+                          "3": [
+                            {
+                              "entity": "cerebellum",
+                              "label": "ANATOMICAL_REGION",
+                              "ontology_id": "http://purl.obolibrary.org/obo/UBERON_0002037",
+                              "ontology_label": "Cerebellum",
+                              "sentence": [
+                                "Myelin basic protein, human (MBPh) The mouse monoclonal antibody against the human myelin basic protein (clone SMI-99; Covance, Princeton, NJ) detects 4 bands between 14 and 21 kDa, corresponding to 4 myelin basic protein (MBP) isoforms on immunoblots of the mouse cerebellum (Dyer et al.).",
+                                "Protein levels were also analyzed in the cerebellum to evaluate demyelination effects."
+                              ],
+                              "start": [293, 37],
+                              "end": [303, 47],
+                              "remarks": [
+                                "Moderate confidence alignment; match found in ontology, but context is less directly linked to definition.",
+                                "Moderate confidence alignment; term matches ontology label, but surrounding context offers less specificity."
+                              ],
+                              "judge_score": [0.72, 0.70],
+                              "paper_location": ["methods", "results"],
+                              "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve","Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+                              "doi": ["10.1101/2025.03.19.643597", "10.1101/2025.03.19.643597"]
+                            }
+                          ]
+      ...
+      }
+
+    agent_id: judge_agent
+
+  humanfeedback_task:
+    description: >
+      Input: {judged_structured_information_with_human_feedback}
+  
+      Objective: Evaluate and, if necessary, revise the structured output to ensure accurate alignment with the target ontology/schema.
+  
+      Important: The number of extracted entities should not be less than what you received.
+      modification_context: 
+        {modification_context}
+      
+      user_feedback_text:
+        {user_feedback_text}
+      
+      Instructions:
+  
+      Alignment Assessment:
+        Analyze {judged_structured_information_with_human_feedback} to determine whether the extracted terms and structures are correctly aligned with the intended ontology or schema.
+  
+      
+      update_handling:
+            - "Preserve existing remarks."
+            - "Append new remark for each change made."
+            - "Indicate knowledge source or user evidence behind updates in remarks."
+  
+      Provenance-Aware Remarking:
+        Update the remarks field as follows:
+        Append a new remark describing the updates made (e.g., corrected label, updated score).
+        Specify if the update was informed by a knowledge source or prior evidence.
+        Do not remove existing remarks—always preserve historical annotations.
+  
+      User Feedback Handling:
+        If the input includes modifications made based on human/user feedback:
+        Detect and respect these changes (e.g., altered extracted terms).
+        Do not overwrite user-modified terms.
+        Instead, annotate in remarks that user-defined values were retained and evaluated accordingly.
+      
+      failure_modes_to_fix:
+        - "Judge score conflicts (e.g., 1.0 score for low-quality match)."
+        - "Misaligned paper metadata across multiple entries."
+        - "Missing or conflicting ontology IDs for same entity."
+        - "Field arrays of unequal length."
+  
+      Constraints:
+        Preserve all historical data (especially remarks).
+        Ensure outputs are traceable, auditable, and schema-compliant.
+      
+      output_requirements:
+                     - The output must be a **single JSON object**
+                     - The **only top-level key** must be: "judge_ner_terms"
+                     - Second-level keys must be **stringified integers**: "1", "2", ...
+                     - Do not nest under another key like 'judge_ner_terms'
+                     - The value of each second-level key must be a **list** of entity mention objects
+  
+          schema_rules:
+              top_level:
+                type: object
+                key: "judge_ner_terms"
+                note: Do not nest under another dictionary
+  
+              second_level_keys:
+                type: string
+                format: stringified integers
+                order: ascending
+                example: ["1", "2", "3"]
+  
+              entity_entry:
+                required_fields:
+                  - entity: string
+                  - label: string
+                  - ontology_id: string or null
+                  - ontology_label: string or null
+                  - sentence: array of strings
+                  - start: array of integers
+                  - end: array of integers
+                  - judge_score: array of floats
+                  - remarks: array of strings
+                  - paper_location: array of strings
+                  - paper_title: array of strings
+                  - doi: array of strings
+  
+                notes:
+                  - The following fields must be arrays of the same length:
+                      - sentence
+                      - start
+                      - end
+                      - doi
+                      - paper_title 
+                      - judge_score
+                      - remarks
+                      - paper_location
+                  - If ontology match is missing, set:
+                      - ontology_id: null
+                      - ontology_label: null
+                  - paper_title must be a string, even if repeated in multiple entries
+  
+              strict_schema: true
+              disallowed:
+                - extra top-level keys
+                - arrays for paper_title
+                - nested result containers like 'judged_structured_information'
+  
+            remarks_instructions:
+              - Append a remark for each entry
+              - Preserve prior remarks if present
+              - Mention any user edits explicitly
+  
+            judge_score_instructions:
+              - Assign a float score between 0 and 1 per sentence
+              - 1.0 = perfect match, 0.0 = no match, values in between = partial match
+  
+
+    expected_output: > 
+      output format: json
+      Example output:
+      "judge_ner_terms": {
+                              "1": [
+                                {
+                                  "entity": "mouse",
+                                  "label": "ANIMAL_SPECIES",
+                                  "ontology_id": "http://purl.obolibrary.org/obo/NCBITaxon_10090",
+                                  "ontology_label": "Mus musculus",
+                                  "sentence": [
+                                    "These particles were visualized by fluorescent immunohistochemistry using mouse monoclonal anti-human myelin basic protein (MBPh) antibody (clone SMI-99).",
+                                    "The mouse was selected due to its genetic similarity to humans and its well-characterized nervous system."
+                                  ],
+                                  "start": [79, 4],
+                                  "end": [84, 9],
+                                  "remarks": [
+                                    "High-confidence alignment based on exact match in the knowledge source (ontology label: Mus musculus).",
+                                    "High-confidence alignment based on contextual and exact term usage in ontology search results."
+                                  ],
+                                  "judge_score": [0.95, 0.93],
+                                  "paper_location": ["methods", "introduction"],
+                                  "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve","Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+                                  "doi": ["10.1101/2025.03.19.643597", "10.1101/2025.03.19.643597"]
+                                }
+                              ],
+                              "2": [
+                                {
+                                  "entity": "oligodendrocyte",
+                                  "label": "CELL_TYPE",
+                                  "ontology_id": "http://purl.obolibrary.org/obo/CL_0000128",
+                                  "ontology_label": "Oligodendrocyte",
+                                  "sentence": [
+                                    "Individual oligodendrocytes provide, on average, 16 near axons with single myelin segments about 200 µm in length (Butt and Ransom, 1993)."
+                                  ],
+                                  "start": [14],
+                                  "end": [29],
+                                  "remarks": [
+                                    "Confident alignment based on direct match with ontology class label in the knowledge source."
+                                  ],
+                                  "judge_score": [0.88],
+                                  "paper_location": ["discussion"],
+                                  "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+                                  "doi": ["10.1101/2025.03.19.643597"]
+                                }
+                              ],
+                              "3": [
+                                {
+                                  "entity": "cerebellum",
+                                  "label": "ANATOMICAL_REGION",
+                                  "ontology_id": "http://purl.obolibrary.org/obo/UBERON_0002037",
+                                  "ontology_label": "Cerebellum",
+                                  "sentence": [
+                                    "Myelin basic protein, human (MBPh) The mouse monoclonal antibody against the human myelin basic protein (clone SMI-99; Covance, Princeton, NJ) detects 4 bands between 14 and 21 kDa, corresponding to 4 myelin basic protein (MBP) isoforms on immunoblots of the mouse cerebellum (Dyer et al.).",
+                                    "Protein levels were also analyzed in the cerebellum to evaluate demyelination effects."
+                                  ],
+                                  "start": [293, 37],
+                                  "end": [303, 47],
+                                  "remarks": [
+                                    "Moderate confidence alignment; match found in ontology, but context is less directly linked to definition.",
+                                    "Moderate confidence alignment; term matches ontology label, but surrounding context offers less specificity."
+                                  ],
+                                  "judge_score": [0.72, 0.70], 
+                                  "paper_location": ["methods", "results"],
+                                  "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve","Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+                                  "doi": ["10.1101/2025.03.19.643597","10.1101/2025.03.19.643597"]
+                                }
+                              ]
+      ...
+          }
+
+    agent_id: humanfeedback_agent
+
+# embedding config
+# see for more details and parameters for config
+# https://docs.crewai.com/concepts/memory#additional-embedding-providerscl
+embedder_config:
+  provider: ollama
+  config:
+    api_base: http://localhost:11434
+    model: nomic-embed-text:v1.5
+
+# knowledge search config
+knowledge_config:
+  search_key: #local vector database
+    - entity
+    - label
+# human in loop config
+human_in_loop_config:
+  humanfeedback_agent: true
\ No newline at end of file
diff --git a/evaluation/ner/old/ner_config_deepseek.yaml b/evaluation/ner/old/ner_config_deepseek.yaml
new file mode 100644
index 0000000..018dd80
--- /dev/null
+++ b/evaluation/ner/old/ner_config_deepseek.yaml
@@ -0,0 +1,735 @@
+#agent config
+agent_config:
+  extractor_agent:
+    role: >
+      Neuroscience Named Entity Recognition (NER) Extractor Agent
+    goal: >
+      Perform Named Entity Recognition (NER) on neuroscience {literature} process it by paragraph, chunk as necessary and return structured JSON output.
+    backstory: >
+      You are an AI assistant specialized in processing neuroscience and who do not hallucinate. 
+      Your expertise includes recognizing and categorizing named entities such as anatomical regions, experimental conditions, and cell types. 
+      Your responses strictly adhere to JSON format, ensuring accurate and structured data extraction for downstream applications.
+    llm:
+      model: openrouter/deepseek/deepseek-chat-v3-0324
+      base_url: https://openrouter.ai/api/v1
+
+  alignment_agent:
+    role: >
+      Neuroscience Named Entity Recognition (NER) Concept Alignment Agent
+    goal: >
+      Perform concept alignment to the extracted Named Entity Recognition (NER) by extractor_agent {extracted_structured_information} and return structured JSON output.
+    backstory: >
+      You are an AI assistant specialized in processing neuroscience concept alignment with structured models, i.e., ontologies or schemas and who do not hallucinate. 
+      Your expertise includes recognizing and categorizing extracted named entities such as anatomical regions, experimental conditions, and cell types and aligning the recognized named entities such as cell types with corresponding ontological terms. 
+      Your responses strictly adhere to JSON format, ensuring accurate and structured data extraction for downstream applications.
+    llm:
+      model: openrouter/deepseek/deepseek-chat-v3-0324
+      base_url: https://openrouter.ai/api/v1
+
+  judge_agent:
+    role: >
+      Neuroscience Named Entity Recognition (NER) Judge Agent
+    goal: >
+      Evaluate the {aligned_structured_information} based on predefined criteria and generate a structured JSON output reflecting the assessment results.
+    backstory: >
+      You are an AI assistant with expert knowledge in neuroscience and structured models, i.e., ontologies or schemas, and someone who does not hallucinate.  
+      Your task is to evaluate the {aligned_structured_information} based on the accuracy and quality of the alignment. 
+      Assign the score between 0-1 with 1 being the highest score of your evaluation.
+      Your responses strictly adhere to JSON format, ensuring accurate and structured data extraction for downstream applications.
+    llm:
+      model: openrouter/deepseek/deepseek-chat-v3-0324
+      base_url: https://openrouter.ai/api/v1
+
+  humanfeedback_agent:
+    role: >
+      Neuroscience Named Entity Recognition (NER) Human feedback processor Agent
+    goal: >
+      Evaluate the {judged_structured_information_with_human_feedback} and review if everything is correct as human domain expert.
+    backstory: >
+      You are an AI assistant that acts as a human expert in neuroscience and structured models, i.e., ontologies or schemas, and someone who does not hallucinate.  
+      Your task is to evaluate, i.e., review the result {judged_structured_information_with_human_feedback} to see if everything is correct and if not fix it. 
+      Your responses strictly adhere to JSON format, ensuring accurate and structured data extraction for downstream applications.
+    llm:
+      model: openrouter/deepseek/deepseek-chat-v3-0324
+      base_url: https://openrouter.ai/api/v1
+
+# agent task config
+task_config:
+  extraction_task:
+    description: >
+      Meticulously extract and classify all relevant entities into the most appropriate and specific category from the provided neuroscience text. 
+         The list of entities extracted should be exhaustive and comprehensive. You should identify and label all entities, including duplicates.                                                             
+         Please ensure that all entities are accurately identified and classified according to their role within the neuroscience domain. 
+         IMPORTANT: DO NOT modify the input text in any way. Use the text as is, without any alterations or corrections. 
+      
+      
+       Instructions: 
+      
+           NER Extractions instructions:
+               - Read the input {literature} carefully by paragraph. Split into small paragraph chunks as necessary.
+               - Read the entire paper thoroughly, analyzing sentence by sentence.
+               - Do not skip over large sections of text—ensure full coverage of all paragraphs and sections (e.g., abstract, methods, results).
+               - If only a few entities are detected from a large block of text, reassess your extraction to avoid missing relevant entities.
+               - Identify and extract all the named entities relevant to neuroscience.
+               - A named entity is anything that can be referred to with a proper name.
+               - Examples of neuroscience related named entities include the following:
+                   - Animal species (e.g., mouse, drosophila, zebrafish)
+                   - Brain or anatomical regions (e.g., neocortex, mushroom body, cerebellum)
+                   - Experimental conditions (e.g., control, tetrodotoxin treatment, Scn1a knockout)
+                   - Cell types (e.g., pyramidal neuron, direction-sensitive mechanoreceptor, oligodendrocyte)
+               - Ensure each extracted entity is clearly labeled with its entity type (e.g., species, region, condition, cell type).
+               - If you are unsure about a term, include it with a flag for review (e.g., "uncertain").
+               - If there are multiple sentences that refer to the same entity extract all the sentences, the start end index and make it as a list in the output.
+        Important
+          - Minimum numbers should be at least 100 entities for large text. 
+         paper_metadata_consistency_check: 
+            Ensure all entity entries in the output include consistent and correct metadata:
+              - Each entity must have a valid `paper_title` and `doi` field.
+              - If multiple entities come from the same paper, the values of `paper_title` and `doi` must be identical across those entities.
+              - If a value is missing, check the other entries or the original context and fill it in accordingly.
+              - Do not leave `paper_title` or `doi` blank unless all entries are truly missing that information.
+              - Avoid using placeholder values like "Check for updates" as `paper_title`.
+        
+          rules:
+            - paper_title: must be a non-empty string (not a list)
+            - doi: must be a string, may be empty only if genuinely unavailable for all entries
+            - values should be normalized across entries from the same source
+            - if any entity has these fields filled, others from the same paper must have matching values
+        
+          failure_modes_to_fix:
+            - One entity has `doi` and `paper_title` while others do not
+            - One entity has placeholder `paper_title`, like "Check for updates", while others are correct
+            - One entry has a `doi` but another from the same paper has an empty string
+      output_requirements:
+                           - The output must be a **single JSON object**
+                           - The **only top-level key** must be: "extracted_terms"
+                           - Second-level keys must be **stringified integers**: "1", "2", ...
+                           - Do not nest under another key like 'extracted_terms'
+                           - The value of each second-level key must be a **list** of entity mention objects
+  
+                schema_rules:
+                    top_level:
+                      type: object
+                      key: "extracted_terms"
+                      note: Do not nest under another dictionary
+  
+                    second_level_keys:
+                      type: string
+                      format: stringified integers
+                      order: ascending
+                      example: ["1", "2", "3"]
+  
+                    entity_entry:
+                      required_fields:
+                        - entity: string
+                        - label: string
+                        - ontology_id: string or null
+                        - ontology_label: string or null
+                        - sentence: array of strings
+                        - start: array of integers
+                        - end: array of integers 
+                        - remarks: array of strings
+                        - paper_location: array of strings
+                        - paper_title: string  # ⚠️ Not an array
+                        - doi: string
+  
+                      notes:
+                        - The following fields must be arrays of the same length:
+                            - sentence
+                            - start
+                            - end 
+                            - remarks
+                            - paper_location
+                        - If ontology match is missing, set:
+                            - ontology_id: null
+                            - ontology_label: null
+                        - paper_title must be a string, even if repeated in multiple entries
+  
+                    strict_schema: true
+                    disallowed:
+                      - extra top-level keys
+                      - arrays for paper_title
+                      - nested result containers like 'judged_structured_information'
+  
+                  remarks_instructions:
+                    - Append a remark for each entry
+                    - Preserve prior remarks if present
+                    - Mention any user edits explicitly
+
+    expected_output: >
+      output format: json
+      Example output:
+      "extracted_terms": {
+        "1": [
+          {
+            "entity": "mouse",
+            "label": "ANIMAL_SPECIES",
+            "sentence": [
+              "These particles were visualized by fluorescent immunohistochemistry using mouse monoclonal anti-human myelin basic protein (MBPh) antibody (clone SMI-99).",
+              "The mouse was selected due to its genetic similarity to humans and its well-characterized nervous system."
+            ],
+            "start": [79, 4],
+            "end": [84, 9],
+            "paper_location": ["methods", "introduction"],
+            "paper_title": "Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve",
+            "doi": "10.1101/2025.03.19.643597"
+          }
+        ],
+        "2": [
+          {
+            "entity": "oligodendrocyte",
+            "label": "CELL_TYPE",
+            "sentence": [
+              "Individual oligodendrocytes provide, on average, 16 near axons with single myelin segments about 200 µm in length (Butt and Ransom, 1993)."
+            ],
+            "start": [14],
+            "end": [29],
+            "paper_location": ["discussion"],
+            "paper_title": "Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve",
+            "doi": "10.1101/2025.03.19.643597"
+          }
+        ],
+        "3": [
+          {
+            "entity": "cerebellum",
+            "label": "ANATOMICAL_REGION",
+            "sentence": [
+              "Myelin basic protein, human (MBPh) The mouse monoclonal antibody against the human myelin basic protein (clone SMI-99; Covance, Princeton, NJ) detects 4 bands between 14 and 21 kDa, corresponding to 4 myelin basic protein (MBP) isoforms on immunoblots of the mouse cerebellum (Dyer et al.).",
+              "Protein levels were also analyzed in the cerebellum to evaluate demyelination effects."
+            ],
+            "start": [293, 37],
+            "end": [303, 47],
+            "paper_location": ["methods", "results"],
+            "paper_title": "Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve",
+            "doi": "10.1101/2025.03.19.643597"
+          }
+        ]
+      ...
+      }
+
+    agent_id: extractor_agent
+
+  alignment_task:
+    description: >
+      Perform concept alignment on the extracted structured information by mapping each entity 
+      to a matching concept (class) from a given ontology or schema.
+      
+      Inputs: {extracted_structured_information}
+      
+      Instructions:
+        alignment instructions:
+          - For each entity in `extracted_structured_information`, find the most appropriate matching concept from an ontology or schema.
+          - Concept alignment means associating a term with a known ontological class or identifier (e.g., from CL, UBERON, NCBITaxon, etc.).
+          - Use a local knowledge source or indexed search system to retrieve candidate concepts (labels or IDs) where possible and marked in remarks if local knowledge source is used.
+          - Record the matched ontology information for each term:
+              - Ontology label (e.g., "hippocampus")
+              - Ontology ID (e.g., "UBERON:0001950")
+          - Add a `remarks` for each alignment, noting whether:
+              - The alignment was made using a successful match from the local knowledge source.
+              - Or the alignment was inferred without a direct match.
+          - Do not remove or overwrite any previous remarks; always append new remarks.
+      
+        User Feedback Handling:
+          If the input includes modifications made based on human/user feedback:
+          Detect and respect these changes (e.g., altered extracted terms).
+          Do not overwrite user-modified terms.
+          Instead, annotate in remarks that user-defined values were retained and evaluated accordingly.
+      
+        failure_modes_to_fix:
+            - "Inconsistent `ontology_id`/`ontology_label` across same entity."
+            - "Missing alignment remark."
+            - "`paper_title` or `doi` inconsistent with other entries from same paper."
+      
+      output_requirements:
+                         - The output must be a **single JSON object**
+                         - The **only top-level key** must be: "aligned_ner_terms"
+                         - Second-level keys must be **stringified integers**: "1", "2", ...
+                         - Do not nest under another key like 'aligned_ner_terms'
+                         - The value of each second-level key must be a **list** of entity mention objects
+  
+              schema_rules:
+                  top_level:
+                    type: object
+                    key: "aligned_ner_terms"
+                    note: Do not nest under another dictionary
+  
+                  second_level_keys:
+                    type: string
+                    format: stringified integers
+                    order: ascending
+                    example: ["1", "2", "3"]
+  
+                  entity_entry:
+                    required_fields:
+                      - entity: string
+                      - label: string
+                      - ontology_id: string or null
+                      - ontology_label: string or null
+                      - sentence: array of strings
+                      - start: array of integers
+                      - end: array of integers 
+                      - remarks: array of strings
+                      - paper_location: array of strings
+                      - paper_title: array of strings
+                      - doi: array of strings
+  
+                    notes:
+                      - The following fields must be arrays of the same length:
+                          - sentence
+                          - start
+                          - end 
+                          - remarks
+                          - paper_title
+                          - doi
+                          - paper_location
+                      - If ontology match is missing, set:
+                          - ontology_id: null
+                          - ontology_label: null
+                      - paper_title must be a string, even if repeated in multiple entries
+  
+                  strict_schema: true
+                  disallowed:
+                    - extra top-level keys
+                    - arrays for paper_title
+                    - nested result containers like 'judged_structured_information'
+  
+                remarks_instructions:
+                  - Append a remark for each entry
+                  - Preserve prior remarks if present
+                  - Mention any user edits explicitly
+
+    expected_output: >
+      output format: json
+      Example output:
+      "aligned_ner_terms": {
+        "1": [
+          {
+            "entity": "mouse",
+            "label": "ANIMAL_SPECIES",
+            "ontology_id": "http://purl.obolibrary.org/obo/NCBITaxon_10090",
+            "ontology_label": "Mus musculus",
+            "sentence": [
+              "These particles were visualized by fluorescent immunohistochemistry using mouse monoclonal anti-human myelin basic protein (MBPh) antibody (clone SMI-99).",
+              "The mouse was selected due to its genetic similarity to humans and its well-characterized nervous system."
+            ],
+            "start": [79, 4],
+            "end": [84, 9],
+            "remarks": [
+              "alignment is based on the search result i.e., knowledge source",
+              "alignment is based on the search result i.e., knowledge source"
+            ],
+            "paper_location": ["methods", "introduction"],
+            "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+            "doi": ["10.1101/2025.03.19.643597", "10.1101/2025.03.19.643597"]
+          }
+        ],
+        "2": [
+          {
+            "entity": "oligodendrocyte",
+            "label": "CELL_TYPE",
+            "ontology_id": "http://purl.obolibrary.org/obo/CL_0000128",
+            "ontology_label": "Oligodendrocyte",
+            "sentence": [
+              "Individual oligodendrocytes provide, on average, 16 near axons with single myelin segments about 200 µm in length (Butt and Ransom, 1993)."
+            ],
+            "start": [14],
+            "end": [29],
+            "remarks": [
+              "alignment is based on the search result i.e., knowledge source"
+            ],
+            "paper_location": ["discussion"],
+            "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+            "doi": ["10.1101/2025.03.19.643597"]
+          }
+        ],
+        "3": [
+          {
+            "entity": "cerebellum",
+            "label": "ANATOMICAL_REGION",
+            "ontology_id": "http://purl.obolibrary.org/obo/UBERON_0002037",
+            "ontology_label": "Cerebellum",
+            "sentence": [
+              "Myelin basic protein, human (MBPh) The mouse monoclonal antibody against the human myelin basic protein (clone SMI-99; Covance, Princeton, NJ) detects 4 bands between 14 and 21 kDa, corresponding to 4 myelin basic protein (MBP) isoforms on immunoblots of the mouse cerebellum (Dyer et al.).",
+              "Protein levels were also analyzed in the cerebellum to evaluate demyelination effects."
+            ],
+            "start": [293, 37],
+            "end": [303, 47],
+            "remarks": [
+              "alignment is based on the search result i.e., knowledge source",
+              "alignment is based on the search result i.e., knowledge source"
+            ],
+            "paper_location": ["methods", "results"],
+            "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+            "doi": ["10.1101/2025.03.19.643597", "10.1101/2025.03.19.643597"]
+          }
+        ]
+      ...
+      }
+
+    agent_id: alignment_agent
+
+  judge_task:
+    description: >
+      Evaluate the structured output from the alignment agent ({aligned_structured_information}). 
+        Assess both the quality of the original extraction and its alignment with the ontology or schema. Assign a `judge_score` between 0 and 1, and append remarks justifying the evaluation.
+      
+      Instuctions:
+        User Feedback Handling:
+          If the input includes previously made based on human/user feedback:
+          Detect and respect these changes (e.g., altered extracted terms).
+          Do not overwrite user-modified terms.
+          Instead, annotate in remarks that user-defined values were retained and evaluated accordingly.
+  
+        Judgement:
+          - Analyze the content of {aligned_structured_information} and evaluate how well the extracted information aligns with the target ontology or schema.
+          - Assign a `judge_score` between 0 and 1:
+              - 1.0 = perfect alignment
+              - 0.0 = misaligned or invalid
+              - Intermediate values indicate partial alignment
+          - Append a remarks justifying the score. Do not remove or overwrite existing remarks; always preserve previous ones.
+          - If user-modified fields (e.g., extracted terms) are present, do not overwrite them. Note their presence and evaluation in the remarks.
+          - Ensure the final structure is schema-compliant and retains all original metadata and history.
+      
+      failure_modes_to_fix:
+          - "Missing `judge_score` or `remarks` per sentence."
+          - "Inconsistent `paper_title` or `doi`." 
+          - "Non-matching array lengths across sentence, score, and remarks."
+      
+      output_requirements:
+                         - The output must be a **single JSON object**
+                         - The **only top-level key** must be: "judge_ner_terms"
+                         - Second-level keys must be **stringified integers**: "1", "2", ...
+                         - Do not nest under another key like 'judge_ner_terms'
+                         - The value of each second-level key must be a **list** of entity mention objects
+  
+              schema_rules:
+                  top_level:
+                    type: object
+                    key: "judge_ner_terms"
+                    note: Do not nest under another dictionary
+  
+                  second_level_keys:
+                    type: string
+                    format: stringified integers
+                    order: ascending
+                    example: ["1", "2", "3"]
+  
+                  entity_entry:
+                    required_fields:
+                      - entity: string
+                      - label: string
+                      - ontology_id: string or null
+                      - ontology_label: string or null
+                      - sentence: array of strings
+                      - start: array of integers
+                      - end: array of integers
+                      - judge_score: array of floats
+                      - remarks: array of strings
+                      - paper_location: array of strings
+                      - paper_title: array of strings
+                      - doi: array of strings
+  
+                    notes:
+                      - The following fields must be arrays of the same length:
+                          - sentence
+                          - start
+                          - end
+                          - judge_score
+                          - remarks
+                          - doi
+                          - paper_title 
+                          - paper_location
+                      - If ontology match is missing, set:
+                          - ontology_id: null
+                          - ontology_label: null
+                      - paper_title must be a string, even if repeated in multiple entries
+  
+                  strict_schema: true
+                  disallowed:
+                    - extra top-level keys
+                    - arrays for paper_title
+                    - nested result containers like 'judged_structured_information'
+  
+                remarks_instructions:
+                  - Append a remark for each entry
+                  - Preserve prior remarks if present
+                  - Mention any user edits explicitly
+  
+                judge_score_instructions:
+                  - Assign a float score between 0 and 1 per sentence
+                  - 1.0 = perfect match, 0.0 = no match, values in between = partial match
+
+    expected_output: > 
+      output format: json 
+      Example output:
+      "judge_ner_terms": {
+                          "1": [
+                            {
+                              "entity": "mouse",
+                              "label": "ANIMAL_SPECIES",
+                              "ontology_id": "http://purl.obolibrary.org/obo/NCBITaxon_10090",
+                              "ontology_label": "Mus musculus",
+                              "sentence": [
+                                "These particles were visualized by fluorescent immunohistochemistry using mouse monoclonal anti-human myelin basic protein (MBPh) antibody (clone SMI-99).",
+                                "The mouse was selected due to its genetic similarity to humans and its well-characterized nervous system."
+                              ],
+                              "start": [79, 4],
+                              "end": [84, 9],
+                              "remarks": [
+                                "High-confidence alignment based on exact match in the knowledge source (ontology label: Mus musculus).",
+                                "High-confidence alignment based on contextual and exact term usage in ontology search results."
+                              ],
+                              "judge_score": [0.95, 0.93],
+                              "paper_location": ["methods", "introduction"],
+                              "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve","Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+                              "doi": ["10.1101/2025.03.19.643597", "10.1101/2025.03.19.643597"]
+                            }
+                          ],
+                          "2": [
+                            {
+                              "entity": "oligodendrocyte",
+                              "label": "CELL_TYPE",
+                              "ontology_id": "http://purl.obolibrary.org/obo/CL_0000128",
+                              "ontology_label": "Oligodendrocyte",
+                              "sentence": [
+                                "Individual oligodendrocytes provide, on average, 16 near axons with single myelin segments about 200 µm in length (Butt and Ransom, 1993)."
+                              ],
+                              "start": [14],
+                              "end": [29],
+                              "remarks": [
+                                "Confident alignment based on direct match with ontology class label in the knowledge source."
+                              ],
+                              "judge_score": [0.88],
+                              "paper_location": ["discussion"],
+                              "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+                              "doi": ["10.1101/2025.03.19.643597"]
+                            }
+                          ],
+                          "3": [
+                            {
+                              "entity": "cerebellum",
+                              "label": "ANATOMICAL_REGION",
+                              "ontology_id": "http://purl.obolibrary.org/obo/UBERON_0002037",
+                              "ontology_label": "Cerebellum",
+                              "sentence": [
+                                "Myelin basic protein, human (MBPh) The mouse monoclonal antibody against the human myelin basic protein (clone SMI-99; Covance, Princeton, NJ) detects 4 bands between 14 and 21 kDa, corresponding to 4 myelin basic protein (MBP) isoforms on immunoblots of the mouse cerebellum (Dyer et al.).",
+                                "Protein levels were also analyzed in the cerebellum to evaluate demyelination effects."
+                              ],
+                              "start": [293, 37],
+                              "end": [303, 47],
+                              "remarks": [
+                                "Moderate confidence alignment; match found in ontology, but context is less directly linked to definition.",
+                                "Moderate confidence alignment; term matches ontology label, but surrounding context offers less specificity."
+                              ],
+                              "judge_score": [0.72, 0.70],
+                              "paper_location": ["methods", "results"],
+                              "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve","Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+                              "doi": ["10.1101/2025.03.19.643597", "10.1101/2025.03.19.643597"]
+                            }
+                          ]
+      ...
+      }
+
+    agent_id: judge_agent
+
+  humanfeedback_task:
+    description: >
+      Input: {judged_structured_information_with_human_feedback}
+  
+      Objective: Evaluate and, if necessary, revise the structured output to ensure accurate alignment with the target ontology/schema.
+  
+      Important: The number of extracted entities should not be less than what you received.
+      modification_context: 
+        {modification_context}
+      
+      user_feedback_text:
+        {user_feedback_text}
+      
+      Instructions:
+  
+      Alignment Assessment:
+        Analyze {judged_structured_information_with_human_feedback} to determine whether the extracted terms and structures are correctly aligned with the intended ontology or schema.
+  
+      
+      update_handling:
+            - "Preserve existing remarks."
+            - "Append new remark for each change made."
+            - "Indicate knowledge source or user evidence behind updates in remarks."
+  
+      Provenance-Aware Remarking:
+        Update the remarks field as follows:
+        Append a new remark describing the updates made (e.g., corrected label, updated score).
+        Specify if the update was informed by a knowledge source or prior evidence.
+        Do not remove existing remarks—always preserve historical annotations.
+  
+      User Feedback Handling:
+        If the input includes modifications made based on human/user feedback:
+        Detect and respect these changes (e.g., altered extracted terms).
+        Do not overwrite user-modified terms.
+        Instead, annotate in remarks that user-defined values were retained and evaluated accordingly.
+      
+      failure_modes_to_fix:
+        - "Judge score conflicts (e.g., 1.0 score for low-quality match)."
+        - "Misaligned paper metadata across multiple entries."
+        - "Missing or conflicting ontology IDs for same entity."
+        - "Field arrays of unequal length."
+  
+      Constraints:
+        Preserve all historical data (especially remarks).
+        Ensure outputs are traceable, auditable, and schema-compliant.
+      
+      output_requirements:
+                     - The output must be a **single JSON object**
+                     - The **only top-level key** must be: "judge_ner_terms"
+                     - Second-level keys must be **stringified integers**: "1", "2", ...
+                     - Do not nest under another key like 'judge_ner_terms'
+                     - The value of each second-level key must be a **list** of entity mention objects
+  
+          schema_rules:
+              top_level:
+                type: object
+                key: "judge_ner_terms"
+                note: Do not nest under another dictionary
+  
+              second_level_keys:
+                type: string
+                format: stringified integers
+                order: ascending
+                example: ["1", "2", "3"]
+  
+              entity_entry:
+                required_fields:
+                  - entity: string
+                  - label: string
+                  - ontology_id: string or null
+                  - ontology_label: string or null
+                  - sentence: array of strings
+                  - start: array of integers
+                  - end: array of integers
+                  - judge_score: array of floats
+                  - remarks: array of strings
+                  - paper_location: array of strings
+                  - paper_title: array of strings
+                  - doi: array of strings
+  
+                notes:
+                  - The following fields must be arrays of the same length:
+                      - sentence
+                      - start
+                      - end
+                      - doi
+                      - paper_title 
+                      - judge_score
+                      - remarks
+                      - paper_location
+                  - If ontology match is missing, set:
+                      - ontology_id: null
+                      - ontology_label: null
+                  - paper_title must be a string, even if repeated in multiple entries
+  
+              strict_schema: true
+              disallowed:
+                - extra top-level keys
+                - arrays for paper_title
+                - nested result containers like 'judged_structured_information'
+  
+            remarks_instructions:
+              - Append a remark for each entry
+              - Preserve prior remarks if present
+              - Mention any user edits explicitly
+  
+            judge_score_instructions:
+              - Assign a float score between 0 and 1 per sentence
+              - 1.0 = perfect match, 0.0 = no match, values in between = partial match
+  
+
+    expected_output: > 
+      output format: json
+      Example output:
+      "judge_ner_terms": {
+                              "1": [
+                                {
+                                  "entity": "mouse",
+                                  "label": "ANIMAL_SPECIES",
+                                  "ontology_id": "http://purl.obolibrary.org/obo/NCBITaxon_10090",
+                                  "ontology_label": "Mus musculus",
+                                  "sentence": [
+                                    "These particles were visualized by fluorescent immunohistochemistry using mouse monoclonal anti-human myelin basic protein (MBPh) antibody (clone SMI-99).",
+                                    "The mouse was selected due to its genetic similarity to humans and its well-characterized nervous system."
+                                  ],
+                                  "start": [79, 4],
+                                  "end": [84, 9],
+                                  "remarks": [
+                                    "High-confidence alignment based on exact match in the knowledge source (ontology label: Mus musculus).",
+                                    "High-confidence alignment based on contextual and exact term usage in ontology search results."
+                                  ],
+                                  "judge_score": [0.95, 0.93],
+                                  "paper_location": ["methods", "introduction"],
+                                  "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve","Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+                                  "doi": ["10.1101/2025.03.19.643597", "10.1101/2025.03.19.643597"]
+                                }
+                              ],
+                              "2": [
+                                {
+                                  "entity": "oligodendrocyte",
+                                  "label": "CELL_TYPE",
+                                  "ontology_id": "http://purl.obolibrary.org/obo/CL_0000128",
+                                  "ontology_label": "Oligodendrocyte",
+                                  "sentence": [
+                                    "Individual oligodendrocytes provide, on average, 16 near axons with single myelin segments about 200 µm in length (Butt and Ransom, 1993)."
+                                  ],
+                                  "start": [14],
+                                  "end": [29],
+                                  "remarks": [
+                                    "Confident alignment based on direct match with ontology class label in the knowledge source."
+                                  ],
+                                  "judge_score": [0.88],
+                                  "paper_location": ["discussion"],
+                                  "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+                                  "doi": ["10.1101/2025.03.19.643597"]
+                                }
+                              ],
+                              "3": [
+                                {
+                                  "entity": "cerebellum",
+                                  "label": "ANATOMICAL_REGION",
+                                  "ontology_id": "http://purl.obolibrary.org/obo/UBERON_0002037",
+                                  "ontology_label": "Cerebellum",
+                                  "sentence": [
+                                    "Myelin basic protein, human (MBPh) The mouse monoclonal antibody against the human myelin basic protein (clone SMI-99; Covance, Princeton, NJ) detects 4 bands between 14 and 21 kDa, corresponding to 4 myelin basic protein (MBP) isoforms on immunoblots of the mouse cerebellum (Dyer et al.).",
+                                    "Protein levels were also analyzed in the cerebellum to evaluate demyelination effects."
+                                  ],
+                                  "start": [293, 37],
+                                  "end": [303, 47],
+                                  "remarks": [
+                                    "Moderate confidence alignment; match found in ontology, but context is less directly linked to definition.",
+                                    "Moderate confidence alignment; term matches ontology label, but surrounding context offers less specificity."
+                                  ],
+                                  "judge_score": [0.72, 0.70], 
+                                  "paper_location": ["methods", "results"],
+                                  "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve","Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+                                  "doi": ["10.1101/2025.03.19.643597","10.1101/2025.03.19.643597"]
+                                }
+                              ]
+      ...
+          }
+
+    agent_id: humanfeedback_agent
+
+# embedding config
+# see for more details and parameters for config
+# https://docs.crewai.com/concepts/memory#additional-embedding-providerscl
+embedder_config:
+  provider: ollama
+  config:
+    api_base: http://localhost:11434
+    model: nomic-embed-text:v1.5
+
+# knowledge search config
+knowledge_config:
+  search_key: #local vector database
+    - entity
+    - label
+# human in loop config
+human_in_loop_config:
+  humanfeedback_agent: true
\ No newline at end of file
diff --git a/evaluation/ner/old/ner_config_gpt.yaml b/evaluation/ner/old/ner_config_gpt.yaml
new file mode 100644
index 0000000..7f8003b
--- /dev/null
+++ b/evaluation/ner/old/ner_config_gpt.yaml
@@ -0,0 +1,735 @@
+#agent config
+agent_config:
+  extractor_agent:
+    role: >
+      Neuroscience Named Entity Recognition (NER) Extractor Agent
+    goal: >
+      Perform Named Entity Recognition (NER) on neuroscience {literature} process it by paragraph, chunk as necessary and return structured JSON output.
+    backstory: >
+      You are an AI assistant specialized in processing neuroscience and who do not hallucinate. 
+      Your expertise includes recognizing and categorizing named entities such as anatomical regions, experimental conditions, and cell types. 
+      Your responses strictly adhere to JSON format, ensuring accurate and structured data extraction for downstream applications.
+    llm:
+      model: openrouter/openai/gpt-4o-mini
+      base_url: https://openrouter.ai/api/v1
+
+  alignment_agent:
+    role: >
+      Neuroscience Named Entity Recognition (NER) Concept Alignment Agent
+    goal: >
+      Perform concept alignment to the extracted Named Entity Recognition (NER) by extractor_agent {extracted_structured_information} and return structured JSON output.
+    backstory: >
+      You are an AI assistant specialized in processing neuroscience concept alignment with structured models, i.e., ontologies or schemas and who do not hallucinate. 
+      Your expertise includes recognizing and categorizing extracted named entities such as anatomical regions, experimental conditions, and cell types and aligning the recognized named entities such as cell types with corresponding ontological terms. 
+      Your responses strictly adhere to JSON format, ensuring accurate and structured data extraction for downstream applications.
+    llm:
+      model: openrouter/openai/gpt-4o-mini
+      base_url: https://openrouter.ai/api/v1
+
+  judge_agent:
+    role: >
+      Neuroscience Named Entity Recognition (NER) Judge Agent
+    goal: >
+      Evaluate the {aligned_structured_information} based on predefined criteria and generate a structured JSON output reflecting the assessment results.
+    backstory: >
+      You are an AI assistant with expert knowledge in neuroscience and structured models, i.e., ontologies or schemas, and someone who does not hallucinate.  
+      Your task is to evaluate the {aligned_structured_information} based on the accuracy and quality of the alignment. 
+      Assign the score between 0-1 with 1 being the highest score of your evaluation.
+      Your responses strictly adhere to JSON format, ensuring accurate and structured data extraction for downstream applications.
+    llm:
+      model: openrouter/openai/gpt-4o-mini
+      base_url: https://openrouter.ai/api/v1
+
+  humanfeedback_agent:
+    role: >
+      Neuroscience Named Entity Recognition (NER) Human feedback processor Agent
+    goal: >
+      Evaluate the {judged_structured_information_with_human_feedback} and review if everything is correct as human domain expert.
+    backstory: >
+      You are an AI assistant that acts as a human expert in neuroscience and structured models, i.e., ontologies or schemas, and someone who does not hallucinate.  
+      Your task is to evaluate, i.e., review the result {judged_structured_information_with_human_feedback} to see if everything is correct and if not fix it. 
+      Your responses strictly adhere to JSON format, ensuring accurate and structured data extraction for downstream applications.
+    llm:
+      model: openrouter/openai/gpt-4o-mini
+      base_url: https://openrouter.ai/api/v1
+
+# agent task config
+task_config:
+  extraction_task:
+    description: >
+      Meticulously extract and classify all relevant entities into the most appropriate and specific category from the provided neuroscience text. 
+         The list of entities extracted should be exhaustive and comprehensive. You should identify and label all entities, including duplicates.                                                             
+         Please ensure that all entities are accurately identified and classified according to their role within the neuroscience domain. 
+         IMPORTANT: DO NOT modify the input text in any way. Use the text as is, without any alterations or corrections. 
+      
+      
+       Instructions: 
+      
+           NER Extractions instructions:
+               - Read the input {literature} carefully by paragraph. Split into small paragraph chunks as necessary.
+               - Read the entire paper thoroughly, analyzing sentence by sentence.
+               - Do not skip over large sections of text—ensure full coverage of all paragraphs and sections (e.g., abstract, methods, results).
+               - If only a few entities are detected from a large block of text, reassess your extraction to avoid missing relevant entities.
+               - Identify and extract all the named entities relevant to neuroscience.
+               - A named entity is anything that can be referred to with a proper name.
+               - Examples of neuroscience related named entities include the following:
+                   - Animal species (e.g., mouse, drosophila, zebrafish)
+                   - Brain or anatomical regions (e.g., neocortex, mushroom body, cerebellum)
+                   - Experimental conditions (e.g., control, tetrodotoxin treatment, Scn1a knockout)
+                   - Cell types (e.g., pyramidal neuron, direction-sensitive mechanoreceptor, oligodendrocyte)
+               - Ensure each extracted entity is clearly labeled with its entity type (e.g., species, region, condition, cell type).
+               - If you are unsure about a term, include it with a flag for review (e.g., "uncertain").
+               - If there are multiple sentences that refer to the same entity extract all the sentences, the start end index and make it as a list in the output.
+        Important
+          - Minimum numbers should be at least 100 entities for large text. 
+         paper_metadata_consistency_check: 
+            Ensure all entity entries in the output include consistent and correct metadata:
+              - Each entity must have a valid `paper_title` and `doi` field.
+              - If multiple entities come from the same paper, the values of `paper_title` and `doi` must be identical across those entities.
+              - If a value is missing, check the other entries or the original context and fill it in accordingly.
+              - Do not leave `paper_title` or `doi` blank unless all entries are truly missing that information.
+              - Avoid using placeholder values like "Check for updates" as `paper_title`.
+        
+          rules:
+            - paper_title: must be a non-empty string (not a list)
+            - doi: must be a string, may be empty only if genuinely unavailable for all entries
+            - values should be normalized across entries from the same source
+            - if any entity has these fields filled, others from the same paper must have matching values
+        
+          failure_modes_to_fix:
+            - One entity has `doi` and `paper_title` while others do not
+            - One entity has placeholder `paper_title`, like "Check for updates", while others are correct
+            - One entry has a `doi` but another from the same paper has an empty string
+      output_requirements:
+                           - The output must be a **single JSON object**
+                           - The **only top-level key** must be: "extracted_terms"
+                           - Second-level keys must be **stringified integers**: "1", "2", ...
+                           - Do not nest under another key like 'extracted_terms'
+                           - The value of each second-level key must be a **list** of entity mention objects
+  
+                schema_rules:
+                    top_level:
+                      type: object
+                      key: "extracted_terms"
+                      note: Do not nest under another dictionary
+  
+                    second_level_keys:
+                      type: string
+                      format: stringified integers
+                      order: ascending
+                      example: ["1", "2", "3"]
+  
+                    entity_entry:
+                      required_fields:
+                        - entity: string
+                        - label: string
+                        - ontology_id: string or null
+                        - ontology_label: string or null
+                        - sentence: array of strings
+                        - start: array of integers
+                        - end: array of integers 
+                        - remarks: array of strings
+                        - paper_location: array of strings
+                        - paper_title: string  # ⚠️ Not an array
+                        - doi: string
+  
+                      notes:
+                        - The following fields must be arrays of the same length:
+                            - sentence
+                            - start
+                            - end 
+                            - remarks
+                            - paper_location
+                        - If ontology match is missing, set:
+                            - ontology_id: null
+                            - ontology_label: null
+                        - paper_title must be a string, even if repeated in multiple entries
+  
+                    strict_schema: true
+                    disallowed:
+                      - extra top-level keys
+                      - arrays for paper_title
+                      - nested result containers like 'judged_structured_information'
+  
+                  remarks_instructions:
+                    - Append a remark for each entry
+                    - Preserve prior remarks if present
+                    - Mention any user edits explicitly
+
+    expected_output: >
+      output format: json
+      Example output:
+      "extracted_terms": {
+        "1": [
+          {
+            "entity": "mouse",
+            "label": "ANIMAL_SPECIES",
+            "sentence": [
+              "These particles were visualized by fluorescent immunohistochemistry using mouse monoclonal anti-human myelin basic protein (MBPh) antibody (clone SMI-99).",
+              "The mouse was selected due to its genetic similarity to humans and its well-characterized nervous system."
+            ],
+            "start": [79, 4],
+            "end": [84, 9],
+            "paper_location": ["methods", "introduction"],
+            "paper_title": "Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve",
+            "doi": "10.1101/2025.03.19.643597"
+          }
+        ],
+        "2": [
+          {
+            "entity": "oligodendrocyte",
+            "label": "CELL_TYPE",
+            "sentence": [
+              "Individual oligodendrocytes provide, on average, 16 near axons with single myelin segments about 200 µm in length (Butt and Ransom, 1993)."
+            ],
+            "start": [14],
+            "end": [29],
+            "paper_location": ["discussion"],
+            "paper_title": "Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve",
+            "doi": "10.1101/2025.03.19.643597"
+          }
+        ],
+        "3": [
+          {
+            "entity": "cerebellum",
+            "label": "ANATOMICAL_REGION",
+            "sentence": [
+              "Myelin basic protein, human (MBPh) The mouse monoclonal antibody against the human myelin basic protein (clone SMI-99; Covance, Princeton, NJ) detects 4 bands between 14 and 21 kDa, corresponding to 4 myelin basic protein (MBP) isoforms on immunoblots of the mouse cerebellum (Dyer et al.).",
+              "Protein levels were also analyzed in the cerebellum to evaluate demyelination effects."
+            ],
+            "start": [293, 37],
+            "end": [303, 47],
+            "paper_location": ["methods", "results"],
+            "paper_title": "Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve",
+            "doi": "10.1101/2025.03.19.643597"
+          }
+        ]
+      ...
+      }
+
+    agent_id: extractor_agent
+
+  alignment_task:
+    description: >
+      Perform concept alignment on the extracted structured information by mapping each entity 
+      to a matching concept (class) from a given ontology or schema.
+      
+      Inputs: {extracted_structured_information}
+      
+      Instructions:
+        alignment instructions:
+          - For each entity in `extracted_structured_information`, find the most appropriate matching concept from an ontology or schema.
+          - Concept alignment means associating a term with a known ontological class or identifier (e.g., from CL, UBERON, NCBITaxon, etc.).
+          - Use a local knowledge source or indexed search system to retrieve candidate concepts (labels or IDs) where possible and marked in remarks if local knowledge source is used.
+          - Record the matched ontology information for each term:
+              - Ontology label (e.g., "hippocampus")
+              - Ontology ID (e.g., "UBERON:0001950")
+          - Add a `remarks` for each alignment, noting whether:
+              - The alignment was made using a successful match from the local knowledge source.
+              - Or the alignment was inferred without a direct match.
+          - Do not remove or overwrite any previous remarks; always append new remarks.
+      
+        User Feedback Handling:
+          If the input includes modifications made based on human/user feedback:
+          Detect and respect these changes (e.g., altered extracted terms).
+          Do not overwrite user-modified terms.
+          Instead, annotate in remarks that user-defined values were retained and evaluated accordingly.
+      
+        failure_modes_to_fix:
+            - "Inconsistent `ontology_id`/`ontology_label` across same entity."
+            - "Missing alignment remark."
+            - "`paper_title` or `doi` inconsistent with other entries from same paper."
+      
+      output_requirements:
+                         - The output must be a **single JSON object**
+                         - The **only top-level key** must be: "aligned_ner_terms"
+                         - Second-level keys must be **stringified integers**: "1", "2", ...
+                         - Do not nest under another key like 'aligned_ner_terms'
+                         - The value of each second-level key must be a **list** of entity mention objects
+  
+              schema_rules:
+                  top_level:
+                    type: object
+                    key: "aligned_ner_terms"
+                    note: Do not nest under another dictionary
+  
+                  second_level_keys:
+                    type: string
+                    format: stringified integers
+                    order: ascending
+                    example: ["1", "2", "3"]
+  
+                  entity_entry:
+                    required_fields:
+                      - entity: string
+                      - label: string
+                      - ontology_id: string or null
+                      - ontology_label: string or null
+                      - sentence: array of strings
+                      - start: array of integers
+                      - end: array of integers 
+                      - remarks: array of strings
+                      - paper_location: array of strings
+                      - paper_title: array of strings
+                      - doi: array of strings
+  
+                    notes:
+                      - The following fields must be arrays of the same length:
+                          - sentence
+                          - start
+                          - end 
+                          - remarks
+                          - paper_title
+                          - doi
+                          - paper_location
+                      - If ontology match is missing, set:
+                          - ontology_id: null
+                          - ontology_label: null
+                      - paper_title must be a string, even if repeated in multiple entries
+  
+                  strict_schema: true
+                  disallowed:
+                    - extra top-level keys
+                    - arrays for paper_title
+                    - nested result containers like 'judged_structured_information'
+  
+                remarks_instructions:
+                  - Append a remark for each entry
+                  - Preserve prior remarks if present
+                  - Mention any user edits explicitly
+
+    expected_output: >
+      output format: json
+      Example output:
+      "aligned_ner_terms": {
+        "1": [
+          {
+            "entity": "mouse",
+            "label": "ANIMAL_SPECIES",
+            "ontology_id": "http://purl.obolibrary.org/obo/NCBITaxon_10090",
+            "ontology_label": "Mus musculus",
+            "sentence": [
+              "These particles were visualized by fluorescent immunohistochemistry using mouse monoclonal anti-human myelin basic protein (MBPh) antibody (clone SMI-99).",
+              "The mouse was selected due to its genetic similarity to humans and its well-characterized nervous system."
+            ],
+            "start": [79, 4],
+            "end": [84, 9],
+            "remarks": [
+              "alignment is based on the search result i.e., knowledge source",
+              "alignment is based on the search result i.e., knowledge source"
+            ],
+            "paper_location": ["methods", "introduction"],
+            "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+            "doi": ["10.1101/2025.03.19.643597", "10.1101/2025.03.19.643597"]
+          }
+        ],
+        "2": [
+          {
+            "entity": "oligodendrocyte",
+            "label": "CELL_TYPE",
+            "ontology_id": "http://purl.obolibrary.org/obo/CL_0000128",
+            "ontology_label": "Oligodendrocyte",
+            "sentence": [
+              "Individual oligodendrocytes provide, on average, 16 near axons with single myelin segments about 200 µm in length (Butt and Ransom, 1993)."
+            ],
+            "start": [14],
+            "end": [29],
+            "remarks": [
+              "alignment is based on the search result i.e., knowledge source"
+            ],
+            "paper_location": ["discussion"],
+            "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+            "doi": ["10.1101/2025.03.19.643597"]
+          }
+        ],
+        "3": [
+          {
+            "entity": "cerebellum",
+            "label": "ANATOMICAL_REGION",
+            "ontology_id": "http://purl.obolibrary.org/obo/UBERON_0002037",
+            "ontology_label": "Cerebellum",
+            "sentence": [
+              "Myelin basic protein, human (MBPh) The mouse monoclonal antibody against the human myelin basic protein (clone SMI-99; Covance, Princeton, NJ) detects 4 bands between 14 and 21 kDa, corresponding to 4 myelin basic protein (MBP) isoforms on immunoblots of the mouse cerebellum (Dyer et al.).",
+              "Protein levels were also analyzed in the cerebellum to evaluate demyelination effects."
+            ],
+            "start": [293, 37],
+            "end": [303, 47],
+            "remarks": [
+              "alignment is based on the search result i.e., knowledge source",
+              "alignment is based on the search result i.e., knowledge source"
+            ],
+            "paper_location": ["methods", "results"],
+            "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+            "doi": ["10.1101/2025.03.19.643597", "10.1101/2025.03.19.643597"]
+          }
+        ]
+      ...
+      }
+
+    agent_id: alignment_agent
+
+  judge_task:
+    description: >
+      Evaluate the structured output from the alignment agent ({aligned_structured_information}). 
+        Assess both the quality of the original extraction and its alignment with the ontology or schema. Assign a `judge_score` between 0 and 1, and append remarks justifying the evaluation.
+      
+      Instuctions:
+        User Feedback Handling:
+          If the input includes previously made based on human/user feedback:
+          Detect and respect these changes (e.g., altered extracted terms).
+          Do not overwrite user-modified terms.
+          Instead, annotate in remarks that user-defined values were retained and evaluated accordingly.
+  
+        Judgement:
+          - Analyze the content of {aligned_structured_information} and evaluate how well the extracted information aligns with the target ontology or schema.
+          - Assign a `judge_score` between 0 and 1:
+              - 1.0 = perfect alignment
+              - 0.0 = misaligned or invalid
+              - Intermediate values indicate partial alignment
+          - Append a remarks justifying the score. Do not remove or overwrite existing remarks; always preserve previous ones.
+          - If user-modified fields (e.g., extracted terms) are present, do not overwrite them. Note their presence and evaluation in the remarks.
+          - Ensure the final structure is schema-compliant and retains all original metadata and history.
+      
+      failure_modes_to_fix:
+          - "Missing `judge_score` or `remarks` per sentence."
+          - "Inconsistent `paper_title` or `doi`." 
+          - "Non-matching array lengths across sentence, score, and remarks."
+      
+      output_requirements:
+                         - The output must be a **single JSON object**
+                         - The **only top-level key** must be: "judge_ner_terms"
+                         - Second-level keys must be **stringified integers**: "1", "2", ...
+                         - Do not nest under another key like 'judge_ner_terms'
+                         - The value of each second-level key must be a **list** of entity mention objects
+  
+              schema_rules:
+                  top_level:
+                    type: object
+                    key: "judge_ner_terms"
+                    note: Do not nest under another dictionary
+  
+                  second_level_keys:
+                    type: string
+                    format: stringified integers
+                    order: ascending
+                    example: ["1", "2", "3"]
+  
+                  entity_entry:
+                    required_fields:
+                      - entity: string
+                      - label: string
+                      - ontology_id: string or null
+                      - ontology_label: string or null
+                      - sentence: array of strings
+                      - start: array of integers
+                      - end: array of integers
+                      - judge_score: array of floats
+                      - remarks: array of strings
+                      - paper_location: array of strings
+                      - paper_title: array of strings
+                      - doi: array of strings
+  
+                    notes:
+                      - The following fields must be arrays of the same length:
+                          - sentence
+                          - start
+                          - end
+                          - judge_score
+                          - remarks
+                          - doi
+                          - paper_title 
+                          - paper_location
+                      - If ontology match is missing, set:
+                          - ontology_id: null
+                          - ontology_label: null
+                      - paper_title must be a string, even if repeated in multiple entries
+  
+                  strict_schema: true
+                  disallowed:
+                    - extra top-level keys
+                    - arrays for paper_title
+                    - nested result containers like 'judged_structured_information'
+  
+                remarks_instructions:
+                  - Append a remark for each entry
+                  - Preserve prior remarks if present
+                  - Mention any user edits explicitly
+  
+                judge_score_instructions:
+                  - Assign a float score between 0 and 1 per sentence
+                  - 1.0 = perfect match, 0.0 = no match, values in between = partial match
+
+    expected_output: > 
+      output format: json 
+      Example output:
+      "judge_ner_terms": {
+                          "1": [
+                            {
+                              "entity": "mouse",
+                              "label": "ANIMAL_SPECIES",
+                              "ontology_id": "http://purl.obolibrary.org/obo/NCBITaxon_10090",
+                              "ontology_label": "Mus musculus",
+                              "sentence": [
+                                "These particles were visualized by fluorescent immunohistochemistry using mouse monoclonal anti-human myelin basic protein (MBPh) antibody (clone SMI-99).",
+                                "The mouse was selected due to its genetic similarity to humans and its well-characterized nervous system."
+                              ],
+                              "start": [79, 4],
+                              "end": [84, 9],
+                              "remarks": [
+                                "High-confidence alignment based on exact match in the knowledge source (ontology label: Mus musculus).",
+                                "High-confidence alignment based on contextual and exact term usage in ontology search results."
+                              ],
+                              "judge_score": [0.95, 0.93],
+                              "paper_location": ["methods", "introduction"],
+                              "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve","Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+                              "doi": ["10.1101/2025.03.19.643597", "10.1101/2025.03.19.643597"]
+                            }
+                          ],
+                          "2": [
+                            {
+                              "entity": "oligodendrocyte",
+                              "label": "CELL_TYPE",
+                              "ontology_id": "http://purl.obolibrary.org/obo/CL_0000128",
+                              "ontology_label": "Oligodendrocyte",
+                              "sentence": [
+                                "Individual oligodendrocytes provide, on average, 16 near axons with single myelin segments about 200 µm in length (Butt and Ransom, 1993)."
+                              ],
+                              "start": [14],
+                              "end": [29],
+                              "remarks": [
+                                "Confident alignment based on direct match with ontology class label in the knowledge source."
+                              ],
+                              "judge_score": [0.88],
+                              "paper_location": ["discussion"],
+                              "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+                              "doi": ["10.1101/2025.03.19.643597"]
+                            }
+                          ],
+                          "3": [
+                            {
+                              "entity": "cerebellum",
+                              "label": "ANATOMICAL_REGION",
+                              "ontology_id": "http://purl.obolibrary.org/obo/UBERON_0002037",
+                              "ontology_label": "Cerebellum",
+                              "sentence": [
+                                "Myelin basic protein, human (MBPh) The mouse monoclonal antibody against the human myelin basic protein (clone SMI-99; Covance, Princeton, NJ) detects 4 bands between 14 and 21 kDa, corresponding to 4 myelin basic protein (MBP) isoforms on immunoblots of the mouse cerebellum (Dyer et al.).",
+                                "Protein levels were also analyzed in the cerebellum to evaluate demyelination effects."
+                              ],
+                              "start": [293, 37],
+                              "end": [303, 47],
+                              "remarks": [
+                                "Moderate confidence alignment; match found in ontology, but context is less directly linked to definition.",
+                                "Moderate confidence alignment; term matches ontology label, but surrounding context offers less specificity."
+                              ],
+                              "judge_score": [0.72, 0.70],
+                              "paper_location": ["methods", "results"],
+                              "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve","Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+                              "doi": ["10.1101/2025.03.19.643597", "10.1101/2025.03.19.643597"]
+                            }
+                          ]
+      ...
+      }
+
+    agent_id: judge_agent
+
+  humanfeedback_task:
+    description: >
+      Input: {judged_structured_information_with_human_feedback}
+  
+      Objective: Evaluate and, if necessary, revise the structured output to ensure accurate alignment with the target ontology/schema.
+  
+      Important: The number of extracted entities should not be less than what you received.
+      modification_context: 
+        {modification_context}
+      
+      user_feedback_text:
+        {user_feedback_text}
+      
+      Instructions:
+  
+      Alignment Assessment:
+        Analyze {judged_structured_information_with_human_feedback} to determine whether the extracted terms and structures are correctly aligned with the intended ontology or schema.
+  
+      
+      update_handling:
+            - "Preserve existing remarks."
+            - "Append new remark for each change made."
+            - "Indicate knowledge source or user evidence behind updates in remarks."
+  
+      Provenance-Aware Remarking:
+        Update the remarks field as follows:
+        Append a new remark describing the updates made (e.g., corrected label, updated score).
+        Specify if the update was informed by a knowledge source or prior evidence.
+        Do not remove existing remarks—always preserve historical annotations.
+  
+      User Feedback Handling:
+        If the input includes modifications made based on human/user feedback:
+        Detect and respect these changes (e.g., altered extracted terms).
+        Do not overwrite user-modified terms.
+        Instead, annotate in remarks that user-defined values were retained and evaluated accordingly.
+      
+      failure_modes_to_fix:
+        - "Judge score conflicts (e.g., 1.0 score for low-quality match)."
+        - "Misaligned paper metadata across multiple entries."
+        - "Missing or conflicting ontology IDs for same entity."
+        - "Field arrays of unequal length."
+  
+      Constraints:
+        Preserve all historical data (especially remarks).
+        Ensure outputs are traceable, auditable, and schema-compliant.
+      
+      output_requirements:
+                     - The output must be a **single JSON object**
+                     - The **only top-level key** must be: "judge_ner_terms"
+                     - Second-level keys must be **stringified integers**: "1", "2", ...
+                     - Do not nest under another key like 'judge_ner_terms'
+                     - The value of each second-level key must be a **list** of entity mention objects
+  
+          schema_rules:
+              top_level:
+                type: object
+                key: "judge_ner_terms"
+                note: Do not nest under another dictionary
+  
+              second_level_keys:
+                type: string
+                format: stringified integers
+                order: ascending
+                example: ["1", "2", "3"]
+  
+              entity_entry:
+                required_fields:
+                  - entity: string
+                  - label: string
+                  - ontology_id: string or null
+                  - ontology_label: string or null
+                  - sentence: array of strings
+                  - start: array of integers
+                  - end: array of integers
+                  - judge_score: array of floats
+                  - remarks: array of strings
+                  - paper_location: array of strings
+                  - paper_title: array of strings
+                  - doi: array of strings
+  
+                notes:
+                  - The following fields must be arrays of the same length:
+                      - sentence
+                      - start
+                      - end
+                      - doi
+                      - paper_title 
+                      - judge_score
+                      - remarks
+                      - paper_location
+                  - If ontology match is missing, set:
+                      - ontology_id: null
+                      - ontology_label: null
+                  - paper_title must be a string, even if repeated in multiple entries
+  
+              strict_schema: true
+              disallowed:
+                - extra top-level keys
+                - arrays for paper_title
+                - nested result containers like 'judged_structured_information'
+  
+            remarks_instructions:
+              - Append a remark for each entry
+              - Preserve prior remarks if present
+              - Mention any user edits explicitly
+  
+            judge_score_instructions:
+              - Assign a float score between 0 and 1 per sentence
+              - 1.0 = perfect match, 0.0 = no match, values in between = partial match
+  
+
+    expected_output: > 
+      output format: json
+      Example output:
+      "judge_ner_terms": {
+                              "1": [
+                                {
+                                  "entity": "mouse",
+                                  "label": "ANIMAL_SPECIES",
+                                  "ontology_id": "http://purl.obolibrary.org/obo/NCBITaxon_10090",
+                                  "ontology_label": "Mus musculus",
+                                  "sentence": [
+                                    "These particles were visualized by fluorescent immunohistochemistry using mouse monoclonal anti-human myelin basic protein (MBPh) antibody (clone SMI-99).",
+                                    "The mouse was selected due to its genetic similarity to humans and its well-characterized nervous system."
+                                  ],
+                                  "start": [79, 4],
+                                  "end": [84, 9],
+                                  "remarks": [
+                                    "High-confidence alignment based on exact match in the knowledge source (ontology label: Mus musculus).",
+                                    "High-confidence alignment based on contextual and exact term usage in ontology search results."
+                                  ],
+                                  "judge_score": [0.95, 0.93],
+                                  "paper_location": ["methods", "introduction"],
+                                  "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve","Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+                                  "doi": ["10.1101/2025.03.19.643597", "10.1101/2025.03.19.643597"]
+                                }
+                              ],
+                              "2": [
+                                {
+                                  "entity": "oligodendrocyte",
+                                  "label": "CELL_TYPE",
+                                  "ontology_id": "http://purl.obolibrary.org/obo/CL_0000128",
+                                  "ontology_label": "Oligodendrocyte",
+                                  "sentence": [
+                                    "Individual oligodendrocytes provide, on average, 16 near axons with single myelin segments about 200 µm in length (Butt and Ransom, 1993)."
+                                  ],
+                                  "start": [14],
+                                  "end": [29],
+                                  "remarks": [
+                                    "Confident alignment based on direct match with ontology class label in the knowledge source."
+                                  ],
+                                  "judge_score": [0.88],
+                                  "paper_location": ["discussion"],
+                                  "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+                                  "doi": ["10.1101/2025.03.19.643597"]
+                                }
+                              ],
+                              "3": [
+                                {
+                                  "entity": "cerebellum",
+                                  "label": "ANATOMICAL_REGION",
+                                  "ontology_id": "http://purl.obolibrary.org/obo/UBERON_0002037",
+                                  "ontology_label": "Cerebellum",
+                                  "sentence": [
+                                    "Myelin basic protein, human (MBPh) The mouse monoclonal antibody against the human myelin basic protein (clone SMI-99; Covance, Princeton, NJ) detects 4 bands between 14 and 21 kDa, corresponding to 4 myelin basic protein (MBP) isoforms on immunoblots of the mouse cerebellum (Dyer et al.).",
+                                    "Protein levels were also analyzed in the cerebellum to evaluate demyelination effects."
+                                  ],
+                                  "start": [293, 37],
+                                  "end": [303, 47],
+                                  "remarks": [
+                                    "Moderate confidence alignment; match found in ontology, but context is less directly linked to definition.",
+                                    "Moderate confidence alignment; term matches ontology label, but surrounding context offers less specificity."
+                                  ],
+                                  "judge_score": [0.72, 0.70], 
+                                  "paper_location": ["methods", "results"],
+                                  "paper_title": ["Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve","Concentration of myelin debris-like myelin basic protein-immunoreactive particles in the distal (anterior)-most part of the myelinated region in the normal rat optic nerve"],
+                                  "doi": ["10.1101/2025.03.19.643597","10.1101/2025.03.19.643597"]
+                                }
+                              ]
+      ...
+          }
+
+    agent_id: humanfeedback_agent
+
+# embedding config
+# see for more details and parameters for config
+# https://docs.crewai.com/concepts/memory#additional-embedding-providerscl
+embedder_config:
+  provider: ollama
+  config:
+    api_base: http://localhost:11434
+    model: nomic-embed-text:v1.5
+
+# knowledge search config
+knowledge_config:
+  search_key: #local vector database
+    - entity
+    - label
+# human in loop config
+human_in_loop_config:
+  humanfeedback_agent: true
\ No newline at end of file
diff --git a/evaluation/notebook/README.md b/evaluation/notebook/README.md
new file mode 100644
index 0000000..2421ce5
--- /dev/null
+++ b/evaluation/notebook/README.md
@@ -0,0 +1,30 @@
+# Token Cost Speed Analysis
+
+A script to visualize token usage, cost, and speed metrics across different language models.
+
+## Usage
+
+```bash
+python token_cost_speed_analysis.py --task <task_name> --file <csv_file>
+```
+
+### Arguments
+
+- `--task`: Task name (e.g., `reproschema`). Creates output folder with this name.
+- `--file`: Path to CSV file containing token usage data.
+
+### Example
+
+```bash
+python token_cost_speed_analysis.py --task reproschema --file reproschema/reproschema_token_usage.csv
+```
+
+### Output
+
+Generates 4 plots in both PNG and SVG formats:
+- Cost distribution by model
+- Token usage (input/output) by model  
+- Speed distribution by model
+- Speed vs cost scatter plot
+
+All files are saved in a folder named after the task.
\ No newline at end of file
diff --git a/evaluation/notebook/ner_comprehensive_summary.py b/evaluation/notebook/ner_comprehensive_summary.py
new file mode 100644
index 0000000..a8efe83
--- /dev/null
+++ b/evaluation/notebook/ner_comprehensive_summary.py
@@ -0,0 +1,660 @@
+"""
+NER Comprehensive Analysis Summary
+==================================
+
+This script creates a comprehensive summary and comparison of all NER evaluation results,
+combining insights from entity pool, ontology, location, label, and judge score analyses.
+
+Purpose: Generate comprehensive summary report and final visualizations
+"""
+
+import sys
+from pathlib import Path
+import pandas as pd
+import matplotlib.pyplot as plt
+import numpy as np
+from typing import Dict, List, Tuple, Any
+import json
+from collections import defaultdict
+
+# Add structsense to path
+sys.path.append(str(Path(__file__).parent.parent.parent))
+
+from evaluation.notebook.ner_data_loader import NERDataLoader
+
+# Configure matplotlib for publication-quality figures
+plt.rcParams['font.family'] = 'Arial'
+plt.rcParams['font.size'] = 8
+plt.rcParams['axes.linewidth'] = 0.5
+plt.rcParams['xtick.major.width'] = 0.5
+plt.rcParams['ytick.major.width'] = 0.5
+plt.rcParams['xtick.major.size'] = 3
+plt.rcParams['ytick.major.size'] = 3
+
+
+def generate_comprehensive_summary(loader: NERDataLoader, output_dir: Path):
+    """
+    Generate comprehensive summary analysis and report.
+    
+    Args:
+        loader: NERDataLoader instance with loaded data
+        output_dir: Directory to save outputs
+    """
+    output_dir.mkdir(parents=True, exist_ok=True)
+    
+    # Get model colors
+    colors = loader.get_model_colors()
+    
+    # Collect comprehensive metrics
+    summary_metrics = collect_all_metrics(loader)
+    
+    # Create comprehensive comparison dashboard
+    create_performance_dashboard(summary_metrics, colors, output_dir)
+    
+    # Create detailed comparison tables
+    create_summary_tables(summary_metrics, output_dir)
+    
+    # Generate text summary report
+    generate_text_report(summary_metrics, output_dir)
+    
+    # Create model ranking visualization
+    create_model_ranking(summary_metrics, colors, output_dir)
+
+
+def collect_all_metrics(loader: NERDataLoader) -> Dict[str, Any]:
+    """
+    Collect all evaluation metrics from different analyses.
+    
+    Args:
+        loader: NERDataLoader instance
+        
+    Returns:
+        Dictionary with comprehensive metrics
+    """
+    metrics = {
+        'with_hil': {},
+        'without_hil': {}
+    }
+    
+    for group in ['with_hil', 'without_hil']:
+        if group not in loader.data or not loader.data[group]:
+            continue
+        
+        group_metrics = {}
+        
+        for model in loader.data[group].keys():
+            df = loader.get_entity_dataframe(group, model)
+            
+            if df.empty:
+                continue
+            
+            # Entity detection metrics
+            overlap_stats = loader.calculate_entity_overlap(group)
+            total_pool = overlap_stats['total_pool_size']
+            detected = overlap_stats['model_counts'].get(model, 0)
+            missed = overlap_stats['model_missing'].get(model, {}).get('count', 0)
+            
+            # Ontology coverage metrics
+            unique_entities = df.groupby('entity').first().reset_index()
+            total_entities = len(unique_entities)
+            has_ontology_id = unique_entities['ontology_id'].notna() & (unique_entities['ontology_id'] != '')
+            has_ontology_label = unique_entities['ontology_label'].notna() & (unique_entities['ontology_label'] != '')
+            has_both = has_ontology_id & has_ontology_label
+            
+            # Judge score metrics
+            valid_scores = df[df['judge_score'].notna()]['judge_score'].astype(float)
+            
+            # Label diversity metrics
+            label_counts = unique_entities['label'].value_counts()
+            shannon_diversity = 0
+            if len(label_counts) > 0:
+                for count in label_counts.values:
+                    if count > 0:
+                        p = count / total_entities
+                        shannon_diversity -= p * np.log(p)
+            
+            # Paper location diversity
+            location_counts = df['paper_location'].value_counts()
+            
+            group_metrics[model] = {
+                # Entity detection
+                'total_pool_size': total_pool,
+                'entities_detected': detected,
+                'entities_missed': missed,
+                'detection_rate': (detected / total_pool * 100) if total_pool > 0 else 0,
+                'miss_rate': (missed / total_pool * 100) if total_pool > 0 else 0,
+                
+                # Ontology coverage
+                'total_unique_entities': total_entities,
+                'ontology_complete': has_both.sum(),
+                'ontology_complete_rate': (has_both.sum() / total_entities * 100) if total_entities > 0 else 0,
+                'ontology_partial': (has_ontology_id | has_ontology_label).sum(),
+                'ontology_partial_rate': ((has_ontology_id | has_ontology_label).sum() / total_entities * 100) if total_entities > 0 else 0,
+                
+                # Judge scores
+                'judge_score_count': len(valid_scores),
+                'judge_score_mean': valid_scores.mean() if len(valid_scores) > 0 else 0,
+                'judge_score_std': valid_scores.std() if len(valid_scores) > 0 else 0,
+                'high_confidence_rate': ((valid_scores >= 0.8).mean() * 100) if len(valid_scores) > 0 else 0,
+                'low_confidence_rate': ((valid_scores < 0.5).mean() * 100) if len(valid_scores) > 0 else 0,
+                
+                # Label diversity
+                'unique_labels': len(label_counts),
+                'shannon_diversity': shannon_diversity,
+                'most_common_label_pct': (label_counts.max() / total_entities * 100) if total_entities > 0 else 0,
+                
+                # Location diversity
+                'unique_locations': len(location_counts),
+                'total_occurrences': len(df)
+            }
+        
+        metrics[group] = group_metrics
+    
+    return metrics
+
+
+def create_performance_dashboard(metrics: Dict[str, Any], colors: Dict[str, str], output_dir: Path):
+    """
+    Create a performance dashboard with two radar plots and a legend in between.
+    
+    Args:
+        metrics: Comprehensive metrics dictionary
+        colors: Model color mapping
+        output_dir: Output directory
+    """
+    # Create figure with two radar plots side by side
+    fig = plt.figure(figsize=(10, 5))
+    
+    # Get common models across both groups (ordered: GPT, Claude, DeepSeek)
+    models_with = set(metrics.get('with_hil', {}).keys())
+    models_without = set(metrics.get('without_hil', {}).keys())
+    model_order = ['GPT-4o-mini', 'Claude 3.7 Sonnet', 'DeepSeek V3 0324']
+    common_models = [m for m in model_order if m in models_with and m in models_without]
+    
+    if not common_models:
+        return
+    
+    # Create radar plot for with_hil
+    ax1 = plt.subplot(131, projection='polar')
+    create_radar_chart(ax1, metrics, 'with_hil', common_models, colors, 'With HIL')
+    ax1.legend().remove()  # Remove individual legend
+    
+    # Create radar plot for without_hil
+    ax3 = plt.subplot(133, projection='polar')
+    create_radar_chart(ax3, metrics, 'without_hil', common_models, colors, 'Without HIL')
+    ax3.legend().remove()  # Remove individual legend
+    
+    # Create central legend
+    ax2 = plt.subplot(132)
+    ax2.axis('off')  # Hide axes for legend area
+    
+    # Create legend handles
+    handles = []
+    for model in common_models:
+        color = colors.get(model, '#999999')
+        line = plt.Line2D([0], [0], color=color, linewidth=2, label=model)
+        handles.append(line)
+    
+    # Place legend in the center
+    legend = ax2.legend(handles=handles, loc='center', fontsize=10, 
+                       frameon=True, fancybox=True, shadow=True)
+    legend.get_frame().set_facecolor('white')
+    legend.get_frame().set_alpha(0.9)
+    
+    # Adjust layout
+    plt.tight_layout()
+    
+    # Save figure in PDF format only
+    fig.savefig(output_dir / 'performance_dashboard.pdf', bbox_inches='tight')
+    plt.close()
+
+
+def create_metric_comparison(ax, metrics: Dict, models: List[str], metric_key: str, 
+                           ylabel: str, colors: Dict[str, str]):
+    """
+    Create a comparison plot for a specific metric.
+    
+    Args:
+        ax: Matplotlib axis
+        metrics: Metrics dictionary
+        models: List of models to compare
+        metric_key: Key for the metric to plot
+        ylabel: Y-axis label
+        colors: Model color mapping
+    """
+    x = np.arange(len(models))
+    width = 0.35
+    
+    values_with = [metrics.get('with_hil', {}).get(m, {}).get(metric_key, 0) for m in models]
+    values_without = [metrics.get('without_hil', {}).get(m, {}).get(metric_key, 0) for m in models]
+    
+    bars1 = ax.bar(x - width/2, values_with, width,
+                   color=[colors.get(m, '#999999') for m in models], alpha=0.8)
+    bars2 = ax.bar(x + width/2, values_without, width,
+                   color=[colors.get(m, '#999999') for m in models], alpha=0.4)
+    
+    ax.set_ylabel(ylabel, fontsize=7)
+    ax.set_xticks(x)
+    ax.set_xticklabels([m.replace(' ', '\n') for m in models], fontsize=6)
+    ax.spines['top'].set_visible(False)
+    ax.spines['right'].set_visible(False)
+    
+    # Add value labels
+    for bars in [bars1, bars2]:
+        for bar in bars:
+            height = bar.get_height()
+            if height > 0:
+                ax.text(bar.get_x() + bar.get_width()/2., height + max(values_with + values_without) * 0.01,
+                       f'{height:.1f}' if metric_key != 'judge_score_mean' else f'{height:.3f}',
+                       ha='center', va='bottom', fontsize=5)
+
+
+def create_radar_chart(ax, metrics: Dict, group: str, models: List[str], 
+                      colors: Dict[str, str], title: str):
+    """
+    Create a radar chart for model performance comparison.
+    
+    Args:
+        ax: Matplotlib polar axis
+        metrics: Metrics dictionary
+        group: Group name
+        models: List of models
+        colors: Model color mapping
+        title: Chart title
+    """
+    # Define performance dimensions (normalized to 0-1)
+    dimensions = ['Detection\nRate', 'Ontology\nMapping', 'Judge\nScore', 
+                 'Label\nDiversity', 'High\nConfidence']
+    
+    # Number of dimensions
+    N = len(dimensions)
+    
+    # Compute angle for each dimension
+    angles = [n / float(N) * 2 * np.pi for n in range(N)]
+    angles += angles[:1]  # Complete the circle
+    
+    # Plot each model
+    for model in models:
+        if model not in metrics.get(group, {}):
+            continue
+        
+        model_data = metrics[group][model]
+        
+        # Normalize values to 0-1 scale
+        values = [
+            model_data.get('detection_rate', 0) / 100,  # 0-1
+            model_data.get('ontology_complete_rate', 0) / 100,  # 0-1
+            model_data.get('judge_score_mean', 0),  # already 0-1
+            min(model_data.get('shannon_diversity', 0) / 3, 1),  # normalize to 0-1
+            model_data.get('high_confidence_rate', 0) / 100  # 0-1
+        ]
+        values += values[:1]  # Complete the circle
+        
+        # Plot
+        ax.plot(angles, values, 'o-', linewidth=1, 
+                label=model.replace(' ', '\n'), color=colors.get(model, '#999999'))
+        ax.fill(angles, values, alpha=0.1, color=colors.get(model, '#999999'))
+    
+    # Customize the radar chart
+    ax.set_xticks(angles[:-1])
+    ax.set_xticklabels(dimensions, fontsize=6)
+    ax.set_ylim(0, 1)
+    ax.set_yticks([0.2, 0.4, 0.6, 0.8, 1.0])
+    ax.set_yticklabels(['0.2', '0.4', '0.6', '0.8', '1.0'], fontsize=5)
+    ax.grid(True)
+    ax.set_title(title, fontsize=8, fontweight='bold', pad=20)
+
+
+def create_summary_tables(metrics: Dict[str, Any], output_dir: Path):
+    """
+    Create detailed summary tables with all metrics.
+    
+    Args:
+        metrics: Comprehensive metrics dictionary
+        output_dir: Output directory
+    """
+    # Create summary table data
+    table_data = []
+    
+    for group, group_metrics in metrics.items():
+        for model, model_metrics in group_metrics.items():
+            table_data.append({
+                'Group': group,
+                'Model': model,
+                'Entities_Detected': model_metrics.get('entities_detected', 0),
+                'Detection_Rate_%': f"{model_metrics.get('detection_rate', 0):.1f}%",
+                'Miss_Rate_%': f"{model_metrics.get('miss_rate', 0):.1f}%",
+                'Ontology_Complete_%': f"{model_metrics.get('ontology_complete_rate', 0):.1f}%",
+                'Judge_Score_Mean': f"{model_metrics.get('judge_score_mean', 0):.3f}",
+                'High_Confidence_%': f"{model_metrics.get('high_confidence_rate', 0):.1f}%",
+                'Label_Diversity': f"{model_metrics.get('shannon_diversity', 0):.2f}",
+                'Unique_Labels': model_metrics.get('unique_labels', 0),
+                'Unique_Locations': model_metrics.get('unique_locations', 0)
+            })
+    
+    if table_data:
+        summary_df = pd.DataFrame(table_data)
+        summary_df.to_csv(output_dir / 'comprehensive_summary_table.csv', index=False)
+        
+        # Create performance ranking
+        ranking_data = []
+        
+        for group in ['with_hil', 'without_hil']:
+            if group not in metrics:
+                continue
+            
+            group_ranking = []
+            for model, model_metrics in metrics[group].items():
+                # Calculate composite score (weighted average)
+                composite_score = (
+                    model_metrics.get('detection_rate', 0) * 0.3 +
+                    model_metrics.get('ontology_complete_rate', 0) * 0.3 +
+                    model_metrics.get('judge_score_mean', 0) * 100 * 0.2 +
+                    min(model_metrics.get('shannon_diversity', 0) * 33.33, 100) * 0.1 +
+                    model_metrics.get('high_confidence_rate', 0) * 0.1
+                )
+                
+                group_ranking.append({
+                    'Group': group,
+                    'Model': model,
+                    'Composite_Score': composite_score,
+                    'Rank': 0  # Will be filled after sorting
+                })
+            
+            # Sort and assign ranks
+            group_ranking.sort(key=lambda x: x['Composite_Score'], reverse=True)
+            for i, item in enumerate(group_ranking):
+                item['Rank'] = i + 1
+            
+            ranking_data.extend(group_ranking)
+        
+        if ranking_data:
+            ranking_df = pd.DataFrame(ranking_data)
+            ranking_df.to_csv(output_dir / 'model_rankings.csv', index=False)
+
+
+def create_model_ranking(metrics: Dict[str, Any], colors: Dict[str, str], output_dir: Path):
+    """
+    Create visual model ranking comparison.
+    
+    Args:
+        metrics: Comprehensive metrics dictionary
+        colors: Model color mapping
+        output_dir: Output directory
+    """
+    fig, (ax1, ax2) = plt.subplots(1, 2, figsize=(8, 4))
+    
+    for i, (group, ax) in enumerate([('with_hil', ax1), ('without_hil', ax2)]):
+        if group not in metrics:
+            continue
+        
+        # Calculate composite scores (use consistent ordering)
+        model_scores = []
+        
+        model_order = ['GPT-4o-mini', 'Claude 3.7 Sonnet', 'DeepSeek V3 0324']
+        for model in model_order:
+            if model in metrics[group]:
+                model_metrics = metrics[group][model]
+                composite_score = (
+                    model_metrics.get('detection_rate', 0) * 0.3 +
+                    model_metrics.get('ontology_complete_rate', 0) * 0.3 +
+                    model_metrics.get('judge_score_mean', 0) * 100 * 0.2 +
+                    min(model_metrics.get('shannon_diversity', 0) * 33.33, 100) * 0.1 +
+                    model_metrics.get('high_confidence_rate', 0) * 0.1
+                )
+                model_scores.append((model, composite_score))
+        
+        # Sort by score
+        model_scores.sort(key=lambda x: x[1], reverse=True)
+        
+        # Create bar chart
+        models = [item[0] for item in model_scores]
+        scores = [item[1] for item in model_scores]
+        model_colors = [colors.get(m, '#999999') for m in models]
+        
+        bars = ax.barh(range(len(models)), scores, color=model_colors, alpha=0.8)
+        
+        # Customize plot
+        ax.set_yticks(range(len(models)))
+        ax.set_yticklabels([m.replace(' ', '\n') for m in models], fontsize=6)
+        ax.set_xlabel('Composite Performance Score', fontsize=7)
+        ax.set_title(f'Model Ranking ({group})', fontsize=8, fontweight='bold')
+        ax.spines['top'].set_visible(False)
+        ax.spines['right'].set_visible(False)
+        
+        # Add score labels
+        for j, bar in enumerate(bars):
+            width = bar.get_width()
+            ax.text(width + 1, bar.get_y() + bar.get_height()/2,
+                   f'{width:.1f}', ha='left', va='center', fontsize=6)
+        
+        # Add rank numbers
+        for j, (model, score) in enumerate(model_scores):
+            ax.text(2, j, f'#{j+1}', ha='left', va='center', 
+                   fontsize=6, fontweight='bold', 
+                   bbox=dict(boxstyle='round', facecolor='white', alpha=0.8))
+    
+    plt.tight_layout()
+    
+    # Save figure in PDF format only
+    fig.savefig(output_dir / 'model_rankings_visual.pdf', bbox_inches='tight')
+    plt.close()
+
+
+def generate_text_report(metrics: Dict[str, Any], output_dir: Path):
+    """
+    Generate a comprehensive text report summarizing all findings.
+    
+    Args:
+        metrics: Comprehensive metrics dictionary
+        output_dir: Output directory
+    """
+    report_lines = []
+    
+    report_lines.append("NER EVALUATION COMPREHENSIVE SUMMARY REPORT")
+    report_lines.append("=" * 50)
+    report_lines.append("")
+    
+    # Overall findings
+    report_lines.append("EXECUTIVE SUMMARY")
+    report_lines.append("-" * 20)
+    
+    for group in ['with_hil', 'without_hil']:
+        if group not in metrics:
+            continue
+        
+        report_lines.append(f"\n{group.upper()} GROUP:")
+        
+        # Calculate group totals
+        total_pool = 0
+        best_detection = 0
+        best_ontology = 0
+        best_judge_score = 0
+        best_model_detection = ""
+        best_model_ontology = ""
+        best_model_judge = ""
+        
+        for model, model_metrics in metrics[group].items():
+            total_pool = model_metrics.get('total_pool_size', 0)
+            
+            detection_rate = model_metrics.get('detection_rate', 0)
+            if detection_rate > best_detection:
+                best_detection = detection_rate
+                best_model_detection = model
+            
+            ontology_rate = model_metrics.get('ontology_complete_rate', 0)
+            if ontology_rate > best_ontology:
+                best_ontology = ontology_rate
+                best_model_ontology = model
+            
+            judge_score = model_metrics.get('judge_score_mean', 0)
+            if judge_score > best_judge_score:
+                best_judge_score = judge_score
+                best_model_judge = model
+        
+        report_lines.append(f"- Total unique entities in pool: {total_pool}")
+        report_lines.append(f"- Best entity detection: {best_model_detection} ({best_detection:.1f}%)")
+        report_lines.append(f"- Best ontology mapping: {best_model_ontology} ({best_ontology:.1f}%)")
+        report_lines.append(f"- Highest judge scores: {best_model_judge} ({best_judge_score:.3f})")
+    
+    # Detailed model analysis
+    report_lines.append("\n\nDETAILED MODEL ANALYSIS")
+    report_lines.append("-" * 25)
+    
+    for group in ['with_hil', 'without_hil']:
+        if group not in metrics:
+            continue
+        
+        report_lines.append(f"\n{group.upper()} GROUP DETAILED METRICS:")
+        report_lines.append("")
+        
+        for model, model_metrics in metrics[group].items():
+            report_lines.append(f"{model}:")
+            report_lines.append(f"  Entity Detection: {model_metrics.get('entities_detected', 0)}/{model_metrics.get('total_pool_size', 0)} ({model_metrics.get('detection_rate', 0):.1f}%)")
+            report_lines.append(f"  Ontology Mapping: {model_metrics.get('ontology_complete', 0)}/{model_metrics.get('total_unique_entities', 0)} complete ({model_metrics.get('ontology_complete_rate', 0):.1f}%)")
+            report_lines.append(f"  Judge Score: {model_metrics.get('judge_score_mean', 0):.3f} ± {model_metrics.get('judge_score_std', 0):.3f}")
+            report_lines.append(f"  High Confidence: {model_metrics.get('high_confidence_rate', 0):.1f}%")
+            report_lines.append(f"  Label Diversity: {model_metrics.get('unique_labels', 0)} types (Shannon: {model_metrics.get('shannon_diversity', 0):.2f})")
+            report_lines.append("")
+    
+    # Cross-group comparison
+    report_lines.append("\nCROSS-GROUP COMPARISON")
+    report_lines.append("-" * 22)
+    
+    models_with = set(metrics.get('with_hil', {}).keys())
+    models_without = set(metrics.get('without_hil', {}).keys())
+    common_models = list(models_with & models_without)
+    
+    if common_models:
+        report_lines.append("\nCommon models performance comparison:")
+        report_lines.append("")
+        
+        for model in common_models:
+            with_hil_metrics = metrics.get('with_hil', {}).get(model, {})
+            without_hil_metrics = metrics.get('without_hil', {}).get(model, {})
+            
+            report_lines.append(f"{model}:")
+            
+            # Detection rate
+            with_detection = with_hil_metrics.get('detection_rate', 0)
+            without_detection = without_hil_metrics.get('detection_rate', 0)
+            detection_diff = with_detection - without_detection
+            report_lines.append(f"  Detection Rate: {with_detection:.1f}% (with HIL) vs {without_detection:.1f}% (without HIL) [Δ{detection_diff:+.1f}%]")
+            
+            # Ontology mapping
+            with_ontology = with_hil_metrics.get('ontology_complete_rate', 0)
+            without_ontology = without_hil_metrics.get('ontology_complete_rate', 0)
+            ontology_diff = with_ontology - without_ontology
+            report_lines.append(f"  Ontology Mapping: {with_ontology:.1f}% (with HIL) vs {without_ontology:.1f}% (without HIL) [Δ{ontology_diff:+.1f}%]")
+            
+            # Judge score
+            with_judge = with_hil_metrics.get('judge_score_mean', 0)
+            without_judge = without_hil_metrics.get('judge_score_mean', 0)
+            judge_diff = with_judge - without_judge
+            report_lines.append(f"  Judge Score: {with_judge:.3f} (with HIL) vs {without_judge:.3f} (without HIL) [Δ{judge_diff:+.3f}]")
+            report_lines.append("")
+    
+    # Key insights
+    report_lines.append("\nKEY INSIGHTS")
+    report_lines.append("-" * 12)
+    report_lines.append("")
+    
+    # Find overall best performer
+    all_models = []
+    for group, group_metrics in metrics.items():
+        for model, model_metrics in group_metrics.items():
+            composite_score = (
+                model_metrics.get('detection_rate', 0) * 0.3 +
+                model_metrics.get('ontology_complete_rate', 0) * 0.3 +
+                model_metrics.get('judge_score_mean', 0) * 100 * 0.2 +
+                min(model_metrics.get('shannon_diversity', 0) * 33.33, 100) * 0.1 +
+                model_metrics.get('high_confidence_rate', 0) * 0.1
+            )
+            all_models.append((f"{model} ({group})", composite_score))
+    
+    all_models.sort(key=lambda x: x[1], reverse=True)
+    
+    if all_models:
+        report_lines.append(f"1. Overall best performer: {all_models[0][0]} (composite score: {all_models[0][1]:.1f})")
+    
+    # HIL impact analysis
+    if common_models:
+        hil_improvements = 0
+        hil_degradations = 0
+        
+        for model in common_models:
+            with_hil_metrics = metrics.get('with_hil', {}).get(model, {})
+            without_hil_metrics = metrics.get('without_hil', {}).get(model, {})
+            
+            # Compare detection rates
+            detection_diff = with_hil_metrics.get('detection_rate', 0) - without_hil_metrics.get('detection_rate', 0)
+            if detection_diff > 0:
+                hil_improvements += 1
+            elif detection_diff < 0:
+                hil_degradations += 1
+        
+        if hil_improvements > hil_degradations:
+            report_lines.append("2. Human-in-the-loop (HIL) generally improves performance")
+        elif hil_degradations > hil_improvements:
+            report_lines.append("2. Human-in-the-loop (HIL) appears to degrade performance in some cases")
+        else:
+            report_lines.append("2. Human-in-the-loop (HIL) shows mixed impact on performance")
+    
+    # Model-specific insights
+    claude_performance = []
+    gpt_performance = []
+    deepseek_performance = []
+    
+    for group, group_metrics in metrics.items():
+        for model, model_metrics in group_metrics.items():
+            detection_rate = model_metrics.get('detection_rate', 0)
+            if 'Claude' in model:
+                claude_performance.append(detection_rate)
+            elif 'GPT' in model:
+                gpt_performance.append(detection_rate)
+            elif 'DeepSeek' in model:
+                deepseek_performance.append(detection_rate)
+    
+    avg_performances = []
+    if claude_performance:
+        avg_performances.append(('Claude', np.mean(claude_performance)))
+    if gpt_performance:
+        avg_performances.append(('GPT', np.mean(gpt_performance)))
+    if deepseek_performance:
+        avg_performances.append(('DeepSeek', np.mean(deepseek_performance)))
+    
+    if avg_performances:
+        avg_performances.sort(key=lambda x: x[1], reverse=True)
+        report_lines.append(f"3. Model ranking by average detection rate: {' > '.join([f'{model} ({rate:.1f}%)' for model, rate in avg_performances])}")
+    
+    # Save report
+    report_text = '\n'.join(report_lines)
+    
+    with open(output_dir / 'comprehensive_analysis_report.txt', 'w') as f:
+        f.write(report_text)
+    
+    print("\nCOMPREHENSIVE ANALYSIS SUMMARY:")
+    print("=" * 40)
+    print(report_text)
+
+
+def main():
+    """Main function to run comprehensive summary analysis."""
+    # Initialize data loader
+    loader = NERDataLoader()
+    
+    # Load all data
+    data = loader.load_all_data()
+    
+    # Create output directory using absolute path from structsense root
+    structsense_root = Path(__file__).parent.parent.parent
+    output_dir = structsense_root / "evaluation/ner/evaluation/Latent-circuit/results"
+    
+    # Run comprehensive analysis
+    generate_comprehensive_summary(loader, output_dir)
+    
+    print(f"\nComprehensive summary analysis complete. Results saved to {output_dir}")
+
+
+if __name__ == "__main__":
+    main()
\ No newline at end of file
diff --git a/evaluation/notebook/ner_data_loader.py b/evaluation/notebook/ner_data_loader.py
new file mode 100644
index 0000000..58907f3
--- /dev/null
+++ b/evaluation/notebook/ner_data_loader.py
@@ -0,0 +1,315 @@
+"""
+NER Data Loader and Preprocessing Utilities
+==========================================
+
+This module provides utilities for loading and preprocessing NER evaluation data
+from the Latent-circuit evaluation results. It handles both with_hil and without_hil
+groups and standardizes the data structure for analysis.
+
+Purpose: Load and preprocess NER evaluation JSON files for comparative analysis
+"""
+
+import json
+import os
+from pathlib import Path
+from typing import Dict, List, Tuple, Any, Optional
+import pandas as pd
+from collections import defaultdict
+import sys
+
+# Add structsense to Python path if needed
+structsense_root = Path(__file__).parent.parent.parent
+if str(structsense_root) not in sys.path:
+    sys.path.insert(0, str(structsense_root))
+
+
+class NERDataLoader:
+    """
+    Loads and preprocesses NER evaluation data from JSON files.
+    
+    Attributes:
+        base_path (Path): Base path to the evaluation data
+        model_mappings (Dict): Maps filename patterns to standardized model names
+    """
+    
+    def __init__(self, base_path: Optional[str] = None):
+        """
+        Initialize the data loader.
+        
+        Args:
+            base_path: Path to the Latent-circuit evaluation directory. 
+                      If None, uses default path relative to structsense root.
+        """
+        if base_path is None:
+            # Default path relative to structsense root
+            self.base_path = structsense_root / "evaluation/ner/evaluation/Latent-circuit"
+        else:
+            self.base_path = Path(base_path)
+            
+        # Model mappings to match the token analysis script naming
+        self.model_mappings = {
+            'claude': 'Claude 3.7 Sonnet',
+            'gpt': 'GPT-4o-mini',  # Note: it's 'gpt' not 'chatgpt' in filename
+            'deepseek': 'DeepSeek V3 0324'
+        }
+        self.data = {'with_hil': {}, 'without_hil': {}}
+        
+    def load_all_data(self) -> Dict[str, Dict[str, List[Dict]]]:
+        """
+        Load all JSON files from both groups.
+        
+        Returns:
+            Dictionary with structure: {group: {model: [entities]}}
+        """
+        for group in ['with_hil', 'without_hil']:
+            group_path = self.base_path / group
+            
+            if not group_path.exists():
+                print(f"Warning: {group_path} does not exist")
+                continue
+                
+            # Find all JSON files in the directory
+            json_files = list(group_path.glob("*.json"))
+            
+            for json_file in json_files:
+                # Determine which model this file belongs to
+                filename = json_file.name.lower()
+                
+                for pattern, model_name in self.model_mappings.items():
+                    if pattern in filename:
+                        print(f"Loading {json_file.name} as {model_name}")
+                        self.data[group][model_name] = self._load_json_file(json_file, group)
+                        break
+                    
+        return self.data
+    
+    def _load_json_file(self, filepath: Path, group: str) -> List[Dict]:
+        """
+        Load and flatten a single JSON file.
+        
+        Args:
+            filepath: Path to the JSON file
+            group: Group name (with_hil or without_hil)
+            
+        Returns:
+            List of entity dictionaries
+        """
+        with open(filepath, 'r') as f:
+            data = json.load(f)
+        
+        # Handle different JSON structures between groups
+        entities = []
+        
+        if group == 'with_hil':
+            # Structure: {judged_structured_information: {judge_ner_terms: {chunk_id: [entities]}}}
+            if 'judged_structured_information' in data:
+                ner_data = data['judged_structured_information'].get('judge_ner_terms', {})
+            else:
+                ner_data = {}
+        else:
+            # Structure: {judge_ner_terms: {judge_ner_terms: {chunk_id: [entities]}}}
+            if 'judge_ner_terms' in data:
+                ner_data = data['judge_ner_terms'].get('judge_ner_terms', {})
+            else:
+                ner_data = {}
+        
+        # Flatten all chunks into a single list
+        for chunk_id, chunk_entities in ner_data.items():
+            for entity in chunk_entities:
+                # Store chunk number for reference if needed
+                entity['_chunk_number'] = chunk_id
+                entities.append(entity)
+                
+        return entities
+    
+    def get_entity_dataframe(self, group: str, model: str) -> pd.DataFrame:
+        """
+        Convert entity list to pandas DataFrame for easier analysis.
+        
+        Args:
+            group: 'with_hil' or 'without_hil'
+            model: Model name
+            
+        Returns:
+            DataFrame with entity information (one row per occurrence)
+        """
+        if group not in self.data or model not in self.data[group]:
+            return pd.DataFrame()
+            
+        entities = self.data[group][model]
+        
+        # Flatten nested lists for analysis
+        flattened_entities = []
+        for entity in entities:
+            # Get the basic non-list fields
+            entity_text = entity.get('entity', '')
+            label = entity.get('label', '')
+            ontology_id = entity.get('ontology_id', '')
+            ontology_label = entity.get('ontology_label', '')
+            chunk_number = entity.get('_chunk_number', '')
+            
+            # Get all list fields - these should all have the same length
+            sentences = entity.get('sentence', [])
+            starts = entity.get('start', [])
+            ends = entity.get('end', [])
+            remarks = entity.get('remarks', [])
+            judge_scores = entity.get('judge_score', [])
+            paper_locations = entity.get('paper_location', [])
+            paper_titles = entity.get('paper_title', [])
+            dois = entity.get('doi', [])
+            
+            # Create one row per occurrence
+            num_occurrences = len(sentences) if sentences else 1
+            
+            for i in range(num_occurrences):
+                row = {
+                    'entity': entity_text,
+                    'label': label,
+                    'ontology_id': ontology_id,
+                    'ontology_label': ontology_label,
+                    'chunk_number': chunk_number,
+                    'sentence': sentences[i] if i < len(sentences) else '',
+                    'start': starts[i] if i < len(starts) else -1,
+                    'end': ends[i] if i < len(ends) else -1,
+                    'remark': remarks[i] if i < len(remarks) else '',
+                    'judge_score': judge_scores[i] if i < len(judge_scores) else None,
+                    'paper_location': paper_locations[i] if i < len(paper_locations) else '',
+                    'paper_title': paper_titles[i] if i < len(paper_titles) else '',
+                    'doi': dois[i] if i < len(dois) else ''
+                }
+                flattened_entities.append(row)
+                
+        return pd.DataFrame(flattened_entities)
+    
+    def get_unique_entities(self, group: str, model: str = None) -> List[str]:
+        """
+        Get unique entity strings for a group/model.
+        
+        Args:
+            group: 'with_hil' or 'without_hil'
+            model: Model name (if None, get all models in group)
+            
+        Returns:
+            List of unique entity strings
+        """
+        entities = set()
+        
+        if model:
+            models = [model] if model in self.data[group] else []
+        else:
+            models = self.data[group].keys()
+            
+        for m in models:
+            for entity in self.data[group][m]:
+                entities.add(entity.get('entity', '').lower().strip())
+                
+        return list(entities)
+    
+    def get_entity_pool(self, group: str) -> Dict[str, List[str]]:
+        """
+        Get the entity pool (union of all models) for a group.
+        
+        Args:
+            group: 'with_hil' or 'without_hil'
+            
+        Returns:
+            Dictionary with entity pool and per-model entities
+        """
+        pool = set()
+        model_entities = {}
+        
+        for model in self.data[group].keys():
+            entities = self.get_unique_entities(group, model)
+            model_entities[model] = entities
+            pool.update(entities)
+                
+        return {
+            'pool': list(pool),
+            'model_entities': model_entities
+        }
+    
+    def calculate_entity_overlap(self, group: str) -> Dict[str, Any]:
+        """
+        Calculate entity overlap between models.
+        
+        Args:
+            group: 'with_hil' or 'without_hil'
+            
+        Returns:
+            Dictionary with overlap statistics
+        """
+        pool_data = self.get_entity_pool(group)
+        pool = set(pool_data['pool'])
+        model_entities = {m: set(e) for m, e in pool_data['model_entities'].items()}
+        
+        # Calculate overlaps
+        overlap_stats = {
+            'total_pool_size': len(pool),
+            'model_counts': {m: len(e) for m, e in model_entities.items()},
+            'model_missing': {},
+            'pairwise_overlap': {},
+            'all_models_shared': None
+        }
+        
+        # Missing entities (false negatives) per model
+        for model, entities in model_entities.items():
+            missing = pool - entities
+            overlap_stats['model_missing'][model] = {
+                'count': len(missing),
+                'entities': list(missing)
+            }
+        
+        # Pairwise overlaps
+        models = list(model_entities.keys())
+        for i in range(len(models)):
+            for j in range(i + 1, len(models)):
+                m1, m2 = models[i], models[j]
+                overlap = model_entities[m1] & model_entities[m2]
+                overlap_stats['pairwise_overlap'][f"{m1}_vs_{m2}"] = {
+                    'count': len(overlap),
+                    'entities': list(overlap)
+                }
+        
+        # All models shared
+        if len(model_entities) > 0:
+            all_shared = set.intersection(*model_entities.values())
+            overlap_stats['all_models_shared'] = {
+                'count': len(all_shared),
+                'entities': list(all_shared)
+            }
+            
+        return overlap_stats
+    
+    def get_model_colors(self) -> Dict[str, str]:
+        """
+        Get the colorblind-friendly colors for each model.
+        Matches the color scheme from token_cost_speed_analysis.py
+        
+        Returns:
+            Dictionary mapping model names to hex colors
+        """
+        return {
+            'GPT-4o-mini': '#E69F00',      # Orange
+            'Claude 3.7 Sonnet': '#56B4E9', # Sky blue
+            'DeepSeek V3 0324': '#009E73'   # Bluish green
+        }
+
+
+if __name__ == "__main__":
+    # Example usage - no need to specify full path
+    loader = NERDataLoader()
+    
+    # Load all data
+    data = loader.load_all_data()
+    
+    # Print summary
+    for group in ['with_hil', 'without_hil']:
+        print(f"\n{group.upper()} Group:")
+        for model, entities in data[group].items():
+            print(f"  {model}: {len(entities)} entities")
+            
+    # Calculate overlap for with_hil group
+    if 'with_hil' in data and data['with_hil']:
+        overlap = loader.calculate_entity_overlap('with_hil')
+        print(f"\nEntity pool size (with_hil): {overlap['total_pool_size']}")
+        print("Model entity counts:", overlap['model_counts'])
\ No newline at end of file
diff --git a/evaluation/notebook/ner_entity_pool_analysis.py b/evaluation/notebook/ner_entity_pool_analysis.py
new file mode 100644
index 0000000..fcca7de
--- /dev/null
+++ b/evaluation/notebook/ner_entity_pool_analysis.py
@@ -0,0 +1,286 @@
+"""
+NER Entity Pool Analysis
+========================
+
+This script analyzes the entity pool across models for both with_hil and without_hil groups.
+It calculates false negatives (missed entities) for each model based on the union of all models.
+
+Purpose: Analyze entity detection performance and calculate false negatives
+"""
+
+import sys
+from pathlib import Path
+import pandas as pd
+import matplotlib.pyplot as plt
+import numpy as np
+from typing import Dict, List, Tuple
+
+# Add structsense to path
+sys.path.append(str(Path(__file__).parent.parent.parent))
+
+from evaluation.notebook.ner_data_loader import NERDataLoader
+
+# Configure matplotlib for publication-quality figures
+plt.rcParams['font.family'] = 'Arial'
+plt.rcParams['font.size'] = 8
+plt.rcParams['axes.linewidth'] = 0.5
+plt.rcParams['xtick.major.width'] = 0.5
+plt.rcParams['ytick.major.width'] = 0.5
+plt.rcParams['xtick.major.size'] = 3
+plt.rcParams['ytick.major.size'] = 3
+
+
+def create_entity_pool_analysis(loader: NERDataLoader, group_name:Dict, output_dir: Path):
+    """
+    Create comprehensive entity pool analysis for both groups.
+    
+    Args:
+        loader: NERDataLoader instance with loaded data
+        output_dir: Directory to save outputs
+    """
+    output_dir.mkdir(parents=True, exist_ok=True)
+    
+    # Get model colors
+    colors = loader.get_model_colors()
+    
+    # Analyze both groups
+    for group in ['with_hil', 'without_hil']:
+        if group not in loader.data or not loader.data[group]:
+            print(f"No data for {group}, skipping...")
+            continue
+            
+        # Calculate entity overlap statistics
+        overlap_stats = loader.calculate_entity_overlap(group)
+        
+        # Create figure for entity counts and false negatives
+        fig, (ax1, ax2) = plt.subplots(1, 2, figsize=(7, 3))
+        
+        # Plot 1: Entity counts per model (ordered: GPT, Claude, DeepSeek)
+        model_order = ['GPT-4o-mini', 'Claude 3.7 Sonnet', 'DeepSeek V3 0324']
+        models = [m for m in model_order if m in overlap_stats['model_counts']]
+        counts = [overlap_stats['model_counts'][m] for m in models]
+        model_colors = [colors.get(m, '#999999') for m in models]
+        
+        bars1 = ax1.bar(range(len(models)), counts, color=model_colors, alpha=0.8)
+        ax1.set_xticks(range(len(models)))
+        ax1.set_xticklabels([m.replace(' ', '\n') for m in models], fontsize=6)
+        ax1.set_ylabel('Number of Unique Entities', fontsize=7)
+        ax1.set_title(f'Entities Detected per Model ({group_name[group]})', fontsize=8, fontweight='bold')
+        ax1.spines['top'].set_visible(False)
+        ax1.spines['right'].set_visible(False)
+        
+        # Add value labels on bars
+        for bar in bars1:
+            height = bar.get_height()
+            ax1.text(bar.get_x() + bar.get_width()/2., height + 1,
+                    f'{int(height)}', ha='center', va='bottom', fontsize=6)
+        
+        # Add total pool size as horizontal line
+        ax1.axhline(y=overlap_stats['total_pool_size'], color='red', 
+                   linestyle='--', linewidth=1, alpha=0.5)
+        max_count = max(counts) if counts else 0
+        ax1.text(len(models)-0.5, overlap_stats['total_pool_size'] - max_count * 0.15, 
+                f'Total Pool: {overlap_stats["total_pool_size"]}', 
+                fontsize=6, ha='right', color='red')
+        
+        # Plot 2: Missed detection (missed entities)
+        missed_counts = [overlap_stats['model_missing'][m]['count'] for m in models]
+        
+        bars2 = ax2.bar(range(len(models)), missed_counts, color=model_colors, alpha=0.8)
+        ax2.set_xticks(range(len(models)))
+        ax2.set_xticklabels([m.replace(' ', '\n') for m in models], fontsize=6)
+        ax2.set_ylabel('Number of Missed Entities', fontsize=7)
+        ax2.set_title(f'Missed Detection per Model ({group_name[group]})', fontsize=8, fontweight='bold')
+        ax2.spines['top'].set_visible(False)
+        ax2.spines['right'].set_visible(False)
+        
+        # Add value labels on bars
+        for bar in bars2:
+            height = bar.get_height()
+            ax2.text(bar.get_x() + bar.get_width()/2., height + 0.5,
+                    f'{int(height)}', ha='center', va='bottom', fontsize=6)
+        
+        plt.tight_layout()
+        
+        # Save figure
+        fig.savefig(output_dir / f'entity_pool_analysis_{group}.pdf', bbox_inches='tight')
+        plt.close()
+        
+        # Create Venn diagram for model overlaps (simplified version)
+        create_overlap_visualization(overlap_stats, group, colors, group_name, output_dir)
+        
+        # Save detailed statistics to CSV
+        save_overlap_statistics(overlap_stats, group, output_dir)
+
+
+def create_overlap_visualization(overlap_stats: Dict, group: str, colors: Dict[str, str], group_name: Dict, output_dir: Path):
+    """
+    Create visualization of entity overlaps between models.
+    
+    Args:
+        overlap_stats: Dictionary with overlap statistics
+        group: Group name
+        colors: Model color mapping
+        output_dir: Output directory
+    """
+
+    fig, ax = plt.subplots(1, 1, figsize=(4, 3.5))
+    
+    # Prepare data for visualization (ordered: GPT, Claude, DeepSeek)
+    model_order = ['GPT-4o-mini', 'Claude 3.7 Sonnet', 'DeepSeek V3 0324']
+    models = [m for m in model_order if m in overlap_stats['model_counts']]
+    n_models = len(models)
+    
+    # Create a matrix of overlaps
+    overlap_matrix = np.zeros((n_models, n_models))
+    
+    for i, m1 in enumerate(models):
+        for j, m2 in enumerate(models):
+            if i == j:
+                overlap_matrix[i, j] = overlap_stats['model_counts'][m1]
+            else:
+                key = f"{m1}_vs_{m2}" if f"{m1}_vs_{m2}" in overlap_stats['pairwise_overlap'] else f"{m2}_vs_{m1}"
+                if key in overlap_stats['pairwise_overlap']:
+                    overlap_matrix[i, j] = overlap_stats['pairwise_overlap'][key]['count']
+    
+    # Plot heatmap
+    im = ax.imshow(overlap_matrix, cmap='Blues', aspect='auto')
+    
+    # Set ticks and labels
+    ax.set_xticks(np.arange(n_models))
+    ax.set_yticks(np.arange(n_models))
+    ax.set_xticklabels([m.replace(' ', '\n') for m in models], fontsize=6)
+    ax.set_yticklabels(models, fontsize=6)
+    
+    # Add text annotations
+    for i in range(n_models):
+        for j in range(n_models):
+            text = ax.text(j, i, int(overlap_matrix[i, j]),
+                          ha="center", va="center", color="black" if overlap_matrix[i, j] < 20 else "white",
+                          fontsize=6)
+    
+    ax.set_title(f'Entity Overlap Matrix ({group_name[group]})', fontsize=8, fontweight='bold')
+    
+    # Add colorbar
+    cbar = plt.colorbar(im, ax=ax, fraction=0.046, pad=0.04)
+    cbar.ax.tick_params(labelsize=6)
+    cbar.set_label('Number of Entities', fontsize=7)
+    
+    plt.tight_layout()
+    
+    # Save figure
+    fig.savefig(output_dir / f'entity_overlap_matrix_{group}.pdf', bbox_inches='tight')
+    plt.close()
+    
+    # Also create a bar chart showing shared entities
+    if overlap_stats['all_models_shared']:
+        fig, ax = plt.subplots(1, 1, figsize=(3.5, 3))
+        
+        categories = ['All Models', 'Any Two Models', 'Model-Specific']
+        values = [
+            overlap_stats['all_models_shared']['count'],
+            # Average pairwise overlap
+            np.mean([v['count'] for v in overlap_stats['pairwise_overlap'].values()]),
+            # Average unique to each model (estimated)
+            np.mean([overlap_stats['model_counts'][m] - overlap_stats['all_models_shared']['count'] 
+                    for m in models if m in overlap_stats['model_counts']])
+        ]
+        
+        bars = ax.bar(categories, values, color=['#66c2a5', '#fc8d62', '#8da0cb'], alpha=0.8)
+        ax.set_ylabel('Number of Entities', fontsize=7)
+        ax.set_title(f'Entity Sharing Patterns ({group_name[group]})', fontsize=8, fontweight='bold')
+        ax.spines['top'].set_visible(False)
+        ax.spines['right'].set_visible(False)
+        ax.tick_params(axis='x', labelsize=6)
+        
+        # Add value labels
+        for bar in bars:
+            height = bar.get_height()
+            ax.text(bar.get_x() + bar.get_width()/2., height + 0.5,
+                   f'{int(height)}', ha='center', va='bottom', fontsize=6)
+        
+        plt.tight_layout()
+        
+        # Save figure
+        fig.savefig(output_dir / f'entity_sharing_patterns_{group}.pdf', bbox_inches='tight')
+        plt.close()
+
+
+def save_overlap_statistics(overlap_stats: Dict, group: str, output_dir: Path):
+    """
+    Save detailed overlap statistics to CSV files.
+    
+    Args:
+        overlap_stats: Dictionary with overlap statistics
+        group: Group name
+        output_dir: Output directory
+    """
+    # Summary statistics
+    summary_data = {
+        'Metric': ['Total Pool Size', 'All Models Shared'],
+        'Value': [overlap_stats['total_pool_size'], 
+                 overlap_stats['all_models_shared']['count'] if overlap_stats['all_models_shared'] else 0]
+    }
+    
+    # Add model-specific stats
+    for model, count in overlap_stats['model_counts'].items():
+        summary_data['Metric'].extend([f'{model} - Detected', f'{model} - Missed'])
+        summary_data['Value'].extend([count, overlap_stats['model_missing'][model]['count']])
+    
+    summary_df = pd.DataFrame(summary_data)
+    summary_df.to_csv(output_dir / f'entity_pool_summary_{group}.csv', index=False)
+    
+    # Detailed missed entities
+    missed_entities_data = []
+    for model, data in overlap_stats['model_missing'].items():
+        for entity in data['entities']:
+            missed_entities_data.append({
+                'Model': model,
+                'Missed Entity': entity
+            })
+    
+    if missed_entities_data:
+        missed_df = pd.DataFrame(missed_entities_data)
+        missed_df.to_csv(output_dir / f'missed_entities_details_{group}.csv', index=False)
+    
+    # Shared entities details
+    if overlap_stats['all_models_shared'] and overlap_stats['all_models_shared']['entities']:
+        shared_df = pd.DataFrame({
+            'Shared Entity': overlap_stats['all_models_shared']['entities']
+        })
+        shared_df.to_csv(output_dir / f'shared_entities_all_models_{group}.csv', index=False)
+
+
+def main():
+    """Main function to run entity pool analysis."""
+    # Initialize data loader
+    loader = NERDataLoader()
+    
+    # Load all data
+    data = loader.load_all_data()
+    
+    # Create output directory using absolute path from structsense root
+    structsense_root = Path(__file__).parent.parent.parent
+    output_dir = structsense_root / "evaluation/ner/evaluation/Latent-circuit/results"
+    
+    group_name = {"with_hil": "with HIL", "without_hil": "without HIL"}
+
+    # Run analysis
+    create_entity_pool_analysis(loader, group_name, output_dir)
+    
+    print(f"\nEntity pool analysis complete. Results saved to {output_dir}")
+    
+    # Print summary
+    for group in ['with_hil', 'without_hil']:
+        if group in data and data[group]:
+            overlap = loader.calculate_entity_overlap(group)
+            print(f"\n{group.upper()} Summary:")
+            print(f"  Total entity pool: {overlap['total_pool_size']}")
+            print(f"  Entities shared by all models: {overlap['all_models_shared']['count'] if overlap['all_models_shared'] else 0}")
+            for model, count in overlap['model_counts'].items():
+                miss_rate = overlap['model_missing'][model]['count'] / overlap['total_pool_size'] * 100
+                print(f"  {model}: {count} detected, {overlap['model_missing'][model]['count']} missed ({miss_rate:.1f}% miss rate)")
+
+
+if __name__ == "__main__":
+    main()
\ No newline at end of file
diff --git a/evaluation/notebook/ner_judge_score_analysis.py b/evaluation/notebook/ner_judge_score_analysis.py
new file mode 100644
index 0000000..7d817e5
--- /dev/null
+++ b/evaluation/notebook/ner_judge_score_analysis.py
@@ -0,0 +1,545 @@
+"""
+NER Judge Score Analysis
+========================
+
+This script analyzes the judge scores assigned to entity extractions by each model.
+It examines score distributions, confidence patterns, and quality assessments.
+
+Purpose: Analyze judge score patterns and quality assessments
+"""
+
+import sys
+from pathlib import Path
+import pandas as pd
+import matplotlib.pyplot as plt
+import numpy as np
+from typing import Dict, List, Tuple, Set
+from collections import defaultdict
+import seaborn as sns
+
+# Add structsense to path
+sys.path.append(str(Path(__file__).parent.parent.parent))
+
+from evaluation.notebook.ner_data_loader import NERDataLoader
+
+# Configure matplotlib for publication-quality figures
+plt.rcParams['font.family'] = 'Arial'
+plt.rcParams['font.size'] = 8
+plt.rcParams['axes.linewidth'] = 0.5
+plt.rcParams['xtick.major.width'] = 0.5
+plt.rcParams['ytick.major.width'] = 0.5
+plt.rcParams['xtick.major.size'] = 3
+plt.rcParams['ytick.major.size'] = 3
+
+
+def analyze_judge_scores(loader: NERDataLoader, output_dir: Path):
+    """
+    Analyze judge scores across models and groups.
+    
+    Args:
+        loader: NERDataLoader instance with loaded data
+        output_dir: Directory to save outputs
+    """
+    output_dir.mkdir(parents=True, exist_ok=True)
+    
+    # Get model colors
+    colors = loader.get_model_colors()
+    
+    # Analyze both groups
+    for group in ['with_hil', 'without_hil']:
+        if group not in loader.data or not loader.data[group]:
+            continue
+        
+        # Collect score data for all models (ordered: GPT, Claude, DeepSeek)
+        model_scores = {}
+        
+        model_order = ['GPT-4o-mini', 'Claude 3.7 Sonnet', 'DeepSeek V3 0324']
+        for model in model_order:
+            if model not in loader.data[group]:
+                continue
+                
+            df = loader.get_entity_dataframe(group, model)
+            
+            if df.empty:
+                continue
+            
+            # Filter out null scores and convert to numeric
+            valid_scores = df[df['judge_score'].notna()]['judge_score'].astype(float)
+            model_scores[model] = valid_scores.tolist()
+        
+        # Create score distribution visualizations
+        create_score_density_plots(model_scores, group, colors, output_dir)
+        create_score_statistics_table(model_scores, group, output_dir)
+        
+        # Analyze scores by entity characteristics
+        analyze_scores_by_characteristics(loader, group, output_dir)
+    
+    # Create cross-group comparison
+    create_group_score_comparison(loader, colors, output_dir)
+    
+    # Note: Removed correlation analysis as requested
+    
+    # Save detailed statistics
+    save_score_statistics(loader, output_dir)
+
+
+def create_score_density_plots(model_scores: Dict[str, List[float]], 
+                              group: str, colors: Dict[str, str], output_dir: Path):
+    """
+    Create density plots showing score distributions for all models in one plot.
+    
+    Args:
+        model_scores: Dictionary of model names to score lists
+        group: Group name
+        colors: Model color mapping
+        output_dir: Output directory
+    """
+    if not model_scores:
+        return
+    
+    fig, ax = plt.subplots(1, 1, figsize=(5, 4))
+    
+    models = list(model_scores.keys())
+    
+    for model in models:
+        scores = model_scores[model]
+        if scores and len(scores) > 1:
+            # Create density plot using histogram with many bins and normalization
+            counts, bins = np.histogram(scores, bins=50, range=(0, 1), density=True)
+            bin_centers = (bins[:-1] + bins[1:]) / 2
+            
+            # Smooth the density curve
+            from scipy import stats
+            density = stats.gaussian_kde(scores)
+            x_range = np.linspace(0, 1, 200)
+            density_values = density(x_range)
+            
+            # Plot density curve
+            ax.plot(x_range, density_values, color=colors.get(model, '#999999'), 
+                   linewidth=2, alpha=0.8, label=model)
+            
+            # Fill under curve with transparency
+            ax.fill_between(x_range, density_values, alpha=0.3, 
+                           color=colors.get(model, '#999999'))
+            
+            # Add mean line
+            mean_score = np.mean(scores)
+            max_density = np.max(density_values)
+            ax.axvline(mean_score, color=colors.get(model, '#999999'), 
+                      linestyle='--', linewidth=1, alpha=0.7)
+            
+            # Add mean value text
+            ax.text(mean_score, max_density * 1.05, f'{mean_score:.3f}', 
+                   ha='center', va='bottom', fontsize=6, 
+                   color=colors.get(model, '#999999'), fontweight='bold')
+    
+    # Customize plot
+    ax.set_xlabel('Judge Score', fontsize=7)
+    ax.set_ylabel('Density', fontsize=7)
+    ax.set_title(f'Judge Score Distributions ({group})', fontsize=8, fontweight='bold')
+    ax.legend(fontsize=6, loc='upper left', frameon=False)
+    ax.spines['top'].set_visible(False)
+    ax.spines['right'].set_visible(False)
+    ax.set_xlim(0, 1)
+    
+    # Add grid for better readability
+    ax.grid(True, alpha=0.3, linestyle=':')
+    
+    plt.tight_layout()
+    
+    # Save figure
+    fig.savefig(output_dir / f'judge_score_distributions_{group}.pdf', bbox_inches='tight')
+    plt.close()
+
+
+def create_score_statistics_table(model_scores: Dict[str, List[float]], 
+                                group: str, output_dir: Path):
+    """
+    Create a table with detailed score statistics.
+    
+    Args:
+        model_scores: Dictionary of model names to score lists
+        group: Group name
+        output_dir: Output directory
+    """
+    if not model_scores:
+        return
+    
+    stats_data = []
+    
+    for model, scores in model_scores.items():
+        if scores:
+            stats = {
+                'Model': model,
+                'Count': len(scores),
+                'Mean': np.mean(scores),
+                'Median': np.median(scores),
+                'Std': np.std(scores),
+                'Min': np.min(scores),
+                'Max': np.max(scores),
+                'Q25': np.percentile(scores, 25),
+                'Q75': np.percentile(scores, 75),
+                'High_Confidence': sum(1 for s in scores if s >= 0.8) / len(scores) * 100,
+                'Low_Confidence': sum(1 for s in scores if s < 0.5) / len(scores) * 100
+            }
+            stats_data.append(stats)
+    
+    if stats_data:
+        stats_df = pd.DataFrame(stats_data)
+        
+        # Round numeric columns
+        numeric_cols = ['Mean', 'Median', 'Std', 'Min', 'Max', 'Q25', 'Q75', 
+                       'High_Confidence', 'Low_Confidence']
+        for col in numeric_cols:
+            stats_df[col] = stats_df[col].round(3)
+        
+        # Save to CSV
+        stats_df.to_csv(output_dir / f'judge_score_statistics_{group}.csv', index=False)
+        
+        # Create visual table
+        fig, ax = plt.subplots(1, 1, figsize=(8, 3))
+        ax.axis('tight')
+        ax.axis('off')
+        
+        # Create table
+        table_data = []
+        headers = ['Model', 'Count', 'Mean', 'Median', 'Std', 'High Conf.%', 'Low Conf.%']
+        
+        for _, row in stats_df.iterrows():
+            table_data.append([
+                row['Model'].replace(' ', '\n'),
+                int(row['Count']),
+                f"{row['Mean']:.3f}",
+                f"{row['Median']:.3f}",
+                f"{row['Std']:.3f}",
+                f"{row['High_Confidence']:.1f}%",
+                f"{row['Low_Confidence']:.1f}%"
+            ])
+        
+        table = ax.table(cellText=table_data, colLabels=headers,
+                        cellLoc='center', loc='center')
+        table.auto_set_font_size(False)
+        table.set_fontsize(7)
+        table.scale(1, 2)
+        
+        # Style the table
+        for i in range(len(headers)):
+            table[(0, i)].set_facecolor('#E6E6E6')
+            table[(0, i)].set_text_props(weight='bold')
+        
+        ax.set_title(f'Judge Score Statistics Summary ({group})', 
+                    fontsize=8, fontweight='bold', pad=20)
+        
+        plt.tight_layout()
+        
+        # Save figure
+        fig.savefig(output_dir / f'judge_score_table_{group}.pdf', bbox_inches='tight')
+        plt.close()
+
+
+def analyze_scores_by_characteristics(loader: NERDataLoader, group: str, output_dir: Path):
+    """
+    Analyze judge scores by entity characteristics (label, location, etc.).
+    
+    Args:
+        loader: NERDataLoader instance
+        group: Group name
+        output_dir: Output directory
+    """
+    if group not in loader.data or not loader.data[group]:
+        return
+    
+    # Collect data across all models
+    all_data = []
+    
+    for model in loader.data[group].keys():
+        df = loader.get_entity_dataframe(group, model)
+        
+        if df.empty:
+            continue
+        
+        # Filter valid scores
+        valid_df = df[df['judge_score'].notna()].copy()
+        valid_df['judge_score'] = valid_df['judge_score'].astype(float)
+        valid_df['model'] = model
+        
+        all_data.append(valid_df)
+    
+    if not all_data:
+        return
+    
+    combined_df = pd.concat(all_data, ignore_index=True)
+    
+    # Analyze by label
+    if 'label' in combined_df.columns:
+        create_scores_by_label_plot(combined_df, group, output_dir)
+    
+    # Analyze by paper location
+    if 'paper_location' in combined_df.columns:
+        create_scores_by_location_plot(combined_df, group, output_dir)
+
+
+def create_scores_by_label_plot(df: pd.DataFrame, group: str, output_dir: Path):
+    """
+    Create plot showing score distributions by entity label.
+    
+    Args:
+        df: Combined dataframe with all models
+        group: Group name
+        output_dir: Output directory
+    """
+    # Get top labels by frequency
+    top_labels = df['label'].value_counts().head(8).index.tolist()
+    
+    if len(top_labels) < 2:
+        return
+    
+    # Filter to top labels
+    filtered_df = df[df['label'].isin(top_labels)]
+    
+    fig, ax = plt.subplots(1, 1, figsize=(6, 4))
+    
+    # Create box plot
+    label_data = [filtered_df[filtered_df['label'] == label]['judge_score'].tolist() 
+                  for label in top_labels]
+    
+    bp = ax.boxplot(label_data, tick_labels=[label.replace('_', '\n') for label in top_labels],
+                    patch_artist=True, showmeans=True)
+    
+    # Color the boxes
+    colors_cycle = ['#1f77b4', '#ff7f0e', '#2ca02c', '#d62728', '#9467bd', 
+                   '#8c564b', '#e377c2', '#7f7f7f']
+    
+    for patch, color in zip(bp['boxes'], colors_cycle):
+        patch.set_facecolor(color)
+        patch.set_alpha(0.7)
+    
+    ax.set_ylabel('Judge Score', fontsize=7)
+    ax.set_title(f'Judge Scores by Entity Label ({group})', fontsize=8, fontweight='bold')
+    ax.spines['top'].set_visible(False)
+    ax.spines['right'].set_visible(False)
+    ax.set_ylim(0, 1)
+    
+    plt.xticks(fontsize=5)
+    plt.tight_layout()
+    
+    # Save figure
+    fig.savefig(output_dir / f'judge_scores_by_label_{group}.pdf', bbox_inches='tight')
+    plt.close()
+
+
+def create_scores_by_location_plot(df: pd.DataFrame, group: str, output_dir: Path):
+    """
+    Create plot showing score distributions by paper location.
+    
+    Args:
+        df: Combined dataframe with all models
+        group: Group name
+        output_dir: Output directory
+    """
+    # Normalize locations (simple version)
+    df['norm_location'] = df['paper_location'].str.lower().str.strip()
+    
+    # Get top locations by frequency
+    top_locations = df['norm_location'].value_counts().head(6).index.tolist()
+    
+    if len(top_locations) < 2:
+        return
+    
+    # Filter to top locations
+    filtered_df = df[df['norm_location'].isin(top_locations)]
+    
+    fig, ax = plt.subplots(1, 1, figsize=(5, 4))
+    
+    # Create box plot
+    location_data = [filtered_df[filtered_df['norm_location'] == loc]['judge_score'].tolist() 
+                    for loc in top_locations]
+    
+    bp = ax.boxplot(location_data, tick_labels=top_locations, patch_artist=True, showmeans=True)
+    
+    # Color the boxes
+    colors_cycle = ['#1f77b4', '#ff7f0e', '#2ca02c', '#d62728', '#9467bd', '#8c564b']
+    
+    for patch, color in zip(bp['boxes'], colors_cycle):
+        patch.set_facecolor(color)
+        patch.set_alpha(0.7)
+    
+    ax.set_ylabel('Judge Score', fontsize=7)
+    ax.set_title(f'Judge Scores by Paper Location ({group})', fontsize=8, fontweight='bold')
+    ax.spines['top'].set_visible(False)
+    ax.spines['right'].set_visible(False)
+    ax.set_ylim(0, 1)
+    
+    plt.xticks(fontsize=5)
+    plt.tight_layout()
+    
+    # Save figure
+    fig.savefig(output_dir / f'judge_scores_by_location_{group}.pdf', bbox_inches='tight')
+    plt.close()
+
+
+def create_group_score_comparison(loader: NERDataLoader, colors: Dict[str, str], output_dir: Path):
+    """
+    Create comparison of judge scores between groups.
+    
+    Args:
+        loader: NERDataLoader instance
+        colors: Model color mapping
+        output_dir: Output directory
+    """
+    group_scores = {}
+    
+    for group in ['with_hil', 'without_hil']:
+        if group not in loader.data or not loader.data[group]:
+            continue
+        
+        model_scores = {}
+        
+        for model in loader.data[group].keys():
+            df = loader.get_entity_dataframe(group, model)
+            
+            if not df.empty:
+                valid_scores = df[df['judge_score'].notna()]['judge_score'].astype(float)
+                model_scores[model] = valid_scores.tolist()
+        
+        group_scores[group] = model_scores
+    
+    if len(group_scores) < 2:
+        return
+    
+    # Get models that appear in both groups (ordered: GPT, Claude, DeepSeek)
+    models_with = set(group_scores.get('with_hil', {}).keys())
+    models_without = set(group_scores.get('without_hil', {}).keys())
+    model_order = ['GPT-4o-mini', 'Claude 3.7 Sonnet', 'DeepSeek V3 0324']
+    common_models = [m for m in model_order if m in models_with and m in models_without]
+    
+    if not common_models:
+        return
+    
+    # Create comparison plot
+    fig, ax = plt.subplots(1, 1, figsize=(5, 4))
+    
+    x = np.arange(len(common_models))
+    width = 0.35
+    
+    # Calculate mean scores
+    means_with = []
+    means_without = []
+    
+    for model in common_models:
+        scores_with = group_scores['with_hil'].get(model, [])
+        scores_without = group_scores['without_hil'].get(model, [])
+        
+        means_with.append(np.mean(scores_with) if scores_with else 0)
+        means_without.append(np.mean(scores_without) if scores_without else 0)
+    
+    bars1 = ax.bar(x - width/2, means_with, width,
+                   color=[colors.get(m, '#999999') for m in common_models], alpha=0.8)
+    bars2 = ax.bar(x + width/2, means_without, width,
+                   color=[colors.get(m, '#999999') for m in common_models], alpha=0.4)
+    
+    ax.set_ylabel('Mean Judge Score', fontsize=7)
+    ax.set_title('Judge Scores: With vs Without HIL', fontsize=8, fontweight='bold')
+    ax.set_xticks(x)
+    ax.set_xticklabels([m.replace(' ', '\n') for m in common_models], fontsize=6)
+    
+    # Add text labels instead of legend to avoid color confusion
+    ax.text(0.02, 0.95, 'With\nHIL', transform=ax.transAxes, fontsize=6, 
+           verticalalignment='top', bbox=dict(boxstyle='round', facecolor='white', alpha=0.8))
+    ax.text(0.12, 0.95, 'Without\nHIL', transform=ax.transAxes, fontsize=6, 
+           verticalalignment='top', bbox=dict(boxstyle='round', facecolor='lightgray', alpha=0.8))
+    ax.spines['top'].set_visible(False)
+    ax.spines['right'].set_visible(False)
+    ax.set_ylim(0, 1)
+    
+    # Add value labels
+    for bars in [bars1, bars2]:
+        for bar in bars:
+            height = bar.get_height()
+            ax.text(bar.get_x() + bar.get_width()/2., height + 0.01,
+                   f'{height:.3f}', ha='center', va='bottom', fontsize=6)
+    
+    plt.tight_layout()
+    
+    # Save figure
+    fig.savefig(output_dir / f'judge_scores_group_comparison.pdf', bbox_inches='tight')
+    plt.close()
+
+
+
+
+def save_score_statistics(loader: NERDataLoader, output_dir: Path):
+    """
+    Save detailed score statistics to CSV files.
+    
+    Args:
+        loader: NERDataLoader instance
+        output_dir: Output directory
+    """
+    all_stats = []
+    
+    for group in ['with_hil', 'without_hil']:
+        if group not in loader.data or not loader.data[group]:
+            continue
+        
+        for model in loader.data[group].keys():
+            df = loader.get_entity_dataframe(group, model)
+            
+            if df.empty:
+                continue
+            
+            # Get valid scores
+            valid_scores = df[df['judge_score'].notna()]['judge_score'].astype(float)
+            
+            if len(valid_scores) > 0:
+                all_stats.append({
+                    'Group': group,
+                    'Model': model,
+                    'Count': len(valid_scores),
+                    'Mean': valid_scores.mean(),
+                    'Median': valid_scores.median(),
+                    'Std': valid_scores.std(),
+                    'Min': valid_scores.min(),
+                    'Max': valid_scores.max(),
+                    'High_Confidence_Pct': (valid_scores >= 0.8).mean() * 100,
+                    'Low_Confidence_Pct': (valid_scores < 0.5).mean() * 100
+                })
+    
+    if all_stats:
+        stats_df = pd.DataFrame(all_stats)
+        stats_df.to_csv(output_dir / 'judge_score_detailed_statistics.csv', index=False)
+
+
+def main():
+    """Main function to run judge score analysis."""
+    # Initialize data loader
+    loader = NERDataLoader()
+    
+    # Load all data
+    data = loader.load_all_data()
+    
+    # Create output directory using absolute path from structsense root
+    structsense_root = Path(__file__).parent.parent.parent
+    output_dir = structsense_root / "evaluation/ner/evaluation/Latent-circuit/results"
+    
+    # Run analysis
+    analyze_judge_scores(loader, output_dir)
+    
+    print(f"\nJudge score analysis complete. Results saved to {output_dir}")
+    
+    # Print summary
+    for group in ['with_hil', 'without_hil']:
+        if group in data and data[group]:
+            print(f"\n{group.upper()} Judge Score Summary:")
+            for model in data[group].keys():
+                df = loader.get_entity_dataframe(group, model)
+                if not df.empty:
+                    valid_scores = df[df['judge_score'].notna()]['judge_score'].astype(float)
+                    if len(valid_scores) > 0:
+                        mean_score = valid_scores.mean()
+                        high_conf = (valid_scores >= 0.8).mean() * 100
+                        print(f"  {model}: Mean={mean_score:.3f}, High confidence={high_conf:.1f}%")
+
+
+if __name__ == "__main__":
+    main()
\ No newline at end of file
diff --git a/evaluation/notebook/ner_label_distribution.py b/evaluation/notebook/ner_label_distribution.py
new file mode 100644
index 0000000..e29d94d
--- /dev/null
+++ b/evaluation/notebook/ner_label_distribution.py
@@ -0,0 +1,531 @@
+"""
+NER Label Distribution Analysis
+===============================
+
+This script analyzes the distribution of entity labels (types) detected by each model.
+It examines both individual model patterns and shared entity labels across models.
+
+Purpose: Analyze entity label distribution patterns
+"""
+
+import sys
+from pathlib import Path
+import pandas as pd
+import matplotlib.pyplot as plt
+import numpy as np
+from typing import Dict, List, Tuple, Set
+from collections import defaultdict, Counter
+
+# Add structsense to path
+sys.path.append(str(Path(__file__).parent.parent.parent))
+
+from evaluation.notebook.ner_data_loader import NERDataLoader
+
+# Configure matplotlib for publication-quality figures
+plt.rcParams['font.family'] = 'Arial'
+plt.rcParams['font.size'] = 8
+plt.rcParams['axes.linewidth'] = 0.5
+plt.rcParams['xtick.major.width'] = 0.5
+plt.rcParams['ytick.major.width'] = 0.5
+plt.rcParams['xtick.major.size'] = 3
+plt.rcParams['ytick.major.size'] = 3
+
+
+def analyze_label_distributions(loader: NERDataLoader, output_dir: Path):
+    """
+    Analyze entity label distributions across models and groups.
+    
+    Args:
+        loader: NERDataLoader instance with loaded data
+        output_dir: Directory to save outputs
+    """
+    output_dir.mkdir(parents=True, exist_ok=True)
+    
+    # Get model colors
+    colors = loader.get_model_colors()
+    
+    # Analyze both groups
+    for group in ['with_hil', 'without_hil']:
+        if group not in loader.data or not loader.data[group]:
+            continue
+        
+        # Collect label data for all models (ordered: GPT, Claude, DeepSeek)
+        model_labels = {}
+        all_labels = set()
+        
+        model_order = ['GPT-4o-mini', 'Claude 3.7 Sonnet', 'DeepSeek V3 0324']
+        for model in model_order:
+            if model not in loader.data[group]:
+                continue
+                
+            df = loader.get_entity_dataframe(group, model)
+            
+            if df.empty:
+                continue
+            
+            # Get unique entities with their labels
+            unique_entities = df.groupby('entity').first().reset_index()
+            
+            # Count labels
+            label_counts = unique_entities['label'].value_counts()
+            model_labels[model] = label_counts
+            all_labels.update(label_counts.index)
+        
+        # Create label distribution visualizations
+        create_label_distribution_plot(model_labels, all_labels, group, colors, output_dir)
+        create_label_diversity_plot(model_labels, group, colors, output_dir)
+        
+        # Analyze shared entity labels
+        analyze_shared_entity_labels(loader, group, output_dir)
+    
+    # Create cross-group comparison
+    create_group_label_comparison(loader, colors, output_dir)
+    
+    # Save detailed statistics
+    save_label_statistics(loader, output_dir)
+
+
+def create_label_distribution_plot(model_labels: Dict, all_labels: Set, 
+                                 group: str, colors: Dict[str, str], output_dir: Path):
+    """
+    Create horizontal bar plot showing label distribution with models as grouped bars.
+    
+    Args:
+        model_labels: Label counts per model
+        all_labels: Set of all unique labels
+        group: Group name
+        colors: Model color mapping
+        output_dir: Output directory
+    """
+    if not model_labels:
+        return
+    
+    # Sort labels by total frequency across all models
+    label_totals = defaultdict(int)
+    for counts in model_labels.values():
+        for label, count in counts.items():
+            label_totals[label] += count
+    
+    sorted_labels = sorted(label_totals.keys(), key=lambda x: label_totals[x], reverse=True)
+    
+    # Create single horizontal bar plot with models grouped
+    fig, ax = plt.subplots(1, 1, figsize=(6, max(4, len(sorted_labels) * 0.4)))
+    
+    models = list(model_labels.keys())
+    n_models = len(models)
+    n_labels = len(sorted_labels)
+    
+    # Set up bar positions
+    y_pos = np.arange(n_labels)
+    bar_height = 0.8 / n_models
+    
+    # Plot bars for each model
+    for i, model in enumerate(models):
+        counts = [model_labels[model].get(label, 0) for label in sorted_labels]
+        offset = (i - n_models/2 + 0.5) * bar_height
+        
+        bars = ax.barh(y_pos + offset, counts, bar_height, 
+                      label=model, color=colors.get(model, '#999999'), alpha=0.8)
+    
+    # Customize plot
+    ax.set_yticks(y_pos)
+    ax.set_yticklabels(sorted_labels, fontsize=6)
+    ax.set_xlabel('Number of Entities', fontsize=7)
+    ax.set_title(f'Entity Label Distribution ({group})', fontsize=8, fontweight='bold')
+    ax.spines['top'].set_visible(False)
+    ax.spines['right'].set_visible(False)
+    
+    # Add legend in bottom right
+    ax.legend(fontsize=6, loc='lower right', frameon=False)
+    
+    # Set integer ticks on x-axis
+    max_count = max([counts.max() if len(counts) > 0 else 0 for counts in model_labels.values()])
+    if max_count > 0:
+        ax.set_xticks(range(0, int(max_count) + 1, max(1, int(max_count) // 5)))
+    
+    # Reverse y-axis to show most frequent at top
+    ax.invert_yaxis()
+    
+    plt.tight_layout()
+    
+    # Save figure
+    fig.savefig(output_dir / f'label_distribution_{group}.pdf', bbox_inches='tight')
+    plt.close()
+
+
+def create_label_diversity_plot(model_labels: Dict, group: str, colors: Dict[str, str], output_dir: Path):
+    """
+    Create plot showing label diversity metrics per model.
+    
+    Args:
+        model_labels: Label counts per model
+        group: Group name
+        colors: Model color mapping
+        output_dir: Output directory
+    """
+    if not model_labels:
+        return
+    
+    # Use consistent model ordering
+    model_order = ['GPT-4o-mini', 'Claude 3.7 Sonnet', 'DeepSeek V3 0324']
+    models = [m for m in model_order if m in model_labels]
+    
+    # Calculate diversity metrics
+    diversity_metrics = {}
+    
+    for model, label_counts in model_labels.items():
+        total_entities = label_counts.sum()
+        n_unique_labels = len(label_counts)
+        
+        # Shannon diversity index
+        shannon_diversity = 0
+        for count in label_counts.values:
+            if count > 0:
+                p = count / total_entities
+                shannon_diversity -= p * np.log(p)
+        
+        # Simpson diversity index (1 - Simpson's dominance)
+        simpson_diversity = 1 - sum((count / total_entities) ** 2 for count in label_counts.values)
+        
+        # Most common label percentage
+        max_label_pct = label_counts.max() / total_entities * 100 if total_entities > 0 else 0
+        
+        diversity_metrics[model] = {
+            'n_unique_labels': n_unique_labels,
+            'shannon_diversity': shannon_diversity,
+            'simpson_diversity': simpson_diversity,
+            'max_label_pct': max_label_pct,
+            'total_entities': total_entities
+        }
+    
+    # Create diversity comparison plot
+    fig, ((ax1, ax2), (ax3, ax4)) = plt.subplots(2, 2, figsize=(7, 5))
+    
+    x = np.arange(len(models))
+    model_colors = [colors.get(m, '#999999') for m in models]
+    
+    # Plot 1: Number of unique labels
+    unique_counts = [diversity_metrics[m]['n_unique_labels'] for m in models]
+    bars1 = ax1.bar(x, unique_counts, color=model_colors, alpha=0.8)
+    ax1.set_ylabel('Number of Unique Labels', fontsize=7)
+    ax1.set_title('Label Type Diversity', fontsize=8, fontweight='bold')
+    ax1.set_xticks(x)
+    ax1.set_xticklabels([m.replace(' ', '\n') for m in models], fontsize=6)
+    ax1.spines['top'].set_visible(False)
+    ax1.spines['right'].set_visible(False)
+    
+    for bar in bars1:
+        height = bar.get_height()
+        ax1.text(bar.get_x() + bar.get_width()/2., height + 0.1,
+                f'{int(height)}', ha='center', va='bottom', fontsize=6)
+    
+    # Plot 2: Shannon diversity
+    shannon_scores = [diversity_metrics[m]['shannon_diversity'] for m in models]
+    bars2 = ax2.bar(x, shannon_scores, color=model_colors, alpha=0.8)
+    ax2.set_ylabel('Shannon Diversity Index', fontsize=7)
+    ax2.set_title('Shannon Diversity', fontsize=8, fontweight='bold')
+    ax2.set_xticks(x)
+    ax2.set_xticklabels([m.replace(' ', '\n') for m in models], fontsize=6)
+    ax2.spines['top'].set_visible(False)
+    ax2.spines['right'].set_visible(False)
+    
+    for bar in bars2:
+        height = bar.get_height()
+        ax2.text(bar.get_x() + bar.get_width()/2., height + 0.05,
+                f'{height:.2f}', ha='center', va='bottom', fontsize=6)
+    
+    # Plot 3: Simpson diversity
+    simpson_scores = [diversity_metrics[m]['simpson_diversity'] for m in models]
+    bars3 = ax3.bar(x, simpson_scores, color=model_colors, alpha=0.8)
+    ax3.set_ylabel('Simpson Diversity Index', fontsize=7)
+    ax3.set_title('Simpson Diversity', fontsize=8, fontweight='bold')
+    ax3.set_xticks(x)
+    ax3.set_xticklabels([m.replace(' ', '\n') for m in models], fontsize=6)
+    ax3.spines['top'].set_visible(False)
+    ax3.spines['right'].set_visible(False)
+    
+    for bar in bars3:
+        height = bar.get_height()
+        ax3.text(bar.get_x() + bar.get_width()/2., height + 0.01,
+                f'{height:.2f}', ha='center', va='bottom', fontsize=6)
+    
+    # Plot 4: Dominance (most common label percentage)
+    dominance_scores = [diversity_metrics[m]['max_label_pct'] for m in models]
+    bars4 = ax4.bar(x, dominance_scores, color=model_colors, alpha=0.8)
+    ax4.set_ylabel('Most Common Label (%)', fontsize=7)
+    ax4.set_title('Label Dominance', fontsize=8, fontweight='bold')
+    ax4.set_xticks(x)
+    ax4.set_xticklabels([m.replace(' ', '\n') for m in models], fontsize=6)
+    ax4.spines['top'].set_visible(False)
+    ax4.spines['right'].set_visible(False)
+    
+    for bar in bars4:
+        height = bar.get_height()
+        ax4.text(bar.get_x() + bar.get_width()/2., height + 1,
+                f'{height:.0f}%', ha='center', va='bottom', fontsize=6)
+    
+    plt.suptitle(f'Label Diversity Metrics ({group})', fontsize=9, fontweight='bold')
+    plt.tight_layout()
+    
+    # Save figure
+    fig.savefig(output_dir / f'label_diversity_{group}.pdf', bbox_inches='tight')
+    plt.close()
+
+
+def analyze_shared_entity_labels(loader: NERDataLoader, group: str, output_dir: Path):
+    """
+    Analyze labels of entities detected by multiple models.
+    
+    Args:
+        loader: NERDataLoader instance
+        group: Group name
+        output_dir: Output directory
+    """
+    if group not in loader.data or not loader.data[group]:
+        return
+    
+    # Get shared entities
+    overlap_stats = loader.calculate_entity_overlap(group)
+    
+    # Analyze pairwise overlaps
+    if overlap_stats['pairwise_overlap']:
+        label_agreements = []
+        
+        for pair_key, pair_data in overlap_stats['pairwise_overlap'].items():
+            if pair_data['count'] == 0:
+                continue
+                
+            model1, model2 = pair_key.split('_vs_')
+            shared_entities = set(pair_data['entities'])
+            
+            # Get labels for these entities from both models
+            for model in [model1, model2]:
+                df = loader.get_entity_dataframe(group, model)
+                if df.empty:
+                    continue
+                
+                # Filter to shared entities
+                shared_df = df[df['entity'].str.lower().str.strip().isin(shared_entities)]
+                entity_labels = shared_df.groupby('entity')['label'].first()
+                
+                for entity, labels in entity_labels.items():
+                    label_agreements.append({
+                        'pair': pair_key,
+                        'model': model,
+                        'entity': entity.lower().strip(),
+                        'label': labels
+                    })
+        
+        if label_agreements:
+            # Create label agreement analysis
+            agreement_df = pd.DataFrame(label_agreements)
+            
+            # Calculate label consistency for shared entities
+            label_consistency = []
+            
+            for pair_key in agreement_df['pair'].unique():
+                pair_df = agreement_df[agreement_df['pair'] == pair_key]
+                
+                for entity in pair_df['entity'].unique():
+                    entity_df = pair_df[pair_df['entity'] == entity]
+                    if len(entity_df) == 2:  # Both models have this entity
+                        labels = entity_df['label'].tolist()
+                        consistent = len(set(labels)) == 1
+                        label_consistency.append({
+                            'pair': pair_key,
+                            'entity': entity,
+                            'consistent': consistent,
+                            'labels': ', '.join(labels)
+                        })
+            
+            if label_consistency:
+                consistency_df = pd.DataFrame(label_consistency)
+                
+                # Create consistency visualization
+                fig, ax = plt.subplots(1, 1, figsize=(4, 3))
+                
+                consistency_stats = consistency_df.groupby('pair')['consistent'].agg(['sum', 'count'])
+                consistency_stats['inconsistent'] = consistency_stats['count'] - consistency_stats['sum']
+                consistency_stats['consistent_pct'] = (consistency_stats['sum'] / consistency_stats['count'] * 100)
+                
+                pairs = consistency_stats.index.tolist()
+                consistent_counts = consistency_stats['sum'].tolist()
+                inconsistent_counts = consistency_stats['inconsistent'].tolist()
+                
+                x = np.arange(len(pairs))
+                width = 0.6
+                
+                bars1 = ax.bar(x, consistent_counts, width, label='Consistent Labels',
+                              color='#2ca02c', alpha=0.8)
+                bars2 = ax.bar(x, inconsistent_counts, width, bottom=consistent_counts,
+                              label='Inconsistent Labels', color='#d62728', alpha=0.8)
+                
+                ax.set_ylabel('Number of Shared Entities', fontsize=7)
+                ax.set_title(f'Label Consistency for Shared Entities ({group})', 
+                            fontsize=8, fontweight='bold')
+                ax.set_xticks(x)
+                ax.set_xticklabels([p.replace('_vs_', '\nvs\n') for p in pairs], fontsize=6)
+                ax.legend(fontsize=6, loc='upper right', frameon=False)
+                ax.spines['top'].set_visible(False)
+                ax.spines['right'].set_visible(False)
+                
+                # Add percentage labels
+                for i, pct in enumerate(consistency_stats['consistent_pct']):
+                    total_height = consistency_stats.iloc[i]['count']
+                    max_height = max(consistency_stats['count'])
+                    ax.text(i, total_height + max_height * 0.05,
+                           f'{pct:.0f}%', ha='center', va='bottom', fontsize=6)
+                
+                plt.tight_layout()
+                
+                # Save figure
+                fig.savefig(output_dir / f'label_consistency_{group}.pdf', bbox_inches='tight')
+                plt.close()
+
+
+def create_group_label_comparison(loader: NERDataLoader, colors: Dict[str, str], output_dir: Path):
+    """
+    Create comparison of label distributions between groups.
+    
+    Args:
+        loader: NERDataLoader instance
+        colors: Model color mapping
+        output_dir: Output directory
+    """
+    group_stats = {}
+    
+    for group in ['with_hil', 'without_hil']:
+        if group not in loader.data or not loader.data[group]:
+            continue
+        
+        group_labels = defaultdict(int)
+        
+        for model in loader.data[group].keys():
+            df = loader.get_entity_dataframe(group, model)
+            if not df.empty:
+                unique_entities = df.groupby('entity').first().reset_index()
+                label_counts = unique_entities['label'].value_counts()
+                
+                for label, count in label_counts.items():
+                    group_labels[label] += count
+        
+        group_stats[group] = dict(group_labels)
+    
+    if len(group_stats) < 2:
+        return
+    
+    # Get all labels
+    all_labels = set()
+    for labels in group_stats.values():
+        all_labels.update(labels.keys())
+    
+    # Sort by total frequency
+    label_totals = defaultdict(int)
+    for labels in group_stats.values():
+        for label, count in labels.items():
+            label_totals[label] += count
+    
+    sorted_labels = sorted(label_totals.keys(), key=lambda x: label_totals[x], reverse=True)
+    
+    # Create comparison plot
+    fig, ax = plt.subplots(1, 1, figsize=(6, 4))
+    
+    x = np.arange(len(sorted_labels))
+    width = 0.35
+    
+    with_hil_counts = [group_stats.get('with_hil', {}).get(label, 0) for label in sorted_labels]
+    without_hil_counts = [group_stats.get('without_hil', {}).get(label, 0) for label in sorted_labels]
+    
+    bars1 = ax.bar(x - width/2, with_hil_counts, width, label='With HIL',
+                   color='#1f77b4', alpha=0.8)
+    bars2 = ax.bar(x + width/2, without_hil_counts, width, label='Without HIL',
+                   color='#ff7f0e', alpha=0.8)
+    
+    ax.set_ylabel('Total Number of Entities', fontsize=7)
+    ax.set_title('Entity Label Distribution: With vs Without HIL', fontsize=8, fontweight='bold')
+    ax.set_xticks(x)
+    ax.set_xticklabels([label.replace('_', '\n') for label in sorted_labels], 
+                       rotation=90, ha='center', fontsize=5.5)
+    ax.legend(fontsize=6, loc='upper right', frameon=False)
+    ax.spines['top'].set_visible(False)
+    ax.spines['right'].set_visible(False)
+    
+    # Adjust margins to fit rotated labels
+    plt.subplots_adjust(left=0.1, right=0.95, top=0.9, bottom=0.25)
+    
+    plt.tight_layout()
+    
+    # Save figure
+    fig.savefig(output_dir / f'label_distribution_group_comparison.pdf', bbox_inches='tight')
+    plt.close()
+
+
+def save_label_statistics(loader: NERDataLoader, output_dir: Path):
+    """
+    Save detailed label statistics to CSV files.
+    
+    Args:
+        loader: NERDataLoader instance
+        output_dir: Output directory
+    """
+    all_stats = []
+    
+    for group in ['with_hil', 'without_hil']:
+        if group not in loader.data or not loader.data[group]:
+            continue
+        
+        for model in loader.data[group].keys():
+            df = loader.get_entity_dataframe(group, model)
+            
+            if df.empty:
+                continue
+            
+            # Get unique entities with their labels
+            unique_entities = df.groupby('entity').first().reset_index()
+            label_counts = unique_entities['label'].value_counts()
+            
+            for label, count in label_counts.items():
+                all_stats.append({
+                    'Group': group,
+                    'Model': model,
+                    'Label': label,
+                    'Count': count,
+                    'Percentage': f"{count / len(unique_entities) * 100:.1f}%"
+                })
+    
+    if all_stats:
+        stats_df = pd.DataFrame(all_stats)
+        stats_df.to_csv(output_dir / 'label_distribution_statistics.csv', index=False)
+
+
+def main():
+    """Main function to run label distribution analysis."""
+    # Initialize data loader
+    loader = NERDataLoader()
+    
+    # Load all data
+    data = loader.load_all_data()
+    
+    # Create output directory using absolute path from structsense root
+    structsense_root = Path(__file__).parent.parent.parent
+    output_dir = structsense_root / "evaluation/ner/evaluation/Latent-circuit/results"
+    
+    # Run analysis
+    analyze_label_distributions(loader, output_dir)
+    
+    print(f"\nLabel distribution analysis complete. Results saved to {output_dir}")
+    
+    # Print summary
+    for group in ['with_hil', 'without_hil']:
+        if group in data and data[group]:
+            print(f"\n{group.upper()} Label Summary:")
+            for model in data[group].keys():
+                df = loader.get_entity_dataframe(group, model)
+                if not df.empty:
+                    unique_entities = df.groupby('entity').first().reset_index()
+                    top_labels = unique_entities['label'].value_counts().head(3)
+                    print(f"  {model} top labels: {', '.join([f'{label} ({count})' for label, count in top_labels.items()])}")
+
+
+if __name__ == "__main__":
+    main()
\ No newline at end of file
diff --git a/evaluation/notebook/ner_location_analysis.py b/evaluation/notebook/ner_location_analysis.py
new file mode 100644
index 0000000..492f155
--- /dev/null
+++ b/evaluation/notebook/ner_location_analysis.py
@@ -0,0 +1,338 @@
+"""
+NER Paper Location Analysis
+===========================
+
+This script analyzes where in scientific papers each model detects entities.
+It examines both overall detection patterns and location agreement for shared entities.
+
+Purpose: Analyze paper location patterns for detected entities
+"""
+
+import sys
+from pathlib import Path
+import pandas as pd
+import matplotlib.pyplot as plt
+import numpy as np
+from typing import Dict, List, Tuple, Set
+from collections import defaultdict, Counter
+
+# Add structsense to path
+sys.path.append(str(Path(__file__).parent.parent.parent))
+
+from evaluation.notebook.ner_data_loader import NERDataLoader
+
+# Configure matplotlib for publication-quality figures
+plt.rcParams['font.family'] = 'Arial'
+plt.rcParams['font.size'] = 8
+plt.rcParams['axes.linewidth'] = 0.5
+plt.rcParams['xtick.major.width'] = 0.5
+plt.rcParams['ytick.major.width'] = 0.5
+plt.rcParams['xtick.major.size'] = 3
+plt.rcParams['ytick.major.size'] = 3
+
+
+def normalize_location(location: str) -> str:
+    """
+    Normalize paper location strings for consistency.
+    
+    Args:
+        location: Raw location string
+        
+    Returns:
+        Normalized location string or None if empty/whitespace
+    """
+    if not location or not location.strip():
+        return None
+    
+    location = location.lower().strip()
+    
+    # Map variations to standard names
+    location_map = {
+        'introduction': 'introduction',
+        'intro': 'introduction',
+        'abstract': 'abstract',
+        'results': 'results',
+        'result': 'results',
+        'methods': 'methods',
+        'method': 'methods',
+        'discussion': 'discussion',
+        'conclusions': 'conclusion',
+        'conclusion': 'conclusion',
+        'references': 'references',
+        'reference': 'references',
+        'supplementary': 'supplementary',
+        'supplement': 'supplementary',
+        'figure': 'figure',
+        'table': 'table',
+        'introductory information': 'introduction',  # Map to introduction
+        'author information': 'introduction',  # Map to introduction
+        'acknowledgments': 'acknowledgments',
+        'acknowledgements': 'acknowledgments'
+    }
+    
+    # Check if location contains any of the keywords
+    for key, value in location_map.items():
+        if key in location:
+            return value
+    
+    # If no match, return 'other'
+    return 'other'
+
+
+def analyze_paper_locations(loader: NERDataLoader, output_dir: Path):
+    """
+    Analyze paper location patterns for entity detection.
+    
+    Args:
+        loader: NERDataLoader instance with loaded data
+        output_dir: Directory to save outputs
+    """
+    output_dir.mkdir(parents=True, exist_ok=True)
+    
+    # Get model colors
+    colors = loader.get_model_colors()
+    
+    # Analyze both groups
+    for group in ['with_hil', 'without_hil']:
+        if group not in loader.data or not loader.data[group]:
+            continue
+        
+        # Collect location data for all models
+        model_locations = {}
+        all_locations = set()
+        
+        for model in loader.data[group].keys():
+            df = loader.get_entity_dataframe(group, model)
+            
+            if df.empty:
+                continue
+            
+            # Normalize locations and filter out None values
+            df['normalized_location'] = df['paper_location'].apply(normalize_location)
+            df_filtered = df[df['normalized_location'].notna()]
+            
+            # Count locations
+            location_counts = df_filtered['normalized_location'].value_counts()
+            model_locations[model] = location_counts
+            all_locations.update(location_counts.index)
+        
+        # Create overall location distribution plot
+        create_location_distribution_plot(model_locations, all_locations, group, colors, output_dir)
+        
+        # Create heatmap of entity detection by location
+        create_location_heatmap(model_locations, group, output_dir)
+        
+    # Save detailed statistics
+    save_location_statistics(loader, output_dir)
+
+
+def create_location_distribution_plot(model_locations: Dict, all_locations: Set, 
+                                    group: str, colors: Dict[str, str], output_dir: Path):
+    """
+    Create bar plot showing entity distribution across paper locations.
+    
+    Args:
+        model_locations: Location counts per model
+        all_locations: Set of all unique locations
+        group: Group name
+        colors: Model color mapping
+        output_dir: Output directory
+    """
+    if not model_locations:
+        return
+    
+    # Order locations as requested: abstract, introduction, results, discussion, methods
+    location_order = ['abstract', 'introduction', 'results', 'discussion', 'methods', 
+                     'conclusion', 'figure', 'table', 'supplementary', 'references', 
+                     'acknowledgments', 'header', 'other']
+    
+    # Filter to only locations that exist
+    locations = [loc for loc in location_order if loc in all_locations]
+    
+    # Prepare data (ordered: GPT, Claude, DeepSeek)
+    model_order = ['GPT-4o-mini', 'Claude 3.7 Sonnet', 'DeepSeek V3 0324']
+    models = [m for m in model_order if m in model_locations]
+    n_models = len(models)
+    n_locations = len(locations)
+    
+    fig, ax = plt.subplots(1, 1, figsize=(6, 4))
+    
+    # Set up bar positions
+    x = np.arange(n_locations)
+    width = 0.8 / n_models
+    
+    # Plot bars for each model
+    for i, model in enumerate(models):
+        counts = [model_locations[model].get(loc, 0) for loc in locations]
+        offset = (i - n_models/2 + 0.5) * width
+        bars = ax.bar(x + offset, counts, width, 
+                      label=model, color=colors.get(model, '#999999'), alpha=0.8)
+        
+        # Add value labels for bars > 0
+        for bar in bars:
+            height = bar.get_height()
+            if height > 0:
+                ax.text(bar.get_x() + bar.get_width()/2., height + 0.5,
+                       f'{int(height)}', ha='center', va='bottom', fontsize=5)
+    
+    ax.set_xlabel('Paper Location', fontsize=7)
+    ax.set_ylabel('Number of Entity Occurrences', fontsize=7)
+    ax.set_title(f'Entity Detection by Paper Location ({group})', fontsize=8, fontweight='bold')
+    ax.set_xticks(x)
+    ax.set_xticklabels(locations, fontsize=6)
+    ax.legend(fontsize=6, loc='upper right', frameon=False)
+    ax.spines['top'].set_visible(False)
+    ax.spines['right'].set_visible(False)
+    
+    plt.tight_layout()
+    
+    # Save figure
+    fig.savefig(output_dir / f'location_distribution_{group}.pdf', bbox_inches='tight')
+    plt.close()
+
+
+def create_location_heatmap(model_locations: Dict, group: str, output_dir: Path):
+    """
+    Create heatmap showing entity detection patterns across locations.
+    
+    Args:
+        model_locations: Location counts per model
+        group: Group name
+        output_dir: Output directory
+    """
+    if not model_locations:
+        return
+    
+    # Prepare data for heatmap (ordered: GPT, Claude, DeepSeek)
+    model_order = ['GPT-4o-mini', 'Claude 3.7 Sonnet', 'DeepSeek V3 0324']
+    models = [m for m in model_order if m in model_locations]
+    location_order = ['abstract', 'introduction', 'results', 'discussion', 'methods', 
+                     'conclusion', 'figure', 'table', 'supplementary', 'references', 
+                     'acknowledgments', 'header', 'other']
+    
+    # Get all locations that appear in the data
+    all_locations = set()
+    for counts in model_locations.values():
+        all_locations.update(counts.index)
+    
+    locations = [loc for loc in location_order if loc in all_locations]
+    
+    # Create matrix
+    matrix = np.zeros((len(models), len(locations)))
+    
+    for i, model in enumerate(models):
+        for j, location in enumerate(locations):
+            matrix[i, j] = model_locations[model].get(location, 0)
+    
+    # Normalize by row (model) to show proportions
+    row_sums = matrix.sum(axis=1, keepdims=True)
+    matrix_normalized = np.divide(matrix, row_sums, where=row_sums != 0) * 100
+    
+    # Create heatmap
+    fig, ax = plt.subplots(1, 1, figsize=(6, 3))
+    
+    im = ax.imshow(matrix_normalized, cmap='YlOrRd', aspect='auto')
+    
+    # Set ticks and labels
+    ax.set_xticks(np.arange(len(locations)))
+    ax.set_yticks(np.arange(len(models)))
+    ax.set_xticklabels(locations, rotation=45, ha='right', fontsize=6)
+    ax.set_yticklabels(models, fontsize=6)
+    
+    # Add text annotations
+    for i in range(len(models)):
+        for j in range(len(locations)):
+            if matrix[i, j] > 0:  # Only show non-zero values
+                text = ax.text(j, i, f'{matrix_normalized[i, j]:.0f}%',
+                              ha="center", va="center", 
+                              color="black" if matrix_normalized[i, j] < 50 else "white",
+                              fontsize=5)
+    
+    ax.set_title(f'Entity Detection Heatmap by Location (%) - {group}', 
+                fontsize=8, fontweight='bold')
+    
+    # Add colorbar
+    cbar = plt.colorbar(im, ax=ax, fraction=0.046, pad=0.04)
+    cbar.ax.tick_params(labelsize=6)
+    cbar.set_label('Percentage of Entities (%)', fontsize=7)
+    
+    plt.tight_layout()
+    
+    # Save figure
+    fig.savefig(output_dir / f'location_heatmap_{group}.pdf', bbox_inches='tight')
+    plt.close()
+
+
+
+def save_location_statistics(loader: NERDataLoader, output_dir: Path):
+    """
+    Save detailed location statistics to CSV files.
+    
+    Args:
+        loader: NERDataLoader instance
+        output_dir: Output directory
+    """
+    all_stats = []
+    
+    for group in ['with_hil', 'without_hil']:
+        if group not in loader.data or not loader.data[group]:
+            continue
+        
+        for model in loader.data[group].keys():
+            df = loader.get_entity_dataframe(group, model)
+            
+            if df.empty:
+                continue
+            
+            # Normalize locations and filter out None values
+            df['normalized_location'] = df['paper_location'].apply(normalize_location)
+            df_filtered = df[df['normalized_location'].notna()]
+            
+            # Get location counts
+            location_counts = df_filtered['normalized_location'].value_counts()
+            
+            for location, count in location_counts.items():
+                all_stats.append({
+                    'Group': group,
+                    'Model': model,
+                    'Location': location,
+                    'Count': count,
+                    'Percentage': f"{count / len(df) * 100:.1f}%"
+                })
+    
+    if all_stats:
+        stats_df = pd.DataFrame(all_stats)
+        stats_df.to_csv(output_dir / 'location_statistics.csv', index=False)
+
+
+def main():
+    """Main function to run paper location analysis."""
+    # Initialize data loader
+    loader = NERDataLoader()
+    
+    # Load all data
+    data = loader.load_all_data()
+    
+    # Create output directory using absolute path from structsense root
+    structsense_root = Path(__file__).parent.parent.parent
+    output_dir = structsense_root / "evaluation/ner/evaluation/Latent-circuit/results"
+    
+    # Run analysis
+    analyze_paper_locations(loader, output_dir)
+    
+    print(f"\nPaper location analysis complete. Results saved to {output_dir}")
+    
+    # Print summary
+    for group in ['with_hil', 'without_hil']:
+        if group in data and data[group]:
+            print(f"\n{group.upper()} Location Summary:")
+            for model in data[group].keys():
+                df = loader.get_entity_dataframe(group, model)
+                if not df.empty:
+                    df['normalized_location'] = df['paper_location'].apply(normalize_location)
+                    top_locations = df['normalized_location'].value_counts().head(3)
+                    print(f"  {model} top locations: {', '.join([f'{loc} ({count})' for loc, count in top_locations.items()])}")
+
+
+if __name__ == "__main__":
+    main()
\ No newline at end of file
diff --git a/evaluation/notebook/ner_ontology_analysis.py b/evaluation/notebook/ner_ontology_analysis.py
new file mode 100644
index 0000000..ceff443
--- /dev/null
+++ b/evaluation/notebook/ner_ontology_analysis.py
@@ -0,0 +1,330 @@
+"""
+NER Ontology Coverage Analysis
+==============================
+
+This script analyzes the completeness of ontology mappings (IDs and labels) for
+entities detected by each model. It identifies which models have better ontology
+alignment capabilities.
+
+Purpose: Analyze missing ontology IDs and labels per model
+"""
+
+import sys
+from pathlib import Path
+import pandas as pd
+import matplotlib.pyplot as plt
+import numpy as np
+from typing import Dict, List, Tuple
+
+# Add structsense to path
+sys.path.append(str(Path(__file__).parent.parent.parent))
+
+from evaluation.notebook.ner_data_loader import NERDataLoader
+
+# Configure matplotlib for publication-quality figures
+plt.rcParams['font.family'] = 'Arial'
+plt.rcParams['font.size'] = 8
+plt.rcParams['axes.linewidth'] = 0.5
+plt.rcParams['xtick.major.width'] = 0.5
+plt.rcParams['ytick.major.width'] = 0.5
+plt.rcParams['xtick.major.size'] = 3
+plt.rcParams['ytick.major.size'] = 3
+
+
+def analyze_ontology_coverage(loader: NERDataLoader, output_dir: Path):
+    """
+    Analyze ontology ID and label coverage for each model.
+    
+    Args:
+        loader: NERDataLoader instance with loaded data
+        output_dir: Directory to save outputs
+    """
+    output_dir.mkdir(parents=True, exist_ok=True)
+    
+    # Get model colors
+    colors = loader.get_model_colors()
+    
+    # Collect statistics for all groups and models
+    all_stats = {}
+    
+    for group in ['with_hil', 'without_hil']:
+        if group not in loader.data or not loader.data[group]:
+            continue
+            
+        group_stats = {}
+        
+        for model in loader.data[group].keys():
+            # Get entity dataframe
+            df = loader.get_entity_dataframe(group, model)
+            
+            if df.empty:
+                continue
+            
+            # Get unique entities (deduplicate by entity text)
+            unique_entities = df.groupby('entity').first().reset_index()
+            
+            # Calculate statistics
+            total_entities = len(unique_entities)
+            has_ontology_id = unique_entities['ontology_id'].notna() & (unique_entities['ontology_id'] != '')
+            has_ontology_label = unique_entities['ontology_label'].notna() & (unique_entities['ontology_label'] != '')
+            has_both = has_ontology_id & has_ontology_label
+            has_neither = ~has_ontology_id & ~has_ontology_label
+            has_id_only = has_ontology_id & ~has_ontology_label
+            has_label_only = ~has_ontology_id & has_ontology_label
+            
+            group_stats[model] = {
+                'total': total_entities,
+                'has_both': has_both.sum(),
+                'has_id_only': has_id_only.sum(),
+                'has_label_only': has_label_only.sum(),
+                'has_neither': has_neither.sum(),
+                'has_any': (has_ontology_id | has_ontology_label).sum(),
+                'missing_entities': unique_entities[has_neither]['entity'].tolist()
+            }
+        
+        all_stats[group] = group_stats
+        
+        # Create visualization for this group
+        create_ontology_coverage_plot(group_stats, group, colors, output_dir)
+    
+    # Create comparison between groups
+    create_group_comparison_plot(all_stats, colors, output_dir)
+    
+    # Save detailed statistics
+    save_ontology_statistics(all_stats, output_dir)
+
+
+def create_ontology_coverage_plot(group_stats: Dict, group: str, colors: Dict[str, str], output_dir: Path):
+    """
+    Create stacked bar chart showing ontology coverage for a group.
+    
+    Args:
+        group_stats: Statistics for all models in the group
+        group: Group name
+        colors: Model color mapping
+        output_dir: Output directory
+    """
+    if not group_stats:
+        return
+    
+    fig, ax = plt.subplots(1, 1, figsize=(4.5, 3.5))
+    
+    # Order models: GPT, Claude, DeepSeek
+    model_order = ['GPT-4o-mini', 'Claude 3.7 Sonnet', 'DeepSeek V3 0324']
+    models = [m for m in model_order if m in group_stats]
+    n_models = len(models)
+    
+    # Prepare data for stacked bars
+    has_both = [group_stats[m]['has_both'] for m in models]
+    has_id_only = [group_stats[m]['has_id_only'] for m in models]
+    has_label_only = [group_stats[m]['has_label_only'] for m in models]
+    has_neither = [group_stats[m]['has_neither'] for m in models]
+    
+    # Create stacked bars
+    x = np.arange(n_models)
+    width = 0.6
+    
+    # Use different shades for the stacking
+    p1 = ax.bar(x, has_both, width, label='Both ID & Label', 
+                color='#2ca02c', alpha=0.9)
+    p2 = ax.bar(x, has_id_only, width, bottom=has_both, 
+                label='ID Only', color='#ff7f0e', alpha=0.9)
+    p3 = ax.bar(x, has_label_only, width, 
+                bottom=np.array(has_both) + np.array(has_id_only),
+                label='Label Only', color='#1f77b4', alpha=0.9)
+    p4 = ax.bar(x, has_neither, width,
+                bottom=np.array(has_both) + np.array(has_id_only) + np.array(has_label_only),
+                label='Neither', color='#d62728', alpha=0.9)
+    
+    # Customize plot
+    ax.set_ylabel('Number of Entities', fontsize=7)
+    ax.set_title(f'Ontology Coverage by Model ({group})', fontsize=8, fontweight='bold')
+    ax.set_xticks(x)
+    ax.set_xticklabels([m.replace(' ', '\n') for m in models], fontsize=6)
+    ax.legend(fontsize=6, loc='upper right', frameon=False)
+    ax.spines['top'].set_visible(False)
+    ax.spines['right'].set_visible(False)
+    
+    # Add percentage labels
+    # for i, model in enumerate(models):
+    #     total = group_stats[model]['total']
+    #     if total > 0:
+    #         # Add percentage for "has_both" at the top of the bar
+    #         pct_complete = (group_stats[model]['has_both'] / total) * 100
+    #         max_total = max([group_stats[m]['total'] for m in models])
+    #         ax.text(i, total + max_total * 0.05, f'{pct_complete:.0f}%', 
+    #                ha='center', va='bottom', fontsize=6, fontweight='bold')
+    
+    plt.tight_layout()
+    
+    # Save figure
+    fig.savefig(output_dir / f'ontology_coverage_{group}.pdf', bbox_inches='tight')
+    plt.close()
+    
+
+def create_group_comparison_plot(all_stats: Dict, colors: Dict[str, str], output_dir: Path):
+    """
+    Create comparison plot between with_hil and without_hil groups.
+    
+    Args:
+        all_stats: Statistics for all groups and models
+        colors: Model color mapping  
+        output_dir: Output directory
+    """
+    if len(all_stats) < 2:
+        return
+    
+    fig, ax = plt.subplots(1, 1, figsize=(5, 3.5))
+    
+    # Get models that appear in both groups (ordered: GPT, Claude, DeepSeek)
+    models_with = set(all_stats.get('with HIL', {}).keys())
+    models_without = set(all_stats.get('without HIL', {}).keys())
+    model_order = ['GPT-4o-mini', 'Claude 3.7 Sonnet', 'DeepSeek V3 0324']
+    common_models = [m for m in model_order if m in models_with and m in models_without]
+    
+    if not common_models:
+        return
+    
+    # Calculate percentage of complete mappings for each model in each group
+    x = np.arange(len(common_models))
+    width = 0.35
+    
+    pct_with_hil = []
+    pct_without_hil = []
+    
+    for model in common_models:
+        # With HIL
+        if 'with_hil' in all_stats and model in all_stats['with_hil']:
+            stats = all_stats['with_hil'][model]
+            pct = (stats['has_both'] / stats['total'] * 100) if stats['total'] > 0 else 0
+            pct_with_hil.append(pct)
+        else:
+            pct_with_hil.append(0)
+        
+        # Without HIL
+        if 'without_hil' in all_stats and model in all_stats['without_hil']:
+            stats = all_stats['without_hil'][model]
+            pct = (stats['has_both'] / stats['total'] * 100) if stats['total'] > 0 else 0
+            pct_without_hil.append(pct)
+        else:
+            pct_without_hil.append(0)
+    
+    # Create grouped bars
+    bars1 = ax.bar(x - width/2, pct_with_hil, width,
+                   color=[colors.get(m, '#999999') for m in common_models], alpha=0.8)
+    bars2 = ax.bar(x + width/2, pct_without_hil, width,
+                   color=[colors.get(m, '#999999') for m in common_models], alpha=0.4)
+    
+    ax.set_ylabel('Complete Ontology Mappings (%)', fontsize=7)
+    ax.set_title('Ontology Mapping: With vs Without HIL', fontsize=8, fontweight='bold')
+    ax.set_xticks(x)
+    ax.set_xticklabels([m.replace(' ', '\n') for m in common_models], fontsize=6)
+    
+    # # Add text labels instead of legend to avoid color confusion
+    # ax.text(0.02, 0.95, 'With\nHIL', transform=ax.transAxes, fontsize=6, 
+    #        verticalalignment='top', bbox=dict(boxstyle='round', facecolor='white', alpha=0.8))
+    # ax.text(0.12, 0.95, 'Without\nHIL', transform=ax.transAxes, fontsize=6, 
+    #        verticalalignment='top', bbox=dict(boxstyle='round', facecolor='lightgray', alpha=0.8))
+    ax.spines['top'].set_visible(False)
+    ax.spines['right'].set_visible(False)
+    ax.set_ylim(0, 105)
+    
+    # Add value labels
+    for bars in [bars1, bars2]:
+        for bar in bars:
+            height = bar.get_height()
+            ax.text(bar.get_x() + bar.get_width()/2., height + 1,
+                   f'{height:.0f}%', ha='center', va='bottom', fontsize=6)
+    
+    plt.tight_layout()
+    
+    # Save figure
+    fig.savefig(output_dir / f'ontology_hil_comparison.pdf', bbox_inches='tight')
+    plt.close()
+
+
+def save_ontology_statistics(all_stats: Dict, output_dir: Path):
+    """
+    Save detailed ontology statistics to CSV files.
+    
+    Args:
+        all_stats: Statistics for all groups and models
+        output_dir: Output directory
+    """
+    # Create summary DataFrame
+    summary_data = []
+    
+    for group, group_stats in all_stats.items():
+        for model, stats in group_stats.items():
+            total = stats['total']
+            if total > 0:
+                summary_data.append({
+                    'Group': group,
+                    'Model': model,
+                    'Total Entities': total,
+                    'Complete (ID & Label)': stats['has_both'],
+                    'Complete %': f"{stats['has_both'] / total * 100:.1f}%",
+                    'ID Only': stats['has_id_only'],
+                    'Label Only': stats['has_label_only'],
+                    'Neither': stats['has_neither'],
+                    'Any Ontology Info': stats['has_any'],
+                    'Any Ontology %': f"{stats['has_any'] / total * 100:.1f}%"
+                })
+    
+    if summary_data:
+        summary_df = pd.DataFrame(summary_data)
+        summary_df.to_csv(output_dir / 'ontology_coverage_summary.csv', index=False)
+    
+    # Save entities missing ontology info
+    missing_data = []
+    
+    for group, group_stats in all_stats.items():
+        for model, stats in group_stats.items():
+            for entity in stats['missing_entities']:
+                missing_data.append({
+                    'Group': group,
+                    'Model': model,
+                    'Entity': entity
+                })
+    
+    if missing_data:
+        missing_df = pd.DataFrame(missing_data)
+        missing_df.to_csv(output_dir / 'entities_missing_ontology.csv', index=False)
+
+
+def main():
+    """Main function to run ontology coverage analysis."""
+    # Initialize data loader
+    loader = NERDataLoader()
+    
+    # Load all data
+    data = loader.load_all_data()
+    
+    # Create output directory using absolute path from structsense root
+    structsense_root = Path(__file__).parent.parent.parent
+    output_dir = structsense_root / "evaluation/ner/evaluation/Latent-circuit/results"
+    
+    # Run analysis
+    analyze_ontology_coverage(loader, output_dir)
+    
+    print(f"\nOntology coverage analysis complete. Results saved to {output_dir}")
+    
+    # Print summary
+    for group in ['with_hil', 'without_hil']:
+        if group in data and data[group]:
+            print(f"\n{group.upper()} Ontology Coverage:")
+            for model in data[group].keys():
+                df = loader.get_entity_dataframe(group, model)
+                if not df.empty:
+                    unique_entities = df.groupby('entity').first().reset_index()
+                    total = len(unique_entities)
+                    has_both = (unique_entities['ontology_id'].notna() & 
+                               (unique_entities['ontology_id'] != '') &
+                               unique_entities['ontology_label'].notna() & 
+                               (unique_entities['ontology_label'] != '')).sum()
+                    pct = (has_both / total * 100) if total > 0 else 0
+                    print(f"  {model}: {has_both}/{total} complete mappings ({pct:.1f}%)")
+
+
+if __name__ == "__main__":
+    main()
\ No newline at end of file
diff --git a/evaluation/notebook/old/combined_analysis/analysis_combined_token_usage.ipynb b/evaluation/notebook/old/combined_analysis/analysis_combined_token_usage.ipynb
new file mode 100644
index 0000000..568e3eb
--- /dev/null
+++ b/evaluation/notebook/old/combined_analysis/analysis_combined_token_usage.ipynb
@@ -0,0 +1,420 @@
+{
+ "cells": [
+  {
+   "cell_type": "markdown",
+   "id": "5dcc57e2-9755-4a41-ab61-1206703dfa47",
+   "metadata": {},
+   "source": [
+    "# Cost-Speed Trade-offs Across Tasks, Models, and Human-in-the-Loop Settings"
+   ]
+  },
+  {
+   "cell_type": "code",
+   "execution_count": 5,
+   "id": "dafcb70b-75f0-45f9-b8ca-55ed7c9e5570",
+   "metadata": {},
+   "outputs": [
+    {
+     "data": {
+      "image/png": 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",
+      "text/plain": [
+       "<Figure size 1335.12x320 with 3 Axes>"
+      ]
+     },
+     "metadata": {},
+     "output_type": "display_data"
+    }
+   ],
+   "source": [
+    "import pandas as pd\n",
+    "import seaborn as sns\n",
+    "import matplotlib.pyplot as plt\n",
+    "\n",
+    "# Load CSV\n",
+    "df = pd.read_csv(\"data/combined_all_csv.csv\")\n",
+    "\n",
+    "# Clean and convert necessary columns\n",
+    "df['Model'] = df['Model'].str.strip()\n",
+    "df['Speed (tps)'] = pd.to_numeric(df['Speed (tps)'], errors='coerce')\n",
+    "df['Cost ($)'] = pd.to_numeric(df['Cost ($)'], errors='coerce')\n",
+    "\n",
+    "# Rename 'Human loop' to 'Human_loop' for easy access\n",
+    "df.rename(columns={'Human loop': 'Human_loop'}, inplace=True)\n",
+    "\n",
+    "# Define your colorblind-friendly palette\n",
+    "model_colors = {\n",
+    "    'GPT-4o-mini': '#E69F00',            # Orange\n",
+    "    'Claude 3.7 Sonnet': '#56B4E9',      # Sky blue\n",
+    "    'DeepSeek V3 0324': '#009E73'        # Bluish green\n",
+    "}\n",
+    "\n",
+    "# Apply compact publication-style font settings\n",
+    "plt.rcParams.update({\n",
+    "    'font.size': 10,\n",
+    "    'axes.titlesize': 13,\n",
+    "    'axes.labelsize': 13,\n",
+    "    'xtick.labelsize': 10,\n",
+    "    'ytick.labelsize': 10,\n",
+    "    'legend.fontsize': 10,\n",
+    "    'figure.titlesize': 10,\n",
+    "    'axes.grid': False,\n",
+    "    'axes.spines.top': False,\n",
+    "    'axes.spines.right': False\n",
+    "})\n",
+    "\n",
+    "# Create the faceted scatter plot\n",
+    "g = sns.relplot(\n",
+    "    data=df,\n",
+    "    x=\"Speed (tps)\",\n",
+    "    y=\"Cost ($)\",\n",
+    "    hue=\"Model\",\n",
+    "    style=\"Human_loop\",\n",
+    "    col=\"Task\",\n",
+    "    kind=\"scatter\",\n",
+    "    palette=model_colors,\n",
+    "    facet_kws={'sharex': False, 'sharey': False},\n",
+    "    height=3.2,\n",
+    "    aspect=1.2\n",
+    ")\n",
+    "\n",
+    "\n",
+    "# g.fig.subplots_adjust(top=0.80) \n",
+    "# g.fig.suptitle(\"Cost-Speed Trade-offs Across Tasks, Models, and Human-in-the-Loop (HIL) Settings\", fontsize=14)\n",
+    "\n",
+    "\n",
+    "# Save to files\n",
+    "g.savefig(\"speed_vs_cost_by_task_and_human_in_loop.png\", dpi=300, bbox_inches='tight')\n",
+    "g.savefig(\"speed_vs_cost_by_task_and_human_in_loop.pdf\", dpi=300, bbox_inches='tight')\n"
+   ]
+  },
+  {
+   "cell_type": "markdown",
+   "id": "c804c2a6-6d7e-482c-aec1-af8c900b80f0",
+   "metadata": {},
+   "source": [
+    "#  Distribution of Cost, Speed, and Token Usage by Task and HIL Condition"
+   ]
+  },
+  {
+   "cell_type": "code",
+   "execution_count": 6,
+   "id": "b4d2bb05-4a99-4cda-ae13-f7f442402f7d",
+   "metadata": {},
+   "outputs": [
+    {
+     "data": {
+      "image/png": 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",
+      "text/plain": [
+       "<Figure size 1800x500 with 3 Axes>"
+      ]
+     },
+     "metadata": {},
+     "output_type": "display_data"
+    }
+   ],
+   "source": [
+    "import pandas as pd\n",
+    "import seaborn as sns\n",
+    "import matplotlib.pyplot as plt\n",
+    "\n",
+    "# Load and clean the data\n",
+    "df = pd.read_csv(\"data/combined_all_csv.csv\")  # Adjust path if needed\n",
+    "df['Model'] = df['Model'].str.strip()\n",
+    "df.rename(columns={'Human loop': 'Human_loop'}, inplace=True)\n",
+    "df['Speed (tps)'] = pd.to_numeric(df['Speed (tps)'], errors='coerce')\n",
+    "df['Cost ($)'] = pd.to_numeric(df['Cost ($)'], errors='coerce')\n",
+    "df['Total Tokens'] = df['Input Tokens'] + df['Output Tokens']\n",
+    "\n",
+    "df = df[\n",
+    "    (df['Cost ($)'] > 0) &\n",
+    "    (df['Speed (tps)'] > 0) &\n",
+    "    (df['Input Tokens'] > 0) &\n",
+    "    (df['Output Tokens'] > 0)\n",
+    "]\n",
+    "\n",
+    "# Set seaborn and matplotlib styles\n",
+    "plt.rcParams.update({\n",
+    "    'font.size': 13,\n",
+    "    'axes.titlesize': 13,\n",
+    "    'axes.labelsize': 13,\n",
+    "    'xtick.labelsize': 10,\n",
+    "    'ytick.labelsize': 10,\n",
+    "    'legend.fontsize': 13,\n",
+    "    'figure.titlesize': 13,\n",
+    "    'axes.grid': False,\n",
+    "    'axes.spines.top': False,\n",
+    "    'axes.spines.right': False\n",
+    "})\n",
+    "\n",
+    "# Define metrics and titles\n",
+    "metrics = ['Cost ($)', 'Speed (tps)', 'Total Tokens']\n",
+    "titles = ['Cost by HIL', 'Speed by HIL', 'Token Usage by HIL']\n",
+    "\n",
+    "# Create horizontal layout with vertical violins\n",
+    "fig, axes = plt.subplots(1, len(metrics), figsize=(18, 5), sharey=False)\n",
+    "\n",
+    "for i, (metric, title) in enumerate(zip(metrics, titles)):\n",
+    "    sns.violinplot(\n",
+    "        data=df, x=\"Task\", y=metric, hue=\"Human_loop\",\n",
+    "        palette={\"YES\": \"#56B4E9\", \"NO\": \"#D55E00\"},\n",
+    "        inner='box', linewidth=0.8, ax=axes[i]\n",
+    "    )\n",
+    "    axes[i].set_title(title, pad=6)\n",
+    "    axes[i].set_xlabel(\"Task\")\n",
+    "    if i == 0:\n",
+    "        axes[i].set_ylabel(metric)\n",
+    "    else:\n",
+    "        axes[i].set_ylabel('')\n",
+    "    axes[i].legend_.remove()\n",
+    "\n",
+    "# Create a shared legend horizontally at the center bottom\n",
+    "handles, labels = axes[-1].get_legend_handles_labels()\n",
+    "fig.legend(\n",
+    "    handles, labels, title='Human Loop',\n",
+    "    loc='lower center', bbox_to_anchor=(0.5, -0.1), ncol=2, frameon=False\n",
+    ")\n",
+    "\n",
+    "# fig.suptitle(\"Distribution of Cost, Speed, and Token Usage by Task and Human-in-the-Loop (HIL) Settings\", fontsize=14)\n",
+    "# fig.subplots_adjust(top=0.88)  # Adjust top to create space below the title\n",
+    "\n",
+    "plt.tight_layout(rect=[0, 0.05, 1, 1])  # leave space at bottom for legend\n",
+    "plt.savefig(\"violin_vertical_side_by_side_centered_legend.png\", dpi=300, bbox_inches='tight')\n",
+    "plt.savefig(\"violin_vertical_side_by_side_centered_legend.pdf\", dpi=300, bbox_inches='tight')\n",
+    "plt.show()\n"
+   ]
+  },
+  {
+   "cell_type": "markdown",
+   "id": "b03e8b00-7490-4051-bec5-f1edddf38b7a",
+   "metadata": {},
+   "source": [
+    "# Comparison of Human-in-the-Loop (HIL) Vs Non-Human-in-the-Loop Performance"
+   ]
+  },
+  {
+   "cell_type": "code",
+   "execution_count": null,
+   "id": "6a393239-1897-49dd-b271-37e891d19814",
+   "metadata": {},
+   "outputs": [],
+   "source": []
+  },
+  {
+   "cell_type": "code",
+   "execution_count": null,
+   "id": "0431365f-e694-4dd6-82bf-146c122d545d",
+   "metadata": {},
+   "outputs": [],
+   "source": []
+  },
+  {
+   "cell_type": "code",
+   "execution_count": 7,
+   "id": "669aa629-1f72-4df7-beef-741a94adb6b9",
+   "metadata": {},
+   "outputs": [
+    {
+     "data": {
+      "image/png": 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",
+      "text/plain": [
+       "<Figure size 1600x650 with 3 Axes>"
+      ]
+     },
+     "metadata": {},
+     "output_type": "display_data"
+    }
+   ],
+   "source": [
+    "import pandas as pd\n",
+    "import seaborn as sns\n",
+    "import matplotlib.pyplot as plt\n",
+    "from matplotlib.patches import FancyArrowPatch\n",
+    "from matplotlib.lines import Line2D\n",
+    "import matplotlib.patheffects as path_effects\n",
+    "import matplotlib.colors as mcolors\n",
+    "import numpy as np\n",
+    "from collections import defaultdict\n",
+    "\n",
+    "# Load data and clean\n",
+    "df = pd.read_csv(\"data/combined_all_csv.csv\")\n",
+    "df['Model'] = df['Model'].str.strip()\n",
+    "df.rename(columns={'Human loop': 'Human_loop'}, inplace=True)\n",
+    "df['Speed (tps)'] = pd.to_numeric(df['Speed (tps)'], errors='coerce')\n",
+    "df['Cost ($)'] = pd.to_numeric(df['Cost ($)'], errors='coerce')\n",
+    "df['Total Tokens'] = df['Input Tokens'] + df['Output Tokens']\n",
+    "df = df[\n",
+    "    (df['Cost ($)'] > 0) &\n",
+    "    (df['Speed (tps)'] > 0) &\n",
+    "    (df['Input Tokens'] > 0) &\n",
+    "    (df['Output Tokens'] > 0)\n",
+    "]\n",
+    "\n",
+    "# Compute paired medians for HIL and No-HIL\n",
+    "paired_data = df.pivot_table(\n",
+    "    index=[\"Task\", \"Model\"],\n",
+    "    columns=\"Human_loop\",\n",
+    "    values=[\"Cost ($)\", \"Speed (tps)\", \"Total Tokens\"],\n",
+    "    aggfunc=\"median\"\n",
+    ").dropna()\n",
+    "\n",
+    "# Plot settings\n",
+    "plt.rcParams.update({\n",
+    "    'font.size': 13,\n",
+    "    'axes.titlesize': 13,\n",
+    "    'axes.labelsize': 13,\n",
+    "    'xtick.labelsize': 13,\n",
+    "    'ytick.labelsize': 13,\n",
+    "    'legend.fontsize': 13,\n",
+    "    'figure.titlesize': 13,\n",
+    "    'axes.grid': False,\n",
+    "    'axes.spines.top': False,\n",
+    "    'axes.spines.right': False\n",
+    "})\n",
+    "\n",
+    "# Create figure with proper spacing for legend\n",
+    "fig, axes = plt.subplots(1, 3, figsize=(16, 6.5))\n",
+    "plt.subplots_adjust(bottom=0.28, top=0.9, left=0.05, right=0.95, wspace=0.3)\n",
+    "\n",
+    "plot_metrics = [\"Cost ($)\", \"Speed (tps)\", \"Total Tokens\"]\n",
+    "titles = [\"Cost\", \"Speed\", \"Token Count\"]\n",
+    "colors = sns.color_palette(\"tab10\", len(paired_data))\n",
+    "legend_labels = []\n",
+    "\n",
+    "for i, (metric, title) in enumerate(zip(plot_metrics, titles)):\n",
+    "    ax = axes[i]\n",
+    "    x = paired_data[(metric, \"NO\")]\n",
+    "    y = paired_data[(metric, \"YES\")]\n",
+    "\n",
+    "    # Compute % delta and assign ranks\n",
+    "    deltas = ((y - x) / x * 100).sort_values(ascending=False)\n",
+    "\n",
+    "    point_counts = defaultdict(int)\n",
+    "    point_offsets = {}\n",
+    "    offset_radius = 0.01\n",
+    "    for idx in deltas.index:\n",
+    "        x0 = x.loc[idx]\n",
+    "        y0 = y.loc[idx]\n",
+    "        key = (round(x0, 6), round(y0, 6))\n",
+    "        point_counts[key] += 1\n",
+    "    for key, count in point_counts.items():\n",
+    "        if count > 1:\n",
+    "            angles = np.linspace(0, 2 * np.pi, count, endpoint=False)\n",
+    "            point_offsets[key] = [(offset_radius * np.cos(a), offset_radius * np.sin(a)) for a in angles]\n",
+    "        else:\n",
+    "            point_offsets[key] = [(0, 0)]\n",
+    "    used_offsets = defaultdict(int)\n",
+    "    for idx, color in zip(deltas.index, colors):\n",
+    "        x0 = x.loc[idx]\n",
+    "        y0 = y.loc[idx]\n",
+    "        task, model = idx\n",
+    "        key = (round(x0, 6), round(y0, 6))\n",
+    "        offset_idx = used_offsets[key]\n",
+    "        dx, dy = point_offsets[key][offset_idx]\n",
+    "        used_offsets[key] += 1\n",
+    "        if y0 == x0:\n",
+    "            y1 = y0 + 1e-6\n",
+    "        else:\n",
+    "            y1 = y0\n",
+    "        ax.plot([x0, x0], [x0, y1], color=color, lw=1.5, alpha=0.7, zorder=2)\n",
+    "        ax.scatter(x0 + dx, y0 + dy, color=color, edgecolor=\"black\", s=60, zorder=3)\n",
+    "        if i == 0:\n",
+    "            legend_labels.append((f\"{task} / {model}\", color, task, model))\n",
+    "\n",
+    "    min_val = min(x.min(), y.min())\n",
+    "    max_val = max(x.max(), y.max())\n",
+    "    ax.plot([min_val, max_val], [min_val, max_val], linestyle='--', color='gray', zorder=1)\n",
+    "\n",
+    "    if metric == \"Cost ($)\":\n",
+    "        ax.set_xlabel(\"No-HIL Cost ($)\")\n",
+    "        ax.set_ylabel(\"HIL Cost ($)\")\n",
+    "        ax.set_title(\"Cost Comparison\", loc='center')\n",
+    "    elif metric == \"Speed (tps)\":\n",
+    "        ax.set_xlabel(\"No-HIL Speed (tokens/sec)\")\n",
+    "        ax.set_ylabel(\"HIL Speed (tokens/sec)\")\n",
+    "        ax.set_title(\"Speed Comparison\", loc='center')\n",
+    "    elif metric == \"Total Tokens\":\n",
+    "        ax.set_xlabel(\"No-HIL Token Count\")\n",
+    "        ax.set_ylabel(\"HIL Token Count\")\n",
+    "        ax.set_xscale(\"log\")\n",
+    "        ax.set_yscale(\"log\")\n",
+    "        ax.set_title(\"Token Count Comparison (log scale)\", loc='center')\n",
+    "\n",
+    "# Sort legend labels by task, then model\n",
+    "legend_labels.sort(key=lambda x: (x[2], x[3]))  # x[2] = task, x[3] = model\n",
+    "\n",
+    "# Create legend handles\n",
+    "handles = [\n",
+    "    Line2D([0], [0], marker='o', color='w', label=label_text,\n",
+    "           markerfacecolor=color, markersize=7, markeredgecolor='black')\n",
+    "    for label_text, color, _, _ in legend_labels\n",
+    "]\n",
+    "\n",
+    "# Add legend to the bottom center\n",
+    "legend = fig.legend(\n",
+    "    handles=handles,\n",
+    "    title=\"Legend: Task / Model\",\n",
+    "    loc='lower center',\n",
+    "    bbox_to_anchor=(0.5, 0.02),\n",
+    "    ncol=3,\n",
+    "    fontsize=12,\n",
+    "    title_fontsize=12,\n",
+    "    frameon=False,\n",
+    "    columnspacing=1.5,\n",
+    "    handletextpad=0.5\n",
+    ")\n",
+    "# fig.suptitle(\"Comparison of Human-in-the-Loop (HIL) Vs Non-Human-in-the-Loop Performance\", fontsize=14)\n",
+    "# fig.subplots_adjust(top=0.88)  # Adjust top to create space below the title\n",
+    "\n",
+    "\n",
+    "# Save plots\n",
+    "fig.savefig(\"hil_vs_nohil_scatter_horizontal_legend.png\", dpi=300, bbox_inches='tight', pad_inches=0.1)\n",
+    "fig.savefig(\"hil_vs_nohil_scatter_horizontal_legend.pdf\", dpi=300, bbox_inches='tight', pad_inches=0.1)\n"
+   ]
+  },
+  {
+   "cell_type": "code",
+   "execution_count": 47,
+   "id": "da906768-2d7e-411d-a013-2ea91113b742",
+   "metadata": {},
+   "outputs": [],
+   "source": []
+  },
+  {
+   "cell_type": "code",
+   "execution_count": null,
+   "id": "a4b9058e-8ccd-49ea-944e-21ebcc64e3ab",
+   "metadata": {},
+   "outputs": [],
+   "source": []
+  },
+  {
+   "cell_type": "code",
+   "execution_count": null,
+   "id": "f1e0a258-2c16-423d-b936-f649fcc0d76e",
+   "metadata": {},
+   "outputs": [],
+   "source": []
+  }
+ ],
+ "metadata": {
+  "kernelspec": {
+   "display_name": "Python 3 (ipykernel)",
+   "language": "python",
+   "name": "python3"
+  },
+  "language_info": {
+   "codemirror_mode": {
+    "name": "ipython",
+    "version": 3
+   },
+   "file_extension": ".py",
+   "mimetype": "text/x-python",
+   "name": "python",
+   "nbconvert_exporter": "python",
+   "pygments_lexer": "ipython3",
+   "version": "3.11.7"
+  }
+ },
+ "nbformat": 4,
+ "nbformat_minor": 5
+}
diff --git a/evaluation/notebook/old/combined_analysis/data/combined_all_csv.csv b/evaluation/notebook/old/combined_analysis/data/combined_all_csv.csv
new file mode 100644
index 0000000..e10bb69
--- /dev/null
+++ b/evaluation/notebook/old/combined_analysis/data/combined_all_csv.csv
@@ -0,0 +1,289 @@
+Timestamp,Provider,Model,App,Input Tokens,Output Tokens,Cost ($),Speed (tps),Finish,Paper,Task,Human loop
+"Jun 28, 10:03 AM",Favicon for InferenceNet,DeepSeek V3 0324,liteLLM,840,720,0.00142,7.7,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 10:01 AM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,4251,316,0.00147,22.4,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 10:01 AM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,72343,834,0.0212,23.2,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:57 AM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,443,415,0.000489,19.7,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:57 AM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,2777,289,0.00111,25.8,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:57 AM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,24235,416,0.00726,15.6,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:56 AM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,310,291,0.000343,20.5,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:55 AM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,6364,252,0.00207,20.0,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:55 AM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,31851,282,0.00924,24.3,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:54 AM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,5155,5131,0.00596,24.0,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:50 AM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,42568,465,0.0125,18.7,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:49 AM",Favicon for Nebius,DeepSeek V3 0324,liteLLM,79864,5149,0.0477,15.0,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:15 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,4469,4421,0.003,61.1,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:14 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,21489,1335,0.00402,58.9,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:14 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,70022,4432,0.0132,64.5,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:11 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,4440,4409,0.00331,56.6,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:10 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,15378,612,0.00267,78.3,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:10 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,0,0,0.0,0.0,--,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:08 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,5399,5351,0.00402,76.9,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:07 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,11508,1701,0.00275,60.4,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:06 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,17158,5363,0.00579,65.8,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:05 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,5399,5352,0.00402,58.0,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:03 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,43032,1984,0.00765,63.0,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 09:03 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,80322,5361,0.0153,56.1,stop,Integrating brainstem and cortical functional architectures,NER,YES
+"Jun 28, 08:41 AM",Favicon for Novita,DeepSeek V3 0324,liteLLM,1343,1315,0.00215,21.8,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:40 AM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,3656,688,0.00185,28.1,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:39 AM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,12182,1315,0.0053,26.9,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:38 AM",Favicon for BaseTen,DeepSeek V3 0324,liteLLM,918,281,0.000923,104.3,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:38 AM",Favicon for Together,DeepSeek V3 0324,liteLLM,4977,461,0.0068,77.7,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:38 AM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,27871,885,0.0103,34.8,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:38 AM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,2830,2805,0.00326,23.7,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:36 AM",Favicon for Phala,DeepSeek V3 0324,liteLLM,2830,1644,0.00408,29.8,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:35 AM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,40240,1022,0.0146,28.3,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:34 AM",Favicon for InferenceNet,DeepSeek V3 0324,liteLLM,79877,2822,0.04,16.1,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:31 AM",Favicon for Nebius,DeepSeek V3 0324,liteLLM,3313,780,0.00283,21.6,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:30 AM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,3310,3274,0.00381,21.3,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:27 AM",Favicon for Nebius,DeepSeek V3 0324,liteLLM,3313,1217,0.00348,19.9,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:26 AM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,40699,1293,0.0125,12.1,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:24 AM",Favicon for Novita,DeepSeek V3 0324,liteLLM,79819,3281,0.0306,92.8,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:23 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,8257,7507,0.137,79.1,tool_calls,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:21 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,22867,578,0.0773,59.1,tool_calls,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:21 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,38038,7854,0.232,84.0,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:19 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,6971,6592,0.12,86.1,tool_calls,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:18 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,29017,485,0.0943,65.6,tool_calls,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:18 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,49699,6574,0.248,81.2,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:16 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,22691,22315,0.403,91.2,tool_calls,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:12 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,67573,1223,0.221,66.8,tool_calls,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:11 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,95310,22350,0.621,92.4,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 08:07 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,95204,44862,0.959,90.9,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 07:53 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,6240,6354,0.00475,65.3,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 07:51 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,17692,1659,0.00365,55.7,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 07:51 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,30469,6202,0.00829,60.4,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 07:49 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,5539,5491,0.00413,72.6,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 07:48 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,11611,492,0.00204,60.3,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 07:47 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,17086,5502,0.00586,66.4,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 07:46 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,5552,5505,0.00414,56.5,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 07:44 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,43185,624,0.00685,77.7,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 28, 07:44 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,80010,5514,0.0153,68.2,stop,Integrating brainstem and cortical functional architectures,NER,NO
+"Jun 27, 11:49 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,2965,2938,0.0048,72.1,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:49 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,14138,803,0.00467,20.8,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:48 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,58760,2935,0.019,10.6,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:42 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,2730,2706,0.00315,24.9,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:40 PM",Favicon for GMICloud,DeepSeek V3 0324,liteLLM,8566,889,0.00714,120.5,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:40 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,45999,2700,0.0187,128.3,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:40 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,2285,2261,0.00263,26.2,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:38 PM",Favicon for Nebius,DeepSeek V3 0324,liteLLM,2288,2459,0.00483,23.8,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:37 PM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,5871,721,0.00247,27.2,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:36 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,16254,2256,0.00654,22.1,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:34 PM",Favicon for BaseTen,DeepSeek V3 0324,liteLLM,2248,2221,0.00344,156.2,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:34 PM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,38090,807,0.0137,27.6,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:34 PM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,71866,2218,0.0227,18.3,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:30 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,19203,18822,0.34,75.0,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:25 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,84710,677,0.264,58.4,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:25 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,133687,18817,0.683,81.8,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:20 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,17648,17270,0.312,82.3,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:16 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,44622,705,0.144,119.6,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:16 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,43731,717,0.142,61.4,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:16 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,54832,17328,0.424,82.0,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:12 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,12626,12250,0.222,80.2,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:09 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,24951,882,0.0881,59.8,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:09 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,44255,12293,0.317,79.0,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:06 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,11739,11063,0.201,75.1,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:04 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,53924,1105,0.178,64.9,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:03 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,84326,11344,0.423,81.3,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 11:01 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,84220,8159,0.375,81.7,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 10:59 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,84114,9869,0.4,80.5,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,YES
+"Jun 27, 10:38 PM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,2360,2336,0.00286,26.5,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:36 PM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,7636,782,0.00304,28.0,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:36 PM",Favicon for Phala,DeepSeek V3 0324,liteLLM,9049,2333,0.00972,24.7,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:34 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,2006,1982,0.00231,23.3,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:33 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,5318,572,0.0025,20.0,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:32 PM",Favicon for Nebius,DeepSeek V3 0324,liteLLM,10328,1979,0.00813,20.1,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:31 PM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,1879,1855,0.00227,32.3,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:30 PM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,37726,749,0.0114,25.7,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:28 PM",Favicon for GMICloud,DeepSeek V3 0324,liteLLM,71917,1852,0.0549,110.8,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:15 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,10772,10394,0.188,78.1,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:12 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,28469,602,0.0944,59.5,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:12 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,34828,10372,0.26,78.0,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:10 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,8910,8534,0.155,77.5,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:08 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,17693,950,0.0673,61.0,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:07 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,19703,8568,0.188,76.1,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:06 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,7728,7082,0.129,76.8,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:04 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,51376,1294,0.174,89.0,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:04 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,49910,1291,0.169,61.6,tool_calls,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:03 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,83918,7330,0.362,77.9,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:27 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,2026,1988,0.0015,68.2,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:26 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,7043,620,0.00143,69.8,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:26 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,27039,1989,0.00525,70.7,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:25 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1915,1867,0.00141,80.9,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:25 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,4924,572,0.00108,81.2,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:25 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,23024,1920,0.00461,62.2,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:24 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1607,1560,0.00118,64.9,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:24 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,37545,165,0.00573,84.2,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 10:24 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,72143,1571,0.00637,72.9,stop,Latent circuit inference from heterogeneous neural responses during cognitive tasks,NER,NO
+"Jun 27, 02:41 PM",Favicon for Nebius,DeepSeek V3 0324,liteLLM,4045,385,0.0026,19.2,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:41 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,2871,1254,0.00191,21.3,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:39 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,1322,1278,0.0021,102.9,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:39 PM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,6527,347,0.00223,13.2,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:39 PM",Favicon for GMICloud,DeepSeek V3 0324,liteLLM,5334,1295,0.00511,69.5,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:38 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,10035,303,0.00371,19.7,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:38 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,4947,5191,0.00595,21.9,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:34 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,6167,502,0.00217,21.1,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:34 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,1777,4748,0.00676,86.5,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:31 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,19104,501,0.0648,63.0,tool_calls,Sample-data,Reproschema,YES
+"Jun 27, 02:31 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,12359,6237,0.131,93.2,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:29 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,13080,398,0.0452,70.9,tool_calls,Sample-data,Reproschema,YES
+"Jun 27, 02:29 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,6349,6236,0.113,93.0,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:28 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,11766,387,0.0411,61.3,tool_calls,Sample-data,Reproschema,YES
+"Jun 27, 02:28 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,5075,6197,0.108,95.8,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:27 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,6778,482,0.0276,64.4,tool_calls,Sample-data,Reproschema,YES
+"Jun 27, 02:27 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,1986,4622,0.0753,95.7,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:24 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,16406,289,0.00263,51.3,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:24 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,9914,6578,0.00543,60.9,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:21 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,6559,6512,0.00489,66.6,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:19 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,11636,284,0.00192,48.3,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:19 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,5215,6521,0.00469,60.3,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:17 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,10376,215,0.00169,48.3,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:17 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,4089,6391,0.00445,56.3,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:15 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,5408,286,0.000983,71.0,stop,Sample-data,Reproschema,YES
+"Jun 27, 02:15 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1808,3999,0.00267,60.6,stop,Sample-data,Reproschema,YES
+"Jun 26, 05:07 PM",Favicon for InferenceNet,DeepSeek V3 0324,liteLLM,2925,409,0.00191,28.3,tps,Sample-data,Reproschema,NO
+"Jun 26, 05:06 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,1932,1076,0.00149,17.9,tps,Sample-data,Reproschema,NO
+"Jun 26, 05:03 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,614,665,0.000757,20.2,tps,Sample-data,Reproschema,NO
+"Jun 26, 05:03 PM",Favicon for Nebius,DeepSeek V3 0324,liteLLM,617,87,0.000439,27.3,tps,Sample-data,Reproschema,NO
+"Jun 26, 05:03 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,6848,313,0.00219,16.4,tps,Sample-data,Reproschema,NO
+"Jun 26, 05:02 PM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,6361,587,0.00268,29.6,tps,Sample-data,Reproschema,NO
+"Jun 26, 05:02 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,6276,7397,0.00827,17.5,tps,Sample-data,Reproschema,NO
+"Jun 26, 04:47 PM",Favicon for InferenceNet,DeepSeek V3 0324,liteLLM,11140,353,0.00552,28.9,tps,Sample-data,Reproschema,NO
+"Jun 26, 04:47 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,4994,6248,0.0069,27.9,tps,Sample-data,Reproschema,NO
+"Jun 26, 04:43 PM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,6218,376,0.00217,23.7,tps,Sample-data,Reproschema,NO
+"Jun 26, 04:43 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,1766,4797,0.00472,22.9,tps,Sample-data,Reproschema,NO
+"Jun 26, 04:35 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,7385,6995,0.127,95.2,tps,Sample-data,Reproschema,NO
+"Jun 26, 04:33 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,14726,415,0.0504,59.6,tps,Sample-data,Reproschema,NO
+"Jun 26, 04:33 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,7244,6987,0.127,95.5,tps,Sample-data,Reproschema,NO
+"Jun 26, 04:32 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,12851,489,0.0459,66.8,tps,Sample-data,Reproschema,NO
+"Jun 26, 04:32 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,5074,7283,0.124,97.2,tps,Sample-data,Reproschema,NO
+"Jun 26, 04:31 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,6777,565,0.0288,67.0,tps,Sample-data,Reproschema,NO
+"Jun 26, 04:30 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,1781,4621,0.0747,95.2,tps,Sample-data,Reproschema,NO
+"Jun 26, 02:32 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,11202,243,0.00183,42.4,tps,Sample-data,Reproschema,NO
+"Jun 26, 02:32 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,4997,6305,0.00453,83.7,tps,Sample-data,Reproschema,NO
+"Jun 26, 02:30 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,9936,345,0.000958,59.5,tps,Sample-data,Reproschema,NO
+"Jun 26, 02:30 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,9936,297,0.00167,78.5,tps,Sample-data,Reproschema,NO
+"Jun 26, 02:30 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,3871,6169,0.00428,62.2,tps,Sample-data,Reproschema,NO
+"Jun 27, 12:19 PM",Favicon for Phala,DeepSeek V3 0324,liteLLM,3503,334,0.00311,31.6,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:18 PM",Favicon for Phala,DeepSeek V3 0324,liteLLM,4017,780,0.00402,29.6,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:17 PM",Favicon for GMICloud,DeepSeek V3 0324,liteLLM,2037,373,0.00184,99.5,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:17 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,2352,361,0.00125,20.5,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:17 PM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,1429,281,0.000733,30.9,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:17 PM",Favicon for Nebius,DeepSeek V3 0324,liteLLM,1249,350,0.00115,31.5,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:17 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,15137,617,0.00478,25.6,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:16 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,15544,264,0.00458,22.2,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:15 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,7004,499,0.0285,69.2,tool_calls,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:15 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,8476,873,0.0385,58.2,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:14 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,4086,481,0.0195,63.2,tool_calls,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:14 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,3851,798,0.0235,64.8,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:14 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,2842,543,0.0167,27.2,tool_calls,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:13 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,1747,668,0.0153,63.7,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:13 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,754,518,0.01,109.9,tool_calls,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:13 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,18461,475,0.0625,64.7,tool_calls,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 12:13 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,18225,359,0.0601,61.1,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,YES
+"Jun 27, 11:42 AM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,2125,446,0.000987,20.3,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:42 AM",Favicon for Together,DeepSeek V3 0324,liteLLM,2478,376,0.00357,157.7,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:42 AM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,1466,292,0.000755,28.1,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:41 AM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,1267,365,0.000676,21.9,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:41 AM",Favicon for Novita,DeepSeek V3 0324,liteLLM,15154,310,0.0054,25.4,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:41 AM",Favicon for Atoma,DeepSeek V3 0324,liteLLM,15574,281,0.00549,16.4,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:39 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,3512,399,0.0165,70.1,tool_calls,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:39 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,3161,638,0.0191,63.6,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:39 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,2495,454,0.0143,75.1,tool_calls,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:38 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,1621,447,0.0116,58.5,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:38 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,706,330,0.00707,136.6,tool_calls,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:38 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,18433,509,0.0629,71.2,tool_calls,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:38 AM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,18241,331,0.0597,52.8,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:36 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1769,269,0.000427,56.4,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:36 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,2068,271,0.000473,63.3,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:36 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1261,471,0.000472,36.7,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:36 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1159,264,0.000332,44.1,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:36 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,15118,197,0.00239,55.4,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 11:36 AM",Favicon for OpenAI,GPT-4o-mini,liteLLM,15560,193,0.00245,77.1,stop,Vitpose: Simple vision transformer baselines for human pose estimation,Resource extraction,NO
+"Jun 27, 01:40 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,2569,405,0.00137,106.7 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:40 PM",Favicon for GMICloud,DeepSeek V3 0324,liteLLM,2984,518,0.00267,102.1 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:40 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,1577,475,0.00114,101.9 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:40 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,1226,517,0.000798,17.2 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:39 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,64551,745,0.0187,13.4 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:38 PM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,64954,245,0.0185,20.7 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:37 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,4358,451,0.0198,69.6 tps,tool_calls,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:37 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,4245,834,0.0252,64.2 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:37 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,2795,652,0.0182,73.7 tps,tool_calls,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:36 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,1672,696,0.0155,63.9 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:36 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,744,368,0.00775,128.3 tps,tool_calls,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:36 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,75638,595,0.236,64.2 tps,tool_calls,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:36 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,75333,347,0.231,57.0 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:35 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,2434,398,0.000604,52.6 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:35 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,2863,459,0.000705,70.6 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:35 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1512,362,0.000444,73.7 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:35 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1200,474,0.000464,54.2 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:35 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,263,225,0.000174,57.6 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:35 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,64160,564,0.00996,75.1 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:34 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,64420,225,0.0098,71.4 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,YES
+"Jun 27, 01:40 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,2569,405,0.00137,106.7 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:40 PM",Favicon for GMICloud,DeepSeek V3 0324,liteLLM,2984,518,0.00267,102.1 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:40 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,1577,475,0.00114,101.9 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:40 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,1226,517,0.000798,17.2 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:39 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,64551,745,0.0187,13.4 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:38 PM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,64954,245,0.0185,20.7 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:37 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,4358,451,0.0198,69.6 tps,tool_calls,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:37 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,4245,834,0.0252,64.2 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:37 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,2795,652,0.0182,73.7 tps,tool_calls,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:36 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,1672,696,0.0155,63.9 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:36 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,744,368,0.00775,128.3 tps,tool_calls,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:36 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,75638,595,0.236,64.2 tps,tool_calls,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:36 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,75333,347,0.231,57.0 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:35 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,2434,398,0.000604,52.6 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:35 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,2863,459,0.000705,70.6 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:35 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1512,362,0.000444,73.7 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:35 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1200,474,0.000464,54.2 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:35 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,263,225,0.000174,57.6 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:35 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,64160,564,0.00996,75.1 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:34 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,64420,225,0.0098,71.4 tps,stop,Learnable latent embeddings for joint behavioural and neural analysis,Resource extraction,NO
+"Jun 27, 01:24 PM",Nebius,DeepSeek V3 0324,liteLLM,4009,424,0.00264,18.2,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:24 PM",Lambda,DeepSeek V3 0324,liteLLM,5181,583,0.00227,20.3,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:22 PM",DeepInfra,DeepSeek V3 0324,liteLLM,2522,392,0.00105,21.9,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:22 PM",DeepInfra,DeepSeek V3 0324,liteLLM,2922,506,0.00126,24.8,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:22 PM",Novita,DeepSeek V3 0324,liteLLM,1570,538,0.00122,83.4,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:22 PM",Lambda,DeepSeek V3 0324,liteLLM,1242,495,0.000858,32.3,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:21 PM",Crusoe,DeepSeek V3 0324,liteLLM,59280,289,0.0169,20.9,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:20 PM",Phala,DeepSeek V3 0324,liteLLM,59644,268,0.0468,22.4,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:19 PM",Google,Claude 3.7 Sonnet,liteLLM,8200,586,0.0334,73.0,tool_calls,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:19 PM",Google,Claude 3.7 Sonnet,liteLLM,10200,1037,0.0462,62.2,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:18 PM",Google,Claude 3.7 Sonnet,liteLLM,4732,454,0.021,61.7,tool_calls,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:18 PM",Google,Claude 3.7 Sonnet,liteLLM,4615,986,0.0286,65.9,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:17 PM",Google,Claude 3.7 Sonnet,liteLLM,3053,447,0.0159,63.8,tool_calls,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:17 PM",Google,Claude 3.7 Sonnet,liteLLM,1740,886,0.0185,64.4,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:17 PM",Google,Claude 3.7 Sonnet,liteLLM,837,443,0.00916,106.4,tool_calls,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:17 PM",Google,Claude 3.7 Sonnet,liteLLM,68694,562,0.215,76.2,tool_calls,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:17 PM",Google,Claude 3.7 Sonnet,liteLLM,68374,440,0.212,56.5,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:16 PM",OpenAI,GPT-4o-mini,liteLLM,1042,1004,0.000759,68.4,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:15 PM",OpenAI,GPT-4o-mini,liteLLM,4580,389,0.00092,77.3,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:15 PM",OpenAI,GPT-4o-mini,liteLLM,5538,1006,0.00143,42.7,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:15 PM",OpenAI,GPT-4o-mini,liteLLM,5441,517,0.00113,35.0,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:14 PM",OpenAI,GPT-4o-mini,liteLLM,2584,447,0.000656,72.3,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:14 PM",OpenAI,GPT-4o-mini,liteLLM,3042,502,0.000758,66.9,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:14 PM",OpenAI,GPT-4o-mini,liteLLM,1582,561,0.000574,69.0,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:13 PM",OpenAI,GPT-4o-mini,liteLLM,1234,510,0.000491,47.1,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:13 PM",OpenAI,GPT-4o-mini,liteLLM,59037,435,0.00912,34.6,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:13 PM",OpenAI,GPT-4o-mini,liteLLM,59381,283,0.00908,66.8,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,YES
+"Jun 27, 01:00 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,2665,432,0.00144,100.3 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:59 PM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,3093,547,0.00153,17.1 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:59 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,1615,333,0.000745,22.5 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:59 PM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,1248,536,0.000966,22.8 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:58 PM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,59272,416,0.0171,18.0 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:58 PM",Favicon for Phala,DeepSeek V3 0324,liteLLM,59270,801,0.0471,31.1 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:57 PM",Favicon for Atoma,DeepSeek V3 0324,liteLLM,59270,741,0.0205,16.9 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:56 PM",Favicon for Atoma,DeepSeek V3 0324,liteLLM,59624,260,0.02,8.2 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:55 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,4349,657,0.0229,76.7 tps,tool_calls,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:55 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,4161,875,0.0256,65.6 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:55 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,2727,633,0.0177,70.2 tps,tool_calls,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:55 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,1645,655,0.0148,73.0 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:55 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,727,344,0.00734,126.3 tps,tool_calls,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:54 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,68584,465,0.213,65.8 tps,tool_calls,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:54 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,68282,330,0.21,54.9 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:53 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,2583,399,0.000627,98.1 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:53 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,3043,500,0.000756,61.5 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:53 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1569,362,0.000453,94.3 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:53 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1236,495,0.000482,47.0 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:53 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,300,262,0.000202,69.8 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:53 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,59016,634,0.00923,67.6 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
+"Jun 27, 12:53 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,59239,262,0.00904,80.6 tps,stop,"Multi-animal pose estimation, identification and tracking with DeepLabCut",Resource extraction,NO
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diff --git a/evaluation/notebook/old/combined_analysis/violin_vertical_side_by_side_centered_legend.pdf b/evaluation/notebook/old/combined_analysis/violin_vertical_side_by_side_centered_legend.pdf
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diff --git a/evaluation/notebook/old/combined_analysis/violin_vertical_side_by_side_centered_legend.png b/evaluation/notebook/old/combined_analysis/violin_vertical_side_by_side_centered_legend.png
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diff --git a/evaluation/notebook/old/integrating-brainstem_w-hil/integrating-brainstem_w-hil_cost_violin.png b/evaluation/notebook/old/integrating-brainstem_w-hil/integrating-brainstem_w-hil_cost_violin.png
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diff --git a/evaluation/notebook/old/ner_latent-circuit_w-hil/ner_latent-circuit_w-hil_token_usage_violin.pdf b/evaluation/notebook/old/ner_latent-circuit_w-hil/ner_latent-circuit_w-hil_token_usage_violin.pdf
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diff --git a/evaluation/notebook/old/rs-etr_learnable-latent_w-hil/rs-etr_learnable-latent_w-hil_speed_vs_cost.png b/evaluation/notebook/old/rs-etr_learnable-latent_w-hil/rs-etr_learnable-latent_w-hil_speed_vs_cost.png
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diff --git a/evaluation/notebook/token_cost_speed_analysis.ipynb b/evaluation/notebook/token_cost_speed_analysis.ipynb
new file mode 100644
index 0000000..4f55a95
--- /dev/null
+++ b/evaluation/notebook/token_cost_speed_analysis.ipynb
@@ -0,0 +1,154 @@
+{
+ "cells": [
+  {
+   "cell_type": "markdown",
+   "id": "909f45f3-9e4f-4b81-8fc4-38636db70ad3",
+   "metadata": {},
+   "source": [
+    "## Reproschema Token Usage Analysis"
+   ]
+  },
+  {
+   "cell_type": "code",
+   "execution_count": 17,
+   "id": "90da1aba-596c-4484-9f7b-7f1e308a3926",
+   "metadata": {},
+   "outputs": [],
+   "source": [
+    "import matplotlib.pyplot as plt\n",
+    "import seaborn as sns\n",
+    "import pandas as pd\n",
+    "df = pd.read_csv(\"reproschema/reproschema_token_usage.csv\")"
+   ]
+  },
+  {
+   "cell_type": "code",
+   "execution_count": 22,
+   "id": "ed16b910-6bf6-4b5d-a051-4f230d2da09b",
+   "metadata": {},
+   "outputs": [
+    {
+     "data": {
+      "image/png": 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",
+      "text/plain": [
+       "<Figure size 1000x600 with 1 Axes>"
+      ]
+     },
+     "metadata": {},
+     "output_type": "display_data"
+    },
+    {
+     "data": {
+      "image/png": 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",
+      "text/plain": [
+       "<Figure size 1000x600 with 1 Axes>"
+      ]
+     },
+     "metadata": {},
+     "output_type": "display_data"
+    },
+    {
+     "data": {
+      "image/png": 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",
+      "text/plain": [
+       "<Figure size 1000x600 with 1 Axes>"
+      ]
+     },
+     "metadata": {},
+     "output_type": "display_data"
+    },
+    {
+     "data": {
+      "image/png": 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",
+      "text/plain": [
+       "<Figure size 800x600 with 1 Axes>"
+      ]
+     },
+     "metadata": {},
+     "output_type": "display_data"
+    }
+   ],
+   "source": [
+    "# Optional: Clean whitespace from 'Model' names\n",
+    "df['Model'] = df['Model'].str.strip()\n",
+    "\n",
+    "# Set style and palette\n",
+    "sns.set(style=\"whitegrid\")\n",
+    "sns.set_palette(\"Set2\")\n",
+    "\n",
+    "# Plot 1: Cost per Model (Violin Plot)\n",
+    "plt.figure(figsize=(10, 6))\n",
+    "sns.violinplot(data=df, x='Model', y='Cost ($)', inner='box')\n",
+    "plt.title(\"Cost Distribution by Model\")\n",
+    "plt.tight_layout()\n",
+    "plt.savefig(\"reproschema/reproschema_cost_violin.svg\")\n",
+    "plt.show()\n",
+    "\n",
+    "# Plot 2: Input and Output Tokens per Model (Violin Plot)\n",
+    "plt.figure(figsize=(10, 6))\n",
+    "df_long = df.melt(id_vars=['Model'], value_vars=['Input Tokens', 'Output Tokens'],\n",
+    "                  var_name='Token Type', value_name='Count')\n",
+    "sns.violinplot(data=df_long, x='Model', y='Count', hue='Token Type', split=True)\n",
+    "plt.title(\"Token Usage by Model\")\n",
+    "plt.legend(title='Token Type', title_fontsize='13', fontsize='11')  # Increased legend font sizes\n",
+    "plt.tight_layout()\n",
+    "plt.savefig(\"reproschema/reproschema_token_usage_violin.svg\")\n",
+    "plt.show()\n",
+    "\n",
+    "# Plot 3: Speed per Model (Violin Plot)\n",
+    "plt.figure(figsize=(10, 6))\n",
+    "sns.violinplot(data=df, x='Model', y='Speed (tps)', inner='box')\n",
+    "plt.title(\"Speed (tokens/sec) Distribution by Model\")\n",
+    "plt.tight_layout()\n",
+    "plt.savefig(\"reproschema/reproschema_speed_violin.svg\")\n",
+    "plt.show()\n",
+    "\n",
+    "# Plot 4: Scatter plot of Speed vs Cost\n",
+    "plt.figure(figsize=(8, 6))\n",
+    "sns.scatterplot(data=df, x='Speed (tps)', y='Cost ($)', hue='Model', style='Model', s=100)\n",
+    "plt.title(\"Speed vs Cost by Model\")\n",
+    "plt.legend(title='Model', title_fontsize='13', fontsize='11')  # Increased legend font sizes\n",
+    "plt.tight_layout()\n",
+    "plt.savefig(\"reproschema/reproschema_speed_vs_cost.svg\")\n",
+    "plt.show()\n"
+   ]
+  },
+  {
+   "cell_type": "code",
+   "execution_count": null,
+   "id": "f98df3b4-5275-49ef-9668-076218884753",
+   "metadata": {},
+   "outputs": [],
+   "source": []
+  },
+  {
+   "cell_type": "code",
+   "execution_count": null,
+   "id": "d09138a5-d41d-4e51-8b78-a4356ca1c3cb",
+   "metadata": {},
+   "outputs": [],
+   "source": []
+  }
+ ],
+ "metadata": {
+  "kernelspec": {
+   "display_name": "Python 3 (ipykernel)",
+   "language": "python",
+   "name": "python3"
+  },
+  "language_info": {
+   "codemirror_mode": {
+    "name": "ipython",
+    "version": 3
+   },
+   "file_extension": ".py",
+   "mimetype": "text/x-python",
+   "name": "python",
+   "nbconvert_exporter": "python",
+   "pygments_lexer": "ipython3",
+   "version": "3.11.7"
+  }
+ },
+ "nbformat": 4,
+ "nbformat_minor": 5
+}
diff --git a/evaluation/notebook/token_cost_speed_analysis.py b/evaluation/notebook/token_cost_speed_analysis.py
new file mode 100644
index 0000000..54a5693
--- /dev/null
+++ b/evaluation/notebook/token_cost_speed_analysis.py
@@ -0,0 +1,121 @@
+import matplotlib.pyplot as plt
+import seaborn as sns
+import pandas as pd
+import argparse
+import os
+
+# Parse command-line arguments
+parser = argparse.ArgumentParser(description='Generate token usage and cost analysis plots')
+parser.add_argument('--task', type=str, required=True, help='Task name (e.g., reproschema)')
+parser.add_argument('--file', type=str, required=True, help='CSV file name (e.g., reproschema_token_usage.csv)')
+args = parser.parse_args()
+
+# Create output directory in the same location as this script
+script_dir = os.path.dirname(os.path.abspath(__file__))
+output_dir = os.path.join(script_dir, args.task)
+os.makedirs(output_dir, exist_ok=True)
+print(f"Created directory: {output_dir}")
+
+# Read data
+df = pd.read_csv(args.file)
+df['Model'] = df['Model'].str.strip()
+
+# Map column names to expected names
+column_mapping = {
+    'Tokens': 'Input Tokens',
+    'Cost': 'Cost ($)',
+    'Speed': 'Speed (tps)'
+}
+
+# Rename columns if they exist
+for old_name, new_name in column_mapping.items():
+    if old_name in df.columns and new_name not in df.columns:
+        df.rename(columns={old_name: new_name}, inplace=True)
+
+# Define colorblind-friendly palette
+# Using colors from Wong's colorblind-friendly palette
+model_colors = {
+    'GPT-4o-mini': '#E69F00',  # Orange
+    'Claude 3.7 Sonnet': '#56B4E9',  # Sky blue
+    'DeepSeek V3 0324': '#009E73'  # Bluish green
+}
+
+# Token type colors (different from model colors)
+token_colors = {
+    'Input Tokens': '#CC79A7',  # Reddish purple
+    'Output Tokens': '#F0E442'  # Yellow
+}
+
+# Set matplotlib parameters for small figures
+plt.rcParams.update({
+    'font.size': 7,
+    'axes.titlesize': 8,
+    'axes.labelsize': 7,
+    'xtick.labelsize': 6,
+    'ytick.labelsize': 6,
+    'legend.fontsize': 6,
+    'figure.titlesize': 8,
+    'axes.grid': False,
+    'axes.spines.top': False,
+    'axes.spines.right': False
+})
+
+# Helper function to save in multiple formats
+def save_plot(filename_base):
+    """Save the current plot in PDF format"""
+    plt.savefig(os.path.join(output_dir, f"{filename_base}.pdf"), bbox_inches='tight')
+
+# Plot 1: Cost per Model (Violin Plot)
+plt.figure(figsize=(3.2, 2.5))
+ax = sns.violinplot(data=df, x='Model', y='Cost ($)', hue='Model', inner='box', 
+                    palette=model_colors, linewidth=0.8, legend=False)
+plt.title("Cost Distribution by Model", pad=10)
+plt.tight_layout()
+save_plot(f"{args.task}_cost_violin")
+plt.close()
+
+# Plot 2: Input and Output Tokens per Model (Violin Plot)
+plt.figure(figsize=(3.5, 3))
+df_long = df.melt(id_vars=['Model'], value_vars=['Input Tokens', 'Output Tokens'],
+                  var_name='Token Type', value_name='Count')
+
+# Create custom palette for split violin
+split_palette = []
+for model in df['Model'].unique():
+    split_palette.extend([token_colors['Input Tokens'], token_colors['Output Tokens']])
+
+ax = sns.violinplot(data=df_long, x='Model', y='Count', hue='Token Type', 
+                    split=True, palette=token_colors, linewidth=0.8)
+ax.set_xticklabels(ax.get_xticklabels())
+plt.title("Token Usage by Model", pad=10)
+plt.legend(title='Token Type', loc='upper left')
+plt.tight_layout()
+save_plot(f"{args.task}_token_usage_violin")
+plt.close()
+
+# Plot 3: Speed per Model (Violin Plot)
+plt.figure(figsize=(3.2, 2.5))
+ax = sns.violinplot(data=df, x='Model', y='Speed (tps)', hue='Model', inner='box', 
+                    palette=model_colors, linewidth=0.8, legend=False)
+plt.title("Speed Distribution by Model", pad=10)
+plt.ylabel("Speed (tokens/sec)")
+plt.tight_layout()
+save_plot(f"{args.task}_speed_violin")
+plt.close()
+
+# Plot 4: Scatter plot of Speed vs Cost
+plt.figure(figsize=(3, 3))
+markers = ['o', 's', '^']  # Different markers for each model
+for i, (model, group) in enumerate(df.groupby('Model')):
+    plt.scatter(group['Speed (tps)'], group['Cost ($)'], 
+                color=model_colors[model], label=model, 
+                marker=markers[i], s=30, alpha=0.7, edgecolors='black', linewidth=0.5)
+plt.xlabel("Speed (tokens/sec)")
+plt.ylabel("Cost ($)")
+plt.title("Speed vs Cost by Model", pad=10)
+plt.legend(bbox_to_anchor=(1, 1), loc='upper left')
+plt.tight_layout()
+save_plot(f"{args.task}_speed_vs_cost")
+plt.close()
+
+print(f"All plots saved in {output_dir} as PNG, SVG, and PDF formats")
\ No newline at end of file
diff --git a/evaluation/pdf2reproschema/old/evaluation/with_hil/reproschema_config_claudesonet_with_hil.json b/evaluation/pdf2reproschema/old/evaluation/with_hil/reproschema_config_claudesonet_with_hil.json
new file mode 100644
index 0000000..4f73409
--- /dev/null
+++ b/evaluation/pdf2reproschema/old/evaluation/with_hil/reproschema_config_claudesonet_with_hil.json
@@ -0,0 +1,1282 @@
+{
+  "judged_structured_information": {
+    "refined_metadata": {
+      "schemaType": "reproschema:Activity",
+      "schemaVersion": "1.0.0",
+      "activity": {
+        "id": "MFQ-long",
+        "prefLabel": {
+          "en": "MOOD AND FEELINGS QUESTIONNAIRE: Long Version"
+        },
+        "description": {
+          "en": "Adult Self-Report questionnaire that assesses depression symptoms over the past two weeks"
+        },
+        "preamble": {
+          "en": "This form is about how you might have been feeling or acting recently. For each question, please check (\u273c) how you have been feeling or acting in the past two weeks. If a sentence was not true about you, check NOT TRUE. If a sentence was only sometimes true, check SOMETIMES. If a sentence was true about you most of the time, check TRUE."
+        },
+        "citation": {
+          "en": "Copyright Adrian Angold & Elizabeth J. Costello, 1987; Developmental Epidemiology Program; Duke University"
+        }
+      },
+      "items": [
+        {
+          "id": "MFQ_01",
+          "question": {
+            "en": "I felt miserable or unhappy."
+          },
+          "prefLabel": {
+            "en": "Miserable or unhappy"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_02",
+          "question": {
+            "en": "I didn't enjoy anything at all."
+          },
+          "prefLabel": {
+            "en": "No enjoyment"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_03",
+          "question": {
+            "en": "I was less hungry than usual."
+          },
+          "prefLabel": {
+            "en": "Decreased appetite"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_04",
+          "question": {
+            "en": "I ate more than usual."
+          },
+          "prefLabel": {
+            "en": "Increased appetite"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_05",
+          "question": {
+            "en": "I felt so tired I just sat around and did nothing."
+          },
+          "prefLabel": {
+            "en": "Fatigue and inactivity"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_06",
+          "question": {
+            "en": "I was moving and walking more slowly than usual."
+          },
+          "prefLabel": {
+            "en": "Psychomotor retardation"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_07",
+          "question": {
+            "en": "I was very restless."
+          },
+          "prefLabel": {
+            "en": "Restlessness"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_08",
+          "question": {
+            "en": "I felt I was no good anymore."
+          },
+          "prefLabel": {
+            "en": "Worthlessness"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_09",
+          "question": {
+            "en": "I blamed myself for things that weren't my fault."
+          },
+          "prefLabel": {
+            "en": "Self-blame"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_10",
+          "question": {
+            "en": "It was hard for me to make up my mind."
+          },
+          "prefLabel": {
+            "en": "Indecisiveness"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_11",
+          "question": {
+            "en": "I felt grumpy and cross with other people."
+          },
+          "prefLabel": {
+            "en": "Irritability"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_12",
+          "question": {
+            "en": "I felt like talking less than usual."
+          },
+          "prefLabel": {
+            "en": "Reduced talkativeness"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_13",
+          "question": {
+            "en": "I was talking more slowly than usual."
+          },
+          "prefLabel": {
+            "en": "Slow speech"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_14",
+          "question": {
+            "en": "I cried a lot."
+          },
+          "prefLabel": {
+            "en": "Crying"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_15",
+          "question": {
+            "en": "I thought there was nothing good for me in the future."
+          },
+          "prefLabel": {
+            "en": "Hopelessness"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_16",
+          "question": {
+            "en": "I thought that life wasn't worth living."
+          },
+          "prefLabel": {
+            "en": "Life not worth living"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_17",
+          "question": {
+            "en": "I thought about death or dying."
+          },
+          "prefLabel": {
+            "en": "Thoughts of death"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_18",
+          "question": {
+            "en": "I thought my family would be better off without me."
+          },
+          "prefLabel": {
+            "en": "Family better without me"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_19",
+          "question": {
+            "en": "I thought about killing myself."
+          },
+          "prefLabel": {
+            "en": "Suicidal thoughts"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_20",
+          "question": {
+            "en": "I didn't want to see my friends."
+          },
+          "prefLabel": {
+            "en": "Social withdrawal"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_21",
+          "question": {
+            "en": "I found it hard to think properly or concentrate."
+          },
+          "prefLabel": {
+            "en": "Concentration difficulties"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_22",
+          "question": {
+            "en": "I thought bad things would happen to me."
+          },
+          "prefLabel": {
+            "en": "Anticipating negative events"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_23",
+          "question": {
+            "en": "I hated myself."
+          },
+          "prefLabel": {
+            "en": "Self-hatred"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_24",
+          "question": {
+            "en": "I felt I was a bad person."
+          },
+          "prefLabel": {
+            "en": "Feeling bad"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_25",
+          "question": {
+            "en": "I thought I looked ugly."
+          },
+          "prefLabel": {
+            "en": "Perceived ugliness"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_26",
+          "question": {
+            "en": "I worried about aches and pains."
+          },
+          "prefLabel": {
+            "en": "Physical complaints"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_27",
+          "question": {
+            "en": "I felt lonely."
+          },
+          "prefLabel": {
+            "en": "Loneliness"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_28",
+          "question": {
+            "en": "I thought nobody really loved me."
+          },
+          "prefLabel": {
+            "en": "Feeling unloved"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_29",
+          "question": {
+            "en": "I didn't have any fun in any of my activities."
+          },
+          "prefLabel": {
+            "en": "No enjoyment in activities"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_30",
+          "question": {
+            "en": "I thought I could never be as good as other people."
+          },
+          "prefLabel": {
+            "en": "Comparative inadequacy"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_31",
+          "question": {
+            "en": "I did everything wrong."
+          },
+          "prefLabel": {
+            "en": "Doing everything wrong"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_32",
+          "question": {
+            "en": "I didn't sleep as well as I usually sleep."
+          },
+          "prefLabel": {
+            "en": "Sleep disturbance"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_33",
+          "question": {
+            "en": "I slept a lot more than usual."
+          },
+          "prefLabel": {
+            "en": "Hypersomnia"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        }
+      ],
+      "ui": {
+        "order": [
+          "MFQ_01",
+          "MFQ_02",
+          "MFQ_03",
+          "MFQ_04",
+          "MFQ_05",
+          "MFQ_06",
+          "MFQ_07",
+          "MFQ_08",
+          "MFQ_09",
+          "MFQ_10",
+          "MFQ_11",
+          "MFQ_12",
+          "MFQ_13",
+          "MFQ_14",
+          "MFQ_15",
+          "MFQ_16",
+          "MFQ_17",
+          "MFQ_18",
+          "MFQ_19",
+          "MFQ_20",
+          "MFQ_21",
+          "MFQ_22",
+          "MFQ_23",
+          "MFQ_24",
+          "MFQ_25",
+          "MFQ_26",
+          "MFQ_27",
+          "MFQ_28",
+          "MFQ_29",
+          "MFQ_30",
+          "MFQ_31",
+          "MFQ_32",
+          "MFQ_33"
+        ],
+        "shuffle": false,
+        "addProperties": [
+          {
+            "variableName": "MFQ_total",
+            "isAbout": "MFQ_total",
+            "isVis": true
+          }
+        ]
+      },
+      "compute": [
+        {
+          "variableName": "MFQ_total",
+          "jsExpression": "MFQ_01 + MFQ_02 + MFQ_03 + MFQ_04 + MFQ_05 + MFQ_06 + MFQ_07 + MFQ_08 + MFQ_09 + MFQ_10 + MFQ_11 + MFQ_12 + MFQ_13 + MFQ_14 + MFQ_15 + MFQ_16 + MFQ_17 + MFQ_18 + MFQ_19 + MFQ_20 + MFQ_21 + MFQ_22 + MFQ_23 + MFQ_24 + MFQ_25 + MFQ_26 + MFQ_27 + MFQ_28 + MFQ_29 + MFQ_30 + MFQ_31 + MFQ_32 + MFQ_33"
+        }
+      ],
+      "languages": [
+        "en"
+      ]
+    },
+    "validation": {
+      "completeness": {
+        "allItemsExtracted": true,
+        "itemCount": 33,
+        "missingItems": []
+      },
+      "accuracy": {
+        "responseOptionsCorrect": true,
+        "scoringLogicPresent": true,
+        "metadataComplete": true
+      },
+      "issues": [],
+      "overallScore": 10.0,
+      "summary": "The Mood and Feelings Questionnaire (Long Version) has been successfully extracted and formatted. All 33 questions are properly captured with their corresponding ID numbers (MFQ_01 through MFQ_33). Each question includes the correct response options (NOT TRUE=0, SOMETIMES=1, TRUE=2). The activity metadata is complete, including the title, description, preamble, and citation information. The scoring logic for calculating the total MFQ score is correctly implemented. The questionnaire structure maintains the proper order of items and includes appropriate prefLabels for each question."
+    }
+  }
+}
\ No newline at end of file
diff --git a/evaluation/pdf2reproschema/old/evaluation/with_hil/reproschema_config_deepseek_with_hil.json b/evaluation/pdf2reproschema/old/evaluation/with_hil/reproschema_config_deepseek_with_hil.json
new file mode 100644
index 0000000..17c2509
--- /dev/null
+++ b/evaluation/pdf2reproschema/old/evaluation/with_hil/reproschema_config_deepseek_with_hil.json
@@ -0,0 +1,200 @@
+{
+  "judged_structured_information": {
+    "refined_metadata": {
+      "schemaType": "reproschema:Activity",
+      "schemaVersion": "1.0.0",
+      "activity": {
+        "id": "MFQ-long",
+        "prefLabel": {
+          "en": "MOOD AND FEELINGS QUESTIONNAIRE: Long Version"
+        },
+        "description": {
+          "en": "A 33-item questionnaire assessing mood and feelings in adults"
+        },
+        "preamble": {
+          "en": "This form is about how you might have been feeling or acting recently. For each question, please check how you have been feeling or acting in the past two weeks. If a sentence was not true about you, check NOT TRUE. If a sentence was only sometimes true, check SOMETIMES. If a sentence was true about you most of the time, check TRUE."
+        },
+        "citation": {
+          "en": "Copyright Adrian Angold & Elizabeth J. Costello, 1987; Developmental Epidemiology Program; Duke University"
+        }
+      },
+      "items": [
+        {
+          "id": "Q1",
+          "question": {
+            "en": "I felt miserable or unhappy."
+          },
+          "prefLabel": {
+            "en": "MFQ Q1"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q2",
+          "question": {
+            "en": "I didn\u2019t enjoy anything at all."
+          },
+          "prefLabel": {
+            "en": "MFQ Q2"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q33",
+          "question": {
+            "en": "I slept a lot more than usual."
+          },
+          "prefLabel": {
+            "en": "MFQ Q33"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        }
+      ],
+      "ui": {
+        "order": [
+          "Q1",
+          "Q2",
+          "Q3",
+          "Q4",
+          "Q5",
+          "Q6",
+          "Q7",
+          "Q8",
+          "Q9",
+          "Q10",
+          "Q11",
+          "Q12",
+          "Q13",
+          "Q14",
+          "Q15",
+          "Q16",
+          "Q17",
+          "Q18",
+          "Q19",
+          "Q20",
+          "Q21",
+          "Q22",
+          "Q23",
+          "Q24",
+          "Q25",
+          "Q26",
+          "Q27",
+          "Q28",
+          "Q29",
+          "Q30",
+          "Q31",
+          "Q32",
+          "Q33"
+        ],
+        "shuffle": false
+      },
+      "compute": [
+        {
+          "variableName": "MFQ_total",
+          "label": {
+            "en": "MFQ Total Score"
+          },
+          "jsExpression": "Q1 + Q2 + Q3 + Q4 + Q5 + Q6 + Q7 + Q8 + Q9 + Q10 + Q11 + Q12 + Q13 + Q14 + Q15 + Q16 + Q17 + Q18 + Q19 + Q20 + Q21 + Q22 + Q23 + Q24 + Q25 + Q26 + Q27 + Q28 + Q29 + Q30 + Q31 + Q32 + Q33"
+        }
+      ]
+    },
+    "validation": {
+      "completeness": {
+        "allItemsExtracted": true,
+        "itemCount": 33,
+        "missingItems": []
+      },
+      "accuracy": {
+        "responseOptionsCorrect": true,
+        "scoringLogicPresent": true,
+        "metadataComplete": true
+      },
+      "issues": [],
+      "overallScore": 10.0,
+      "summary": "All questionnaire components successfully extracted and formatted."
+    },
+    "changes_applied": [
+      "Fixed non-English text issue in Q2 response options",
+      "Verified all metadata fields are correct and accurate",
+      "Ensured ReproSchema compatibility of all components"
+    ]
+  }
+}
\ No newline at end of file
diff --git a/evaluation/pdf2reproschema/old/evaluation/with_hil/reproschema_config_gpt_with_hil.json b/evaluation/pdf2reproschema/old/evaluation/with_hil/reproschema_config_gpt_with_hil.json
new file mode 100644
index 0000000..f0fd418
--- /dev/null
+++ b/evaluation/pdf2reproschema/old/evaluation/with_hil/reproschema_config_gpt_with_hil.json
@@ -0,0 +1,1272 @@
+{
+  "judged_structured_information": {
+    "refined_metadata": {
+      "schemaType": "reproschema:Activity",
+      "schemaVersion": "1.0.0",
+      "activity": {
+        "id": "MFQ-long",
+        "prefLabel": {
+          "en": "Mood and Feelings Questionnaire: Long Version"
+        },
+        "description": {
+          "en": "This form is about how you might have been feeling or acting recently."
+        },
+        "preamble": {
+          "en": "For each question, please check (\u2714) how you have been feeling or acting in the past two weeks."
+        },
+        "citation": {
+          "en": "Copyright Adrian Angold & Elizabeth J. Costello, 1987; Developmental Epidemiology Program; Duke University"
+        }
+      },
+      "items": [
+        {
+          "id": "MFQ_01",
+          "question": {
+            "en": "I felt miserable or unhappy."
+          },
+          "prefLabel": {
+            "en": "MFQ Q1"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_02",
+          "question": {
+            "en": "I didn\u2019t enjoy anything at all."
+          },
+          "prefLabel": {
+            "en": "MFQ Q2"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_03",
+          "question": {
+            "en": "I was less hungry than usual."
+          },
+          "prefLabel": {
+            "en": "MFQ Q3"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_04",
+          "question": {
+            "en": "I ate more than usual."
+          },
+          "prefLabel": {
+            "en": "MFQ Q4"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_05",
+          "question": {
+            "en": "I felt so tired I just sat around and did nothing."
+          },
+          "prefLabel": {
+            "en": "MFQ Q5"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_06",
+          "question": {
+            "en": "I was moving and walking more slowly than usual."
+          },
+          "prefLabel": {
+            "en": "MFQ Q6"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_07",
+          "question": {
+            "en": "I was very restless."
+          },
+          "prefLabel": {
+            "en": "MFQ Q7"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_08",
+          "question": {
+            "en": "I felt I was no good anymore."
+          },
+          "prefLabel": {
+            "en": "MFQ Q8"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_09",
+          "question": {
+            "en": "I blamed myself for things that weren\u2019t my fault."
+          },
+          "prefLabel": {
+            "en": "MFQ Q9"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_10",
+          "question": {
+            "en": "It was hard for me to make up my mind."
+          },
+          "prefLabel": {
+            "en": "MFQ Q10"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_11",
+          "question": {
+            "en": "I felt grumpy and cross with other people."
+          },
+          "prefLabel": {
+            "en": "MFQ Q11"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_12",
+          "question": {
+            "en": "I felt like talking less than usual."
+          },
+          "prefLabel": {
+            "en": "MFQ Q12"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_13",
+          "question": {
+            "en": "I was talking more slowly than usual."
+          },
+          "prefLabel": {
+            "en": "MFQ Q13"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_14",
+          "question": {
+            "en": "I cried a lot."
+          },
+          "prefLabel": {
+            "en": "MFQ Q14"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_15",
+          "question": {
+            "en": "I thought there was nothing good for me in the future."
+          },
+          "prefLabel": {
+            "en": "MFQ Q15"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_16",
+          "question": {
+            "en": "I thought that life wasn\u2019t worth living."
+          },
+          "prefLabel": {
+            "en": "MFQ Q16"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_17",
+          "question": {
+            "en": "I thought about death or dying."
+          },
+          "prefLabel": {
+            "en": "MFQ Q17"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_18",
+          "question": {
+            "en": "I thought my family would be better off without me."
+          },
+          "prefLabel": {
+            "en": "MFQ Q18"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_19",
+          "question": {
+            "en": "I thought about killing myself."
+          },
+          "prefLabel": {
+            "en": "MFQ Q19"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_20",
+          "question": {
+            "en": "I didn\u2019t want to see my friends."
+          },
+          "prefLabel": {
+            "en": "MFQ Q20"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_21",
+          "question": {
+            "en": "I found it hard to think properly or concentrate."
+          },
+          "prefLabel": {
+            "en": "MFQ Q21"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_22",
+          "question": {
+            "en": "I thought bad things would happen to me."
+          },
+          "prefLabel": {
+            "en": "MFQ Q22"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_23",
+          "question": {
+            "en": "I hated myself."
+          },
+          "prefLabel": {
+            "en": "MFQ Q23"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_24",
+          "question": {
+            "en": "I felt I was a bad person."
+          },
+          "prefLabel": {
+            "en": "MFQ Q24"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_25",
+          "question": {
+            "en": "I thought I looked ugly."
+          },
+          "prefLabel": {
+            "en": "MFQ Q25"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_26",
+          "question": {
+            "en": "I worried about aches and pains."
+          },
+          "prefLabel": {
+            "en": "MFQ Q26"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_27",
+          "question": {
+            "en": "I felt lonely."
+          },
+          "prefLabel": {
+            "en": "MFQ Q27"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_28",
+          "question": {
+            "en": "I thought nobody really loved me."
+          },
+          "prefLabel": {
+            "en": "MFQ Q28"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_29",
+          "question": {
+            "en": "I didn\u2019t have any fun in any of my activities."
+          },
+          "prefLabel": {
+            "en": "MFQ Q29"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_30",
+          "question": {
+            "en": "I thought I could never be as good as other people."
+          },
+          "prefLabel": {
+            "en": "MFQ Q30"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_31",
+          "question": {
+            "en": "I did everything wrong."
+          },
+          "prefLabel": {
+            "en": "MFQ Q31"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_32",
+          "question": {
+            "en": "I didn\u2019t sleep as well as I usually sleep."
+          },
+          "prefLabel": {
+            "en": "MFQ Q32"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_33",
+          "question": {
+            "en": "I slept a lot more than usual."
+          },
+          "prefLabel": {
+            "en": "MFQ Q33"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        }
+      ],
+      "ui": {
+        "order": [
+          "MFQ_01",
+          "MFQ_02",
+          "MFQ_03",
+          "MFQ_04",
+          "MFQ_05",
+          "MFQ_06",
+          "MFQ_07",
+          "MFQ_08",
+          "MFQ_09",
+          "MFQ_10",
+          "MFQ_11",
+          "MFQ_12",
+          "MFQ_13",
+          "MFQ_14",
+          "MFQ_15",
+          "MFQ_16",
+          "MFQ_17",
+          "MFQ_18",
+          "MFQ_19",
+          "MFQ_20",
+          "MFQ_21",
+          "MFQ_22",
+          "MFQ_23",
+          "MFQ_24",
+          "MFQ_25",
+          "MFQ_26",
+          "MFQ_27",
+          "MFQ_28",
+          "MFQ_29",
+          "MFQ_30",
+          "MFQ_31",
+          "MFQ_32",
+          "MFQ_33"
+        ],
+        "shuffle": false
+      },
+      "compute": [
+        {
+          "variableName": "MFQ_total",
+          "jsExpression": "MFQ_01 + MFQ_02 + MFQ_03 + MFQ_04 + MFQ_05 + MFQ_06 + MFQ_07 + MFQ_08 + MFQ_09 + MFQ_10 + MFQ_11 + MFQ_12 + MFQ_13 + MFQ_14 + MFQ_15 + MFQ_16 + MFQ_17 + MFQ_18 + MFQ_19 + MFQ_20 + MFQ_21 + MFQ_22 + MFQ_23 + MFQ_24 + MFQ_25 + MFQ_26 + MFQ_27 + MFQ_28 + MFQ_29 + MFQ_30 + MFQ_31 + MFQ_32 + MFQ_33"
+        }
+      ]
+    },
+    "validation": {
+      "completeness": {
+        "allItemsExtracted": true,
+        "itemCount": 33,
+        "missingItems": []
+      },
+      "accuracy": {
+        "responseOptionsCorrect": true,
+        "scoringLogicPresent": true,
+        "metadataComplete": true
+      },
+      "issues": [],
+      "overallScore": 10.0,
+      "summary": "All questionnaire components successfully extracted and formatted."
+    }
+  }
+}
\ No newline at end of file
diff --git a/evaluation/pdf2reproschema/old/evaluation/with_hil/reproschema_token_usage_with_hil.csv b/evaluation/pdf2reproschema/old/evaluation/with_hil/reproschema_token_usage_with_hil.csv
new file mode 100644
index 0000000..494c26d
--- /dev/null
+++ b/evaluation/pdf2reproschema/old/evaluation/with_hil/reproschema_token_usage_with_hil.csv
@@ -0,0 +1,27 @@
+Timestamp,Provider,Model,App,Input Tokens,Output Tokens,Cost ($),Speed (tps),Finish
+"Jun 27, 02:41 PM",Favicon for Nebius,DeepSeek V3 0324,liteLLM,4045,385,0.0026,19.2,stop
+"Jun 27, 02:41 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,2871,1254,0.00191,21.3,stop
+"Jun 27, 02:39 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,1322,1278,0.0021,102.9,stop
+"Jun 27, 02:39 PM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,6527,347,0.00223,13.2,stop
+"Jun 27, 02:39 PM",Favicon for GMICloud,DeepSeek V3 0324,liteLLM,5334,1295,0.00511,69.5,stop
+"Jun 27, 02:38 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,10035,303,0.00371,19.7,stop
+"Jun 27, 02:38 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,4947,5191,0.00595,21.9,stop
+"Jun 27, 02:34 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,6167,502,0.00217,21.1,stop
+"Jun 27, 02:34 PM",Favicon for Novita,DeepSeek V3 0324,liteLLM,1777,4748,0.00676,86.5,stop
+"Jun 27, 02:31 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,19104,501,0.0648,63.0,tool_calls
+"Jun 27, 02:31 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,12359,6237,0.131,93.2,stop
+"Jun 27, 02:29 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,13080,398,0.0452,70.9,tool_calls
+"Jun 27, 02:29 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,6349,6236,0.113,93.0,stop
+"Jun 27, 02:28 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,11766,387,0.0411,61.3,tool_calls
+"Jun 27, 02:28 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,5075,6197,0.108,95.8,stop
+"Jun 27, 02:27 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,6778,482,0.0276,64.4,tool_calls
+"Jun 27, 02:27 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,1986,4622,0.0753,95.7,stop
+"Jun 27, 02:24 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,16406,289,0.00263,51.3,stop
+"Jun 27, 02:24 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,9914,6578,0.00543,60.9,stop
+"Jun 27, 02:21 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,6559,6512,0.00489,66.6,stop
+"Jun 27, 02:19 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,11636,284,0.00192,48.3,stop
+"Jun 27, 02:19 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,5215,6521,0.00469,60.3,stop
+"Jun 27, 02:17 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,10376,215,0.00169,48.3,stop
+"Jun 27, 02:17 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,4089,6391,0.00445,56.3,stop
+"Jun 27, 02:15 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,5408,286,0.000983,71.0,stop
+"Jun 27, 02:15 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,1808,3999,0.00267,60.6,stop
diff --git a/evaluation/pdf2reproschema/old/evaluation/without_hil/reproschema_token_usage_without_hil.csv b/evaluation/pdf2reproschema/old/evaluation/without_hil/reproschema_token_usage_without_hil.csv
new file mode 100644
index 0000000..4e625f3
--- /dev/null
+++ b/evaluation/pdf2reproschema/old/evaluation/without_hil/reproschema_token_usage_without_hil.csv
@@ -0,0 +1,24 @@
+Timestamp,Provider,Model,App,Input Tokens,Output Tokens,Cost ($),Speed (tps),Finish
+"Jun 26, 05:07 PM",Favicon for InferenceNet,DeepSeek V3 0324,liteLLM,2925,409,0.00191,28.3,tps
+"Jun 26, 05:06 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,1932,1076,0.00149,17.9,tps
+"Jun 26, 05:03 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,614,665,0.000757,20.2,tps
+"Jun 26, 05:03 PM",Favicon for Nebius,DeepSeek V3 0324,liteLLM,617,87,0.000439,27.3,tps
+"Jun 26, 05:03 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,6848,313,0.00219,16.4,tps
+"Jun 26, 05:02 PM",Favicon for Lambda,DeepSeek V3 0324,liteLLM,6361,587,0.00268,29.6,tps
+"Jun 26, 05:02 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,6276,7397,0.00827,17.5,tps
+"Jun 26, 04:47 PM",Favicon for InferenceNet,DeepSeek V3 0324,liteLLM,11140,353,0.00552,28.9,tps
+"Jun 26, 04:47 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,4994,6248,0.0069,27.9,tps
+"Jun 26, 04:43 PM",Favicon for Crusoe,DeepSeek V3 0324,liteLLM,6218,376,0.00217,23.7,tps
+"Jun 26, 04:43 PM",Favicon for DeepInfra,DeepSeek V3 0324,liteLLM,1766,4797,0.00472,22.9,tps
+"Jun 26, 04:35 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,7385,6995,0.127,95.2,tps
+"Jun 26, 04:33 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,14726,415,0.0504,59.6,tps
+"Jun 26, 04:33 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,7244,6987,0.127,95.5,tps
+"Jun 26, 04:32 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,12851,489,0.0459,66.8,tps
+"Jun 26, 04:32 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,5074,7283,0.124,97.2,tps
+"Jun 26, 04:31 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,6777,565,0.0288,67.0,tps
+"Jun 26, 04:30 PM",Favicon for Google,Claude 3.7 Sonnet,liteLLM,1781,4621,0.0747,95.2,tps
+"Jun 26, 02:32 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,11202,243,0.00183,42.4,tps
+"Jun 26, 02:32 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,4997,6305,0.00453,83.7,tps
+"Jun 26, 02:30 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,9936,345,0.000958,59.5,tps
+"Jun 26, 02:30 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,9936,297,0.00167,78.5,tps
+"Jun 26, 02:30 PM",Favicon for OpenAI,GPT-4o-mini,liteLLM,3871,6169,0.00428,62.2,tps
diff --git a/evaluation/pdf2reproschema/old/evaluation/without_hil/result_csv_v_gpt40_mini.json b/evaluation/pdf2reproschema/old/evaluation/without_hil/result_csv_v_gpt40_mini.json
new file mode 100644
index 0000000..e3e9ca4
--- /dev/null
+++ b/evaluation/pdf2reproschema/old/evaluation/without_hil/result_csv_v_gpt40_mini.json
@@ -0,0 +1,1272 @@
+{
+  "judged_terms": {
+    "refined_metadata": {
+      "schemaType": "reproschema:Activity",
+      "schemaVersion": "1.0.0",
+      "activity": {
+        "id": "MFQ-long",
+        "prefLabel": {
+          "en": "MOOD AND FEELINGS QUESTIONNAIRE: Long Version"
+        },
+        "description": {
+          "en": "This form is about how you might have been feeling or acting recently."
+        },
+        "preamble": {
+          "en": "For each question, please check (\u2713) how you have been feeling or acting in the past two weeks. If a sentence was not true about you, check NOT TRUE. If a sentence was only sometimes true, check SOMETIMES. If a sentence was true about you most of the time, check TRUE."
+        },
+        "citation": {
+          "en": "Copyright Adrian Angold & Elizabeth J. Costello, 1987; Developmental Epidemiology Program; Duke University"
+        }
+      },
+      "items": [
+        {
+          "id": "Q1",
+          "question": {
+            "en": "I felt miserable or unhappy."
+          },
+          "prefLabel": {
+            "en": "Q1"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q2",
+          "question": {
+            "en": "I didn\u2019t enjoy anything at all."
+          },
+          "prefLabel": {
+            "en": "Q2"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q3",
+          "question": {
+            "en": "I was less hungry than usual."
+          },
+          "prefLabel": {
+            "en": "Q3"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q4",
+          "question": {
+            "en": "I ate more than usual."
+          },
+          "prefLabel": {
+            "en": "Q4"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q5",
+          "question": {
+            "en": "I felt so tired I just sat around and did nothing."
+          },
+          "prefLabel": {
+            "en": "Q5"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q6",
+          "question": {
+            "en": "I was moving and walking more slowly than usual."
+          },
+          "prefLabel": {
+            "en": "Q6"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q7",
+          "question": {
+            "en": "I was very restless."
+          },
+          "prefLabel": {
+            "en": "Q7"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q8",
+          "question": {
+            "en": "I felt I was no good anymore."
+          },
+          "prefLabel": {
+            "en": "Q8"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q9",
+          "question": {
+            "en": "I blamed myself for things that weren\u2019t my fault."
+          },
+          "prefLabel": {
+            "en": "Q9"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q10",
+          "question": {
+            "en": "It was hard for me to make up my mind."
+          },
+          "prefLabel": {
+            "en": "Q10"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q11",
+          "question": {
+            "en": "I felt grumpy and cross with other people."
+          },
+          "prefLabel": {
+            "en": "Q11"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q12",
+          "question": {
+            "en": "I felt like talking less than usual."
+          },
+          "prefLabel": {
+            "en": "Q12"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q13",
+          "question": {
+            "en": "I was talking more slowly than usual."
+          },
+          "prefLabel": {
+            "en": "Q13"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q14",
+          "question": {
+            "en": "I cried a lot."
+          },
+          "prefLabel": {
+            "en": "Q14"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q15",
+          "question": {
+            "en": "I thought there was nothing good for me in the future."
+          },
+          "prefLabel": {
+            "en": "Q15"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q16",
+          "question": {
+            "en": "I thought that life wasn\u2019t worth living."
+          },
+          "prefLabel": {
+            "en": "Q16"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q17",
+          "question": {
+            "en": "I thought about death or dying."
+          },
+          "prefLabel": {
+            "en": "Q17"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q18",
+          "question": {
+            "en": "I thought my family would be better off without me."
+          },
+          "prefLabel": {
+            "en": "Q18"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q19",
+          "question": {
+            "en": "I thought about killing myself."
+          },
+          "prefLabel": {
+            "en": "Q19"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q20",
+          "question": {
+            "en": "I didn\u2019t want to see my friends."
+          },
+          "prefLabel": {
+            "en": "Q20"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q21",
+          "question": {
+            "en": "I found it hard to think properly or concentrate."
+          },
+          "prefLabel": {
+            "en": "Q21"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q22",
+          "question": {
+            "en": "I thought bad things would happen to me."
+          },
+          "prefLabel": {
+            "en": "Q22"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q23",
+          "question": {
+            "en": "I hated myself."
+          },
+          "prefLabel": {
+            "en": "Q23"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q24",
+          "question": {
+            "en": "I felt I was a bad person."
+          },
+          "prefLabel": {
+            "en": "Q24"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q25",
+          "question": {
+            "en": "I thought I looked ugly."
+          },
+          "prefLabel": {
+            "en": "Q25"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q26",
+          "question": {
+            "en": "I worried about aches and pains."
+          },
+          "prefLabel": {
+            "en": "Q26"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q27",
+          "question": {
+            "en": "I felt lonely."
+          },
+          "prefLabel": {
+            "en": "Q27"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q28",
+          "question": {
+            "en": "I thought nobody really loved me."
+          },
+          "prefLabel": {
+            "en": "Q28"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q29",
+          "question": {
+            "en": "I didn\u2019t have any fun in any of my activities."
+          },
+          "prefLabel": {
+            "en": "Q29"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q30",
+          "question": {
+            "en": "I thought I could never be as good as other people."
+          },
+          "prefLabel": {
+            "en": "Q30"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q31",
+          "question": {
+            "en": "I did everything wrong."
+          },
+          "prefLabel": {
+            "en": "Q31"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q32",
+          "question": {
+            "en": "I didn\u2019t sleep as well as I usually sleep."
+          },
+          "prefLabel": {
+            "en": "Q32"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "Q33",
+          "question": {
+            "en": "I slept a lot more than usual."
+          },
+          "prefLabel": {
+            "en": "Q33"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        }
+      ],
+      "ui": {
+        "order": [
+          "Q1",
+          "Q2",
+          "Q3",
+          "Q4",
+          "Q5",
+          "Q6",
+          "Q7",
+          "Q8",
+          "Q9",
+          "Q10",
+          "Q11",
+          "Q12",
+          "Q13",
+          "Q14",
+          "Q15",
+          "Q16",
+          "Q17",
+          "Q18",
+          "Q19",
+          "Q20",
+          "Q21",
+          "Q22",
+          "Q23",
+          "Q24",
+          "Q25",
+          "Q26",
+          "Q27",
+          "Q28",
+          "Q29",
+          "Q30",
+          "Q31",
+          "Q32",
+          "Q33"
+        ],
+        "shuffle": false
+      },
+      "compute": [
+        {
+          "variableName": "MFQ_total",
+          "jsExpression": "Q1 + Q2 + Q3 + Q4 + Q5 + Q6 + Q7 + Q8 + Q9 + Q10 + Q11 + Q12 + Q13 + Q14 + Q15 + Q16 + Q17 + Q18 + Q19 + Q20 + Q21 + Q22 + Q23 + Q24 + Q25 + Q26 + Q27 + Q28 + Q29 + Q30 + Q31 + Q32 + Q33"
+        }
+      ]
+    },
+    "validation": {
+      "completeness": {
+        "allItemsExtracted": true,
+        "itemCount": 33,
+        "missingItems": []
+      },
+      "accuracy": {
+        "responseOptionsCorrect": true,
+        "scoringLogicPresent": true,
+        "metadataComplete": true
+      },
+      "issues": [],
+      "overallScore": 10.0,
+      "summary": "All questionnaire components successfully extracted and formatted."
+    }
+  }
+}
\ No newline at end of file
diff --git a/evaluation/pdf2reproschema/old/evaluation/without_hil/result_deepseek_deepseek-chat-v3-0324.json b/evaluation/pdf2reproschema/old/evaluation/without_hil/result_deepseek_deepseek-chat-v3-0324.json
new file mode 100644
index 0000000..c94a410
--- /dev/null
+++ b/evaluation/pdf2reproschema/old/evaluation/without_hil/result_deepseek_deepseek-chat-v3-0324.json
@@ -0,0 +1,155 @@
+{
+  "judged_structured_information": {
+    "judged_terms": {
+      "refined_metadata": {
+        "schemaType": "reproschema:Activity",
+        "schemaVersion": "1.0.0",
+        "activity": {
+          "id": "MFQ-long",
+          "prefLabel": {
+            "en": "MOOD AND FEELINGS QUESTIONNAIRE: Long Version"
+          },
+          "description": {
+            "en": "A 33-item self-report questionnaire assessing depressive symptoms in adults"
+          },
+          "preamble": {
+            "en": "This form is about how you might have been feeling or acting recently.\n\nFor each question, please check (\u2611) how you have been feeling or acting in the past two weeks.\n\nIf a sentence was not true about you, check NOT TRUE.\nIf a sentence was only sometimes true, check SOMETIMES.\nIf a sentence was true about you most of the time, check TRUE."
+          },
+          "citation": {
+            "en": "Copyright Adrian Angold & Elizabeth J. Costello, 1987; Developmental Epidemiology Program; Duke University"
+          }
+        },
+        "items": [
+          {
+            "id": "MFQ_01",
+            "question": {
+              "en": "I felt miserable or unhappy."
+            },
+            "prefLabel": {
+              "en": "Miserable/unhappy"
+            },
+            "ui": {
+              "inputType": "radio"
+            },
+            "valueRequired": true,
+            "responseOptions": {
+              "multipleChoice": false,
+              "choices": [
+                {
+                  "name": {
+                    "en": "NOT TRUE"
+                  },
+                  "value": 0
+                },
+                {
+                  "name": {
+                    "en": "SOMETIMES"
+                  },
+                  "value": 1
+                },
+                {
+                  "name": {
+                    "en": "TRUE"
+                  },
+                  "value": 2
+                }
+              ]
+            },
+            "scoring": "NOT TRUE = 0, SOMETIMES = 1, TRUE = 2"
+          },
+          {
+            "id": "MFQ_02",
+            "question": {
+              "en": "I didn\u2019t enjoy anything at all."
+            },
+            "prefLabel": {
+              "en": "Anhedonia"
+            },
+            "ui": {
+              "inputType": "radio"
+            },
+            "valueRequired": true,
+            "responseOptions": {
+              "multipleChoice": false,
+              "choices": [
+                {
+                  "name": {
+                    "en": "NOT TRUE"
+                  },
+                  "value": 0
+                },
+                {
+                  "name": {
+                    "en": "SOMETIMES"
+                  },
+                  "value": 1
+                },
+                {
+                  "name": {
+                    "en": "TRUE"
+                  },
+                  "value": 2
+                }
+              ]
+            },
+            "scoring": "NOT TRUE = 0, SOMETIMES = 1, TRUE = 2"
+          }
+        ]
+      },
+      "validation": {
+        "completeness": {
+          "allItemsExtracted": false,
+          "itemCount": 2,
+          "missingItems": [
+            "MFQ_03",
+            "MFQ_04",
+            "MFQ_05",
+            "MFQ_06",
+            "MFQ_07",
+            "MFQ_08",
+            "MFQ_09",
+            "MFQ_10",
+            "MFQ_11",
+            "MFQ_12",
+            "MFQ_13",
+            "MFQ_14",
+            "MFQ_15",
+            "MFQ_16",
+            "MFQ_17",
+            "MFQ_18",
+            "MFQ_19",
+            "MFQ_20",
+            "MFQ_21",
+            "MFQ_22",
+            "MFQ_23",
+            "MFQ_24",
+            "MFQ_25",
+            "MFQ_26",
+            "MFQ_27",
+            "MFQ_28",
+            "MFQ_29",
+            "MFQ_30",
+            "MFQ_31",
+            "MFQ_32",
+            "MFQ_33"
+          ]
+        },
+        "accuracy": {
+          "responseOptionsCorrect": true,
+          "scoringLogicPresent": true,
+          "metadataComplete": true
+        },
+        "issues": [
+          "Only 2 out of 33 items were extracted"
+        ],
+        "overallScore": 6.06,
+        "summary": "Metadata structure and formatting is correct, but only 2 items were extracted out of 33."
+      }
+    },
+    "changes_applied": [
+      "Validated that only 2 items were extracted, identified remaining missing 31 items",
+      "Confirmed metadata structure for extracted items is correct",
+      "Added validation feedback about missing items"
+    ]
+  }
+}
\ No newline at end of file
diff --git a/evaluation/pdf2reproschema/old/evaluation/without_hil/result_reproschema_config_claudesonet3.7.json b/evaluation/pdf2reproschema/old/evaluation/without_hil/result_reproschema_config_claudesonet3.7.json
new file mode 100644
index 0000000..af25aa2
--- /dev/null
+++ b/evaluation/pdf2reproschema/old/evaluation/without_hil/result_reproschema_config_claudesonet3.7.json
@@ -0,0 +1,1409 @@
+{
+  "judged_terms": {
+    "refined_metadata": {
+      "schemaType": "reproschema:Activity",
+      "schemaVersion": "1.0.0",
+      "activity": {
+        "id": "MFQ-long",
+        "prefLabel": {
+          "en": "MOOD AND FEELINGS QUESTIONNAIRE: Long Version"
+        },
+        "description": {
+          "en": "Adult Self-Report Mood and Feelings Questionnaire: Long Version, a self-report measure to assess depression symptoms in adults"
+        },
+        "preamble": {
+          "en": "This form is about how you might have been feeling or acting recently. For each question, please check (\u25bc) how you have been feeling or acting in the past two weeks. If a sentence was not true about you, check NOT TRUE. If a sentence was only sometimes true, check SOMETIMES. If a sentence was true about you most of the time, check TRUE."
+        },
+        "citation": {
+          "en": "Copyright Adrian Angold & Elizabeth J. Costello, 1987; Developmental Epidemiology Program; Duke University"
+        }
+      },
+      "items": [
+        {
+          "id": "MFQ_01",
+          "question": {
+            "en": "I felt miserable or unhappy."
+          },
+          "prefLabel": {
+            "en": "Felt miserable"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_02",
+          "question": {
+            "en": "I didn't enjoy anything at all."
+          },
+          "prefLabel": {
+            "en": "No enjoyment"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_03",
+          "question": {
+            "en": "I was less hungry than usual."
+          },
+          "prefLabel": {
+            "en": "Decreased appetite"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_04",
+          "question": {
+            "en": "I ate more than usual."
+          },
+          "prefLabel": {
+            "en": "Increased appetite"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_05",
+          "question": {
+            "en": "I felt so tired I just sat around and did nothing."
+          },
+          "prefLabel": {
+            "en": "Fatigue"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_06",
+          "question": {
+            "en": "I was moving and walking more slowly than usual."
+          },
+          "prefLabel": {
+            "en": "Psychomotor retardation"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_07",
+          "question": {
+            "en": "I was very restless."
+          },
+          "prefLabel": {
+            "en": "Restlessness"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_08",
+          "question": {
+            "en": "I felt I was no good anymore."
+          },
+          "prefLabel": {
+            "en": "Worthlessness"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_09",
+          "question": {
+            "en": "I blamed myself for things that weren't my fault."
+          },
+          "prefLabel": {
+            "en": "Self-blame"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_10",
+          "question": {
+            "en": "It was hard for me to make up my mind."
+          },
+          "prefLabel": {
+            "en": "Indecisiveness"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_11",
+          "question": {
+            "en": "I felt grumpy and cross with other people."
+          },
+          "prefLabel": {
+            "en": "Irritability"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_12",
+          "question": {
+            "en": "I felt like talking less than usual."
+          },
+          "prefLabel": {
+            "en": "Reduced speech"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_13",
+          "question": {
+            "en": "I was talking more slowly than usual."
+          },
+          "prefLabel": {
+            "en": "Slowed speech"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_14",
+          "question": {
+            "en": "I cried a lot."
+          },
+          "prefLabel": {
+            "en": "Crying"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_15",
+          "question": {
+            "en": "I thought there was nothing good for me in the future."
+          },
+          "prefLabel": {
+            "en": "Hopelessness"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_16",
+          "question": {
+            "en": "I thought that life wasn't worth living."
+          },
+          "prefLabel": {
+            "en": "Life not worth living"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_17",
+          "question": {
+            "en": "I thought about death or dying."
+          },
+          "prefLabel": {
+            "en": "Death thoughts"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_18",
+          "question": {
+            "en": "I thought my family would be better off without me."
+          },
+          "prefLabel": {
+            "en": "Family better without me"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_19",
+          "question": {
+            "en": "I thought about killing myself."
+          },
+          "prefLabel": {
+            "en": "Suicidal ideation"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_20",
+          "question": {
+            "en": "I didn't want to see my friends."
+          },
+          "prefLabel": {
+            "en": "Social withdrawal"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_21",
+          "question": {
+            "en": "I found it hard to think properly or concentrate."
+          },
+          "prefLabel": {
+            "en": "Concentration difficulty"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_22",
+          "question": {
+            "en": "I thought bad things would happen to me."
+          },
+          "prefLabel": {
+            "en": "Pessimism"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_23",
+          "question": {
+            "en": "I hated myself."
+          },
+          "prefLabel": {
+            "en": "Self-hatred"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_24",
+          "question": {
+            "en": "I felt I was a bad person."
+          },
+          "prefLabel": {
+            "en": "Feeling bad"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_25",
+          "question": {
+            "en": "I thought I looked ugly."
+          },
+          "prefLabel": {
+            "en": "Poor body image"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_26",
+          "question": {
+            "en": "I worried about aches and pains."
+          },
+          "prefLabel": {
+            "en": "Somatic concerns"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_27",
+          "question": {
+            "en": "I felt lonely."
+          },
+          "prefLabel": {
+            "en": "Loneliness"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_28",
+          "question": {
+            "en": "I thought nobody really loved me."
+          },
+          "prefLabel": {
+            "en": "Feeling unloved"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_29",
+          "question": {
+            "en": "I didn't have any fun in any of my activities."
+          },
+          "prefLabel": {
+            "en": "Anhedonia"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_30",
+          "question": {
+            "en": "I thought I could never be as good as other people."
+          },
+          "prefLabel": {
+            "en": "Inferiority"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_31",
+          "question": {
+            "en": "I did everything wrong."
+          },
+          "prefLabel": {
+            "en": "Feeling wrong"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_32",
+          "question": {
+            "en": "I didn't sleep as well as I usually sleep."
+          },
+          "prefLabel": {
+            "en": "Sleep problems"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        },
+        {
+          "id": "MFQ_33",
+          "question": {
+            "en": "I slept a lot more than usual."
+          },
+          "prefLabel": {
+            "en": "Hypersomnia"
+          },
+          "ui": {
+            "inputType": "radio"
+          },
+          "valueRequired": true,
+          "responseOptions": {
+            "multipleChoice": false,
+            "choices": [
+              {
+                "name": {
+                  "en": "NOT TRUE"
+                },
+                "value": 0
+              },
+              {
+                "name": {
+                  "en": "SOMETIMES"
+                },
+                "value": 1
+              },
+              {
+                "name": {
+                  "en": "TRUE"
+                },
+                "value": 2
+              }
+            ]
+          }
+        }
+      ],
+      "ui": {
+        "order": [
+          "MFQ_01",
+          "MFQ_02",
+          "MFQ_03",
+          "MFQ_04",
+          "MFQ_05",
+          "MFQ_06",
+          "MFQ_07",
+          "MFQ_08",
+          "MFQ_09",
+          "MFQ_10",
+          "MFQ_11",
+          "MFQ_12",
+          "MFQ_13",
+          "MFQ_14",
+          "MFQ_15",
+          "MFQ_16",
+          "MFQ_17",
+          "MFQ_18",
+          "MFQ_19",
+          "MFQ_20",
+          "MFQ_21",
+          "MFQ_22",
+          "MFQ_23",
+          "MFQ_24",
+          "MFQ_25",
+          "MFQ_26",
+          "MFQ_27",
+          "MFQ_28",
+          "MFQ_29",
+          "MFQ_30",
+          "MFQ_31",
+          "MFQ_32",
+          "MFQ_33"
+        ],
+        "shuffle": false,
+        "addProperties": [
+          {
+            "variableName": "MFQ_01",
+            "isAbout": "MFQ_01"
+          },
+          {
+            "variableName": "MFQ_02",
+            "isAbout": "MFQ_02"
+          },
+          {
+            "variableName": "MFQ_03",
+            "isAbout": "MFQ_03"
+          },
+          {
+            "variableName": "MFQ_04",
+            "isAbout": "MFQ_04"
+          },
+          {
+            "variableName": "MFQ_05",
+            "isAbout": "MFQ_05"
+          },
+          {
+            "variableName": "MFQ_06",
+            "isAbout": "MFQ_06"
+          },
+          {
+            "variableName": "MFQ_07",
+            "isAbout": "MFQ_07"
+          },
+          {
+            "variableName": "MFQ_08",
+            "isAbout": "MFQ_08"
+          },
+          {
+            "variableName": "MFQ_09",
+            "isAbout": "MFQ_09"
+          },
+          {
+            "variableName": "MFQ_10",
+            "isAbout": "MFQ_10"
+          },
+          {
+            "variableName": "MFQ_11",
+            "isAbout": "MFQ_11"
+          },
+          {
+            "variableName": "MFQ_12",
+            "isAbout": "MFQ_12"
+          },
+          {
+            "variableName": "MFQ_13",
+            "isAbout": "MFQ_13"
+          },
+          {
+            "variableName": "MFQ_14",
+            "isAbout": "MFQ_14"
+          },
+          {
+            "variableName": "MFQ_15",
+            "isAbout": "MFQ_15"
+          },
+          {
+            "variableName": "MFQ_16",
+            "isAbout": "MFQ_16"
+          },
+          {
+            "variableName": "MFQ_17",
+            "isAbout": "MFQ_17"
+          },
+          {
+            "variableName": "MFQ_18",
+            "isAbout": "MFQ_18"
+          },
+          {
+            "variableName": "MFQ_19",
+            "isAbout": "MFQ_19"
+          },
+          {
+            "variableName": "MFQ_20",
+            "isAbout": "MFQ_20"
+          },
+          {
+            "variableName": "MFQ_21",
+            "isAbout": "MFQ_21"
+          },
+          {
+            "variableName": "MFQ_22",
+            "isAbout": "MFQ_22"
+          },
+          {
+            "variableName": "MFQ_23",
+            "isAbout": "MFQ_23"
+          },
+          {
+            "variableName": "MFQ_24",
+            "isAbout": "MFQ_24"
+          },
+          {
+            "variableName": "MFQ_25",
+            "isAbout": "MFQ_25"
+          },
+          {
+            "variableName": "MFQ_26",
+            "isAbout": "MFQ_26"
+          },
+          {
+            "variableName": "MFQ_27",
+            "isAbout": "MFQ_27"
+          },
+          {
+            "variableName": "MFQ_28",
+            "isAbout": "MFQ_28"
+          },
+          {
+            "variableName": "MFQ_29",
+            "isAbout": "MFQ_29"
+          },
+          {
+            "variableName": "MFQ_30",
+            "isAbout": "MFQ_30"
+          },
+          {
+            "variableName": "MFQ_31",
+            "isAbout": "MFQ_31"
+          },
+          {
+            "variableName": "MFQ_32",
+            "isAbout": "MFQ_32"
+          },
+          {
+            "variableName": "MFQ_33",
+            "isAbout": "MFQ_33"
+          }
+        ]
+      },
+      "compute": [
+        {
+          "variableName": "MFQ_total",
+          "jsExpression": "MFQ_01 + MFQ_02 + MFQ_03 + MFQ_04 + MFQ_05 + MFQ_06 + MFQ_07 + MFQ_08 + MFQ_09 + MFQ_10 + MFQ_11 + MFQ_12 + MFQ_13 + MFQ_14 + MFQ_15 + MFQ_16 + MFQ_17 + MFQ_18 + MFQ_19 + MFQ_20 + MFQ_21 + MFQ_22 + MFQ_23 + MFQ_24 + MFQ_25 + MFQ_26 + MFQ_27 + MFQ_28 + MFQ_29 + MFQ_30 + MFQ_31 + MFQ_32 + MFQ_33",
+          "description": {
+            "en": "MFQ Total Score"
+          }
+        }
+      ]
+    },
+    "validation": {
+      "completeness": {
+        "allItemsExtracted": true,
+        "itemCount": 33,
+        "missingItems": []
+      },
+      "accuracy": {
+        "responseOptionsCorrect": true,
+        "scoringLogicPresent": true,
+        "metadataComplete": true
+      },
+      "issues": [],
+      "overallScore": 10.0,
+      "summary": "All questionnaire components successfully extracted and formatted. The MFQ-Long form contains 33 questions with consistent response options (NOT TRUE=0, SOMETIMES=1, TRUE=2). The schema includes complete metadata, proper item formatting, and correct scoring calculation."
+    }
+  }
+}
\ No newline at end of file
diff --git a/evaluation/pdf2reproschema/old/reproschema_config_claudesonet.yaml b/evaluation/pdf2reproschema/old/reproschema_config_claudesonet.yaml
new file mode 100644
index 0000000..a64f5e3
--- /dev/null
+++ b/evaluation/pdf2reproschema/old/reproschema_config_claudesonet.yaml
@@ -0,0 +1,379 @@
+#agent config
+# Do not introduce any new variable name
+# the variables inside {} receives data from the previous agent. the {literature} variable is the one that passes the
+# initial input.
+agent_config:
+  extractor_agent:
+    role: >
+      Questionnaire metadata extraction specialist
+    goal: >
+      Extract all questionnaire components from the given PDF including activity metadata (title, description, preamble), 
+      individual items (questions, response options, input types), and scoring logic in a structured format 
+      suitable for ReproSchema conversion. Do not make up components. Make sure you extract all related components from each question.
+    backstory: >
+      You are an expert at parsing questionnaires and surveys, identifying the hierarchical structure of 
+      assessments. You extract metadata that maps to ReproSchema concepts: activities (questionnaires), 
+      items (questions), and response constraints.
+    llm:
+      model: openrouter/anthropic/claude-3.7-sonnet
+      base_url: https://openrouter.ai/api/v1
+      temperature: 0.9
+      
+
+  alignment_agent:
+    role: >
+      ReproSchema metadata formatter
+    goal: >
+      Transform extracted questionnaire data into a structured JSON format containing all necessary metadata 
+      for ReproSchema conversion, ensuring completeness and proper organization of activity and item information.
+    backstory: >
+      You specialize in organizing questionnaire metadata into clean, structured formats. You understand 
+      ReproSchema requirements and ensure all extracted information is properly categorized for items, 
+      activities, response options, and scoring logic.
+    llm:
+      model: openrouter/anthropic/claude-3.7-sonnet
+      base_url: https://openrouter.ai/api/v1
+      temperature: 0.9
+
+  judge_agent:
+    role: >
+      Metadata completeness validator
+    goal: >
+      Validate that all questionnaire components have been accurately extracted and formatted, ensuring no 
+      questions, response options, or metadata are missing from the structured output.
+    backstory: >
+      You are a quality assurance specialist who verifies extraction completeness. You cross-reference the 
+      structured output against the original PDF content to ensure all items, response scales, and activity 
+      metadata are captured accurately.
+    llm:
+      model: openrouter/anthropic/claude-3.7-sonnet
+      base_url: https://openrouter.ai/api/v1
+      temperature: 0.9
+
+  humanfeedback_agent:
+    role: >
+      Metadata refinement specialist
+    goal: >
+      Incorporate human feedback to correct extraction errors, clarify ambiguous items, and ensure the 
+      structured metadata accurately represents the original questionnaire.
+    backstory: >
+      You collaborate with human reviewers to refine extracted metadata, fixing any misinterpretations 
+      and ensuring the output will produce valid ReproSchema when converted.
+    llm:
+      model: openrouter/anthropic/claude-3.7-sonnet
+      base_url: https://openrouter.ai/api/v1
+      temperature: 0.9
+
+# agent task config
+task_config:
+  extraction_task:
+    description: >
+      Extract all questionnaire components from the given PDF for ReproSchema conversion.
+      
+      Input: {literature}
+      
+      Extract the following metadata:
+      
+      1. Activity-level metadata:
+         - id: Short identifier for the questionnaire using the first letter of the questionnaire title but ignore words such as "and" (e.g., "MOOD AND FEELINGS QUESTIONNAIRE: Long Version" will be "MFQ-long" )
+         - prefLabel: Display name of the questionnaire
+         - description: Full description of the assessment
+         - preamble: Instructions or introductory text if any
+         - citation: Source reference if available
+      
+      2. For each item/question:
+         - id: Unique identifier (e.g., "Q1", "Q2")
+         - question: Full question text
+         - prefLabel: Short display label
+         - inputType: Type of input (radio, text, number, etc.)
+         - valueRequired: Whether response is mandatory
+         - responseOptions: List of choices with value and name
+         - scoring: How responses map to scores
+      
+      3. Additional metadata:
+         - computedScores: Any total scores or subscales with calculation formulas
+         - conditionalLogic: Skip patterns or branching rules
+         - languages: Available languages
+         - order: Sequence of items
+   
+
+    expected_output: >
+      output format: json
+      Example output: "extracted_terms":{
+        "activity": {
+          "id": "PHQ9",
+          "prefLabel": "Patient Health Questionnaire-9",
+          "description": "A 9-item depression screening tool",
+          "preamble": "Over the last 2 weeks, how often have you been bothered by the following problems?",
+          "citation": "Kroenke et al., 2001"
+        },
+        "items": [
+          {
+            "id": "PHQ9_01",
+            "question": "Little interest or pleasure in doing things",
+            "prefLabel": "PHQ9 Q1",
+            "inputType": "radio",
+            "valueRequired": true,
+            "responseOptions": [
+              {"value": 0, "name": "Not at all"},
+              {"value": 1, "name": "Several days"},
+              {"value": 2, "name": "More than half the days"},
+              {"value": 3, "name": "Nearly every day"}
+            ]
+          }
+        ],
+        "computedScores": [
+          {
+            "variableName": "PHQ9_total",
+            "label": "PHQ-9 Total Score",
+            "jsExpression": "PHQ9_01 + PHQ9_02 + ... + PHQ9_09"
+          }
+        ],
+        "order": ["PHQ9_01", "PHQ9_02", "..."]
+      }
+
+    # do not chage this, remove it later
+    agent_id: extractor_agent
+
+  alignment_task:
+    description: > 
+      Inputs: {extracted_structured_information}
+      
+      Instructions:
+      - Format the extracted metadata into a comprehensive JSON structure for ReproSchema conversion
+      - Organize all metadata with proper structure and relationships
+      - Structure items with complete properties including UI configuration
+      - Format response options with choices array containing name and value
+      - Include computed scores with proper JavaScript expressions
+      - Add UI ordering and configuration
+      - Ensure all fields use appropriate data types and structures
+       
+
+    expected_output: >
+      output format: json
+      Example output: "aligned_terms":{
+        "schemaType": "reproschema:Activity",
+        "schemaVersion": "1.0.0",
+        "activity": {
+          "id": "ACE_schema",
+          "prefLabel": {"en": "Adverse Childhood Experiences"},
+          "description": {"en": "10-item questionnaire about childhood experiences"},
+          "preamble": {"en": "Prior to your 18th birthday:"},
+          "citation": {"en": "https://www.cdc.gov/violenceprevention/aces/"}
+        },
+        "items": [
+          {
+            "id": "ACE_01",
+            "question": {"en": "Did a parent or other adult in the household often..."},
+            "prefLabel": {"en": "ACE Q1"},
+            "ui": {
+              "inputType": "radio"
+            },
+            "valueRequired": true,
+            "responseOptions": {
+              "multipleChoice": false,
+              "choices": [
+                {"name": {"en": "No"}, "value": 0},
+                {"name": {"en": "Yes"}, "value": 1}
+              ]
+            }
+          }
+        ],
+        "ui": {
+          "order": ["ACE_01", "ACE_02"],
+          "shuffle": false
+        },
+        "compute": [
+          {
+            "variableName": "ACE_total_score",
+            "jsExpression": "ACE_01 + ACE_02 + ..."
+          }
+        ]
+      }
+
+    # do not chage this, remove it later
+    agent_id: alignment_agent
+
+  judge_task:
+    description: >
+      {aligned_structured_information} 
+         
+      Instructions: 
+      - Validate that all questions from the original PDF are captured in the structured output
+      - Check that response options match exactly with the source
+      - Verify activity metadata (title, description, preamble) is complete and accurate
+      - Ensure item properties (question text, input type, required status) are correct
+      - Confirm scoring logic and computed scores are properly represented
+      - Identify any missing, incomplete, or misrepresented information
+      - Provide a completeness score and detailed feedback
+    
+      Important: "judged_terms" should also include the output from previous agents
+
+    expected_output: > 
+      output format: json 
+      Example output: "judged_terms":{
+      "refined_metadata":{
+              "schemaType": "reproschema:Activity",
+              "schemaVersion": "1.0.0",
+              "activity": {
+                "id": "ACE_schema",
+                "prefLabel": {"en": "Adverse Childhood Experiences"},
+                "description": {"en": "10-item questionnaire about childhood experiences"},
+                "preamble": {"en": "Prior to your 18th birthday:"},
+                "citation": {"en": "https://www.cdc.gov/violenceprevention/aces/"}
+              },
+              "items": [
+                {
+                  "id": "ACE_01",
+                  "question": {"en": "Did a parent or other adult in the household often..."},
+                  "prefLabel": {"en": "ACE Q1"},
+                  "ui": {
+                    "inputType": "radio"
+                  },
+                  "valueRequired": true,
+                  "responseOptions": {
+                    "multipleChoice": false,
+                    "choices": [
+                      {"name": {"en": "No"}, "value": 0},
+                      {"name": {"en": "Yes"}, "value": 1}
+                    ]
+                  }
+                }
+              ],
+              "ui": {
+                "order": ["ACE_01", "ACE_02"],
+                "shuffle": false
+              },
+              "compute": [
+                {
+                  "variableName": "ACE_total_score",
+                  "jsExpression": "ACE_01 + ACE_02 + ..."
+                }
+              ]
+            },
+        "validation": {
+          "completeness": {
+            "allItemsExtracted": true,
+            "itemCount": 10,
+            "missingItems": []
+          },
+          "accuracy": {
+            "responseOptionsCorrect": true,
+            "scoringLogicPresent": true,
+            "metadataComplete": true
+          },
+          "issues": [],
+          "overallScore": 10.0,
+          "summary": "All questionnaire components successfully extracted and formatted."
+        }
+      }
+
+    # do not chage this, remove it later
+    agent_id: judge_agent
+
+  humanfeedback_task:
+    description: >
+      Input: {judged_structured_information_with_human_feedback}
+
+      modification_context: 
+        {modification_context}
+      
+      user_feedback_text:
+        {user_feedback_text}
+      
+      Instructions:
+      - Apply human feedback to refine the extracted metadata
+      - Correct any extraction errors identified by the reviewer
+      - Clarify ambiguous items or response options
+      - Add any missing metadata or properties
+      - Improve formatting and structure based on feedback
+      - Ensure the refined output maintains ReproSchema compatibility
+      - Document all changes made based on feedback
+      
+      
+  
+
+    expected_output: > 
+      output format: json
+      Example output: "judged_terms":{
+         "refined_metadata":{
+              "schemaType": "reproschema:Activity",
+              "schemaVersion": "1.0.0",
+              "activity": {
+                "id": "ACE_schema",
+                "prefLabel": {"en": "Adverse Childhood Experiences"},
+                "description": {"en": "10-item questionnaire about childhood experiences"},
+                "preamble": {"en": "Prior to your 18th birthday:"},
+                "citation": {"en": "https://www.cdc.gov/violenceprevention/aces/"}
+              },
+              "items": [
+                {
+                  "id": "ACE_01",
+                  "question": {"en": "Did a parent or other adult in the household often..."},
+                  "prefLabel": {"en": "ACE Q1"},
+                  "ui": {
+                    "inputType": "radio"
+                  },
+                  "valueRequired": true,
+                  "responseOptions": {
+                    "multipleChoice": false,
+                    "choices": [
+                      {"name": {"en": "No"}, "value": 0},
+                      {"name": {"en": "Yes"}, "value": 1}
+                    ]
+                  }
+                }
+              ],
+              "ui": {
+                "order": ["ACE_01", "ACE_02"],
+                "shuffle": false
+              },
+              "compute": [
+                {
+                  "variableName": "ACE_total_score",
+                  "jsExpression": "ACE_01 + ACE_02 + ..."
+                }
+              ]
+            },
+        "validation": {
+          "completeness": {
+            "allItemsExtracted": true,
+            "itemCount": 10,
+            "missingItems": []
+          },
+          "accuracy": {
+            "responseOptionsCorrect": true,
+            "scoringLogicPresent": true,
+            "metadataComplete": true
+          },
+          "issues": [],
+          "overallScore": 10.0,
+          "summary": "All questionnaire components successfully extracted and formatted."
+        }
+      },
+        "changes_applied": [
+          "Corrected questionnaire title to include '(ACE)' abbreviation",
+          "Updated citation to original authors",
+          "Fixed response option text for item 3"
+        ]
+      }
+
+    agent_id: humanfeedback_agent
+
+# embedding config
+# see for more details and parameters for config
+# https://docs.crewai.com/concepts/memory#additional-embedding-providerscl
+embedder_config:
+  provider: ollama
+  config:
+    api_base: http://localhost:11434
+    model: nomic-embed-text:v1.5
+
+# knowledge search config
+knowledge_config:
+  search_key: #local vector database
+    - entity
+    - label
+# human in loop config
+human_in_loop_config:
+  humanfeedback_agent: true
diff --git a/evaluation/pdf2reproschema/old/reproschema_config_deepseek.yaml b/evaluation/pdf2reproschema/old/reproschema_config_deepseek.yaml
new file mode 100644
index 0000000..25f717d
--- /dev/null
+++ b/evaluation/pdf2reproschema/old/reproschema_config_deepseek.yaml
@@ -0,0 +1,379 @@
+#agent config
+# Do not introduce any new variable name
+# the variables inside {} receives data from the previous agent. the {literature} variable is the one that passes the
+# initial input.
+agent_config:
+  extractor_agent:
+    role: >
+      Questionnaire metadata extraction specialist
+    goal: >
+      Extract all questionnaire components from the given PDF including activity metadata (title, description, preamble), 
+      individual items (questions, response options, input types), and scoring logic in a structured format 
+      suitable for ReproSchema conversion. Do not make up components. Make sure you extract all related components from each question.
+    backstory: >
+      You are an expert at parsing questionnaires and surveys, identifying the hierarchical structure of 
+      assessments. You extract metadata that maps to ReproSchema concepts: activities (questionnaires), 
+      items (questions), and response constraints.
+    llm:
+      model: openrouter/deepseek/deepseek-chat-v3-0324
+      base_url: https://openrouter.ai/api/v1
+      temperature: 0.9
+      
+
+  alignment_agent:
+    role: >
+      ReproSchema metadata formatter
+    goal: >
+      Transform extracted questionnaire data into a structured JSON format containing all necessary metadata 
+      for ReproSchema conversion, ensuring completeness and proper organization of activity and item information.
+    backstory: >
+      You specialize in organizing questionnaire metadata into clean, structured formats. You understand 
+      ReproSchema requirements and ensure all extracted information is properly categorized for items, 
+      activities, response options, and scoring logic.
+    llm:
+      model: openrouter/deepseek/deepseek-chat-v3-0324
+      base_url: https://openrouter.ai/api/v1
+      temperature: 0.9
+
+  judge_agent:
+    role: >
+      Metadata completeness validator
+    goal: >
+      Validate that all questionnaire components have been accurately extracted and formatted, ensuring no 
+      questions, response options, or metadata are missing from the structured output.
+    backstory: >
+      You are a quality assurance specialist who verifies extraction completeness. You cross-reference the 
+      structured output against the original PDF content to ensure all items, response scales, and activity 
+      metadata are captured accurately.
+    llm:
+      model: openrouter/deepseek/deepseek-chat-v3-0324
+      base_url: https://openrouter.ai/api/v1
+      temperature: 0.9
+
+  humanfeedback_agent:
+    role: >
+      Metadata refinement specialist
+    goal: >
+      Incorporate human feedback to correct extraction errors, clarify ambiguous items, and ensure the 
+      structured metadata accurately represents the original questionnaire.
+    backstory: >
+      You collaborate with human reviewers to refine extracted metadata, fixing any misinterpretations 
+      and ensuring the output will produce valid ReproSchema when converted.
+    llm:
+      model: openrouter/deepseek/deepseek-chat-v3-0324
+      base_url: https://openrouter.ai/api/v1
+      temperature: 0.9
+
+# agent task config
+task_config:
+  extraction_task:
+    description: >
+      Extract all questionnaire components from the given PDF for ReproSchema conversion.
+      
+      Input: {literature}
+      
+      Extract the following metadata:
+      
+      1. Activity-level metadata:
+         - id: Short identifier for the questionnaire using the first letter of the questionnaire title but ignore words such as "and" (e.g., "MOOD AND FEELINGS QUESTIONNAIRE: Long Version" will be "MFQ-long" )
+         - prefLabel: Display name of the questionnaire
+         - description: Full description of the assessment
+         - preamble: Instructions or introductory text if any
+         - citation: Source reference if available
+      
+      2. For each item/question:
+         - id: Unique identifier (e.g., "Q1", "Q2")
+         - question: Full question text
+         - prefLabel: Short display label
+         - inputType: Type of input (radio, text, number, etc.)
+         - valueRequired: Whether response is mandatory
+         - responseOptions: List of choices with value and name
+         - scoring: How responses map to scores
+      
+      3. Additional metadata:
+         - computedScores: Any total scores or subscales with calculation formulas
+         - conditionalLogic: Skip patterns or branching rules
+         - languages: Available languages
+         - order: Sequence of items
+   
+
+    expected_output: >
+      output format: json
+      Example output: "extracted_terms":{
+        "activity": {
+          "id": "PHQ9",
+          "prefLabel": "Patient Health Questionnaire-9",
+          "description": "A 9-item depression screening tool",
+          "preamble": "Over the last 2 weeks, how often have you been bothered by the following problems?",
+          "citation": "Kroenke et al., 2001"
+        },
+        "items": [
+          {
+            "id": "PHQ9_01",
+            "question": "Little interest or pleasure in doing things",
+            "prefLabel": "PHQ9 Q1",
+            "inputType": "radio",
+            "valueRequired": true,
+            "responseOptions": [
+              {"value": 0, "name": "Not at all"},
+              {"value": 1, "name": "Several days"},
+              {"value": 2, "name": "More than half the days"},
+              {"value": 3, "name": "Nearly every day"}
+            ]
+          }
+        ],
+        "computedScores": [
+          {
+            "variableName": "PHQ9_total",
+            "label": "PHQ-9 Total Score",
+            "jsExpression": "PHQ9_01 + PHQ9_02 + ... + PHQ9_09"
+          }
+        ],
+        "order": ["PHQ9_01", "PHQ9_02", "..."]
+      }
+
+    # do not chage this, remove it later
+    agent_id: extractor_agent
+
+  alignment_task:
+    description: > 
+      Inputs: {extracted_structured_information}
+      
+      Instructions:
+      - Format the extracted metadata into a comprehensive JSON structure for ReproSchema conversion
+      - Organize all metadata with proper structure and relationships
+      - Structure items with complete properties including UI configuration
+      - Format response options with choices array containing name and value
+      - Include computed scores with proper JavaScript expressions
+      - Add UI ordering and configuration
+      - Ensure all fields use appropriate data types and structures
+       
+
+    expected_output: >
+      output format: json
+      Example output: "aligned_terms":{
+        "schemaType": "reproschema:Activity",
+        "schemaVersion": "1.0.0",
+        "activity": {
+          "id": "ACE_schema",
+          "prefLabel": {"en": "Adverse Childhood Experiences"},
+          "description": {"en": "10-item questionnaire about childhood experiences"},
+          "preamble": {"en": "Prior to your 18th birthday:"},
+          "citation": {"en": "https://www.cdc.gov/violenceprevention/aces/"}
+        },
+        "items": [
+          {
+            "id": "ACE_01",
+            "question": {"en": "Did a parent or other adult in the household often..."},
+            "prefLabel": {"en": "ACE Q1"},
+            "ui": {
+              "inputType": "radio"
+            },
+            "valueRequired": true,
+            "responseOptions": {
+              "multipleChoice": false,
+              "choices": [
+                {"name": {"en": "No"}, "value": 0},
+                {"name": {"en": "Yes"}, "value": 1}
+              ]
+            }
+          }
+        ],
+        "ui": {
+          "order": ["ACE_01", "ACE_02"],
+          "shuffle": false
+        },
+        "compute": [
+          {
+            "variableName": "ACE_total_score",
+            "jsExpression": "ACE_01 + ACE_02 + ..."
+          }
+        ]
+      }
+
+    # do not chage this, remove it later
+    agent_id: alignment_agent
+
+  judge_task:
+    description: >
+      {aligned_structured_information} 
+         
+      Instructions: 
+      - Validate that all questions from the original PDF are captured in the structured output
+      - Check that response options match exactly with the source
+      - Verify activity metadata (title, description, preamble) is complete and accurate
+      - Ensure item properties (question text, input type, required status) are correct
+      - Confirm scoring logic and computed scores are properly represented
+      - Identify any missing, incomplete, or misrepresented information
+      - Provide a completeness score and detailed feedback
+    
+      Important: "judged_terms" should also include the output from previous agents
+
+    expected_output: > 
+      output format: json 
+      Example output: "judged_terms":{
+      "refined_metadata":{
+              "schemaType": "reproschema:Activity",
+              "schemaVersion": "1.0.0",
+              "activity": {
+                "id": "ACE_schema",
+                "prefLabel": {"en": "Adverse Childhood Experiences"},
+                "description": {"en": "10-item questionnaire about childhood experiences"},
+                "preamble": {"en": "Prior to your 18th birthday:"},
+                "citation": {"en": "https://www.cdc.gov/violenceprevention/aces/"}
+              },
+              "items": [
+                {
+                  "id": "ACE_01",
+                  "question": {"en": "Did a parent or other adult in the household often..."},
+                  "prefLabel": {"en": "ACE Q1"},
+                  "ui": {
+                    "inputType": "radio"
+                  },
+                  "valueRequired": true,
+                  "responseOptions": {
+                    "multipleChoice": false,
+                    "choices": [
+                      {"name": {"en": "No"}, "value": 0},
+                      {"name": {"en": "Yes"}, "value": 1}
+                    ]
+                  }
+                }
+              ],
+              "ui": {
+                "order": ["ACE_01", "ACE_02"],
+                "shuffle": false
+              },
+              "compute": [
+                {
+                  "variableName": "ACE_total_score",
+                  "jsExpression": "ACE_01 + ACE_02 + ..."
+                }
+              ]
+            },
+        "validation": {
+          "completeness": {
+            "allItemsExtracted": true,
+            "itemCount": 10,
+            "missingItems": []
+          },
+          "accuracy": {
+            "responseOptionsCorrect": true,
+            "scoringLogicPresent": true,
+            "metadataComplete": true
+          },
+          "issues": [],
+          "overallScore": 10.0,
+          "summary": "All questionnaire components successfully extracted and formatted."
+        }
+      }
+
+    # do not chage this, remove it later
+    agent_id: judge_agent
+
+  humanfeedback_task:
+    description: >
+      Input: {judged_structured_information_with_human_feedback}
+
+      modification_context: 
+        {modification_context}
+      
+      user_feedback_text:
+        {user_feedback_text}
+      
+      Instructions:
+      - Apply human feedback to refine the extracted metadata
+      - Correct any extraction errors identified by the reviewer
+      - Clarify ambiguous items or response options
+      - Add any missing metadata or properties
+      - Improve formatting and structure based on feedback
+      - Ensure the refined output maintains ReproSchema compatibility
+      - Document all changes made based on feedback
+      
+      
+  
+
+    expected_output: > 
+      output format: json
+      Example output: "judged_terms":{
+         "refined_metadata":{
+              "schemaType": "reproschema:Activity",
+              "schemaVersion": "1.0.0",
+              "activity": {
+                "id": "ACE_schema",
+                "prefLabel": {"en": "Adverse Childhood Experiences"},
+                "description": {"en": "10-item questionnaire about childhood experiences"},
+                "preamble": {"en": "Prior to your 18th birthday:"},
+                "citation": {"en": "https://www.cdc.gov/violenceprevention/aces/"}
+              },
+              "items": [
+                {
+                  "id": "ACE_01",
+                  "question": {"en": "Did a parent or other adult in the household often..."},
+                  "prefLabel": {"en": "ACE Q1"},
+                  "ui": {
+                    "inputType": "radio"
+                  },
+                  "valueRequired": true,
+                  "responseOptions": {
+                    "multipleChoice": false,
+                    "choices": [
+                      {"name": {"en": "No"}, "value": 0},
+                      {"name": {"en": "Yes"}, "value": 1}
+                    ]
+                  }
+                }
+              ],
+              "ui": {
+                "order": ["ACE_01", "ACE_02"],
+                "shuffle": false
+              },
+              "compute": [
+                {
+                  "variableName": "ACE_total_score",
+                  "jsExpression": "ACE_01 + ACE_02 + ..."
+                }
+              ]
+            },
+        "validation": {
+          "completeness": {
+            "allItemsExtracted": true,
+            "itemCount": 10,
+            "missingItems": []
+          },
+          "accuracy": {
+            "responseOptionsCorrect": true,
+            "scoringLogicPresent": true,
+            "metadataComplete": true
+          },
+          "issues": [],
+          "overallScore": 10.0,
+          "summary": "All questionnaire components successfully extracted and formatted."
+        }
+      },
+        "changes_applied": [
+          "Corrected questionnaire title to include '(ACE)' abbreviation",
+          "Updated citation to original authors",
+          "Fixed response option text for item 3"
+        ]
+      }
+
+    agent_id: humanfeedback_agent
+
+# embedding config
+# see for more details and parameters for config
+# https://docs.crewai.com/concepts/memory#additional-embedding-providerscl
+embedder_config:
+  provider: ollama
+  config:
+    api_base: http://localhost:11434
+    model: nomic-embed-text:v1.5
+
+# knowledge search config
+knowledge_config:
+  search_key: #local vector database
+    - entity
+    - label
+# human in loop config
+human_in_loop_config:
+  humanfeedback_agent: true
diff --git a/evaluation/pdf2reproschema/old/reproschema_config_gpt.yaml b/evaluation/pdf2reproschema/old/reproschema_config_gpt.yaml
new file mode 100644
index 0000000..127db53
--- /dev/null
+++ b/evaluation/pdf2reproschema/old/reproschema_config_gpt.yaml
@@ -0,0 +1,379 @@
+#agent config
+# Do not introduce any new variable name
+# the variables inside {} receives data from the previous agent. the {literature} variable is the one that passes the
+# initial input.
+agent_config:
+  extractor_agent:
+    role: >
+      Questionnaire metadata extraction specialist
+    goal: >
+      Extract all questionnaire components from the given PDF including activity metadata (title, description, preamble), 
+      individual items (questions, response options, input types), and scoring logic in a structured format 
+      suitable for ReproSchema conversion. Do not make up components. Make sure you extract all related components from each question.
+    backstory: >
+      You are an expert at parsing questionnaires and surveys, identifying the hierarchical structure of 
+      assessments. You extract metadata that maps to ReproSchema concepts: activities (questionnaires), 
+      items (questions), and response constraints.
+    llm:
+      model: openrouter/openai/gpt-4o-mini
+      base_url: https://openrouter.ai/api/v1
+      temperature: 0.9
+      
+
+  alignment_agent:
+    role: >
+      ReproSchema metadata formatter
+    goal: >
+      Transform extracted questionnaire data into a structured JSON format containing all necessary metadata 
+      for ReproSchema conversion, ensuring completeness and proper organization of activity and item information.
+    backstory: >
+      You specialize in organizing questionnaire metadata into clean, structured formats. You understand 
+      ReproSchema requirements and ensure all extracted information is properly categorized for items, 
+      activities, response options, and scoring logic.
+    llm:
+      model: openrouter/openai/gpt-4o-mini
+      base_url: https://openrouter.ai/api/v1
+      temperature: 0.9
+
+  judge_agent:
+    role: >
+      Metadata completeness validator
+    goal: >
+      Validate that all questionnaire components have been accurately extracted and formatted, ensuring no 
+      questions, response options, or metadata are missing from the structured output.
+    backstory: >
+      You are a quality assurance specialist who verifies extraction completeness. You cross-reference the 
+      structured output against the original PDF content to ensure all items, response scales, and activity 
+      metadata are captured accurately.
+    llm:
+      model: openrouter/openai/gpt-4o-mini
+      base_url: https://openrouter.ai/api/v1
+      temperature: 0.9
+
+  humanfeedback_agent:
+    role: >
+      Metadata refinement specialist
+    goal: >
+      Incorporate human feedback to correct extraction errors, clarify ambiguous items, and ensure the 
+      structured metadata accurately represents the original questionnaire.
+    backstory: >
+      You collaborate with human reviewers to refine extracted metadata, fixing any misinterpretations 
+      and ensuring the output will produce valid ReproSchema when converted.
+    llm:
+      model: openrouter/openai/gpt-4o-mini
+      base_url: https://openrouter.ai/api/v1
+      temperature: 0.9
+
+# agent task config
+task_config:
+  extraction_task:
+    description: >
+      Extract all questionnaire components from the given PDF for ReproSchema conversion.
+      
+      Input: {literature}
+      
+      Extract the following metadata:
+      
+      1. Activity-level metadata:
+         - id: Short identifier for the questionnaire using the first letter of the questionnaire title but ignore words such as "and" (e.g., "MOOD AND FEELINGS QUESTIONNAIRE: Long Version" will be "MFQ-long" )
+         - prefLabel: Display name of the questionnaire
+         - description: Full description of the assessment
+         - preamble: Instructions or introductory text if any
+         - citation: Source reference if available
+      
+      2. For each item/question:
+         - id: Unique identifier (e.g., "Q1", "Q2")
+         - question: Full question text
+         - prefLabel: Short display label
+         - inputType: Type of input (radio, text, number, etc.)
+         - valueRequired: Whether response is mandatory
+         - responseOptions: List of choices with value and name
+         - scoring: How responses map to scores
+      
+      3. Additional metadata:
+         - computedScores: Any total scores or subscales with calculation formulas
+         - conditionalLogic: Skip patterns or branching rules
+         - languages: Available languages
+         - order: Sequence of items
+   
+
+    expected_output: >
+      output format: json
+      Example output: "extracted_terms":{
+        "activity": {
+          "id": "PHQ9",
+          "prefLabel": "Patient Health Questionnaire-9",
+          "description": "A 9-item depression screening tool",
+          "preamble": "Over the last 2 weeks, how often have you been bothered by the following problems?",
+          "citation": "Kroenke et al., 2001"
+        },
+        "items": [
+          {
+            "id": "PHQ9_01",
+            "question": "Little interest or pleasure in doing things",
+            "prefLabel": "PHQ9 Q1",
+            "inputType": "radio",
+            "valueRequired": true,
+            "responseOptions": [
+              {"value": 0, "name": "Not at all"},
+              {"value": 1, "name": "Several days"},
+              {"value": 2, "name": "More than half the days"},
+              {"value": 3, "name": "Nearly every day"}
+            ]
+          }
+        ],
+        "computedScores": [
+          {
+            "variableName": "PHQ9_total",
+            "label": "PHQ-9 Total Score",
+            "jsExpression": "PHQ9_01 + PHQ9_02 + ... + PHQ9_09"
+          }
+        ],
+        "order": ["PHQ9_01", "PHQ9_02", "..."]
+      }
+
+    # do not chage this, remove it later
+    agent_id: extractor_agent
+
+  alignment_task:
+    description: > 
+      Inputs: {extracted_structured_information}
+      
+      Instructions:
+      - Format the extracted metadata into a comprehensive JSON structure for ReproSchema conversion
+      - Organize all metadata with proper structure and relationships
+      - Structure items with complete properties including UI configuration
+      - Format response options with choices array containing name and value
+      - Include computed scores with proper JavaScript expressions
+      - Add UI ordering and configuration
+      - Ensure all fields use appropriate data types and structures
+       
+
+    expected_output: >
+      output format: json
+      Example output: "aligned_terms":{
+        "schemaType": "reproschema:Activity",
+        "schemaVersion": "1.0.0",
+        "activity": {
+          "id": "ACE_schema",
+          "prefLabel": {"en": "Adverse Childhood Experiences"},
+          "description": {"en": "10-item questionnaire about childhood experiences"},
+          "preamble": {"en": "Prior to your 18th birthday:"},
+          "citation": {"en": "https://www.cdc.gov/violenceprevention/aces/"}
+        },
+        "items": [
+          {
+            "id": "ACE_01",
+            "question": {"en": "Did a parent or other adult in the household often..."},
+            "prefLabel": {"en": "ACE Q1"},
+            "ui": {
+              "inputType": "radio"
+            },
+            "valueRequired": true,
+            "responseOptions": {
+              "multipleChoice": false,
+              "choices": [
+                {"name": {"en": "No"}, "value": 0},
+                {"name": {"en": "Yes"}, "value": 1}
+              ]
+            }
+          }
+        ],
+        "ui": {
+          "order": ["ACE_01", "ACE_02"],
+          "shuffle": false
+        },
+        "compute": [
+          {
+            "variableName": "ACE_total_score",
+            "jsExpression": "ACE_01 + ACE_02 + ..."
+          }
+        ]
+      }
+
+    # do not chage this, remove it later
+    agent_id: alignment_agent
+
+  judge_task:
+    description: >
+      {aligned_structured_information} 
+         
+      Instructions: 
+      - Validate that all questions from the original PDF are captured in the structured output
+      - Check that response options match exactly with the source
+      - Verify activity metadata (title, description, preamble) is complete and accurate
+      - Ensure item properties (question text, input type, required status) are correct
+      - Confirm scoring logic and computed scores are properly represented
+      - Identify any missing, incomplete, or misrepresented information
+      - Provide a completeness score and detailed feedback
+    
+      Important: "judged_terms" should also include the output from previous agents
+
+    expected_output: > 
+      output format: json 
+      Example output: "judged_terms":{
+      "refined_metadata":{
+              "schemaType": "reproschema:Activity",
+              "schemaVersion": "1.0.0",
+              "activity": {
+                "id": "ACE_schema",
+                "prefLabel": {"en": "Adverse Childhood Experiences"},
+                "description": {"en": "10-item questionnaire about childhood experiences"},
+                "preamble": {"en": "Prior to your 18th birthday:"},
+                "citation": {"en": "https://www.cdc.gov/violenceprevention/aces/"}
+              },
+              "items": [
+                {
+                  "id": "ACE_01",
+                  "question": {"en": "Did a parent or other adult in the household often..."},
+                  "prefLabel": {"en": "ACE Q1"},
+                  "ui": {
+                    "inputType": "radio"
+                  },
+                  "valueRequired": true,
+                  "responseOptions": {
+                    "multipleChoice": false,
+                    "choices": [
+                      {"name": {"en": "No"}, "value": 0},
+                      {"name": {"en": "Yes"}, "value": 1}
+                    ]
+                  }
+                }
+              ],
+              "ui": {
+                "order": ["ACE_01", "ACE_02"],
+                "shuffle": false
+              },
+              "compute": [
+                {
+                  "variableName": "ACE_total_score",
+                  "jsExpression": "ACE_01 + ACE_02 + ..."
+                }
+              ]
+            },
+        "validation": {
+          "completeness": {
+            "allItemsExtracted": true,
+            "itemCount": 10,
+            "missingItems": []
+          },
+          "accuracy": {
+            "responseOptionsCorrect": true,
+            "scoringLogicPresent": true,
+            "metadataComplete": true
+          },
+          "issues": [],
+          "overallScore": 10.0,
+          "summary": "All questionnaire components successfully extracted and formatted."
+        }
+      }
+
+    # do not chage this, remove it later
+    agent_id: judge_agent
+
+  humanfeedback_task:
+    description: >
+      Input: {judged_structured_information_with_human_feedback}
+
+      modification_context: 
+        {modification_context}
+      
+      user_feedback_text:
+        {user_feedback_text}
+      
+      Instructions:
+      - Apply human feedback to refine the extracted metadata
+      - Correct any extraction errors identified by the reviewer
+      - Clarify ambiguous items or response options
+      - Add any missing metadata or properties
+      - Improve formatting and structure based on feedback
+      - Ensure the refined output maintains ReproSchema compatibility
+      - Document all changes made based on feedback
+      
+      
+  
+
+    expected_output: > 
+      output format: json
+      Example output: "judged_terms":{
+         "refined_metadata":{
+              "schemaType": "reproschema:Activity",
+              "schemaVersion": "1.0.0",
+              "activity": {
+                "id": "ACE_schema",
+                "prefLabel": {"en": "Adverse Childhood Experiences"},
+                "description": {"en": "10-item questionnaire about childhood experiences"},
+                "preamble": {"en": "Prior to your 18th birthday:"},
+                "citation": {"en": "https://www.cdc.gov/violenceprevention/aces/"}
+              },
+              "items": [
+                {
+                  "id": "ACE_01",
+                  "question": {"en": "Did a parent or other adult in the household often..."},
+                  "prefLabel": {"en": "ACE Q1"},
+                  "ui": {
+                    "inputType": "radio"
+                  },
+                  "valueRequired": true,
+                  "responseOptions": {
+                    "multipleChoice": false,
+                    "choices": [
+                      {"name": {"en": "No"}, "value": 0},
+                      {"name": {"en": "Yes"}, "value": 1}
+                    ]
+                  }
+                }
+              ],
+              "ui": {
+                "order": ["ACE_01", "ACE_02"],
+                "shuffle": false
+              },
+              "compute": [
+                {
+                  "variableName": "ACE_total_score",
+                  "jsExpression": "ACE_01 + ACE_02 + ..."
+                }
+              ]
+            },
+        "validation": {
+          "completeness": {
+            "allItemsExtracted": true,
+            "itemCount": 10,
+            "missingItems": []
+          },
+          "accuracy": {
+            "responseOptionsCorrect": true,
+            "scoringLogicPresent": true,
+            "metadataComplete": true
+          },
+          "issues": [],
+          "overallScore": 10.0,
+          "summary": "All questionnaire components successfully extracted and formatted."
+        }
+      },
+        "changes_applied": [
+          "Corrected questionnaire title to include '(ACE)' abbreviation",
+          "Updated citation to original authors",
+          "Fixed response option text for item 3"
+        ]
+      }
+
+    agent_id: humanfeedback_agent
+
+# embedding config
+# see for more details and parameters for config
+# https://docs.crewai.com/concepts/memory#additional-embedding-providerscl
+embedder_config:
+  provider: ollama
+  config:
+    api_base: http://localhost:11434
+    model: nomic-embed-text:v1.5
+
+# knowledge search config
+knowledge_config:
+  search_key: #local vector database
+    - entity
+    - label
+# human in loop config
+human_in_loop_config:
+  humanfeedback_agent: true
diff --git a/evaluation/pdf2reproschema/readme.md b/evaluation/pdf2reproschema/readme.md
new file mode 100644
index 0000000..a7288ec
--- /dev/null
+++ b/evaluation/pdf2reproschema/readme.md
@@ -0,0 +1,106 @@
+# 🧠 ReproSchema Conversion Pipeline
+
+This project uses `structsense` to automate the extraction, transformation, and validation of questionnaire content from PDF files into ReproSchema-compatible schema files. The goal is to standardize survey-based data collection workflows by producing machine-readable, interoperable, and reusable JSON-LD representations of assessments.
+
+---
+
+## 🔧 What This System Does
+
+Given a questionnaire PDF, this pipeline:
+
+1. **Extracts structured information** (e.g., items, response options, languages, scoring) from the raw document.
+2. **Generates a ReproSchema-compatible folder structure**, including:
+   - `items/`: individual question files (`item.jsonld`)
+   - `activities/`: composite assessment (`activity.jsonld`)
+   - `activity_schema.jsonld`: metadata and UI behavior
+3. **Evaluates schema fidelity** against the original questionnaire.
+4. **Applies human-in-the-loop feedback** to revise and improve schema quality.
+
+---
+
+## 🧑‍💼 Agents & Their Roles
+
+| Agent Name           | Description |
+|----------------------|-------------|
+| `extractor_agent`    | Parses the questionnaire PDF and extracts questions, options, logic, and metadata. |
+| `alignment_agent`    | Converts the extracted structure into a ReproSchema JSON-LD folder layout. |
+| `judge_agent`        | Evaluates whether the generated schema matches the source content and highlights issues. |
+| `humanfeedback_agent`| Applies human-provided feedback to revise and align the schema output more accurately. |
+
+---
+
+## 📁 Expected Output Structure
+
+The pipeline produces a JSON file containing the final output from the judge agent. 
+
+Key points about the output:
+1. **Format**: The output is always a JSON file
+2. **Content**: The specific structure and content of the JSON depends on how you define the `expected_output` in the judge task configuration
+
+For example, if your config specifies the judge agent to evaluate ReproSchema compliance, the output might include:
+- Schema validation results
+- Fidelity scores
+- Identified issues or discrepancies
+- Recommendations for improvements
+
+The exact JSON structure is fully customizable through your configuration file's `task_config.judge_task.expected_output` field.
+
+---
+
+## 🧠 Human-in-the-Loop
+
+After the automated processing and evaluation steps, human feedback can be used to:
+- Correct extraction mistakes
+- Improve ontology mappings (e.g., add SSSOM-aligned terms)
+- Clarify ambiguous response options or language labels
+- Trigger regeneration of files with updated logic
+
+---
+
+## 🤖 Language Models
+
+The configuration specifies `openrouter/openai/gpt-4o-mini` as the default LLM. However, for evaluation purposes, this pipeline has been tested with:
+
+- **GPT-4o-mini** by OpenAI
+- **Claude 3.5 Sonnet** by Anthropic
+- **DeepSeek V3** (open-source model) by DeepSeek
+
+You can modify the LLM settings in the `agent_config` section of your configuration file to use different models based on your requirements.
+
+---
+
+## 🧪 Usage
+
+### Using OpenRouter
+```bash
+structsense-cli extract \
+  --source sample_pdf.pdf \
+  --api_key <YOUR_API_KEY> \
+  --config <config-file>.yaml \
+  --env_file .env \
+  --save_file result.json  # optional
+```
+
+### Using Ollama (Local)
+```bash
+structsense-cli extract \
+  --source sample_pdf.pdf \
+  --config <config-file>.yaml \
+  --env_file .env \
+  --save_file result.json  # optional
+```
+
+### Tips
+
+- Best used with source questionnaires similar to PHQ-9, GAD-7, or eCOBIDAS formats
+- The configuration file should define the expected ReproSchema structure
+- Human-in-the-loop feedback can significantly improve schema accuracy
+
+---
+
+## 📚 References
+
+- [ReproSchema Documentation](https://www.repronim.org/reproschema/)
+- [CrewAI Docs](https://docs.crewai.com/)
+- [LinkML](https://linkml.io)
+- [FAIR Principles](https://www.go-fair.org/fair-principles/)
diff --git a/evaluation/pdf2reproschema/sample_pdf.pdf b/evaluation/pdf2reproschema/sample_pdf.pdf
new file mode 100644
index 0000000..bd4c562
Binary files /dev/null and b/evaluation/pdf2reproschema/sample_pdf.pdf differ
diff --git a/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/with_hil/resource_result_claude-3.7-sonnet_s41592-022-01443-0_with_hil.json b/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/with_hil/resource_result_claude-3.7-sonnet_s41592-022-01443-0_with_hil.json
new file mode 100644
index 0000000..4f09d19
--- /dev/null
+++ b/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/with_hil/resource_result_claude-3.7-sonnet_s41592-022-01443-0_with_hil.json
@@ -0,0 +1,74 @@
+{
+  "judged_structured_information": {
+    "1": [
+      {
+    "name": "DeepLabCut",
+    "description": "An open-source toolbox for multi-animal pose estimation, identification, and tracking. DeepLabCut provides high-performance animal assembly and tracking capabilities for multi-animal scenarios, with the ability to predict animal identities to assist tracking in case of occlusions. The tool includes several components: (1) multi-task CNN architectures that predict keypoints, limbs, and animal identity; (2) a data-driven method for animal assembly that finds optimal skeletons without user input; (3) a tracking module that uses network flow optimization; (4) unsupervised animal ID tracking features; and (5) graphical user interfaces for keypoint annotation, refinement and trajectory verification.",
+    "type": "Software Tool",
+    "category": "Pose Estimation",
+    "target": "Animal",
+    "mapped_target_concept": [
+      {
+        "id": "http://purl.obolibrary.org/obo/BTO_0000042",
+        "label": "animal",
+        "ontology": "BTO"
+      }
+    ],
+    "specific_target": "Mice, Marmosets, Fish",
+    "mapped_specific_target_concept": [
+      {
+        "specific_target": "Mice",
+        "mapped_target_concept": {
+          "label": "Mus musculus",
+          "id": "NCBITaxon:10090",
+          "ontology": "NCBITaxon"
+        }
+      },
+      {
+        "specific_target": "Marmosets",
+        "mapped_target_concept": {
+          "label": "Callithrix",
+          "id": "NCBITaxon:9481",
+          "ontology": "NCBITaxon"
+        }
+      },
+      {
+        "specific_target": "Fish",
+        "mapped_target_concept": {
+          "label": "Actinopterygii",
+          "id": "NCBITaxon:7898",
+          "ontology": "NCBITaxon"
+        }
+      }
+    ],
+    "url": "https://github.com/DeepLabCut/DeepLabCut",
+    "models": [
+      "DLCRNet_ms5",
+      "ResNet50",
+      "EfficientNets",
+      "HRNet-AE",
+      "ResNet-AE"
+    ],
+    "datasets": [
+      "Tri-mouse dataset",
+      "Parenting mice dataset",
+      "Marmoset dataset",
+      "Fish schooling dataset"
+    ],
+    "benchmarks": [
+      "https://benchmark.deeplabcut.org/"
+    ],
+    "tools": [
+      "DeepLabCut-Live!",
+      "idtracker.ai"
+    ],
+    "papers": [
+      "DeepLabCut: markerless pose estimation of user-defined body parts with deep learning (2018)",
+      "Using deeplabcut for 3D markerless pose estimation across species and behaviors (2019)"
+    ],
+    "judge_score": 0.94,
+    "judge_rationale": "The DeepLabCut resource entry is well-structured and comprehensive, conforming to BBQS standards. Upon reviewing the alignments as requested in the user feedback, I can confirm that the ontology mappings are accurate and appropriate. The general target 'Animal' is correctly mapped to BTO:0000042, and the specific targets are accurately mapped to appropriate NCBITaxon entries: Mice to Mus musculus (NCBITaxon:10090), Marmosets to Callithrix (NCBITaxon:9481), and Fish to Actinopterygii (NCBITaxon:7898). These taxonomic alignments represent the correct scientific classifications for the species mentioned. The resource provides clear categorization as a Software Tool for Pose Estimation, lists relevant models, datasets, tools, and seminal papers. The URL points to the official repository. Minor improvements could include more detailed benchmark information and complete paper citations with DOIs. Overall, this is a high-quality entry that would be valuable for researchers looking for animal pose estimation tools."
+  }
+    ]
+  }
+}
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/with_hil/resource_result_claude-3.7-sonnet_s41592-022-01443-0_with_hil_eval.json b/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/with_hil/resource_result_claude-3.7-sonnet_s41592-022-01443-0_with_hil_eval.json
new file mode 100644
index 0000000..8837b2f
--- /dev/null
+++ b/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/with_hil/resource_result_claude-3.7-sonnet_s41592-022-01443-0_with_hil_eval.json
@@ -0,0 +1,89 @@
+{
+  "judged_structured_information.1": {
+    "1": [
+      {
+        "name": "DeepLabCut",
+        "description": "An open-source toolbox for multi-animal pose estimation, identification, and tracking. DeepLabCut provides high-performance animal assembly and tracking capabilities for multi-animal scenarios, with the ability to predict animal identities to assist tracking in case of occlusions. The tool includes several components: (1) multi-task CNN architectures that predict keypoints, limbs, and animal identity; (2) a data-driven method for animal assembly that finds optimal skeletons without user input; (3) a tracking module that uses network flow optimization; (4) unsupervised animal ID tracking features; and (5) graphical user interfaces for keypoint annotation, refinement and trajectory verification.",
+        "type": "Model",
+        "category": "Pose Estimation",
+        "target": "Animal",
+        "mapped_target_concept": [
+          {
+            "id": "http://purl.obolibrary.org/obo/BTO_0000042",
+            "label": "animal",
+            "ontology": "BTO"
+          }
+        ],
+        "specific_target": "Mice, Marmosets, Fish",
+        "mapped_specific_target_concept": [
+          {
+            "specific_target": "Mice",
+            "mapped_target_concept": {
+              "label": "Mus musculus",
+              "id": "NCBITaxon:10090",
+              "ontology": "NCBITaxon"
+            }
+          },
+          {
+            "specific_target": "Marmosets",
+            "mapped_target_concept": {
+              "label": "Callitrichinae sp.",
+              "id": "NCBITaxon:38020",
+              "ontology": "NCBITaxon"
+            }
+          },
+          {
+            "specific_target": "Fish",
+            "mapped_target_concept": {
+              "label": "Actinopterygii",
+              "id": "NCBITaxon:7898",
+              "ontology": "NCBITaxon"
+            }
+          }
+        ],
+        "url": "https://github.com/DeepLabCut/DeepLabCut",
+        "models": [
+          "DLCRNet_ms5",
+          "ResNet50",
+          "EfficientNets",
+          "HRNet-AE",
+          "ResNet-AE"
+        ],
+        "datasets": [
+          "Tri-mouse dataset",
+          "Parenting mice dataset",
+          "Marmoset dataset",
+          "Fish schooling dataset"
+        ],
+        "benchmarks": [
+          "https://benchmark.deeplabcut.org/"
+        ],
+        "tools": [
+          "DeepLabCut-Live!",
+          "idtracker.ai"
+        ],
+        "papers": [
+          "DeepLabCut: markerless pose estimation of user-defined body parts with deep learning (2018)",
+          "Using deeplabcut for 3D markerless pose estimation across species and behaviors (2019)"
+        ],
+        "judge_score": 0.94,
+        "judge_rationale": "The DeepLabCut resource entry is well-structured and comprehensive, conforming to BBQS standards. Upon reviewing the alignments as requested in the user feedback, I can confirm that the ontology mappings are accurate and appropriate. The general target 'Animal' is correctly mapped to BTO:0000042, and the specific targets are accurately mapped to appropriate NCBITaxon entries: Mice to Mus musculus (NCBITaxon:10090), Marmosets to Callithrix (NCBITaxon:9481), and Fish to Actinopterygii (NCBITaxon:7898). These taxonomic alignments represent the correct scientific classifications for the species mentioned. The resource provides clear categorization as a Software Tool for Pose Estimation, lists relevant models, datasets, tools, and seminal papers. The URL points to the official repository. Minor improvements could include more detailed benchmark information and complete paper citations with DOIs. Overall, this is a high-quality entry that would be valuable for researchers looking for animal pose estimation tools.",
+        "approved": false,
+        "corrected": true,
+        "corrections": {
+          "type": "Software Tool",
+          "mapped_specific_target_concept": [
+            null,
+            {
+              "mapped_target_concept": {
+                "label": "Callithrix",
+                "id": "NCBITaxon:9481"
+              }
+            },
+            null
+          ]
+        }
+      }
+    ]
+  }
+}
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/with_hil/resource_result_deepseek-chat-v3-0324_s41592-022-01443-0_with_hil.json b/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/with_hil/resource_result_deepseek-chat-v3-0324_s41592-022-01443-0_with_hil.json
new file mode 100644
index 0000000..982b003
--- /dev/null
+++ b/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/with_hil/resource_result_deepseek-chat-v3-0324_s41592-022-01443-0_with_hil.json
@@ -0,0 +1,68 @@
+{
+  "judged_structured_information": {
+    "1": [
+      {
+        "name": "Multi-animal DeepLabCut",
+        "description": "An open-source toolbox for multi-animal pose estimation and tracking that extends DeepLabCut. It includes high-performance animal assembly and tracking features required for multi-animal scenarios, with the ability to predict an animal's identity to assist tracking in case of occlusions.",
+        "type": "Tool",
+        "category": "Pose Estimation",
+        "target": "Animal",
+        "mapped_target_concept": [
+          {
+            "id": "http://purl.obolibrary.org/obo/BTO_0000042",
+            "label": "animal",
+            "ontology": "BTO"
+          }
+        ],
+        "specific_targets": [
+          {
+            "specific_target": "Mice",
+            "mapped_target_concept": {
+              "label": "Mus musculus",
+              "id": "NCBITaxon:10090",
+              "ontology": "NCBITaxon"
+            }
+          },
+          {
+            "specific_target": "Marmosets",
+            "mapped_target_concept": {
+              "label": "Callithrix",
+              "id": "NCBITaxon:9489",
+              "ontology": "NCBITaxon"
+            }
+          },
+          {
+            "specific_target": "Fish",
+            "mapped_target_concept": {
+              "label": "Actinopterygii",
+              "id": "NCBITaxon:7898",
+              "ontology": "NCBITaxon"
+            }
+          }
+        ],
+        "url": "https://benchmark.deeplabcut.org/",
+        "mentions": {
+          "datasets": [
+            "tri-mouse dataset",
+            "parenting behavior dataset",
+            "marmoset home-cage behavior dataset",
+            "fish schooling behavior dataset"
+          ],
+          "benchmarks": [
+            "COCO"
+          ],
+          "models": [
+            "DLCRNet_ms5",
+            "ResNet50_stride8",
+            "EfficientNets"
+          ],
+          "papers": [
+            "DeepLabCut: markerless pose estimation of user-defined body parts with deep learning"
+          ]
+        },
+        "judge_score": 0.95,
+        "remarks": "The alignment of concepts is accurate and complete. The user feedback has been respected, and the mapped concepts for 'Mice', 'Marmosets', and 'Fish' are correctly aligned with their respective ontologies (NCBITaxon). The general 'animal' target is correctly mapped to BTO ontology. No modifications were needed as the original alignment was correct."
+      }
+    ]
+  }
+}
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/with_hil/resource_result_deepseek-chat-v3-0324_s41592-022-01443-0_with_hil_eval.json b/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/with_hil/resource_result_deepseek-chat-v3-0324_s41592-022-01443-0_with_hil_eval.json
new file mode 100644
index 0000000..d488c71
--- /dev/null
+++ b/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/with_hil/resource_result_deepseek-chat-v3-0324_s41592-022-01443-0_with_hil_eval.json
@@ -0,0 +1,89 @@
+{
+  "judged_structured_information.1": {
+    "1": [
+      {
+        "name": "Multi-animal DeepLabCut",
+        "description": "An open-source toolbox for multi-animal pose estimation and tracking that extends DeepLabCut. It includes high-performance animal assembly and tracking features required for multi-animal scenarios, with the ability to predict an animal's identity to assist tracking in case of occlusions.",
+        "type": "Model",
+        "category": "Pose Estimation",
+        "target": "Animal",
+        "mapped_target_concept": [
+          {
+            "id": "http://purl.obolibrary.org/obo/BTO_0000042",
+            "label": "animal",
+            "ontology": "BTO"
+          }
+        ],
+        "specific_targets": [
+          {
+            "specific_target": "Mice",
+            "mapped_target_concept": {
+              "label": "Mus musculus",
+              "id": "NCBITaxon:10090",
+              "ontology": "NCBITaxon"
+            }
+          },
+          {
+            "specific_target": "Marmosets",
+            "mapped_target_concept": {
+              "label": "Callitrichinae sp.",
+              "id": "NCBITaxon:38020",
+              "ontology": "NCBITaxon"
+            }
+          },
+          {
+            "specific_target": "Fish",
+            "mapped_target_concept": {
+              "label": "Actinopterygii",
+              "id": "NCBITaxon:7898",
+              "ontology": "NCBITaxon"
+            }
+          }
+        ],
+        "url": "https://github.com/DeepLabCut/DeepLabCut",
+        "mentions": {
+          "datasets": [
+            "tri-mouse dataset",
+            "parenting behavior dataset",
+            "marmoset home-cage behavior dataset",
+            "fish schooling behavior dataset"
+          ],
+          "benchmarks": [
+            "https://benchmark.deeplabcut.org/"
+          ],
+          "models": [
+            "DLCRNet_ms5",
+            "ResNet50_stride8",
+            "EfficientNets"
+          ],
+          "papers": [
+            "DeepLabCut: markerless pose estimation of user-defined body parts with deep learning"
+          ]
+        },
+        "judge_score": 0.95,
+        "remarks": "The alignment of concepts is accurate and complete. The user feedback has been respected, and the mapped concepts for 'Mice', 'Marmosets', and 'Fish' are correctly aligned with their respective ontologies (NCBITaxon). The general 'animal' target is correctly mapped to BTO ontology. No modifications were needed as the original alignment was correct.",
+        "approved": false,
+        "corrected": true,
+        "corrections": {
+          "type": "Tool",
+          "specific_targets": [
+            null,
+            {
+              "mapped_target_concept": {
+                "label": "Callithrix",
+                "id": "NCBITaxon:9489"
+              }
+            },
+            null
+          ],
+          "url": "https://benchmark.deeplabcut.org/",
+          "mentions": {
+            "benchmarks": [
+              "COCO"
+            ]
+          }
+        }
+      }
+    ]
+  }
+}
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/with_hil/resource_result_gpt_4o_mini_s41592-022-01443-0_with_hil.json b/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/with_hil/resource_result_gpt_4o_mini_s41592-022-01443-0_with_hil.json
new file mode 100644
index 0000000..b4926cf
--- /dev/null
+++ b/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/with_hil/resource_result_gpt_4o_mini_s41592-022-01443-0_with_hil.json
@@ -0,0 +1,64 @@
+{
+  "judged_structured_information": {
+        "1": [
+          {
+            "name": "Multi-animal pose estimation, identification and tracking with DeepLabCut",
+            "description": "This paper describes the development of a multi-animal pose estimation and tracking system extending DeepLabCut, which employs advanced deep-learning architectures and a data-driven assembly method. It presents the release of four benchmark datasets that vary in complexity for evaluating pose estimation in multi-animal scenarios. The proposed framework leverages identity prediction to enhance animal tracking accuracy across occlusions, demonstrating a wide application in neuroscience and ethology. Published on April 12, 2022.",
+            "type": "Research Article",
+            "category": "Pose Estimation",
+            "target": "Animal",
+            "mapped_target_concept": [
+              {
+                "id": "http://purl.obolibrary.org/obo/BTO_0000042",
+                "label": "animal",
+                "ontology": "BTO"
+              }
+            ],
+            "specific_target": "Mice, Marmosets, Fish",
+            "mapped_specific_target_concept": [
+              {
+                "specific_target": "Mice",
+                "mapped_target_concept": {
+                  "label": "Mus musculus",
+                  "id": "NCBITaxon:10090",
+                  "ontology": "NCBITaxon"
+                }
+              },
+              {
+                "specific_target": "Marmosets",
+                "mapped_target_concept": {
+                  "label": "Marmoset",
+                  "id": "NCBITaxon:9483",
+                  "ontology": "NCBITaxon"
+                }
+              },
+              {
+                "specific_target": "Fish",
+                "mapped_target_concept": {
+                  "label": "Actinopterygii",
+                  "id": "NCBITaxon:7896",
+                  "ontology": "NCBITaxon"
+                }
+              }
+            ],
+            "url": "https://doi.org/10.1038/s41592-022-01443-0",
+            "mentions": {
+              "datasets": [
+                "Tri-mouse dataset",
+                "Parenting behavior dataset",
+                "Marmoset home-cage behavior dataset",
+                "Fish schooling behavior dataset"
+              ],
+              "models": [
+                "DeepLabCut",
+                "DLCRNet"
+              ],
+              "benchmarks": [
+                "DeepLabCut benchmark challenge"
+              ]
+            },
+            "judge_score": 0.96
+          }
+        ]
+  }
+}
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/with_hil/resource_result_gpt_4o_mini_s41592-022-01443-0_with_hil_eval.json b/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/with_hil/resource_result_gpt_4o_mini_s41592-022-01443-0_with_hil_eval.json
new file mode 100644
index 0000000..64ffdb0
--- /dev/null
+++ b/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/with_hil/resource_result_gpt_4o_mini_s41592-022-01443-0_with_hil_eval.json
@@ -0,0 +1,84 @@
+{
+  "judged_structured_information.1": {
+    "1": [
+      {
+        "name": "Multi-animal pose estimation, identification and tracking with DeepLabCut",
+        "description": "This paper describes the development of a multi-animal pose estimation and tracking system extending DeepLabCut, which employs advanced deep-learning architectures and a data-driven assembly method. It presents the release of four benchmark datasets that vary in complexity for evaluating pose estimation in multi-animal scenarios. The proposed framework leverages identity prediction to enhance animal tracking accuracy across occlusions, demonstrating a wide application in neuroscience and ethology. Published on April 12, 2022.",
+        "type": "Model",
+        "category": "Pose Estimation",
+        "target": "Animal",
+        "mapped_target_concept": [
+          {
+            "id": "http://purl.obolibrary.org/obo/BTO_0000042",
+            "label": "animal",
+            "ontology": "BTO"
+          }
+        ],
+        "specific_target": "Mice, Marmosets, Fish",
+        "mapped_specific_target_concept": [
+          {
+            "specific_target": "Mice",
+            "mapped_target_concept": {
+              "label": "Mus musculus",
+              "id": "NCBITaxon:10090",
+              "ontology": "NCBITaxon"
+            }
+          },
+          {
+            "specific_target": "Marmosets",
+            "mapped_target_concept": {
+              "label": "Callitrichinae sp.",
+              "id": "NCBITaxon:38020",
+              "ontology": "NCBITaxon"
+            }
+          },
+          {
+            "specific_target": "Fish",
+            "mapped_target_concept": {
+              "label": "Actinopterygii",
+              "id": "NCBITaxon:7898",
+              "ontology": "NCBITaxon"
+            }
+          }
+        ],
+        "url": "https://github.com/DeepLabCut/DeepLabCut",
+        "mentions": {
+          "datasets": [
+            "Tri-mouse dataset",
+            "Parenting behavior dataset",
+            "Marmoset home-cage behavior dataset",
+            "Fish schooling behavior dataset"
+          ],
+          "models": [
+            "DeepLabCut",
+            "DLCRNet"
+          ],
+          "benchmarks": [
+            "DeepLabCut benchmark challenge"
+          ]
+        },
+        "judge_score": 0.96,
+        "approved": false,
+        "corrected": true,
+        "corrections": {
+          "type": "Research Article",
+          "mapped_specific_target_concept": [
+            null,
+            {
+              "mapped_target_concept": {
+                "label": "Marmoset",
+                "id": "NCBITaxon:9483"
+              }
+            },
+            {
+              "mapped_target_concept": {
+                "id": "NCBITaxon:7896"
+              }
+            }
+          ],
+          "url": "https://doi.org/10.1038/s41592-022-01443-0"
+        }
+      }
+    ]
+  }
+}
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/without_hil/resource_result_claude-3.7-sonnet_s41592-022-01443-0_without_hil.json b/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/without_hil/resource_result_claude-3.7-sonnet_s41592-022-01443-0_without_hil.json
new file mode 100644
index 0000000..4b0ef28
--- /dev/null
+++ b/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/without_hil/resource_result_claude-3.7-sonnet_s41592-022-01443-0_without_hil.json
@@ -0,0 +1,79 @@
+{
+  "judge_resource": {
+    "aligned_resources": [
+      {
+        "resource_name": "DeepLabCut",
+        "resource_type": "Tool",
+        "resource_category": "Pose Estimation",
+        "resource_description": "An open-source toolbox for multi-animal pose estimation, identification and tracking. The tool provides high-performance animal assembly and tracking features for multi-animal scenarios, and integrates the ability to predict an animal's identity to assist tracking in case of occlusions.",
+        "target_application": "Animal",
+        "mapped_target_concept": [
+          {
+            "id": "http://purl.obolibrary.org/obo/BTO_0000042",
+            "label": "animal",
+            "ontology": "BTO"
+          }
+        ],
+        "specific_targets": [
+          "Mice",
+          "Fish",
+          "Marmosets"
+        ],
+        "mapped_specific_target_concept": [
+          {
+            "specific_target": "Mice",
+            "mapped_target_concept": {
+              "label": "Mus musculus",
+              "id": "NCBITaxon:10090",
+              "ontology": "NCBITaxon"
+            }
+          },
+          {
+            "specific_target": "Fish",
+            "mapped_target_concept": {
+              "label": "Actinopterygii",
+              "id": "NCBITaxon:7898",
+              "ontology": "NCBITaxon"
+            }
+          },
+          {
+            "specific_target": "Marmosets",
+            "mapped_target_concept": {
+              "label": "Callithrix",
+              "id": "NCBITaxon:9481",
+              "ontology": "NCBITaxon"
+            }
+          }
+        ],
+        "url": "https://github.com/DeepLabCut/DeepLabCut",
+        "models": [
+          "DLCRNet",
+          "DLCRNet_ms5",
+          "ResNet",
+          "EfficientNet",
+          "ReIDTransformer"
+        ],
+        "datasets": [
+          "Tri-mouse dataset",
+          "Parenting mice dataset",
+          "Marmoset dataset",
+          "Fish schooling dataset"
+        ],
+        "benchmarks": [
+          "https://benchmark.deeplabcut.org/"
+        ],
+        "papers": [
+          "DeepLabCut: markerless pose estimation of user-defined body parts with deep learning"
+        ],
+        "related_tools": [
+          "DeepLabCut-Live!",
+          "idtracker.ai",
+          "SLEAP",
+          "AlphaTracker"
+        ],
+        "judge_score": 0.92,
+        "judge_rationale": "The DeepLabCut resource alignment is excellent, with properly structured information following BBQS standards. All essential fields are populated with relevant information. The resource name, type, category, and description accurately represent the tool's purpose for animal pose estimation. The target application has been properly mapped to a BTO ontology concept. Specific animal targets (Mice, Fish, Marmosets) have been appropriately mapped to corresponding NCBITaxon ontology concepts with correct IDs. The URL leads to the official repository. The resource includes comprehensive lists of associated models, datasets, benchmarks, papers, and related tools. The only minor improvement could be adding full citation information for the papers and more specific dataset descriptions. Overall, this is a well-structured and accurately mapped resource."
+      }
+    ]
+  }
+}
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/without_hil/resource_result_claude-3.7-sonnet_s41592-022-01443-0_without_hil_eval.json b/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/without_hil/resource_result_claude-3.7-sonnet_s41592-022-01443-0_without_hil_eval.json
new file mode 100644
index 0000000..4e79cda
--- /dev/null
+++ b/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/without_hil/resource_result_claude-3.7-sonnet_s41592-022-01443-0_without_hil_eval.json
@@ -0,0 +1,100 @@
+{
+  "judge_resource.aligned_resources.1": {
+    "1": [
+      {
+        "resource_name": "DeepLabCut",
+        "resource_type": "Model",
+        "resource_category": "Pose Estimation",
+        "resource_description": "An open-source toolbox for multi-animal pose estimation, identification and tracking. The tool provides high-performance animal assembly and tracking features for multi-animal scenarios, and integrates the ability to predict an animal's identity to assist tracking in case of occlusions.",
+        "target_application": "Animal",
+        "mapped_target_concept": [
+          {
+            "id": "http://purl.obolibrary.org/obo/BTO_0000042",
+            "label": "animal",
+            "ontology": "BTO"
+          }
+        ],
+        "specific_targets": [
+          "Mice",
+          "Fish",
+          "Marmosets"
+        ],
+        "mapped_specific_target_concept": [
+          {
+            "specific_target": "Mice",
+            "mapped_target_concept": {
+              "label": "Mus musculus",
+              "id": "NCBITaxon:10090",
+              "ontology": "NCBITaxon"
+            }
+          },
+          {
+            "specific_target": "Fish",
+            "mapped_target_concept": {
+              "label": "Actinopterygii",
+              "id": "NCBITaxon:7898",
+              "ontology": "NCBITaxon"
+            }
+          },
+          {
+            "specific_target": "Marmosets",
+            "mapped_target_concept": {
+              "label": "Callitrichinae sp.",
+              "id": "NCBITaxon:38020",
+              "ontology": "NCBITaxon"
+            }
+          }
+        ],
+        "url": "https://github.com/DeepLabCut/DeepLabCut",
+        "models": [
+          "DLCRNet",
+          "DLCRNet_ms5",
+          "ResNet",
+          "EfficientNet",
+          "ReIDTransformer"
+        ],
+        "datasets": [
+          "Tri-mouse dataset",
+          "Parenting mice dataset",
+          "Marmoset dataset",
+          "Fish schooling dataset"
+        ],
+        "benchmarks": [
+          "https://benchmark.deeplabcut.org/"
+        ],
+        "papers": [
+          "DeepLabCut: markerless pose estimation of user-defined body parts with deep learning"
+        ],
+        "related_tools": [
+          "DeepLabCut-Live!",
+          "idtracker.ai",
+          "-",
+          "-"
+        ],
+        "judge_score": 0.92,
+        "judge_rationale": "The DeepLabCut resource alignment is excellent, with properly structured information following BBQS standards. All essential fields are populated with relevant information. The resource name, type, category, and description accurately represent the tool's purpose for animal pose estimation. The target application has been properly mapped to a BTO ontology concept. Specific animal targets (Mice, Fish, Marmosets) have been appropriately mapped to corresponding NCBITaxon ontology concepts with correct IDs. The URL leads to the official repository. The resource includes comprehensive lists of associated models, datasets, benchmarks, papers, and related tools. The only minor improvement could be adding full citation information for the papers and more specific dataset descriptions. Overall, this is a well-structured and accurately mapped resource.",
+        "approved": false,
+        "corrected": true,
+        "corrections": {
+          "resource_type": "Tool",
+          "mapped_specific_target_concept": [
+            null,
+            null,
+            {
+              "mapped_target_concept": {
+                "label": "Callithrix",
+                "id": "NCBITaxon:9481"
+              }
+            }
+          ],
+          "related_tools": [
+            null,
+            null,
+            "SLEAP",
+            "AlphaTracker"
+          ]
+        }
+      }
+    ]
+  }
+}
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/without_hil/resource_result_deepseek-chat-v3-0324_s41592-022-01443-0_without_hil.json b/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/without_hil/resource_result_deepseek-chat-v3-0324_s41592-022-01443-0_without_hil.json
new file mode 100644
index 0000000..8ee98d6
--- /dev/null
+++ b/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/without_hil/resource_result_deepseek-chat-v3-0324_s41592-022-01443-0_without_hil.json
@@ -0,0 +1,73 @@
+{
+  "judge_resource": {
+    "aligned_resources": [
+      {
+        "name": "Multi-animal DeepLabCut",
+        "description": "An extension of DeepLabCut toolbox for multi-animal pose estimation, identification, and tracking. It includes new multi-task convolutional architectures, data-driven assembly methods, and tracking modules. Published in Nature Methods 2022.",
+        "type": "Tool",
+        "category": "Pose Estimation",
+        "target": "Animal",
+        "mapped_target_concept": [
+          {
+            "id": "http://purl.obolibrary.org/obo/BTO_0000042",
+            "label": "animal",
+            "ontology": "BTO"
+          }
+        ],
+        "specific_target": [
+          "Mice",
+          "Fish",
+          "Marmoset"
+        ],
+        "mapped_specific_target_concept": [
+          {
+            "specific_target": "Mice",
+            "mapped_target_concept": {
+              "label": "Mus musculus",
+              "id": "NCBITaxon:10090",
+              "ontology": "NCBITaxon"
+            }
+          },
+          {
+            "specific_target": "Fish",
+            "mapped_target_concept": {
+              "label": "Actinopterygii",
+              "id": "NCBITaxon:7898",
+              "ontology": "NCBITaxon"
+            }
+          },
+          {
+            "specific_target": "Marmoset",
+            "mapped_target_concept": {
+              "label": "Callithrix jacchus",
+              "id": "NCBITaxon:9483",
+              "ontology": "NCBITaxon"
+            }
+          }
+        ],
+        "url": "https://github.com/DeepLabCut/DeepLabCut",
+        "mentions": {
+          "datasets": [
+            "Tri-mouse dataset",
+            "Parenting behavior dataset",
+            "Marmoset home-cage dataset",
+            "Fish schooling dataset"
+          ],
+          "benchmarks": [
+            "COCO"
+          ],
+          "models": [
+            "DLCRNet_ms5",
+            "ResNet50",
+            "EfficientNet"
+          ],
+          "papers": [
+            "DeepLabCut: markerless pose estimation of user-defined body parts with deep learning",
+            "Using deeplabcut for 3D markerless pose estimation across species and behaviors"
+          ]
+        },
+        "judge_score": 0.95
+      }
+    ]
+  }
+}
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/without_hil/resource_result_deepseek-chat-v3-0324_s41592-022-01443-0_without_hil_eval.json b/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/without_hil/resource_result_deepseek-chat-v3-0324_s41592-022-01443-0_without_hil_eval.json
new file mode 100644
index 0000000..dcb1efb
--- /dev/null
+++ b/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/without_hil/resource_result_deepseek-chat-v3-0324_s41592-022-01443-0_without_hil_eval.json
@@ -0,0 +1,93 @@
+{
+  "judge_resource.aligned_resources": {
+    "1": [
+      {
+        "name": "Multi-animal DeepLabCut",
+        "description": "An extension of DeepLabCut toolbox for multi-animal pose estimation, identification, and tracking. It includes new multi-task convolutional architectures, data-driven assembly methods, and tracking modules. Published in Nature Methods 2022.",
+        "type": "Model",
+        "category": "Pose Estimation",
+        "target": "Animal",
+        "mapped_target_concept": [
+          {
+            "id": "http://purl.obolibrary.org/obo/BTO_0000042",
+            "label": "animal",
+            "ontology": "BTO"
+          }
+        ],
+        "specific_target": [
+          "Mice",
+          "Fish",
+          "Marmoset"
+        ],
+        "mapped_specific_target_concept": [
+          {
+            "specific_target": "Mice",
+            "mapped_target_concept": {
+              "label": "Mus musculus",
+              "id": "NCBITaxon:10090",
+              "ontology": "NCBITaxon"
+            }
+          },
+          {
+            "specific_target": "Fish",
+            "mapped_target_concept": {
+              "label": "Actinopterygii",
+              "id": "NCBITaxon:7898",
+              "ontology": "NCBITaxon"
+            }
+          },
+          {
+            "specific_target": "Marmoset",
+            "mapped_target_concept": {
+              "label": "Callitrichinae sp.",
+              "id": "NCBITaxon:38020",
+              "ontology": "NCBITaxon"
+            }
+          }
+        ],
+        "url": "https://github.com/DeepLabCut/DeepLabCut",
+        "mentions": {
+          "datasets": [
+            "Tri-mouse dataset",
+            "Parenting behavior dataset",
+            "Marmoset home-cage dataset",
+            "Fish schooling dataset"
+          ],
+          "benchmarks": [
+            "the DeepLabCut Benchmark! (https://benchmark.deeplabcut.org/)"
+          ],
+          "models": [
+            "DLCRNet_ms5",
+            "ResNet50",
+            "EfficientNet"
+          ],
+          "papers": [
+            "DeepLabCut: markerless pose estimation of user-defined body parts with deep learning",
+            "Using deeplabcut for 3D markerless pose estimation across species and behaviors"
+          ]
+        },
+        "judge_score": 0.95,
+        "approved": false,
+        "corrected": true,
+        "corrections": {
+          "type": "Tool",
+          "mapped_specific_target_concept": [
+            null,
+            null,
+            {
+              "mapped_target_concept": {
+                "label": "Callithrix jacchus",
+                "id": "NCBITaxon:9483"
+              }
+            }
+          ],
+          "mentions": {
+            "benchmarks": [
+              "COCO"
+            ]
+          }
+        }
+      }
+    ]
+  }
+}
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/without_hil/resource_result_gpt_4o_mini_s41592-022-01443-0_without_hil.json b/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/without_hil/resource_result_gpt_4o_mini_s41592-022-01443-0_without_hil.json
new file mode 100644
index 0000000..a0410cc
--- /dev/null
+++ b/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/without_hil/resource_result_gpt_4o_mini_s41592-022-01443-0_without_hil.json
@@ -0,0 +1,69 @@
+{
+  "judge_resource": {
+    "1": [
+      {
+        "name": "Multi-animal pose estimation, identification and tracking with DeepLabCut",
+        "description": "This paper presents an advanced system for multi-animal pose estimation and tracking using DeepLabCut. It introduces novel architectures, a data-driven assembly method for identifying and linking keypoints to individual animals, and unsupervised identity tracking to address common challenges in animal behavior analysis.",
+        "type": "Article",
+        "category": "Pose Estimation",
+        "target": "Animal",
+        "mapped_target_concept": [
+          {
+            "id": "http://purl.obolibrary.org/obo/BTO_0000042",
+            "label": "animal",
+            "ontology": "BTO"
+          }
+        ],
+        "specific_target": "Mice, Marmosets, Fish",
+        "mapped_specific_target_concept": [
+          {
+            "specific_target": "Mice",
+            "mapped_target_concept": {
+              "label": "Mus musculus",
+              "id": "NCBITaxon:10090",
+              "ontology": "NCBITaxon"
+            }
+          },
+          {
+            "specific_target": "Marmosets",
+            "mapped_target_concept": {
+              "label": "Callithrix",
+              "id": "NCBITaxon:9490",
+              "ontology": "NCBITaxon"
+            }
+          },
+          {
+            "specific_target": "Fish",
+            "mapped_target_concept": {
+              "label": "Actinopterygii",
+              "id": "NCBITaxon:7898",
+              "ontology": "NCBITaxon"
+            }
+          }
+        ],
+        "url": "https://doi.org/10.1038/s41592-022-01443-0",
+        "mentions": {
+          "models": [
+            "DeepLabCut",
+            "DLCRNet"
+          ],
+          "datasets": [
+            "Tri-mouse dataset",
+            "Parenting behavior dataset",
+            "Marmoset home-cage behavior dataset",
+            "Fish schooling behavior dataset"
+          ],
+          "benchmarks": [
+            "COCO",
+            "DeepLabCut benchmarks"
+          ],
+          "papers": [
+            "DeepLabCut: markerless pose estimation of user-defined body parts with deep learning",
+            "SLEAP: multi-animal pose tracking"
+          ]
+        },
+        "judge_score": 0.92
+      }
+    ]
+  }
+}
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/without_hil/resource_result_gpt_4o_mini_s41592-022-01443-0_without_hil_eval.json b/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/without_hil/resource_result_gpt_4o_mini_s41592-022-01443-0_without_hil_eval.json
new file mode 100644
index 0000000..8eda1b7
--- /dev/null
+++ b/evaluation/resource_extraction/old/evaluation/Multi-animal-pose-estimation/without_hil/resource_result_gpt_4o_mini_s41592-022-01443-0_without_hil_eval.json
@@ -0,0 +1,91 @@
+{
+  "judge_resource.1": {
+    "1": [
+      {
+        "name": "Multi-animal pose estimation, identification and tracking with DeepLabCut",
+        "description": "This paper presents an advanced system for multi-animal pose estimation and tracking using DeepLabCut. It introduces novel architectures, a data-driven assembly method for identifying and linking keypoints to individual animals, and unsupervised identity tracking to address common challenges in animal behavior analysis.",
+        "type": "Model",
+        "category": "Pose Estimation",
+        "target": "Animal",
+        "mapped_target_concept": [
+          {
+            "id": "http://purl.obolibrary.org/obo/BTO_0000042",
+            "label": "animal",
+            "ontology": "BTO"
+          }
+        ],
+        "specific_target": "Mice, Marmosets, Fish",
+        "mapped_specific_target_concept": [
+          {
+            "specific_target": "Mice",
+            "mapped_target_concept": {
+              "label": "Mus musculus",
+              "id": "NCBITaxon:10090",
+              "ontology": "NCBITaxon"
+            }
+          },
+          {
+            "specific_target": "Marmosets",
+            "mapped_target_concept": {
+              "label": "Callitrichinae sp.",
+              "id": "NCBITaxon:38020",
+              "ontology": "NCBITaxon"
+            }
+          },
+          {
+            "specific_target": "Fish",
+            "mapped_target_concept": {
+              "label": "Actinopterygii",
+              "id": "NCBITaxon:7898",
+              "ontology": "NCBITaxon"
+            }
+          }
+        ],
+        "url": "https://github.com/DeepLabCut/DeepLabCut",
+        "mentions": {
+          "models": [
+            "DeepLabCut",
+            "DLCRNet"
+          ],
+          "datasets": [
+            "Tri-mouse dataset",
+            "Parenting behavior dataset",
+            "Marmoset home-cage behavior dataset",
+            "Fish schooling behavior dataset"
+          ],
+          "benchmarks": [
+            "-",
+            "DeepLabCut benchmarks"
+          ],
+          "papers": [
+            "DeepLabCut: markerless pose estimation of user-defined body parts with deep learning",
+            "SLEAP: multi-animal pose tracking"
+          ]
+        },
+        "judge_score": 0.92,
+        "approved": false,
+        "corrected": true,
+        "corrections": {
+          "type": "Article",
+          "mapped_specific_target_concept": [
+            null,
+            {
+              "mapped_target_concept": {
+                "label": "Callithrix",
+                "id": "NCBITaxon:9490"
+              }
+            },
+            null
+          ],
+          "url": "https://doi.org/10.1038/s41592-022-01443-0",
+          "mentions": {
+            "benchmarks": [
+              "COCO",
+              null
+            ]
+          }
+        }
+      }
+    ]
+  }
+}
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/evaluation/vitpose/with_hil/resource_result_claude-3.7-sonnet_vitpose_hil.json b/evaluation/resource_extraction/old/evaluation/vitpose/with_hil/resource_result_claude-3.7-sonnet_vitpose_hil.json
new file mode 100644
index 0000000..2a9378f
--- /dev/null
+++ b/evaluation/resource_extraction/old/evaluation/vitpose/with_hil/resource_result_claude-3.7-sonnet_vitpose_hil.json
@@ -0,0 +1,62 @@
+{
+  "judged_structured_information": { 
+      "1": [
+        {
+          "resource_name": "ViTPose",
+          "description": "A simple vision transformer baseline model for human pose estimation that employs plain and non-hierarchical vision transformers as backbones to extract features for person instances and a lightweight decoder for pose estimation. It demonstrates capabilities such as structural simplicity, model size scalability, training paradigm flexibility, and knowledge transferability between models. The largest model achieves 80.9 AP on the MS COCO test-dev set.",
+          "type": "Model",
+          "category": "Pose Estimation",
+          "target": "Human",
+          "mapped_target_concept": [
+            {
+              "id": "http://purl.obolibrary.org/obo/NCBITaxon_9606",
+              "label": "Homo sapiens",
+              "ontology": "NCBITaxon"
+            }
+          ],
+          "specific_target": "N/A",
+          "mapped_specific_target_concept": [],
+          "key_features": [
+            "Structural simplicity",
+            "Model size scalability",
+            "Training paradigm flexibility",
+            "Knowledge transferability between models"
+          ],
+          "performance": "80.9 AP on the MS COCO test-dev set (largest model)",
+          "url": "https://github.com/ViTAE-Transformer/ViTPose",
+          "model_architecture": "Vision transformer with lightweight decoder",
+          "mentions": {
+            "datasets": [
+              "MS COCO Keypoint",
+              "ImageNet-1K",
+              "AI Challenger",
+              "MPII"
+            ],
+            "related_models": [
+              "ViTPose-B",
+              "ViTPose-L",
+              "ViTPose-H",
+              "ViTPose-G",
+              "ViT-B",
+              "ViT-L",
+              "ViT-H",
+              "ViTAE-G",
+              "SimpleBaseline",
+              "HRNet",
+              "TokenPose",
+              "TransPose",
+              "HRFormer",
+              "PRTR",
+              "MAE"
+            ],
+            "related_papers": [
+              "Masked autoencoders are scalable vision learners"
+            ]
+          },
+          "judge_score": 0.92,
+          "judge_rationale": "The resource information is well-structured and comprehensive. It clearly identifies ViTPose as a human pose estimation model with appropriate ontology mapping (Homo sapiens in NCBITaxon). The description is informative, covering the model's architecture, capabilities, and performance metrics. Key features are concisely listed, and the performance is quantified with the appropriate metric (AP) on a standard benchmark (MS COCO). The model architecture is accurately described, and the URL points to the official repository. The mentions section provides valuable context with relevant datasets and related models. Minor improvements could include more detailed performance metrics across different model variants (ViTPose-B/L/H/G) and adding DOIs or full citations for related papers.",
+          "feedback_response": "Regarding the user question about empty 'specific_target' and 'mapped_specific_target_concept' fields: These fields are empty (with 'N/A' for specific_target) because ViTPose is designed specifically for general human pose estimation without focusing on particular human subpopulations or body regions. The model targets humans as a whole species (properly mapped to 'Homo sapiens' in NCBITaxon), and does not specialize in specific demographic groups, age ranges, or particular body parts. This is appropriate for this resource as it is designed as a general-purpose human pose estimation model."
+        }
+      ]
+    }
+}
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/evaluation/vitpose/with_hil/resource_result_claude-3.7-sonnet_vitpose_hil_eval.json b/evaluation/resource_extraction/old/evaluation/vitpose/with_hil/resource_result_claude-3.7-sonnet_vitpose_hil_eval.json
new file mode 100644
index 0000000..c1a5e57
--- /dev/null
+++ b/evaluation/resource_extraction/old/evaluation/vitpose/with_hil/resource_result_claude-3.7-sonnet_vitpose_hil_eval.json
@@ -0,0 +1,64 @@
+{
+  "judged_structured_information.1": {
+    "1": [
+      {
+        "resource_name": "ViTPose",
+        "description": "A simple vision transformer baseline model for human pose estimation that employs plain and non-hierarchical vision transformers as backbones to extract features for person instances and a lightweight decoder for pose estimation. It demonstrates capabilities such as structural simplicity, model size scalability, training paradigm flexibility, and knowledge transferability between models. The largest model achieves 80.9 AP on the MS COCO test-dev set.",
+        "type": "Model",
+        "category": "Pose Estimation",
+        "target": "Human",
+        "mapped_target_concept": [
+          {
+            "id": "http://purl.obolibrary.org/obo/NCBITaxon_9606",
+            "label": "Homo sapiens",
+            "ontology": "NCBITaxon"
+          }
+        ],
+        "specific_target": "N/A",
+        "mapped_specific_target_concept": [],
+        "key_features": [
+          "Structural simplicity",
+          "Model size scalability",
+          "Training paradigm flexibility",
+          "Knowledge transferability between models"
+        ],
+        "performance": "80.9 AP on the MS COCO test-dev set (largest model)",
+        "url": "https://github.com/ViTAE-Transformer/ViTPose",
+        "model_architecture": "Vision transformer with lightweight decoder",
+        "mentions": {
+          "datasets": [
+            "MS COCO Keypoint",
+            "ImageNet-1K",
+            "AI Challenger",
+            "MPII"
+          ],
+          "related_models": [
+            "ViTPose-B",
+            "ViTPose-L",
+            "ViTPose-H",
+            "ViTPose-G",
+            "ViT-B",
+            "ViT-L",
+            "ViT-H",
+            "ViTAE-G",
+            "SimpleBaseline",
+            "HRNet",
+            "TokenPose",
+            "TransPose",
+            "HRFormer",
+            "PRTR",
+            "MAE"
+          ],
+          "related_papers": [
+            "Masked autoencoders are scalable vision learners"
+          ]
+        },
+        "judge_score": 0.92,
+        "judge_rationale": "The resource information is well-structured and comprehensive. It clearly identifies ViTPose as a human pose estimation model with appropriate ontology mapping (Homo sapiens in NCBITaxon). The description is informative, covering the model's architecture, capabilities, and performance metrics. Key features are concisely listed, and the performance is quantified with the appropriate metric (AP) on a standard benchmark (MS COCO). The model architecture is accurately described, and the URL points to the official repository. The mentions section provides valuable context with relevant datasets and related models. Minor improvements could include more detailed performance metrics across different model variants (ViTPose-B/L/H/G) and adding DOIs or full citations for related papers.",
+        "feedback_response": "Regarding the user question about empty 'specific_target' and 'mapped_specific_target_concept' fields: These fields are empty (with 'N/A' for specific_target) because ViTPose is designed specifically for general human pose estimation without focusing on particular human subpopulations or body regions. The model targets humans as a whole species (properly mapped to 'Homo sapiens' in NCBITaxon), and does not specialize in specific demographic groups, age ranges, or particular body parts. This is appropriate for this resource as it is designed as a general-purpose human pose estimation model.",
+        "approved": true,
+        "corrected": false
+      }
+    ]
+  }
+}
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/evaluation/vitpose/with_hil/resource_result_deepseek-chat-v3-0324_vitpose_hil.json b/evaluation/resource_extraction/old/evaluation/vitpose/with_hil/resource_result_deepseek-chat-v3-0324_vitpose_hil.json
new file mode 100644
index 0000000..5539ed0
--- /dev/null
+++ b/evaluation/resource_extraction/old/evaluation/vitpose/with_hil/resource_result_deepseek-chat-v3-0324_vitpose_hil.json
@@ -0,0 +1,47 @@
+{
+  "judged_structured_information": {
+      "1": [
+        {
+          "name": "ViTPose",
+          "description": "A simple yet effective vision transformer baseline for human pose estimation. ViTPose employs plain and non-hierarchical vision transformers as backbones to extract features for a given person instance and a lightweight decoder for pose estimation. It demonstrates simplicity in model structure, scalability in model size, flexibility in training paradigm, and transferability of knowledge between models.",
+          "type": "Model",
+          "category": "Pose Estimation",
+          "target": "Human",
+          "mapped_target_concept": [
+            {
+              "id": "http://purl.obolibrary.org/obo/NCBITaxon_9606",
+              "label": "Homo sapiens",
+              "ontology": "NCBITaxon"
+            }
+          ],
+          "specific_target": null,
+          "url": "https://github.com/ViTAE-Transformer/ViTPose",
+          "mentions": {
+            "models": [
+              "ViTPose-B",
+              "ViTPose-L",
+              "ViTPose-H",
+              "ViTPose-G"
+            ],
+            "datasets": [
+              "MS COCO",
+              "AI Challenger",
+              "MPII"
+            ],
+            "benchmarks": [
+              "MS COCO Keypoint Detection"
+            ],
+            "papers": [
+              "SimpleBaseline",
+              "HRNet",
+              "TokenPose",
+              "TransPose",
+              "HRFormer"
+            ]
+          },
+          "judge_score": 0.9,
+          "remarks": "The 'specific_target' field is empty as no specific human subpopulation or body parts are targeted by this model, which is correct for general human pose estimation."
+        }
+      ]
+    }
+}
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/evaluation/vitpose/with_hil/resource_result_deepseek-chat-v3-0324_vitpose_hil_eval.json b/evaluation/resource_extraction/old/evaluation/vitpose/with_hil/resource_result_deepseek-chat-v3-0324_vitpose_hil_eval.json
new file mode 100644
index 0000000..1152757
--- /dev/null
+++ b/evaluation/resource_extraction/old/evaluation/vitpose/with_hil/resource_result_deepseek-chat-v3-0324_vitpose_hil_eval.json
@@ -0,0 +1,49 @@
+{
+  "judged_structured_information.1": {
+    "1": [
+      {
+        "name": "ViTPose",
+        "description": "A simple yet effective vision transformer baseline for human pose estimation. ViTPose employs plain and non-hierarchical vision transformers as backbones to extract features for a given person instance and a lightweight decoder for pose estimation. It demonstrates simplicity in model structure, scalability in model size, flexibility in training paradigm, and transferability of knowledge between models.",
+        "type": "Model",
+        "category": "Pose Estimation",
+        "target": "Human",
+        "mapped_target_concept": [
+          {
+            "id": "http://purl.obolibrary.org/obo/NCBITaxon_9606",
+            "label": "Homo sapiens",
+            "ontology": "NCBITaxon"
+          }
+        ],
+        "specific_target": null,
+        "url": "https://github.com/ViTAE-Transformer/ViTPose",
+        "mentions": {
+          "models": [
+            "ViTPose-B",
+            "ViTPose-L",
+            "ViTPose-H",
+            "ViTPose-G"
+          ],
+          "datasets": [
+            "MS COCO",
+            "AI Challenger",
+            "MPII"
+          ],
+          "benchmarks": [
+            "MS COCO Keypoint Detection"
+          ],
+          "papers": [
+            "SimpleBaseline",
+            "HRNet",
+            "TokenPose",
+            "TransPose",
+            "HRFormer"
+          ]
+        },
+        "judge_score": 0.9,
+        "remarks": "The 'specific_target' field is empty as no specific human subpopulation or body parts are targeted by this model, which is correct for general human pose estimation.",
+        "approved": true,
+        "corrected": false
+      }
+    ]
+  }
+}
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/evaluation/vitpose/with_hil/resource_result_gpt_4o_mini_vitpose_hil.json b/evaluation/resource_extraction/old/evaluation/vitpose/with_hil/resource_result_gpt_4o_mini_vitpose_hil.json
new file mode 100644
index 0000000..c76c9a8
--- /dev/null
+++ b/evaluation/resource_extraction/old/evaluation/vitpose/with_hil/resource_result_gpt_4o_mini_vitpose_hil.json
@@ -0,0 +1,40 @@
+{
+  "judged_structured_information": {
+        "1": [
+          {
+            "name": "ViTPose: Simple Vision Transformer Baselines for Human Pose Estimation",
+            "description": "ViTPose is a baseline model that leverages plain vision transformers for human pose estimation. It achieves state-of-the-art performance, with 80.9 AP on the MS COCO Keypoint Detection benchmark, while maintaining a simple model structure which enhances scalability, flexibility in training paradigms, and knowledge transferability. ViTPose can easily adapt to varying model sizes, input resolutions, and different datasets, setting a new standard for pose estimation tasks.",
+            "type": "Model",
+            "category": "Pose Estimation",
+            "target": "Human",
+            "mapped_target_concept": [
+              {
+                "id": "http://purl.obolibrary.org/obo/BTO_0000015",
+                "label": "human",
+                "ontology": "BTO"
+              }
+            ],
+            "specific_target": "N/A",
+            "mapped_specific_target_concept": "Homo sapiens",
+            "url": "https://github.com/ViTAE-Transformer/ViTPose",
+            "mentions": {
+              "models": [
+                "ViTPose-B",
+                "ViTPose-L",
+                "ViTPose-H"
+              ],
+              "datasets": [
+                "MS COCO",
+                "AI Challenger",
+                "MPII"
+              ],
+              "benchmarks": [
+                "MS COCO Keypoint Detection"
+              ],
+              "papers": []
+            },
+            "judge_score": 0.95
+          }
+        ]
+      }
+}
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/evaluation/vitpose/with_hil/resource_result_gpt_4o_mini_vitpose_hil_eval.json b/evaluation/resource_extraction/old/evaluation/vitpose/with_hil/resource_result_gpt_4o_mini_vitpose_hil_eval.json
new file mode 100644
index 0000000..ac5fdc3
--- /dev/null
+++ b/evaluation/resource_extraction/old/evaluation/vitpose/with_hil/resource_result_gpt_4o_mini_vitpose_hil_eval.json
@@ -0,0 +1,59 @@
+{
+  "judged_structured_information.1": {
+    "1": [
+      {
+        "name": "ViTPose: Simple Vision Transformer Baselines for Human Pose Estimation",
+        "description": "ViTPose is a baseline model that leverages plain vision transformers for human pose estimation. It achieves state-of-the-art performance, with 80.9 AP on the MS COCO Keypoint Detection benchmark, while maintaining a simple model structure which enhances scalability, flexibility in training paradigms, and knowledge transferability. ViTPose can easily adapt to varying model sizes, input resolutions, and different datasets, setting a new standard for pose estimation tasks.",
+        "type": "Model",
+        "category": "Pose Estimation",
+        "target": "Human",
+        "mapped_target_concept": [
+          {
+            "id": "http://purl.obolibrary.org/obo/NCBITaxon_9606",
+            "label": "Homo sapiens",
+            "ontology": "NCBITaxon"
+          }
+        ],
+        "specific_target": "N/A",
+        "mapped_specific_target_concept": "N/A",
+        "url": "https://github.com/ViTAE-Transformer/ViTPose",
+        "mentions": {
+          "models": [
+            "ViTPose-B",
+            "ViTPose-L",
+            "ViTPose-H"
+          ],
+          "datasets": [
+            "MS COCO",
+            "AI Challenger",
+            "MPII"
+          ],
+          "benchmarks": [
+            "MS COCO Keypoint Detection"
+          ],
+          "papers": [
+            "N/A"
+          ]
+        },
+        "judge_score": 0.95,
+        "approved": false,
+        "corrected": true,
+        "corrections": {
+          "mapped_target_concept": [
+            {
+              "id": "http://purl.obolibrary.org/obo/BTO_0000015",
+              "label": "human",
+              "ontology": "BTO"
+            }
+          ],
+          "mapped_specific_target_concept": "Homo sapiens",
+          "mentions": {
+            "papers": [
+              "N/A"
+            ]
+          }
+        }
+      }
+    ]
+  }
+}
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/evaluation/vitpose/without_hil/resource_result_claude-3.7-sonnet_vitpose_nohil.json b/evaluation/resource_extraction/old/evaluation/vitpose/without_hil/resource_result_claude-3.7-sonnet_vitpose_nohil.json
new file mode 100644
index 0000000..2293f7a
--- /dev/null
+++ b/evaluation/resource_extraction/old/evaluation/vitpose/without_hil/resource_result_claude-3.7-sonnet_vitpose_nohil.json
@@ -0,0 +1,49 @@
+{
+  "judge_resource": {
+    "1": [
+      {
+        "name": "ViTPose",
+        "description": "A simple yet effective vision transformer baseline for human pose estimation that employs plain and non-hierarchical vision transformers as backbones to extract features for person instances with a lightweight decoder for keypoint detection. It demonstrates good capabilities in structural simplicity, model size scalability, training paradigm flexibility, and knowledge transferability.",
+        "type": "Model",
+        "category": "Pose Estimation",
+        "target": "Human",
+        "mapped_target_concept": [
+          {
+            "id": "http://purl.obolibrary.org/obo/NCBITaxon_9606",
+            "label": "Homo sapiens",
+            "ontology": "NCBITaxon"
+          }
+        ],
+        "specific_targets": null,
+        "mapped_specific_target_concept": [],
+        "url": "https://github.com/ViTAE-Transformer/ViTPose",
+        "mentions": {
+          "models": [
+            "ViTPose-B",
+            "ViTPose-L",
+            "ViTPose-H",
+            "ViTPose-G",
+            "SimpleBaseline",
+            "HRNet",
+            "TokenPose",
+            "TransPose",
+            "HRFormer",
+            "ViT"
+          ],
+          "datasets": [
+            "MS COCO Keypoint",
+            "ImageNet-1K",
+            "AI Challenger",
+            "MPII"
+          ],
+          "benchmarks": [
+            "MS COCO Keypoint Detection benchmark",
+            "MS COCO test-dev set"
+          ]
+        },
+        "judge_score": 0.9,
+        "judge_rationale": "This resource alignment scores high for several reasons: (1) Proper categorization as a 'Model' type and 'Pose Estimation' category; (2) Appropriate target mapping to Homo sapiens with correct ontology reference; (3) Comprehensive description that clearly explains the model's purpose and advantages; (4) Valid URL to the resource repository; (5) Well-structured mentions of related models, datasets, and benchmarks that provide context. The only minor limitations are the absence of specific_targets (though not strictly needed for this human-only model) and the absence of related papers in the mentions section, which would have provided additional scientific context. Overall, this is a well-aligned resource that meets BBQS standards."
+      }
+    ]
+  }
+}
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/evaluation/vitpose/without_hil/resource_result_claude-3.7-sonnet_vitpose_nohil_eval.json b/evaluation/resource_extraction/old/evaluation/vitpose/without_hil/resource_result_claude-3.7-sonnet_vitpose_nohil_eval.json
new file mode 100644
index 0000000..8a68a58
--- /dev/null
+++ b/evaluation/resource_extraction/old/evaluation/vitpose/without_hil/resource_result_claude-3.7-sonnet_vitpose_nohil_eval.json
@@ -0,0 +1,65 @@
+{
+  "judge_resource.1.1": {
+    "1": [
+      {
+        "name": "ViTPose",
+        "description": "A simple yet effective vision transformer baseline for human pose estimation that employs plain and non-hierarchical vision transformers as backbones to extract features for person instances with a lightweight decoder for keypoint detection. It demonstrates good capabilities in structural simplicity, model size scalability, training paradigm flexibility, and knowledge transferability.",
+        "type": "Model",
+        "category": "Pose Estimation",
+        "target": "Human",
+        "mapped_target_concept": [
+          {
+            "id": "http://purl.obolibrary.org/obo/NCBITaxon_9606",
+            "label": "Homo sapiens",
+            "ontology": "NCBITaxon"
+          }
+        ],
+        "specific_targets": null,
+        "mapped_specific_target_concept": [],
+        "url": "https://github.com/ViTAE-Transformer/ViTPose",
+        "mentions": {
+          "models": [
+            "ViTPose-B",
+            "ViTPose-L",
+            "ViTPose-H",
+            "ViTPose-G",
+            "SimpleBaseline",
+            "HRNet",
+            "TokenPose",
+            "TransPose",
+            "HRFormer",
+            "ViT"
+          ],
+          "datasets": [
+            "MS COCO",
+            "ImageNet-1K",
+            "AI Challenger",
+            "MPII"
+          ],
+          "benchmarks": [
+            "MS COCO Keypoint Detection",
+            "-"
+          ]
+        },
+        "judge_score": 0.9,
+        "judge_rationale": "This resource alignment scores high for several reasons: (1) Proper categorization as a 'Model' type and 'Pose Estimation' category; (2) Appropriate target mapping to Homo sapiens with correct ontology reference; (3) Comprehensive description that clearly explains the model's purpose and advantages; (4) Valid URL to the resource repository; (5) Well-structured mentions of related models, datasets, and benchmarks that provide context. The only minor limitations are the absence of specific_targets (though not strictly needed for this human-only model) and the absence of related papers in the mentions section, which would have provided additional scientific context. Overall, this is a well-aligned resource that meets BBQS standards.",
+        "approved": false,
+        "corrected": true,
+        "corrections": {
+          "mentions": {
+            "datasets": [
+              "MS COCO Keypoint",
+              null,
+              null,
+              null
+            ],
+            "benchmarks": [
+              "MS COCO Keypoint Detection benchmark",
+              "MS COCO test-dev set"
+            ]
+          }
+        }
+      }
+    ]
+  }
+}
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/evaluation/vitpose/without_hil/resource_result_deepseek-chat-v3-0324_vitpose_nohil.json b/evaluation/resource_extraction/old/evaluation/vitpose/without_hil/resource_result_deepseek-chat-v3-0324_vitpose_nohil.json
new file mode 100644
index 0000000..a65439c
--- /dev/null
+++ b/evaluation/resource_extraction/old/evaluation/vitpose/without_hil/resource_result_deepseek-chat-v3-0324_vitpose_nohil.json
@@ -0,0 +1,38 @@
+{
+  "judge_resource": {
+    "1": [
+      {
+        "name": "ViTPose",
+        "description": "ViTPose is a vision transformer-based model for human pose estimation. It employs plain and non-hierarchical vision transformers as backbones to extract features for a given person instance and a lightweight decoder for pose estimation. The model demonstrates simplicity in structure, scalability in model size, flexibility in training paradigm, and transferability of knowledge between models. ViTPose-B, ViTPose-L, and ViTPose-H variants are available, with the largest model achieving 80.9 AP on the MS COCO test-dev set.",
+        "type": "Model",
+        "category": "Pose Estimation",
+        "target": "Human",
+        "mapped_target_concept": [
+          {
+            "id": "http://purl.obolibrary.org/obo/NCBITaxon_9606",
+            "label": "Homo sapiens",
+            "ontology": "NCBITaxon"
+          }
+        ],
+        "specific_target": null,
+        "url": "https://github.com/ViTAE-Transformer/ViTPose",
+        "mentions": {
+          "datasets": [
+            "MS COCO Keypoint Detection",
+            "AI Challenger",
+            "MPII"
+          ],
+          "benchmarks": [
+            "MS COCO Keypoint Detection"
+          ],
+          "papers": [
+            "Simple Baselines for Human Pose Estimation and Tracking",
+            "Deep High-Resolution Representation Learning for Human Pose Estimation",
+            "UDP: The Devil is in the Details"
+          ]
+        },
+        "judge_score": 0.9
+      }
+    ]
+  }
+}
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/evaluation/vitpose/without_hil/resource_result_deepseek-chat-v3-0324_vitpose_nohil_eval.json b/evaluation/resource_extraction/old/evaluation/vitpose/without_hil/resource_result_deepseek-chat-v3-0324_vitpose_nohil_eval.json
new file mode 100644
index 0000000..6782db6
--- /dev/null
+++ b/evaluation/resource_extraction/old/evaluation/vitpose/without_hil/resource_result_deepseek-chat-v3-0324_vitpose_nohil_eval.json
@@ -0,0 +1,49 @@
+{
+  "judge_resource.1.1": {
+    "1": [
+      {
+        "name": "ViTPose",
+        "description": "ViTPose is a vision transformer-based model for human pose estimation. It employs plain and non-hierarchical vision transformers as backbones to extract features for a given person instance and a lightweight decoder for pose estimation. The model demonstrates simplicity in structure, scalability in model size, flexibility in training paradigm, and transferability of knowledge between models. ViTPose-B, ViTPose-L, and ViTPose-H variants are available, with the largest model achieving 80.9 AP on the MS COCO test-dev set.",
+        "type": "Model",
+        "category": "Pose Estimation",
+        "target": "Human",
+        "mapped_target_concept": [
+          {
+            "id": "http://purl.obolibrary.org/obo/NCBITaxon_9606",
+            "label": "Homo sapiens",
+            "ontology": "NCBITaxon"
+          }
+        ],
+        "specific_target": null,
+        "url": "https://github.com/ViTAE-Transformer/ViTPose",
+        "mentions": {
+          "datasets": [
+            "MS COCO",
+            "AI Challenger",
+            "MPII"
+          ],
+          "benchmarks": [
+            "MS COCO Keypoint Detection"
+          ],
+          "papers": [
+            "Simple Baselines for Human Pose Estimation and Tracking",
+            "Deep High-Resolution Representation Learning for Human Pose Estimation",
+            "UDP: The Devil is in the Details"
+          ]
+        },
+        "judge_score": 0.9,
+        "approved": false,
+        "corrected": true,
+        "corrections": {
+          "mentions": {
+            "datasets": [
+              "MS COCO Keypoint Detection",
+              null,
+              null
+            ]
+          }
+        }
+      }
+    ]
+  }
+}
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/evaluation/vitpose/without_hil/resource_result_gpt_4o_mini_vitpose_nohil.json b/evaluation/resource_extraction/old/evaluation/vitpose/without_hil/resource_result_gpt_4o_mini_vitpose_nohil.json
new file mode 100644
index 0000000..bbe7eb1
--- /dev/null
+++ b/evaluation/resource_extraction/old/evaluation/vitpose/without_hil/resource_result_gpt_4o_mini_vitpose_nohil.json
@@ -0,0 +1,38 @@
+{
+  "judge_resource": {
+    "1": [
+      {
+        "name": "ViTPose",
+        "description": "ViTPose presents a minimalistic yet effective vision transformer baseline for human pose estimation, demonstrating state-of-the-art performance on the MS COCO dataset with a new approach that emphasizes simplicity, scalability, flexibility, and transferability through empirical evidence.",
+        "type": "Paper",
+        "category": "Pose Estimation",
+        "target": "Human",
+        "mapped_target_concept": [
+          {
+            "id": "http://purl.obolibrary.org/obo/NCIT_C76232",
+            "label": "Human",
+            "ontology": "NCIT"
+          }
+        ],
+        "specific_target": "N/A",
+        "mapped_specific_target_concept": "N/A",
+        "url": "https://github.com/ViTAE-Transformer/ViTPose",
+        "mentions": {
+          "models": [
+            "ViTPose-B",
+            "ViTPose-L",
+            "ViTPose-H"
+          ],
+          "datasets": [
+            "MS COCO",
+            "AI Challenger",
+            "MPII"
+          ],
+          "benchmarks": [],
+          "papers": []
+        },
+        "judge_score": 0.9
+      }
+    ]
+  }
+}
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/evaluation/vitpose/without_hil/resource_result_gpt_4o_mini_vitpose_nohil_eval.json b/evaluation/resource_extraction/old/evaluation/vitpose/without_hil/resource_result_gpt_4o_mini_vitpose_nohil_eval.json
new file mode 100644
index 0000000..cc931c5
--- /dev/null
+++ b/evaluation/resource_extraction/old/evaluation/vitpose/without_hil/resource_result_gpt_4o_mini_vitpose_nohil_eval.json
@@ -0,0 +1,61 @@
+{
+  "judge_resource.1": {
+    "1": [
+      {
+        "name": "ViTPose",
+        "description": "ViTPose presents a minimalistic yet effective vision transformer baseline for human pose estimation, demonstrating state-of-the-art performance on the MS COCO dataset with a new approach that emphasizes simplicity, scalability, flexibility, and transferability through empirical evidence.",
+        "type": "Paper",
+        "category": "Pose Estimation",
+        "target": "Human",
+        "mapped_target_concept": [
+          {
+            "id": "http://purl.obolibrary.org/obo/NCBITaxon_9606",
+            "label": "Homo Sapiens",
+            "ontology": "NCBITaxon"
+          }
+        ],
+        "specific_target": "N/A",
+        "mapped_specific_target_concept": "N/A",
+        "url": "https://github.com/ViTAE-Transformer/ViTPose",
+        "mentions": {
+          "models": [
+            "ViTPose-B",
+            "ViTPose-L",
+            "ViTPose-H"
+          ],
+          "datasets": [
+            "MS COCO",
+            "AI Challenger",
+            "MPII"
+          ],
+          "benchmarks": [
+            "MS COCO Keypoint Detection"
+          ],
+          "papers": [
+            "ViTPose: Simple Vision Transformer Baselines for Human Pose Estimation"
+          ]
+        },
+        "judge_score": 0.9,
+        "approved": false,
+        "corrected": true,
+        "corrections": {
+          "mapped_target_concept": [
+            {
+              "id": "http://purl.obolibrary.org/obo/NCIT_C76232",
+              "label": "Human",
+              "ontology": "NCIT"
+            }
+          ],
+          "mentions": {
+            "benchmarks": [
+              "MS COCO Keypoint Detection"
+            ],
+            "papers": [
+              "ViTPose: Simple Vision Transformer Baselines for Human Pose Estimation"
+            ]
+          }
+        }
+      }
+    ]
+  }
+}
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/resource_config_calude.yaml b/evaluation/resource_extraction/old/resource_config_calude.yaml
new file mode 100644
index 0000000..67eeaae
--- /dev/null
+++ b/evaluation/resource_extraction/old/resource_config_calude.yaml
@@ -0,0 +1,420 @@
+#agent config
+agent_config:
+  extractor_agent:
+    role: >
+     Brain and Behavior Quantification and Synchronization (BBQS) Resource Extractor Agent
+    goal: >
+      Extract a single structured resource entry per input relevant to the Brain Behavior Quantification and Synchronization (BBQS) consortium. Capture related subjects as secondary mentions.
+    backstory: >
+      You are a research assistant working with the Brain Behavior Quantification and Synchronization (BBQS) consortium.
+      BBQS is an NIH-funded research effort focused on tools, datasets, models, and benchmarks that advance understanding of brain-behavior relationships.
+
+            The consortium tracks resources in the following categories:
+            - Models (e.g., pose estimation models, embedding models)
+            - Datasets (e.g., annotated video data, behavioral recordings)
+            - Papers (e.g., methods or applications related to behavioral quantification)
+            - Tools (e.g., analysis software, labeling interfaces)
+            - Benchmarks (e.g., standardized datasets or protocols for evaluating performance)
+            - Leaderboards (e.g., systems ranking models based on performance on a task)
+
+            Your input will be a description, webpage, or paper about a **single primary resource**. However, that resource may mention other entities like datasets, benchmarks, or tools. These should not be extracted as separate resources.
+
+            Instead, extract the primary resource with the following fields:
+            - name
+            - description
+            - type (Model, Dataset, Paper, Tool, Benchmark, Leaderboard)
+            - category (e.g., Pose Estimation, Gaze Detection, Behavioral Quantification)
+            - target (e.g., Animal, Human, Mammals)
+            - specific targets (e.g., Mice, Fish, Macaque)
+            - url (GitHub, HuggingFace, arXiv, lab site, etc.)
+            - mentions (optional: dictionary with fields like models, datasets, benchmarks, papers)
+
+            Also include a `mentions` field if applicable. This is a dictionary that may include referenced datasets, models, benchmarks, or tools used or described within the resource. 
+            Be mindful that webpages may contain many extraneous references and links that are not relevant to the primary resource and should not be included in mentions.
+            If a field is missing or unknown, use `null`. Only return a single JSON object under the key `resource`.
+    llm:
+      model: openrouter/anthropic/claude-3.7-sonnet
+      base_url: https://openrouter.ai/api/v1
+
+  alignment_agent:
+    role: >
+      Brain and Behavior Quantification and Synchronization (BBQS) Concept Alignment Agent
+    goal: >
+      Align extracted resource information with controlled vocabularies or domain-specific schemas used by BBQS.
+    backstory: >
+      You are an alignment assistant trained to normalize resource metadata according to the BBQS standard. 
+      Your task is to align fields such as `type`, `category`, `target`, and `specific_target` using existing schemas, correcting typos or ambiguities as needed. 
+      You take one resource object and update it accordingly.
+      You return the updated structured resources in JSON format, maintaining the original format but with aligned values.
+      Mentions may be left as-is or annotated if appropriate, using knowledge from existing schemas.
+    llm:
+      model: openrouter/anthropic/claude-3.7-sonnet
+      base_url: https://openrouter.ai/api/v1
+
+  judge_agent:
+    role: >
+      Brain and Behavior Quantification and Synchronization (BBQS) Judge Agent
+    goal: >
+      Evaluate the {aligned_structured_information} based on predefined criteria and generate a structured JSON output reflecting the assessment results.
+    backstory: >
+      You are a reviewer and evaluator for the BBQS resource curation pipeline, and someone who does not hallucinate.  
+      Your job is to assess how well the {aligned_structured_information} conform to BBQS standards. 
+      You return a confidence score between 0 and 1, along with a rationale. 
+      You only score the primary resource, not its mentions.
+      Your responses are in JSON and preserve the original fields while appending evaluation metadata.
+    llm:
+      model: openrouter/anthropic/claude-3.7-sonnet
+      base_url: https://openrouter.ai/api/v1
+
+  humanfeedback_agent:
+    role: >
+      Brain and Behavior Quantification and Synchronization (BBQS) Human feedback processor Agent
+    goal: >
+      Evaluate the {judged_structured_information_with_human_feedback} and review if everything is correct as human domain expert.
+    backstory: >
+      You are a human reviewer and evaluator for the BBQS resource curation pipeline, and someone who does not hallucinate.  
+      Your job is to assess how well the {judged_structured_information_with_human_feedback} conform to BBQS standards. 
+      You return a confidence score between 0 and 1, along with a rationale. 
+      You only score the primary resource, not its mentions.
+      Your responses are in JSON and preserve the original fields while appending evaluation metadata.
+
+    llm:
+      model: openrouter/anthropic/claude-3.7-sonnet
+      base_url: https://openrouter.ai/api/v1
+
+# agent task config
+task_config:
+  extraction_task:
+    description: >
+      Extract structured metadata about scientific resources relevant to BBQS from the given {literature}
+      Each input should yield **one resource** only. If the input mentions other resources, include them under a `mentions` field but do not extract them as separate entries.
+
+      Return the following fields in JSON format:
+              - name
+              - description
+              - type (Model, Dataset, Tool, Paper, Benchmark, Leaderboard)
+              - category (e.g., Pose Estimation, Behavioral Quantification)
+              - target (e.g., Animal, Human, Mammals)
+              - specific target (e.g., Mice, Macaque, Bird)
+              - url
+              - mentions (optional: dictionary with fields like models, datasets, benchmarks, papers)
+
+      Use `null` if information is missing.
+      
+      Important:
+        Do not copy the example output.
+
+    Resource:
+      { literature }
+
+    expected_output: >
+      output format: json
+      Example output:
+      "extracted_resources": {
+      
+        "1": [{ 
+           "name": "DeepLabCut Model Zoo - SuperAnimal-Quadruped",
+            "description": "Pre-trained model for quadruped animal pose estimation using DeepLabCut.",
+            "type": "Model",
+            "category": "Pose Estimation",
+            "target": "Animal",
+            "specific_target": "Quadruped, Horse, Mice",
+            "mentions": {
+                "datasets": ["Quadruped-80K", "AnimalPose", "AwA-Pose", "AcinoSet", "Horse-30", "StanfordDogs", "AP-10K", "iRodent"],
+                "benchmarks": ["AP-10K", "AnimalPose", "Horse-10", "iRodent"],
+                "models": ["DeepLabCut"],
+            }
+        }],
+      ...
+      }
+
+    agent_id: extractor_agent
+
+  alignment_task:
+    description: >
+      Take the output of extractor_agent as input and perform the concept alignment based on existing resources. 
+      A concept alignment is anything where you align the given entity to the matching concept aka class from the existing set of resources. If you can't align just place N/A.
+      
+      Inputs: {extracted_structured_information}
+
+    expected_output: >
+      output format: json
+      Example output:
+      "aligned_resources": {
+       "1":[{
+          "name": "DeepLabCut Model Zoo - SuperAnimal-Quadruped",
+            "description": "A DeepLabCut SuperAnimal pre-trained model for quadruped animal pose estimation using DeepLabCut, trained on the TopViewMouse-5K dataset.",
+            "type": "Model",
+            "category": "Pose Estimation",
+            "target": "Animal",
+             "mapped_target_concept": [
+                             {
+                               "id": "http://purl.obolibrary.org/obo/BTO_0000042",
+                               "label": "animal",
+                               "ontology": "BTO"
+            }],
+            "specific_target": "Quadruped, Horse, Mice, Primate, Macaque, Dogs, Rodents",
+             "mapped_specific_target_concept": [
+                                                 {
+                                                   "specific_target": "Quadruped",
+                                                   "mapped_target_concept": {
+                                                     "label": "Tetrapoda",
+                                                     "id": "NCBITaxon:32523",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Horse",
+                                                   "mapped_target_concept": {
+                                                     "label": "Equus caballus",
+                                                     "id": "NCBITaxon:9796",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Mice",
+                                                   "mapped_target_concept": {
+                                                     "label": "Mus musculus",
+                                                     "id": "NCBITaxon:10090",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Primate",
+                                                   "mapped_target_concept": {
+                                                     "label": "Primates",
+                                                     "id": "NCBITaxon:9443",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Macaque",
+                                                   "mapped_target_concept": {
+                                                     "label": "Macaca",
+                                                     "id": "NCBITaxon:9541",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Dogs",
+                                                   "mapped_target_concept": {
+                                                     "label": "Canis lupus familiaris",
+                                                     "id": "NCBITaxon:9615",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 }
+             ],
+            "url": "https://deeplabcut.github.io/DeepLabCut/docs/ModelZoo.html"
+            "mentions": {
+                "datasets": ["Quadruped-80K", "AnimalPose", "AwA-Pose", "AcinoSet", "Horse-30", "StanfordDogs", "AP-10K", "iRodent"],
+                "benchmarks": ["AP-10K", "AnimalPose", "Horse-10", "iRodent"],
+                "models": ["DeepLabCut"],
+                "papers": ["10.48550/arXiv.2203.07436"]
+           }
+       }],
+      ...
+      }
+
+    agent_id: alignment_agent
+
+  judge_task:
+    description: >
+      Take the output of alignment agent {aligned_structured_information} as input and perform the following evaluation: 
+      1. Assess the quality and accuracy of the alignment with the BBQS standards in {aligned_structured_information}.
+      2. Assign a score between 0 and 1 as a judge_score.
+      3. Update the {aligned_structured_information} adding the judge_score.
+
+    expected_output: > 
+      output format: json 
+      Example output:
+      "judge_resource": {
+                        "1": [{
+                    "name": "DeepLabCut Model Zoo - SuperAnimal-Quadruped",
+                  "description": "A DeepLabCut SuperAnimal pre-trained model for quadruped animal pose estimation using DeepLabCut, trained on the TopViewMouse-5K dataset.",
+                  "type": "Model",
+                  "category": "Pose Estimation",
+      "target": "Animal",
+            "mapped_target_concept": [
+                             {
+                               "id": "http://purl.obolibrary.org/obo/BTO_0000042",
+                               "label": "animal",
+                               "ontology": "BTO"
+            }],
+            "specific_target": "Quadruped, Horse, Mice, Primate, Macaque, Dogs, Rodents",
+             "mapped_specific_target_concept": [
+                                                 {
+                                                   "specific_target": "Quadruped",
+                                                   "mapped_target_concept": {
+                                                     "label": "Tetrapoda",
+                                                     "id": "NCBITaxon:32523",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Horse",
+                                                   "mapped_target_concept": {
+                                                     "label": "Equus caballus",
+                                                     "id": "NCBITaxon:9796",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Mice",
+                                                   "mapped_target_concept": {
+                                                     "label": "Mus musculus",
+                                                     "id": "NCBITaxon:10090",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Primate",
+                                                   "mapped_target_concept": {
+                                                     "label": "Primates",
+                                                     "id": "NCBITaxon:9443",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Macaque",
+                                                   "mapped_target_concept": {
+                                                     "label": "Macaca",
+                                                     "id": "NCBITaxon:9541",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Dogs",
+                                                   "mapped_target_concept": {
+                                                     "label": "Canis lupus familiaris",
+                                                     "id": "NCBITaxon:9615",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 }
+             ],
+                  "url": "https://deeplabcut.github.io/DeepLabCut/docs/ModelZoo.html"
+                  "mentions": {
+                      "datasets": ["Quadruped-80K", "AnimalPose", "AwA-Pose", "AcinoSet", "Horse-30", "StanfordDogs", "AP-10K", "iRodent"],
+                      "benchmarks": ["AP-10K", "AnimalPose", "Horse-10", "iRodent"],
+                      "models": ["DeepLabCut"],
+                      "papers": ["10.48550/arXiv.2203.07436"]
+                  }
+                  "judge_score": 0.95
+      }],
+      ...
+      }
+
+    agent_id: judge_agent
+
+  humanfeedback_task:
+    description: > 
+      Take the output of alignment agent {judged_structured_information_with_human_feedback} as input and perform the following evaluation as an human expert: 
+            1. Assess the quality and accuracy of the alignment with the BBQS standards in {aligned_structured_information}.
+            2. Assign a score between 0 and 1 as a judge_score.
+            3. Update the {judged_structured_information_with_human_feedback} adding the judge_score.
+  
+      Additionally process the received human feedback.
+      Important: The number of extracted entities should not be less than what you received.
+      modification_context: 
+        {modification_context}
+      
+      user_feedback_text:
+        {user_feedback_text} 
+
+    expected_output: > 
+      output format: json
+      Example output:
+      "judge_resource": {
+                              "1":[{
+                          "name": "DeepLabCut Model Zoo - SuperAnimal-Quadruped",
+                        "description": "A DeepLabCut SuperAnimal pre-trained model for quadruped animal pose estimation using DeepLabCut, trained on the TopViewMouse-5K dataset.",
+                        "type": "Model",
+                        "category": "Pose Estimation",
+      "target": "Animal",
+            "mapped_target_concept": [
+                             {
+                               "id": "http://purl.obolibrary.org/obo/BTO_0000042",
+                               "label": "animal",
+                               "ontology": "BTO"
+            }],
+            "specific_target": "Quadruped, Horse, Mice, Primate, Macaque, Dogs, Rodents",
+             "mapped_specific_target_concept": [
+                                                 {
+                                                   "specific_target": "Quadruped",
+                                                   "mapped_target_concept": {
+                                                     "label": "Tetrapoda",
+                                                     "id": "NCBITaxon:32523",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Horse",
+                                                   "mapped_target_concept": {
+                                                     "label": "Equus caballus",
+                                                     "id": "NCBITaxon:9796",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Mice",
+                                                   "mapped_target_concept": {
+                                                     "label": "Mus musculus",
+                                                     "id": "NCBITaxon:10090",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Primate",
+                                                   "mapped_target_concept": {
+                                                     "label": "Primates",
+                                                     "id": "NCBITaxon:9443",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Macaque",
+                                                   "mapped_target_concept": {
+                                                     "label": "Macaca",
+                                                     "id": "NCBITaxon:9541",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Dogs",
+                                                   "mapped_target_concept": {
+                                                     "label": "Canis lupus familiaris",
+                                                     "id": "NCBITaxon:9615",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 }
+             ],
+                        "url": "https://deeplabcut.github.io/DeepLabCut/docs/ModelZoo.html"
+                        "mentions": {
+                            "datasets": ["Quadruped-80K", "AnimalPose", "AwA-Pose", "AcinoSet", "Horse-30", "StanfordDogs", "AP-10K", "iRodent"],
+                            "benchmarks": ["AP-10K", "AnimalPose", "Horse-10", "iRodent"],
+                            "models": ["DeepLabCut"],
+                            "papers": ["10.48550/arXiv.2203.07436"]
+                        }
+                        "judge_score": 0.95
+            }],
+            ...
+            }
+
+    agent_id: humanfeedback_agent
+
+# embedding config
+# see for more details and parameters for config
+# https://docs.crewai.com/concepts/memory#additional-embedding-providerscl
+embedder_config:
+  provider: ollama
+  config:
+    api_base: http://localhost:11434
+    model: nomic-embed-text:latest
+
+# knowledge search config
+knowledge_config:
+  search_key: #local vector database
+    - entity
+    - label
+# human in loop config
+human_in_loop_config:
+  humanfeedback_agent: true
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/resource_config_deepseek.yaml b/evaluation/resource_extraction/old/resource_config_deepseek.yaml
new file mode 100644
index 0000000..5bbc28c
--- /dev/null
+++ b/evaluation/resource_extraction/old/resource_config_deepseek.yaml
@@ -0,0 +1,420 @@
+#agent config
+agent_config:
+  extractor_agent:
+    role: >
+     Brain and Behavior Quantification and Synchronization (BBQS) Resource Extractor Agent
+    goal: >
+      Extract a single structured resource entry per input relevant to the Brain Behavior Quantification and Synchronization (BBQS) consortium. Capture related subjects as secondary mentions.
+    backstory: >
+      You are a research assistant working with the Brain Behavior Quantification and Synchronization (BBQS) consortium.
+      BBQS is an NIH-funded research effort focused on tools, datasets, models, and benchmarks that advance understanding of brain-behavior relationships.
+
+            The consortium tracks resources in the following categories:
+            - Models (e.g., pose estimation models, embedding models)
+            - Datasets (e.g., annotated video data, behavioral recordings)
+            - Papers (e.g., methods or applications related to behavioral quantification)
+            - Tools (e.g., analysis software, labeling interfaces)
+            - Benchmarks (e.g., standardized datasets or protocols for evaluating performance)
+            - Leaderboards (e.g., systems ranking models based on performance on a task)
+
+            Your input will be a description, webpage, or paper about a **single primary resource**. However, that resource may mention other entities like datasets, benchmarks, or tools. These should not be extracted as separate resources.
+
+            Instead, extract the primary resource with the following fields:
+            - name
+            - description
+            - type (Model, Dataset, Paper, Tool, Benchmark, Leaderboard)
+            - category (e.g., Pose Estimation, Gaze Detection, Behavioral Quantification)
+            - target (e.g., Animal, Human, Mammals)
+            - specific targets (e.g., Mice, Fish, Macaque)
+            - url (GitHub, HuggingFace, arXiv, lab site, etc.)
+            - mentions (optional: dictionary with fields like models, datasets, benchmarks, papers)
+
+            Also include a `mentions` field if applicable. This is a dictionary that may include referenced datasets, models, benchmarks, or tools used or described within the resource. 
+            Be mindful that webpages may contain many extraneous references and links that are not relevant to the primary resource and should not be included in mentions.
+            If a field is missing or unknown, use `null`. Only return a single JSON object under the key `resource`.
+    llm:
+      model: openrouter/deepseek/deepseek-chat-v3-0324
+      base_url: https://openrouter.ai/api/v1
+
+  alignment_agent:
+    role: >
+      Brain and Behavior Quantification and Synchronization (BBQS) Concept Alignment Agent
+    goal: >
+      Align extracted resource information with controlled vocabularies or domain-specific schemas used by BBQS.
+    backstory: >
+      You are an alignment assistant trained to normalize resource metadata according to the BBQS standard. 
+      Your task is to align fields such as `type`, `category`, `target`, and `specific_target` using existing schemas, correcting typos or ambiguities as needed. 
+      You take one resource object and update it accordingly.
+      You return the updated structured resources in JSON format, maintaining the original format but with aligned values.
+      Mentions may be left as-is or annotated if appropriate, using knowledge from existing schemas.
+    llm:
+      model: openrouter/deepseek/deepseek-chat-v3-0324
+      base_url: https://openrouter.ai/api/v1
+
+  judge_agent:
+    role: >
+      Brain and Behavior Quantification and Synchronization (BBQS) Judge Agent
+    goal: >
+      Evaluate the {aligned_structured_information} based on predefined criteria and generate a structured JSON output reflecting the assessment results.
+    backstory: >
+      You are a reviewer and evaluator for the BBQS resource curation pipeline, and someone who does not hallucinate.  
+      Your job is to assess how well the {aligned_structured_information} conform to BBQS standards. 
+      You return a confidence score between 0 and 1, along with a rationale. 
+      You only score the primary resource, not its mentions.
+      Your responses are in JSON and preserve the original fields while appending evaluation metadata.
+    llm:
+      model: openrouter/deepseek/deepseek-chat-v3-0324
+      base_url: https://openrouter.ai/api/v1
+
+  humanfeedback_agent:
+    role: >
+      Brain and Behavior Quantification and Synchronization (BBQS) Human feedback processor Agent
+    goal: >
+      Evaluate the {judged_structured_information_with_human_feedback} and review if everything is correct as human domain expert.
+    backstory: >
+      You are a human reviewer and evaluator for the BBQS resource curation pipeline, and someone who does not hallucinate.  
+      Your job is to assess how well the {judged_structured_information_with_human_feedback} conform to BBQS standards. 
+      You return a confidence score between 0 and 1, along with a rationale. 
+      You only score the primary resource, not its mentions.
+      Your responses are in JSON and preserve the original fields while appending evaluation metadata.
+
+    llm:
+      model: openrouter/deepseek/deepseek-chat-v3-0324
+      base_url: https://openrouter.ai/api/v1
+
+# agent task config
+task_config:
+  extraction_task:
+    description: >
+      Extract structured metadata about scientific resources relevant to BBQS from the given {literature}
+      Each input should yield **one resource** only. If the input mentions other resources, include them under a `mentions` field but do not extract them as separate entries.
+
+      Return the following fields in JSON format:
+              - name
+              - description
+              - type (Model, Dataset, Tool, Paper, Benchmark, Leaderboard)
+              - category (e.g., Pose Estimation, Behavioral Quantification)
+              - target (e.g., Animal, Human, Mammals)
+              - specific target (e.g., Mice, Macaque, Bird)
+              - url
+              - mentions (optional: dictionary with fields like models, datasets, benchmarks, papers)
+
+      Use `null` if information is missing.
+      
+      Important:
+        Do not copy the example output.
+
+    Resource:
+      { literature }
+
+    expected_output: >
+      output format: json
+      Example output:
+      "extracted_resources": {
+      
+        "1": [{ 
+           "name": "DeepLabCut Model Zoo - SuperAnimal-Quadruped",
+            "description": "Pre-trained model for quadruped animal pose estimation using DeepLabCut.",
+            "type": "Model",
+            "category": "Pose Estimation",
+            "target": "Animal",
+            "specific_target": "Quadruped, Horse, Mice",
+            "mentions": {
+                "datasets": ["Quadruped-80K", "AnimalPose", "AwA-Pose", "AcinoSet", "Horse-30", "StanfordDogs", "AP-10K", "iRodent"],
+                "benchmarks": ["AP-10K", "AnimalPose", "Horse-10", "iRodent"],
+                "models": ["DeepLabCut"],
+            }
+        }],
+      ...
+      }
+
+    agent_id: extractor_agent
+
+  alignment_task:
+    description: >
+      Take the output of extractor_agent as input and perform the concept alignment based on existing resources. 
+      A concept alignment is anything where you align the given entity to the matching concept aka class from the existing set of resources. If you can't align just place N/A.
+      
+      Inputs: {extracted_structured_information}
+
+    expected_output: >
+      output format: json
+      Example output:
+      "aligned_resources": {
+       "1":[{
+          "name": "DeepLabCut Model Zoo - SuperAnimal-Quadruped",
+            "description": "A DeepLabCut SuperAnimal pre-trained model for quadruped animal pose estimation using DeepLabCut, trained on the TopViewMouse-5K dataset.",
+            "type": "Model",
+            "category": "Pose Estimation",
+            "target": "Animal",
+             "mapped_target_concept": [
+                             {
+                               "id": "http://purl.obolibrary.org/obo/BTO_0000042",
+                               "label": "animal",
+                               "ontology": "BTO"
+            }],
+            "specific_target": "Quadruped, Horse, Mice, Primate, Macaque, Dogs, Rodents",
+             "mapped_specific_target_concept": [
+                                                 {
+                                                   "specific_target": "Quadruped",
+                                                   "mapped_target_concept": {
+                                                     "label": "Tetrapoda",
+                                                     "id": "NCBITaxon:32523",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Horse",
+                                                   "mapped_target_concept": {
+                                                     "label": "Equus caballus",
+                                                     "id": "NCBITaxon:9796",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Mice",
+                                                   "mapped_target_concept": {
+                                                     "label": "Mus musculus",
+                                                     "id": "NCBITaxon:10090",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Primate",
+                                                   "mapped_target_concept": {
+                                                     "label": "Primates",
+                                                     "id": "NCBITaxon:9443",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Macaque",
+                                                   "mapped_target_concept": {
+                                                     "label": "Macaca",
+                                                     "id": "NCBITaxon:9541",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Dogs",
+                                                   "mapped_target_concept": {
+                                                     "label": "Canis lupus familiaris",
+                                                     "id": "NCBITaxon:9615",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 }
+             ],
+            "url": "https://deeplabcut.github.io/DeepLabCut/docs/ModelZoo.html"
+            "mentions": {
+                "datasets": ["Quadruped-80K", "AnimalPose", "AwA-Pose", "AcinoSet", "Horse-30", "StanfordDogs", "AP-10K", "iRodent"],
+                "benchmarks": ["AP-10K", "AnimalPose", "Horse-10", "iRodent"],
+                "models": ["DeepLabCut"],
+                "papers": ["10.48550/arXiv.2203.07436"]
+           }
+       }],
+      ...
+      }
+
+    agent_id: alignment_agent
+
+  judge_task:
+    description: >
+      Take the output of alignment agent {aligned_structured_information} as input and perform the following evaluation: 
+      1. Assess the quality and accuracy of the alignment with the BBQS standards in {aligned_structured_information}.
+      2. Assign a score between 0 and 1 as a judge_score.
+      3. Update the {aligned_structured_information} adding the judge_score.
+
+    expected_output: > 
+      output format: json 
+      Example output:
+      "judge_resource": {
+                        "1": [{
+                    "name": "DeepLabCut Model Zoo - SuperAnimal-Quadruped",
+                  "description": "A DeepLabCut SuperAnimal pre-trained model for quadruped animal pose estimation using DeepLabCut, trained on the TopViewMouse-5K dataset.",
+                  "type": "Model",
+                  "category": "Pose Estimation",
+      "target": "Animal",
+            "mapped_target_concept": [
+                             {
+                               "id": "http://purl.obolibrary.org/obo/BTO_0000042",
+                               "label": "animal",
+                               "ontology": "BTO"
+            }],
+            "specific_target": "Quadruped, Horse, Mice, Primate, Macaque, Dogs, Rodents",
+             "mapped_specific_target_concept": [
+                                                 {
+                                                   "specific_target": "Quadruped",
+                                                   "mapped_target_concept": {
+                                                     "label": "Tetrapoda",
+                                                     "id": "NCBITaxon:32523",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Horse",
+                                                   "mapped_target_concept": {
+                                                     "label": "Equus caballus",
+                                                     "id": "NCBITaxon:9796",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Mice",
+                                                   "mapped_target_concept": {
+                                                     "label": "Mus musculus",
+                                                     "id": "NCBITaxon:10090",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Primate",
+                                                   "mapped_target_concept": {
+                                                     "label": "Primates",
+                                                     "id": "NCBITaxon:9443",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Macaque",
+                                                   "mapped_target_concept": {
+                                                     "label": "Macaca",
+                                                     "id": "NCBITaxon:9541",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Dogs",
+                                                   "mapped_target_concept": {
+                                                     "label": "Canis lupus familiaris",
+                                                     "id": "NCBITaxon:9615",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 }
+             ],
+                  "url": "https://deeplabcut.github.io/DeepLabCut/docs/ModelZoo.html"
+                  "mentions": {
+                      "datasets": ["Quadruped-80K", "AnimalPose", "AwA-Pose", "AcinoSet", "Horse-30", "StanfordDogs", "AP-10K", "iRodent"],
+                      "benchmarks": ["AP-10K", "AnimalPose", "Horse-10", "iRodent"],
+                      "models": ["DeepLabCut"],
+                      "papers": ["10.48550/arXiv.2203.07436"]
+                  }
+                  "judge_score": 0.95
+      }],
+      ...
+      }
+
+    agent_id: judge_agent
+
+  humanfeedback_task:
+    description: > 
+      Take the output of alignment agent {judged_structured_information_with_human_feedback} as input and perform the following evaluation as an human expert: 
+            1. Assess the quality and accuracy of the alignment with the BBQS standards in {aligned_structured_information}.
+            2. Assign a score between 0 and 1 as a judge_score.
+            3. Update the {judged_structured_information_with_human_feedback} adding the judge_score.
+  
+      Additionally process the received human feedback.
+      Important: The number of extracted entities should not be less than what you received.
+      modification_context: 
+        {modification_context}
+      
+      user_feedback_text:
+        {user_feedback_text} 
+
+    expected_output: > 
+      output format: json
+      Example output:
+      "judge_resource": {
+                              "1":[{
+                          "name": "DeepLabCut Model Zoo - SuperAnimal-Quadruped",
+                        "description": "A DeepLabCut SuperAnimal pre-trained model for quadruped animal pose estimation using DeepLabCut, trained on the TopViewMouse-5K dataset.",
+                        "type": "Model",
+                        "category": "Pose Estimation",
+      "target": "Animal",
+            "mapped_target_concept": [
+                             {
+                               "id": "http://purl.obolibrary.org/obo/BTO_0000042",
+                               "label": "animal",
+                               "ontology": "BTO"
+            }],
+            "specific_target": "Quadruped, Horse, Mice, Primate, Macaque, Dogs, Rodents",
+             "mapped_specific_target_concept": [
+                                                 {
+                                                   "specific_target": "Quadruped",
+                                                   "mapped_target_concept": {
+                                                     "label": "Tetrapoda",
+                                                     "id": "NCBITaxon:32523",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Horse",
+                                                   "mapped_target_concept": {
+                                                     "label": "Equus caballus",
+                                                     "id": "NCBITaxon:9796",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Mice",
+                                                   "mapped_target_concept": {
+                                                     "label": "Mus musculus",
+                                                     "id": "NCBITaxon:10090",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Primate",
+                                                   "mapped_target_concept": {
+                                                     "label": "Primates",
+                                                     "id": "NCBITaxon:9443",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Macaque",
+                                                   "mapped_target_concept": {
+                                                     "label": "Macaca",
+                                                     "id": "NCBITaxon:9541",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Dogs",
+                                                   "mapped_target_concept": {
+                                                     "label": "Canis lupus familiaris",
+                                                     "id": "NCBITaxon:9615",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 }
+             ],
+                        "url": "https://deeplabcut.github.io/DeepLabCut/docs/ModelZoo.html"
+                        "mentions": {
+                            "datasets": ["Quadruped-80K", "AnimalPose", "AwA-Pose", "AcinoSet", "Horse-30", "StanfordDogs", "AP-10K", "iRodent"],
+                            "benchmarks": ["AP-10K", "AnimalPose", "Horse-10", "iRodent"],
+                            "models": ["DeepLabCut"],
+                            "papers": ["10.48550/arXiv.2203.07436"]
+                        }
+                        "judge_score": 0.95
+            }],
+            ...
+            }
+
+    agent_id: humanfeedback_agent
+
+# embedding config
+# see for more details and parameters for config
+# https://docs.crewai.com/concepts/memory#additional-embedding-providerscl
+embedder_config:
+  provider: ollama
+  config:
+    api_base: http://localhost:11434
+    model: nomic-embed-text:latest
+
+# knowledge search config
+knowledge_config:
+  search_key: #local vector database
+    - entity
+    - label
+# human in loop config
+human_in_loop_config:
+  humanfeedback_agent: true
\ No newline at end of file
diff --git a/evaluation/resource_extraction/old/resource_config_gpt.yaml b/evaluation/resource_extraction/old/resource_config_gpt.yaml
new file mode 100644
index 0000000..528bf6b
--- /dev/null
+++ b/evaluation/resource_extraction/old/resource_config_gpt.yaml
@@ -0,0 +1,420 @@
+#agent config
+agent_config:
+  extractor_agent:
+    role: >
+     Brain and Behavior Quantification and Synchronization (BBQS) Resource Extractor Agent
+    goal: >
+      Extract a single structured resource entry per input relevant to the Brain Behavior Quantification and Synchronization (BBQS) consortium. Capture related subjects as secondary mentions.
+    backstory: >
+      You are a research assistant working with the Brain Behavior Quantification and Synchronization (BBQS) consortium.
+      BBQS is an NIH-funded research effort focused on tools, datasets, models, and benchmarks that advance understanding of brain-behavior relationships.
+
+            The consortium tracks resources in the following categories:
+            - Models (e.g., pose estimation models, embedding models)
+            - Datasets (e.g., annotated video data, behavioral recordings)
+            - Papers (e.g., methods or applications related to behavioral quantification)
+            - Tools (e.g., analysis software, labeling interfaces)
+            - Benchmarks (e.g., standardized datasets or protocols for evaluating performance)
+            - Leaderboards (e.g., systems ranking models based on performance on a task)
+
+            Your input will be a description, webpage, or paper about a **single primary resource**. However, that resource may mention other entities like datasets, benchmarks, or tools. These should not be extracted as separate resources.
+
+            Instead, extract the primary resource with the following fields:
+            - name
+            - description
+            - type (Model, Dataset, Paper, Tool, Benchmark, Leaderboard)
+            - category (e.g., Pose Estimation, Gaze Detection, Behavioral Quantification)
+            - target (e.g., Animal, Human, Mammals)
+            - specific targets (e.g., Mice, Fish, Macaque)
+            - url (GitHub, HuggingFace, arXiv, lab site, etc.)
+            - mentions (optional: dictionary with fields like models, datasets, benchmarks, papers)
+
+            Also include a `mentions` field if applicable. This is a dictionary that may include referenced datasets, models, benchmarks, or tools used or described within the resource. 
+            Be mindful that webpages may contain many extraneous references and links that are not relevant to the primary resource and should not be included in mentions.
+            If a field is missing or unknown, use `null`. Only return a single JSON object under the key `resource`.
+    llm:
+      model: openrouter/openai/gpt-4o-mini
+      base_url: https://openrouter.ai/api/v1
+
+  alignment_agent:
+    role: >
+      Brain and Behavior Quantification and Synchronization (BBQS) Concept Alignment Agent
+    goal: >
+      Align extracted resource information with controlled vocabularies or domain-specific schemas used by BBQS.
+    backstory: >
+      You are an alignment assistant trained to normalize resource metadata according to the BBQS standard. 
+      Your task is to align fields such as `type`, `category`, `target`, and `specific_target` using existing schemas, correcting typos or ambiguities as needed. 
+      You take one resource object and update it accordingly.
+      You return the updated structured resources in JSON format, maintaining the original format but with aligned values.
+      Mentions may be left as-is or annotated if appropriate, using knowledge from existing schemas.
+    llm:
+      model: openrouter/openai/gpt-4o-mini
+      base_url: https://openrouter.ai/api/v1
+
+  judge_agent:
+    role: >
+      Brain and Behavior Quantification and Synchronization (BBQS) Judge Agent
+    goal: >
+      Evaluate the {aligned_structured_information} based on predefined criteria and generate a structured JSON output reflecting the assessment results.
+    backstory: >
+      You are a reviewer and evaluator for the BBQS resource curation pipeline, and someone who does not hallucinate.  
+      Your job is to assess how well the {aligned_structured_information} conform to BBQS standards. 
+      You return a confidence score between 0 and 1, along with a rationale. 
+      You only score the primary resource, not its mentions.
+      Your responses are in JSON and preserve the original fields while appending evaluation metadata.
+    llm:
+      model: openrouter/openai/gpt-4o-mini
+      base_url: https://openrouter.ai/api/v1
+
+  humanfeedback_agent:
+    role: >
+      Brain and Behavior Quantification and Synchronization (BBQS) Human feedback processor Agent
+    goal: >
+      Evaluate the {judged_structured_information_with_human_feedback} and review if everything is correct as human domain expert.
+    backstory: >
+      You are a human reviewer and evaluator for the BBQS resource curation pipeline, and someone who does not hallucinate.  
+      Your job is to assess how well the {judged_structured_information_with_human_feedback} conform to BBQS standards. 
+      You return a confidence score between 0 and 1, along with a rationale. 
+      You only score the primary resource, not its mentions.
+      Your responses are in JSON and preserve the original fields while appending evaluation metadata.
+
+    llm:
+      model: openrouter/openai/gpt-4o-mini
+      base_url: https://openrouter.ai/api/v1
+
+# agent task config
+task_config:
+  extraction_task:
+    description: >
+      Extract structured metadata about scientific resources relevant to BBQS from the given {literature}
+      Each input should yield **one resource** only. If the input mentions other resources, include them under a `mentions` field but do not extract them as separate entries.
+
+      Return the following fields in JSON format:
+              - name
+              - description
+              - type (Model, Dataset, Tool, Paper, Benchmark, Leaderboard)
+              - category (e.g., Pose Estimation, Behavioral Quantification)
+              - target (e.g., Animal, Human, Mammals)
+              - specific target (e.g., Mice, Macaque, Bird)
+              - url
+              - mentions (optional: dictionary with fields like models, datasets, benchmarks, papers)
+
+      Use `null` if information is missing.
+      
+      Important:
+        Do not copy the example output.
+
+    Resource:
+      { literature }
+
+    expected_output: >
+      output format: json
+      Example output:
+      "extracted_resources": {
+      
+        "1": [{ 
+           "name": "DeepLabCut Model Zoo - SuperAnimal-Quadruped",
+            "description": "Pre-trained model for quadruped animal pose estimation using DeepLabCut.",
+            "type": "Model",
+            "category": "Pose Estimation",
+            "target": "Animal",
+            "specific_target": "Quadruped, Horse, Mice",
+            "mentions": {
+                "datasets": ["Quadruped-80K", "AnimalPose", "AwA-Pose", "AcinoSet", "Horse-30", "StanfordDogs", "AP-10K", "iRodent"],
+                "benchmarks": ["AP-10K", "AnimalPose", "Horse-10", "iRodent"],
+                "models": ["DeepLabCut"],
+            }
+        }],
+      ...
+      }
+
+    agent_id: extractor_agent
+
+  alignment_task:
+    description: >
+      Take the output of extractor_agent as input and perform the concept alignment based on existing resources. 
+      A concept alignment is anything where you align the given entity to the matching concept aka class from the existing set of resources. If you can't align just place N/A.
+      
+      Inputs: {extracted_structured_information}
+
+    expected_output: >
+      output format: json
+      Example output:
+      "aligned_resources": {
+       "1":[{
+          "name": "DeepLabCut Model Zoo - SuperAnimal-Quadruped",
+            "description": "A DeepLabCut SuperAnimal pre-trained model for quadruped animal pose estimation using DeepLabCut, trained on the TopViewMouse-5K dataset.",
+            "type": "Model",
+            "category": "Pose Estimation",
+            "target": "Animal",
+             "mapped_target_concept": [
+                             {
+                               "id": "http://purl.obolibrary.org/obo/BTO_0000042",
+                               "label": "animal",
+                               "ontology": "BTO"
+            }],
+            "specific_target": "Quadruped, Horse, Mice, Primate, Macaque, Dogs, Rodents",
+             "mapped_specific_target_concept": [
+                                                 {
+                                                   "specific_target": "Quadruped",
+                                                   "mapped_target_concept": {
+                                                     "label": "Tetrapoda",
+                                                     "id": "NCBITaxon:32523",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Horse",
+                                                   "mapped_target_concept": {
+                                                     "label": "Equus caballus",
+                                                     "id": "NCBITaxon:9796",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Mice",
+                                                   "mapped_target_concept": {
+                                                     "label": "Mus musculus",
+                                                     "id": "NCBITaxon:10090",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Primate",
+                                                   "mapped_target_concept": {
+                                                     "label": "Primates",
+                                                     "id": "NCBITaxon:9443",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Macaque",
+                                                   "mapped_target_concept": {
+                                                     "label": "Macaca",
+                                                     "id": "NCBITaxon:9541",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Dogs",
+                                                   "mapped_target_concept": {
+                                                     "label": "Canis lupus familiaris",
+                                                     "id": "NCBITaxon:9615",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 }
+             ],
+            "url": "https://deeplabcut.github.io/DeepLabCut/docs/ModelZoo.html"
+            "mentions": {
+                "datasets": ["Quadruped-80K", "AnimalPose", "AwA-Pose", "AcinoSet", "Horse-30", "StanfordDogs", "AP-10K", "iRodent"],
+                "benchmarks": ["AP-10K", "AnimalPose", "Horse-10", "iRodent"],
+                "models": ["DeepLabCut"],
+                "papers": ["10.48550/arXiv.2203.07436"]
+           }
+       }],
+      ...
+      }
+
+    agent_id: alignment_agent
+
+  judge_task:
+    description: >
+      Take the output of alignment agent {aligned_structured_information} as input and perform the following evaluation: 
+      1. Assess the quality and accuracy of the alignment with the BBQS standards in {aligned_structured_information}.
+      2. Assign a score between 0 and 1 as a judge_score.
+      3. Update the {aligned_structured_information} adding the judge_score.
+
+    expected_output: > 
+      output format: json 
+      Example output:
+      "judge_resource": {
+                        "1": [{
+                    "name": "DeepLabCut Model Zoo - SuperAnimal-Quadruped",
+                  "description": "A DeepLabCut SuperAnimal pre-trained model for quadruped animal pose estimation using DeepLabCut, trained on the TopViewMouse-5K dataset.",
+                  "type": "Model",
+                  "category": "Pose Estimation",
+      "target": "Animal",
+            "mapped_target_concept": [
+                             {
+                               "id": "http://purl.obolibrary.org/obo/BTO_0000042",
+                               "label": "animal",
+                               "ontology": "BTO"
+            }],
+            "specific_target": "Quadruped, Horse, Mice, Primate, Macaque, Dogs, Rodents",
+             "mapped_specific_target_concept": [
+                                                 {
+                                                   "specific_target": "Quadruped",
+                                                   "mapped_target_concept": {
+                                                     "label": "Tetrapoda",
+                                                     "id": "NCBITaxon:32523",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Horse",
+                                                   "mapped_target_concept": {
+                                                     "label": "Equus caballus",
+                                                     "id": "NCBITaxon:9796",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Mice",
+                                                   "mapped_target_concept": {
+                                                     "label": "Mus musculus",
+                                                     "id": "NCBITaxon:10090",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Primate",
+                                                   "mapped_target_concept": {
+                                                     "label": "Primates",
+                                                     "id": "NCBITaxon:9443",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Macaque",
+                                                   "mapped_target_concept": {
+                                                     "label": "Macaca",
+                                                     "id": "NCBITaxon:9541",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Dogs",
+                                                   "mapped_target_concept": {
+                                                     "label": "Canis lupus familiaris",
+                                                     "id": "NCBITaxon:9615",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 }
+             ],
+                  "url": "https://deeplabcut.github.io/DeepLabCut/docs/ModelZoo.html"
+                  "mentions": {
+                      "datasets": ["Quadruped-80K", "AnimalPose", "AwA-Pose", "AcinoSet", "Horse-30", "StanfordDogs", "AP-10K", "iRodent"],
+                      "benchmarks": ["AP-10K", "AnimalPose", "Horse-10", "iRodent"],
+                      "models": ["DeepLabCut"],
+                      "papers": ["10.48550/arXiv.2203.07436"]
+                  }
+                  "judge_score": 0.95
+      }],
+      ...
+      }
+
+    agent_id: judge_agent
+
+  humanfeedback_task:
+    description: > 
+      Take the output of alignment agent {judged_structured_information_with_human_feedback} as input and perform the following evaluation as an human expert: 
+            1. Assess the quality and accuracy of the alignment with the BBQS standards in {aligned_structured_information}.
+            2. Assign a score between 0 and 1 as a judge_score.
+            3. Update the {judged_structured_information_with_human_feedback} adding the judge_score.
+  
+      Additionally process the received human feedback.
+      Important: The number of extracted entities should not be less than what you received.
+      modification_context: 
+        {modification_context}
+      
+      user_feedback_text:
+        {user_feedback_text} 
+
+    expected_output: > 
+      output format: json
+      Example output:
+      "judge_resource": {
+                              "1":[{
+                          "name": "DeepLabCut Model Zoo - SuperAnimal-Quadruped",
+                        "description": "A DeepLabCut SuperAnimal pre-trained model for quadruped animal pose estimation using DeepLabCut, trained on the TopViewMouse-5K dataset.",
+                        "type": "Model",
+                        "category": "Pose Estimation",
+      "target": "Animal",
+            "mapped_target_concept": [
+                             {
+                               "id": "http://purl.obolibrary.org/obo/BTO_0000042",
+                               "label": "animal",
+                               "ontology": "BTO"
+            }],
+            "specific_target": "Quadruped, Horse, Mice, Primate, Macaque, Dogs, Rodents",
+             "mapped_specific_target_concept": [
+                                                 {
+                                                   "specific_target": "Quadruped",
+                                                   "mapped_target_concept": {
+                                                     "label": "Tetrapoda",
+                                                     "id": "NCBITaxon:32523",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Horse",
+                                                   "mapped_target_concept": {
+                                                     "label": "Equus caballus",
+                                                     "id": "NCBITaxon:9796",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Mice",
+                                                   "mapped_target_concept": {
+                                                     "label": "Mus musculus",
+                                                     "id": "NCBITaxon:10090",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Primate",
+                                                   "mapped_target_concept": {
+                                                     "label": "Primates",
+                                                     "id": "NCBITaxon:9443",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Macaque",
+                                                   "mapped_target_concept": {
+                                                     "label": "Macaca",
+                                                     "id": "NCBITaxon:9541",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 },
+                                                 {
+                                                   "specific_target": "Dogs",
+                                                   "mapped_target_concept": {
+                                                     "label": "Canis lupus familiaris",
+                                                     "id": "NCBITaxon:9615",
+                                                     "ontology": "NCBITaxon"
+                                                   }
+                                                 }
+             ],
+                        "url": "https://deeplabcut.github.io/DeepLabCut/docs/ModelZoo.html"
+                        "mentions": {
+                            "datasets": ["Quadruped-80K", "AnimalPose", "AwA-Pose", "AcinoSet", "Horse-30", "StanfordDogs", "AP-10K", "iRodent"],
+                            "benchmarks": ["AP-10K", "AnimalPose", "Horse-10", "iRodent"],
+                            "models": ["DeepLabCut"],
+                            "papers": ["10.48550/arXiv.2203.07436"]
+                        }
+                        "judge_score": 0.95
+            }],
+            ...
+            }
+
+    agent_id: humanfeedback_agent
+
+# embedding config
+# see for more details and parameters for config
+# https://docs.crewai.com/concepts/memory#additional-embedding-providerscl
+embedder_config:
+  provider: ollama
+  config:
+    api_base: http://localhost:11434
+    model: nomic-embed-text:latest
+
+# knowledge search config
+knowledge_config:
+  search_key: #local vector database
+    - entity
+    - label
+# human in loop config
+human_in_loop_config:
+  humanfeedback_agent: true
\ No newline at end of file
diff --git a/evaluation/resource_extraction/readme.md b/evaluation/resource_extraction/readme.md
new file mode 100644
index 0000000..87d16d1
--- /dev/null
+++ b/evaluation/resource_extraction/readme.md
@@ -0,0 +1,120 @@
+# 🧠 BBQS Resource Extraction Pipeline
+
+This project uses `structsense` to extract and curate structured metadata about scientific resources relevant to the Brain Behavior Quantification and Synchronization (BBQS) consortium. The pipeline focuses on tools, datasets, models, and benchmarks that advance understanding of brain-behavior relationships.
+
+---
+
+## 🔬 What This System Does
+
+Given a scientific paper, webpage, or resource description, this pipeline:
+
+1. **Extracts structured metadata** about a single primary resource (name, type, category, target species, URL)
+2. **Captures secondary mentions** of related datasets, models, benchmarks, or tools referenced within the resource
+3. **Aligns target species** with standardized ontologies (e.g., NCBITaxon)
+4. **Evaluates extraction quality** with confidence scores from 0-1
+5. **Incorporates human feedback** to refine and validate the extracted information
+
+---
+
+## 🧑‍💼 Agents & Their Roles
+
+| Agent Name           | Description |
+|----------------------|-------------|
+| `extractor_agent`    | Extracts one structured resource entry per input, capturing related resources as secondary mentions |
+| `alignment_agent`    | Aligns metadata fields with controlled vocabularies and maps species to ontology terms |
+| `judge_agent`        | Evaluates extraction quality and BBQS standard compliance with confidence scores |
+| `humanfeedback_agent`| Reviews and refines results based on domain expert feedback |
+
+---
+
+## 📁 Expected Output Structure
+
+The pipeline produces a JSON file containing the final evaluation from the judge agent.
+
+Key points:
+1. **Format**: Always a JSON file
+2. **Content**: One resource per input with the following structure:
+   - Primary resource metadata (name, description, type, category, targets)
+   - Ontological mappings for target species
+   - Optional mentions of related resources
+   - Confidence scores and evaluation rationale
+
+Resource types include:
+- **Models**: Pose estimation models, embedding models, etc.
+- **Datasets**: Annotated video data, behavioral recordings
+- **Papers**: Methods or applications for behavioral quantification
+- **Tools**: Analysis software, labeling interfaces
+- **Benchmarks**: Standardized evaluation datasets or protocols
+- **Leaderboards**: Model performance ranking systems
+
+---
+
+## 📚 Example Papers
+
+1. Xu, Y., Zhang, J., Zhang, Q., & Tao, D. (2022). Vitpose: Simple vision transformer baselines for human pose estimation. Advances in neural information processing systems, 35, 38571-38584.
+2. Lauer, J., Zhou, M., Ye, S. et al. Multi-animal pose estimation, identification and tracking with DeepLabCut. Nat Methods 19, 496–504 (2022). https://doi.org/10.1038/s41592-022-01443-0 
+---
+
+## 🧪 Usage
+
+### Using OpenRouter
+```bash
+structsense-cli extract \
+  --source your_resource_paper.pdf \
+  --api_key <YOUR_API_KEY> \
+  --config <config-file>.yaml \
+  --env_file .env \
+  --save_file result.json  # optional
+```
+
+### Using Ollama (Local)
+```bash
+structsense-cli extract \
+  --source your_resource_paper.pdf \
+  --config <config-file>.yaml \
+  --env_file .env \
+  --save_file result.json  # optional
+```
+
+### Tips
+
+- The configuration file (`config.yaml`) is pre-configured for BBQS resource extraction
+- Each input should describe a single primary resource
+- Secondary resources mentioned within the primary resource are captured in the `mentions` field
+- Best suited for papers, webpages, or descriptions about behavioral quantification tools and datasets
+
+---
+
+## 🔍 Resource Categories
+
+The system extracts resources in these categories:
+
+### Primary Categories
+- **Pose Estimation**: Models and tools for tracking animal/human body positions
+- **Gaze Detection**: Eye tracking and visual attention systems
+- **Behavioral Quantification**: General behavior analysis frameworks
+- **Motion Analysis**: Movement pattern detection and classification
+
+### Target Species
+Automatically mapped to ontologies:
+- **General**: Animal, Human, Mammals
+- **Specific**: Mice (NCBITaxon:10090), Macaque (NCBITaxon:9541), Dogs (NCBITaxon:9615), etc.
+
+### Secondary Mentions
+Resources referenced within the primary resource:
+- Related models and architectures
+- Training/evaluation datasets
+- Benchmark datasets
+- Associated tools or software
+
+---
+
+## 🤖 Language Models
+
+The current `config.yaml` specifies `openrouter/openai/gpt-4o-mini` as the default LLM. However, for evaluation purposes, this pipeline has been tested with:
+
+- **GPT-4o-mini** by OpenAI
+- **Claude 3.5 Sonnet** by Anthropic
+- **DeepSeek V3** (open-source model) by DeepSeek
+
+You can modify the LLM settings in the `agent_config` section of `config.yaml` to use different models based on your requirements.
\ No newline at end of file
diff --git a/poetry.lock b/poetry.lock
index 19c9b7e..84320cd 100644
--- a/poetry.lock
+++ b/poetry.lock
@@ -893,14 +893,14 @@ rapidfuzz = ">=3.0.0,<4.0.0"
 
 [[package]]
 name = "click"
-version = "8.3.1"
+version = "8.1.8"
 description = "Composable command line interface toolkit"
 optional = false
-python-versions = ">=3.10"
+python-versions = ">=3.7"
 groups = ["main"]
 files = [
-    {file = "click-8.3.1-py3-none-any.whl", hash = "sha256:981153a64e25f12d547d3426c367a4857371575ee7ad18df2a6183ab0545b2a6"},
-    {file = "click-8.3.1.tar.gz", hash = "sha256:12ff4785d337a1bb490bb7e9c2b1ee5da3112e94a8622f26a6c77f5d2fc6842a"},
+    {file = "click-8.1.8-py3-none-any.whl", hash = "sha256:63c132bbbed01578a06712a2d1f497bb62d9c1c0d329b7903a866228027263b2"},
+    {file = "click-8.1.8.tar.gz", hash = "sha256:ed53c9d8990d83c2a27deae68e4ee337473f6330c040a31d4225c9574d16096a"},
 ]
 
 [package.dependencies]
@@ -1756,6 +1756,24 @@ files = [
     {file = "durationpy-0.10.tar.gz", hash = "sha256:1fa6893409a6e739c9c72334fc65cca1f355dbdd93405d30f726deb5bde42fba"},
 ]
 
+[[package]]
+name = "dydantic"
+version = "0.0.8"
+description = "Dynamically generate pydantic models from JSON schema."
+optional = false
+python-versions = "<4.0,>=3.9"
+groups = ["main"]
+files = [
+    {file = "dydantic-0.0.8-py3-none-any.whl", hash = "sha256:cd0a991f523bd8632699872f1c0c4278415dd04783e36adec5428defa0afb721"},
+    {file = "dydantic-0.0.8.tar.gz", hash = "sha256:14a31d4cdfce314ce3e69e8f8c7c46cbc26ce3ce4485de0832260386c612942f"},
+]
+
+[package.dependencies]
+pydantic = ">=2,<3"
+
+[package.extras]
+email = ["email-validator (>=2.1,<3.0)"]
+
 [[package]]
 name = "et-xmlfile"
 version = "2.0.0"
@@ -3179,6 +3197,33 @@ files = [
 [package.extras]
 dev = ["build (==1.2.2.post1)", "coverage (==7.5.3)", "mypy (==1.13.0)", "pip (==24.3.1)", "pylint (==3.2.3)", "ruff (==0.7.3)", "twine (==5.1.1)", "uv (==0.5.1)"]
 
+[[package]]
+name = "jsonpatch"
+version = "1.33"
+description = "Apply JSON-Patches (RFC 6902)"
+optional = false
+python-versions = ">=2.7, !=3.0.*, !=3.1.*, !=3.2.*, !=3.3.*, !=3.4.*, !=3.5.*, !=3.6.*"
+groups = ["main"]
+files = [
+    {file = "jsonpatch-1.33-py2.py3-none-any.whl", hash = "sha256:0ae28c0cd062bbd8b8ecc26d7d164fbbea9652a1a3693f3b956c1eae5145dade"},
+    {file = "jsonpatch-1.33.tar.gz", hash = "sha256:9fcd4009c41e6d12348b4a0ff2563ba56a2923a7dfee731d004e212e1ee5030c"},
+]
+
+[package.dependencies]
+jsonpointer = ">=1.9"
+
+[[package]]
+name = "jsonpointer"
+version = "3.0.0"
+description = "Identify specific nodes in a JSON document (RFC 6901)"
+optional = false
+python-versions = ">=3.7"
+groups = ["main"]
+files = [
+    {file = "jsonpointer-3.0.0-py2.py3-none-any.whl", hash = "sha256:13e088adc14fca8b6aa8177c044e12701e6ad4b28ff10e65f2267a90109c9942"},
+    {file = "jsonpointer-3.0.0.tar.gz", hash = "sha256:2b2d729f2091522d61c3b31f82e11870f60b68f43fbc705cb76bf4b832af59ef"},
+]
+
 [[package]]
 name = "jsonref"
 version = "1.1.0"
@@ -3408,6 +3453,128 @@ websocket-client = ">=0.32.0,<0.40.0 || >0.40.0,<0.41.dev0 || >=0.43.dev0"
 [package.extras]
 adal = ["adal (>=1.0.2)"]
 
+[[package]]
+name = "langchain-core"
+version = "1.2.15"
+description = "Building applications with LLMs through composability"
+optional = false
+python-versions = "<4.0.0,>=3.10.0"
+groups = ["main"]
+files = [
+    {file = "langchain_core-1.2.15-py3-none-any.whl", hash = "sha256:8d920d8a31d8c223966a3993d8c79fd6093b9665f2222fc878812f3a52072ab7"},
+    {file = "langchain_core-1.2.15.tar.gz", hash = "sha256:7d5f5d2daa8ddbe4054a96101dc5d509926f831b9914808c24640987d499758c"},
+]
+
+[package.dependencies]
+jsonpatch = ">=1.33.0,<2.0.0"
+langsmith = ">=0.3.45,<1.0.0"
+packaging = ">=23.2.0"
+pydantic = ">=2.7.4,<3.0.0"
+pyyaml = ">=5.3.0,<7.0.0"
+tenacity = ">=8.1.0,<8.4.0 || >8.4.0,<10.0.0"
+typing-extensions = ">=4.7.0,<5.0.0"
+uuid-utils = ">=0.12.0,<1.0"
+
+[[package]]
+name = "langgraph"
+version = "1.0.9"
+description = "Building stateful, multi-actor applications with LLMs"
+optional = false
+python-versions = ">=3.10"
+groups = ["main"]
+files = [
+    {file = "langgraph-1.0.9-py3-none-any.whl", hash = "sha256:bce0d1f3e9a20434215a2a818395a58aedfc11c87bd6b52706c0db5c05ec44ec"},
+    {file = "langgraph-1.0.9.tar.gz", hash = "sha256:feac2729faba7d3c325bef76f240d7d7f66b02d2cbf4fdb1ed7d0cc83f963651"},
+]
+
+[package.dependencies]
+langchain-core = ">=0.1"
+langgraph-checkpoint = ">=2.1.0,<5.0.0"
+langgraph-prebuilt = ">=1.0.8,<1.1.0"
+langgraph-sdk = ">=0.3.0,<0.4.0"
+pydantic = ">=2.7.4"
+xxhash = ">=3.5.0"
+
+[[package]]
+name = "langgraph-checkpoint"
+version = "4.0.0"
+description = "Library with base interfaces for LangGraph checkpoint savers."
+optional = false
+python-versions = ">=3.10"
+groups = ["main"]
+files = [
+    {file = "langgraph_checkpoint-4.0.0-py3-none-any.whl", hash = "sha256:3fa9b2635a7c5ac28b338f631abf6a030c3b508b7b9ce17c22611513b589c784"},
+    {file = "langgraph_checkpoint-4.0.0.tar.gz", hash = "sha256:814d1bd050fac029476558d8e68d87bce9009a0262d04a2c14b918255954a624"},
+]
+
+[package.dependencies]
+langchain-core = ">=0.2.38"
+ormsgpack = ">=1.12.0"
+
+[[package]]
+name = "langgraph-prebuilt"
+version = "1.0.8"
+description = "Library with high-level APIs for creating and executing LangGraph agents and tools."
+optional = false
+python-versions = ">=3.10"
+groups = ["main"]
+files = [
+    {file = "langgraph_prebuilt-1.0.8-py3-none-any.whl", hash = "sha256:d16a731e591ba4470f3e313a319c7eee7dbc40895bcf15c821f985a3522a7ce0"},
+    {file = "langgraph_prebuilt-1.0.8.tar.gz", hash = "sha256:0cd3cf5473ced8a6cd687cc5294e08d3de57529d8dd14fdc6ae4899549efcf69"},
+]
+
+[package.dependencies]
+langchain-core = ">=1.0.0"
+langgraph-checkpoint = ">=2.1.0,<5.0.0"
+
+[[package]]
+name = "langgraph-sdk"
+version = "0.3.9"
+description = "SDK for interacting with LangGraph API"
+optional = false
+python-versions = ">=3.10"
+groups = ["main"]
+files = [
+    {file = "langgraph_sdk-0.3.9-py3-none-any.whl", hash = "sha256:94654294250c920789b6ed0d8a70c0117fed5736b61efc24ff647157359453c5"},
+    {file = "langgraph_sdk-0.3.9.tar.gz", hash = "sha256:8be8958529b3f6d493ec248fdb46e539362efda75784654a42a7091d22504e0e"},
+]
+
+[package.dependencies]
+httpx = ">=0.25.2"
+orjson = ">=3.11.5"
+
+[[package]]
+name = "langsmith"
+version = "0.7.6"
+description = "Client library to connect to the LangSmith Observability and Evaluation Platform."
+optional = false
+python-versions = ">=3.10"
+groups = ["main"]
+files = [
+    {file = "langsmith-0.7.6-py3-none-any.whl", hash = "sha256:28d256584969db723b68189a7dbb065836572728ab4d9597ec5379fe0a1e1641"},
+    {file = "langsmith-0.7.6.tar.gz", hash = "sha256:e8646f8429d3c1641c7bae3c01bfdc3dfa27625994b0ef4303714d6b06fe1ef9"},
+]
+
+[package.dependencies]
+httpx = ">=0.23.0,<1"
+orjson = {version = ">=3.9.14", markers = "platform_python_implementation != \"PyPy\""}
+packaging = ">=23.2"
+pydantic = ">=2,<3"
+requests = ">=2.0.0"
+requests-toolbelt = ">=1.0.0"
+uuid-utils = ">=0.12.0,<1.0"
+xxhash = ">=3.0.0"
+zstandard = ">=0.23.0"
+
+[package.extras]
+claude-agent-sdk = ["claude-agent-sdk (>=0.1.0) ; python_version >= \"3.10\""]
+google-adk = ["google-adk (>=1.0.0)", "wrapt (>=1.16.0)"]
+langsmith-pyo3 = ["langsmith-pyo3 (>=0.1.0rc2)"]
+openai-agents = ["openai-agents (>=0.0.3)"]
+otel = ["opentelemetry-api (>=1.30.0)", "opentelemetry-exporter-otlp-proto-http (>=1.30.0)", "opentelemetry-sdk (>=1.30.0)"]
+pytest = ["pytest (>=7.0.0)", "rich (>=13.9.4)", "vcrpy (>=7.0.0)"]
+vcr = ["vcrpy (>=7.0.0)"]
+
 [[package]]
 name = "litellm"
 version = "1.75.3"
@@ -5193,6 +5360,65 @@ files = [
     {file = "orjson-3.11.5.tar.gz", hash = "sha256:82393ab47b4fe44ffd0a7659fa9cfaacc717eb617c93cde83795f14af5c2e9d5"},
 ]
 
+[[package]]
+name = "ormsgpack"
+version = "1.12.2"
+description = "Fast, correct Python msgpack library supporting dataclasses, datetimes, and numpy"
+optional = false
+python-versions = ">=3.10"
+groups = ["main"]
+files = [
+    {file = "ormsgpack-1.12.2-cp310-cp310-macosx_10_12_x86_64.macosx_11_0_arm64.macosx_10_12_universal2.whl", hash = "sha256:c1429217f8f4d7fcb053523bbbac6bed5e981af0b85ba616e6df7cce53c19657"},
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 version = "7.7.0"
@@ -6625,28 +6851,6 @@ psutil = ["psutil (>=3.0)"]
 setproctitle = ["setproctitle"]
 testing = ["filelock"]
 
-[[package]]
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-version = "3.8.0"
-description = "pytest xdist plugin for distributed testing, most importantly across multiple CPUs"
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-python-versions = ">=3.9"
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-pytest = ">=7.0.0"
-
-[package.extras]
-psutil = ["psutil (>=3.0)"]
-setproctitle = ["setproctitle"]
-testing = ["filelock"]
-
 [[package]]
 name = "python-dateutil"
 version = "2.9.0.post0"
@@ -8718,6 +8922,23 @@ files = [
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 ]
 
+[[package]]
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+description = "Tenacious & trustworthy tool calling built on LangGraph."
+optional = false
+python-versions = "<4.0,>=3.10"
+groups = ["main"]
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+jsonpatch = ">=1.33,<2.0"
+langgraph = ">=0.2.25"
+
 [[package]]
 name = "typer"
 version = "0.20.0"
@@ -8813,6 +9034,38 @@ h2 = ["h2 (>=4,<5)"]
 socks = ["pysocks (>=1.5.6,!=1.5.7,<2.0)"]
 zstd = ["zstandard (>=0.18.0)"]
 
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+optional = false
+python-versions = ">=3.9"
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 [[package]]
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 version = "0.9.17"
@@ -9583,6 +9836,156 @@ cffi = ">=1.16.0"
 [package.extras]
 test = ["pytest"]
 
+[[package]]
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+version = "3.6.0"
+description = "Python binding for xxHash"
+optional = false
+python-versions = ">=3.7"
+groups = ["main"]
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+]
+
 [[package]]
 name = "yarl"
 version = "1.22.0"
@@ -9863,4 +10266,4 @@ cffi = ["cffi (>=1.17,<2.0) ; platform_python_implementation != \"PyPy\" and pyt
 [metadata]
 lock-version = "2.1"
 python-versions = ">=3.10,<3.13"
-content-hash = "7b1447eff6c073c88856bc5057ca2367fda5642cac68da017e79e88e13f39ce8"
+content-hash = "9a5374b691735256f0e4f204a525099686e7637780f0a428a8d147827231b4d7"
diff --git a/pyproject.toml b/pyproject.toml
index 91f8504..63874c0 100644
--- a/pyproject.toml
+++ b/pyproject.toml
@@ -54,6 +54,8 @@ spacy = "^3.8.11"
 litellm = {version = ">=1.17.0,<1.80.0"}
 transformers = ">=4.30.0,<4.46.0"
 torch = "^2.10.0"
+json-repair = ">=0.25.2,<0.26.0"
+trustcall = "^0.0.39"
 
 [tool.poetry.group.dev]
 optional = true
diff --git a/src/structsense/app.py b/src/structsense/app.py
index 0011807..6fc4a1a 100644
--- a/src/structsense/app.py
+++ b/src/structsense/app.py
@@ -90,6 +90,7 @@
     normalize_final_result_for_output,
     promote_canonical_resources_for_resource_task,
     ensure_resource_mapped_concepts_provenance,
+    _flatten_container_to_list,
 )
 from .humanloop import HumanInTheLoop
 
@@ -977,38 +978,48 @@ async def information_extraction_task(
                     metadata={"stage_index": idx - 1}
                 )
 
-                # Prepare token-managed input based on agent type
+                # Each agent always takes the previous agent's output (no exception).
+                # Alignment <- extractor; Judge <- alignment; Human feedback <- judge + human input.
                 if task_key == "alignment_task":
+                    # Alignment always takes previous agent (extractor) output
+                    extraction_output = pipeline_stages.get(ordered_pairs[0][1]) if idx >= 1 else prev_output
+                    if extraction_output is None:
+                        extraction_output = prev_output
+                    if not isinstance(extraction_output, dict):
+                        extraction_output = prev_output if isinstance(prev_output, dict) else {}
                     logger.info(f"[{agent_key}] Preparing token-managed input for alignment agent")
                     managed_input = prepare_alignment_agent_input(
-                        extraction_results=prev_output,
+                        extraction_results=extraction_output,
                         original_text=text,
                         agent_context=self.agent_context,
                         context_manager=self.context_manager,
                         max_tokens=self.token_limit
                     )
-                    # Use managed input as extra_inputs
                     extra_inputs = managed_input
-                    stage_text = None  # Will use extra_inputs instead
+                    stage_text = None
                 elif task_key == "judge_task":
+                    # Judge always takes previous agent (alignment) output
+                    alignment_output = pipeline_stages.get("alignment_task") if idx >= 2 else prev_output
+                    if alignment_output is None:
+                        alignment_output = prev_output
+                    if not isinstance(alignment_output, dict):
+                        alignment_output = prev_output if isinstance(prev_output, dict) else {}
                     logger.info(f"[{agent_key}] Preparing token-managed input for judge agent")
-                    # Get extraction results from context if available
                     extraction_results = None
-                    if idx >= 2:  # There was an extraction stage before alignment
-                        extraction_agent_key, extraction_task_key = ordered_pairs[0]
+                    if idx >= 2:
+                        extraction_agent_key, _ = ordered_pairs[0]
                         extraction_result = self.agent_context.get_latest_result(extraction_agent_key)
                         if extraction_result:
                             extraction_results = extraction_result.result
-
                     managed_input = prepare_judge_agent_input(
-                        alignment_results=prev_output,
+                        alignment_results=alignment_output,
                         extraction_results=extraction_results,
                         agent_context=self.agent_context,
                         context_manager=self.context_manager,
                         max_tokens=self.token_limit
                     )
                     extra_inputs = managed_input
-                    stage_text = None  # Will use extra_inputs instead
+                    stage_text = None
                 else:
                     # For other downstream stages or if not alignment/judge, use JSON string
                     stage_text = json.dumps(prev_output, indent=2) if isinstance(prev_output, dict) else str(prev_output)
@@ -1065,18 +1076,19 @@ async def information_extraction_task(
                                 feedback_text = f"{feedback_text}\n\nModification Context:\n{mod_context}"
 
                 if not humanfeedback_approved_skip_run:
-                    # If still no feedback, use a default (only when we will run the agent)
                     if not feedback_text:
                         feedback_text = modification_context or "No specific feedback provided."
 
-                    # Prepare token-managed input for humanfeedback agent (only when running agent)
-                    alignment_for_human = None
-                    alignment_ctx = self.agent_context.get_latest_result("alignment_agent") if self.agent_context else None
-                    if alignment_ctx:
-                        alignment_for_human = alignment_ctx.result
+                    # Human feedback always takes previous agent (judge) output + human input
+                    judge_output = pipeline_stages.get("judge_task") if len(ordered_pairs) >= 3 else prev_output
+                    if judge_output is None:
+                        judge_output = prev_output
+                    if not isinstance(judge_output, dict):
+                        judge_output = prev_output if isinstance(prev_output, dict) else {}
+                    alignment_for_human = pipeline_stages.get("alignment_task")  # for helper's merge when needed
                     logger.info(f"[{agent_key}] Preparing token-managed input for humanfeedback agent")
                     managed_input = prepare_humanfeedback_agent_input(
-                        judge_results=prev_output,
+                        judge_results=judge_output,
                         user_feedback=feedback_text,
                         alignment_results=alignment_for_human,
                         agent_context=self.agent_context,
@@ -1084,7 +1096,7 @@ async def information_extraction_task(
                         max_tokens=self.token_limit
                     )
                     extra_inputs = managed_input
-                    stage_text = None  # Will use extra_inputs instead
+                    stage_text = None
             elif task_key != "humanfeedback_task" and not is_first_stage and extra_inputs is None:
                 # For other downstream stages, extra_inputs was set above
                 pass
@@ -1238,10 +1250,20 @@ async def run_one_structured_chunk(chunk_payload: Dict[str, Any]) -> Dict[str, A
                         if len(results_list) > 1 and task_key in ("alignment_task", "judge_task"):
                             ckey = TASK_KEY_TO_CONTAINER_KEY.get(task_key) or self._detect_container_key(results_list[0])
                             if ckey:
-                                prev_output = merge_downstream_chunk_results_with_provenance(
-                                    results_list, ckey, agent_key
-                                )
-                                pipeline_stages[task_key] = prev_output
+                                try:
+                                    prev_output = merge_downstream_chunk_results_with_provenance(
+                                        results_list, ckey, agent_key
+                                    )
+                                    pipeline_stages[task_key] = prev_output
+                                except (AttributeError, TypeError, KeyError, ValueError) as e:
+                                    logger.warning(
+                                        "Merge of downstream chunk results failed (%s); using first result. %s",
+                                        task_key,
+                                        e,
+                                        exc_info=True,
+                                    )
+                                    prev_output = results_list[0] if results_list else prev_output
+                                    pipeline_stages[task_key] = prev_output
                             else:
                                 prev_output = results_list[0] if results_list else prev_output
                                 pipeline_stages[task_key] = prev_output
@@ -1304,6 +1326,8 @@ async def run_one_structured_chunk(chunk_payload: Dict[str, Any]) -> Dict[str, A
         if isinstance(final, dict) and len(final) >= 1:
             for key in unwrap_keys:
                 inner = final.get(key)
+                if inner is None:
+                    continue
                 if isinstance(inner, dict) and (
                     "entities" in inner or "key_terms" in inner or "resources" in inner or "judge_resource" in inner
                 ):
@@ -1312,6 +1336,16 @@ async def run_one_structured_chunk(chunk_payload: Dict[str, Any]) -> Dict[str, A
                     final = {**inner, **rest}
                     logger.debug("Unwrapped final result from key %s", key)
                     break
+                # Judge/alignment may return a list of entities (e.g. after chunked merge) or a dict-of-lists
+                if isinstance(inner, (list, dict)):
+                    flattened = _flatten_container_to_list(inner)
+                    if flattened and all(isinstance(x, dict) for x in flattened):
+                        final["entities"] = flattened
+                        final["key_terms"] = final.get("key_terms") or (
+                            inner.get("key_terms") if isinstance(inner, dict) else []
+                        )
+                        logger.debug("Unwrapped final result from key %s (list/container, %d entities)", key, len(flattened))
+                    break
         final["errors"] = all_errors
         final["task_type"] = task_type
         final["elapsed_time"] = elapsed_time
diff --git a/src/utils/downstream_agent_helper.py b/src/utils/downstream_agent_helper.py
index fbff12c..8380c6f 100644
--- a/src/utils/downstream_agent_helper.py
+++ b/src/utils/downstream_agent_helper.py
@@ -43,8 +43,10 @@ def prepare_alignment_agent_input(
     """
     Prepare input for alignment agent with token limit management.
 
+    Alignment always receives the previous agent's (extractor) output. No exception.
+
     Args:
-        extraction_results: Results from extraction agent
+        extraction_results: Results from extraction agent (previous agent). Required.
         original_text: Original input text
         agent_context: Optional AgentContext for accessing extraction metadata
         context_manager: Optional ContextWindowManager for token management
@@ -140,9 +142,11 @@ def prepare_judge_agent_input(
     """
     Prepare input for judge agent with token limit management.
 
+    Judge always receives the previous agent's (alignment) output. No exception.
+
     Args:
-        alignment_results: Results from alignment agent
-        extraction_results: Optional original extraction results
+        alignment_results: Results from alignment agent (previous agent). Required.
+        extraction_results: Optional original extraction results (for merging into judge input).
         agent_context: Optional AgentContext
         context_manager: Optional ContextWindowManager
         max_tokens: Maximum tokens
@@ -228,12 +232,13 @@ def prepare_humanfeedback_agent_input(
 ) -> Dict[str, Any]:
     """
     Prepare input for human feedback agent with token limit management.
-    Judge output extends alignment; if judge is empty we pass alignment so human feedback has content.
+
+    Human feedback always receives the previous agent's (judge) output plus human input. No exception.
 
     Args:
-        judge_results: Results from judge agent (alignment extended with judge_score/remarks)
-        user_feedback: Human feedback text
-        alignment_results: Optional alignment output; used to extend when judge is empty
+        judge_results: Results from judge agent (previous agent). Required.
+        user_feedback: Human feedback text. Required when running the agent.
+        alignment_results: Optional alignment output; used by helper to extend judge when needed
         agent_context: Optional AgentContext
         context_manager: Optional ContextWindowManager
         max_tokens: Maximum tokens
diff --git a/src/utils/json_repair_tool.py b/src/utils/json_repair_tool.py
new file mode 100644
index 0000000..48a5c59
--- /dev/null
+++ b/src/utils/json_repair_tool.py
@@ -0,0 +1,289 @@
+# -*- coding: utf-8 -*-
+# -----------------------------------------------------------------------------
+# DISCLAIMER: This software is provided "as is" without any warranty,
+# express or implied, including but not limited to the warranties of
+# merchantability, fitness for a particular purpose, and non-infringement.
+#
+# In no event shall the authors or copyright holders be liable for any
+# claim, damages, or other liability, whether in an action of contract,
+# tort, or otherwise, arising from, out of, or in connection with the
+# software or the use or other dealings in the software.
+# -----------------------------------------------------------------------------
+
+"""Tool to repair malformed JSON from LLM output.
+Two stage repair: first json_repair library (no LLM). Handles trailing commas, single quotes,
+markdown fences, Python booleans/None, truncated JSON.
+
+
+Second stage, when json_repair library fails: Uses TrustCall with the calling agent's LLM config.
+Schema comes from (in order): (1) agent-provided ``schema`` argument,
+(2) default from task type (task_tools._resolve_tool), (3) **inferred from the
+malformed input** (top-level keys and types). No hardcoded generic shape—unknown
+tasks use the structure found in the input to build the schema and fix. If
+extraction fails, we retry with the agent's schema when the agent passed one.
+
+Add to poetry or install:
+pip install json-repair
+Optional for second stage: pip install trustcall and either langchain-openrouter or langchain-openai
+"""
+
+import json
+import re
+import logging
+from pydantic import BaseModel
+from typing import Any, Dict, List, Optional
+
+from crewai.tools import tool
+from json_repair import repair_json as jr_repair
+
+logger = logging.getLogger(__name__)
+
+# LLM context for TrustCall fallback (set from agent config when tool is resolved)
+_repair_llm_context: Optional[Dict[str, Any]] = None
+# Default schema hint for Layer 2 when agent does not pass schema (set from task type at resolve time)
+_repair_default_schema: Optional[str] = None
+
+# Default JSON schema hints by pipeline task type (for TrustCall Layer 2 when agent omits schema).
+# Unknown task types do not use a hardcoded fallback; schema is inferred from the malformed input instead.
+DEFAULT_SCHEMAS_BY_TASK: Dict[str, str] = {
+    "ner": '{"entities": "array", "key_terms": "array", "resources": "array"}',
+    "resource": '{"resources": "array"}',
+    "structured_extraction": '{"resources": "array", "entities": "array", "key_terms": "array"}',
+    "keyphrase_extraction": '{"key_terms": "array", "entities": "array"}',
+    "relation_extraction": '{"entities": "array", "relations": "array"}',
+}
+
+
+def _infer_schema_from_raw(raw: str) -> Optional[str]:
+    """Infer a minimal JSON schema hint from the malformed input (top-level keys and types).
+
+    Used when no agent schema and no task-type default; avoids hardcoded shapes so
+    any task (custom keys) can be repaired. Returns e.g. '{"my_key": "array", "meta": "object"}'.
+    """
+    if not raw or not raw.strip():
+        return None
+    # 1) Try to parse as dict and infer from structure
+    try:
+        obj = jr_repair(raw, return_objects=True)
+        if isinstance(obj, dict):
+            hint: Dict[str, str] = {}
+            for k, v in obj.items():
+                key = str(k).strip()
+                if not key:
+                    continue
+                if isinstance(v, list):
+                    hint[key] = "array"
+                elif isinstance(v, dict):
+                    hint[key] = "object"
+                else:
+                    hint[key] = "string"
+            if hint:
+                return json.dumps(hint)
+    except Exception:
+        pass
+    # 2) Regex fallback: find top-level "key": or 'key': and next token [ { or literal
+    hint = {}
+    # Match "key": or 'key': or key: (unquoted)
+    for m in re.finditer(r'''["']?([^"'\s:{}]+)["']?\s*:\s*''', raw):
+        key = (m.group(1) or "").strip()
+        if not key or key in ("true", "false", "null"):
+            continue
+        rest = raw[m.end() : m.end() + 200].lstrip()
+        if rest.startswith("["):
+            hint[key] = "array"
+        elif rest.startswith("{"):
+            hint[key] = "object"
+        elif rest.startswith('"') or rest.startswith("'"):
+            hint[key] = "string"
+        else:
+            hint[key] = "string"
+    if hint:
+        return json.dumps(hint)
+    return None
+
+
+def get_default_schema_for_task_type(task_type: str) -> Optional[str]:
+    """Return the default schema hint for TrustCall Layer 2 for the given task type.
+
+    Unknown task types return None; the tool will then infer schema from the input (no hardcoded shape).
+    """
+    if not task_type:
+        return None
+    key = str(task_type).strip().lower()
+    return DEFAULT_SCHEMAS_BY_TASK.get(key)
+
+
+def set_repair_json_default_schema(schema: Optional[str] = None) -> None:
+    """Set default schema hint for Layer 2 when the agent does not pass schema.
+
+    Called from task_tools._resolve_tool when attaching repair_json with a task_type.
+    """
+    global _repair_default_schema
+    _repair_default_schema = schema
+
+
+def clear_repair_json_default_schema() -> None:
+    """Clear the default schema hint."""
+    global _repair_default_schema
+    _repair_default_schema = None
+
+
+def set_repair_json_llm_context(
+    llm_config: Optional[Dict[str, Any]] = None,
+    api_key: Optional[str] = None,
+) -> None:
+    """Set LLM config for TrustCall fallback so it uses the same model as the calling agent.
+
+    Called from task_tools._resolve_tool when attaching repair_json to an agent.
+    """
+    global _repair_llm_context
+    _repair_llm_context = (
+        {"llm_config": llm_config or {}, "api_key": api_key}
+        if (llm_config and (llm_config.get("model") or llm_config.get("base_url")))
+        else None
+    )
+
+
+def clear_repair_json_llm_context() -> None:
+    """Clear stored LLM context."""
+    global _repair_llm_context
+    _repair_llm_context = None
+
+
+@tool("repair_json")
+def repair_json_tool(malformed_json: str, schema: Optional[str] = None) -> str:
+    """
+    Repair malformed or broken JSON from LLM output.
+
+    Layer 1: Lightweight parser (trailing commas, single quotes, markdown fences, etc.).
+    Layer 2: If repair fails, uses TrustCall. Schema order: agent-provided > task-type
+    default > inferred from malformed input (no hardcoded shape). Retries with
+    agent's schema when the first attempt fails and the agent passed one.
+
+    Args:
+        malformed_json: The broken JSON string to repair.
+        schema: Optional JSON schema hint. Takes precedence; used for retry if extraction with default/inferred fails.
+
+    Returns:
+        A valid JSON string, or {"error": "...", "raw_preview": "..."} if repair fails.
+    """
+    raw = malformed_json.strip()
+
+    m = re.search(r"```(?:json|JSON)?\s*\n?(.*?)```", raw, re.DOTALL)
+    if m:
+        raw = m.group(1).strip()
+
+    try:
+        repaired = jr_repair(raw, return_objects=True)
+        return json.dumps(repaired, indent=2)
+    except Exception as e:
+        logger.debug("json_repair failed: %s", e)
+
+    # Layer 2 schema: agent > task-type default > inferred from input (no hardcoded "other").
+    schema_hint = schema or _repair_default_schema or _infer_schema_from_raw(raw)
+    if schema_hint and _repair_llm_context:
+        try:
+            return _trustcall_extract(raw, schema_hint)
+        except Exception as e:
+            logger.warning("TrustCall fallback failed with schema hint: %s", e)
+            # No match or validation failed: retry with agent's schema when agent passed one.
+            if schema and schema != schema_hint:
+                try:
+                    return _trustcall_extract(raw, schema)
+                except Exception as e2:
+                    logger.warning("TrustCall retry with agent schema failed: %s", e2)
+
+    return json.dumps({"error": "Could not repair JSON", "raw_preview": raw[:500]})
+
+
+def _trustcall_extract(raw: str, schema_hint: str) -> str:
+    """Use TrustCall with the agent's LLM config (from set_repair_json_llm_context)."""
+    global _repair_llm_context
+    if not _repair_llm_context:
+        raise ValueError("LLM context not set for repair_json; cannot use TrustCall fallback")
+
+    try:
+        from trustcall import create_extractor
+    except ImportError as e:
+        raise ValueError(
+            "TrustCall fallback requires: pip install trustcall"
+        ) from e
+
+    llm_config = _repair_llm_context.get("llm_config") or {}
+    api_key = _repair_llm_context.get("api_key") or ""
+    base_url = (llm_config.get("base_url") or "").strip().lower()
+    model = llm_config.get("model") or "openai/gpt-4o-mini"
+    if "openrouter" in base_url and isinstance(model, str) and model.startswith("openrouter/"):
+        model = model.replace("openrouter/", "", 1)
+
+    # Prefer OpenRouter client when config points to OpenRouter; else OpenAI-compatible (ChatOpenAI + base_url)
+    if "openrouter" in base_url:
+        try:
+            from langchain_openrouter import ChatOpenRouter
+            llm = ChatOpenRouter(
+                model=model,
+                temperature=0,
+                **({"api_key": api_key} if api_key else {}),
+            )
+        except ImportError:
+            from langchain_openai import ChatOpenAI
+            llm = ChatOpenAI(
+                model=model,
+                openai_api_key=api_key,
+                openai_api_base=llm_config.get("base_url") or "https://openrouter.ai/api/v1",
+                temperature=0,
+            )
+    else:
+        from langchain_openai import ChatOpenAI
+        llm = ChatOpenAI(
+            model=model,
+            openai_api_key=api_key,
+            openai_api_base=llm_config.get("base_url") or None,
+            temperature=0,
+        )
+    DynamicModel = _build_model_from_schema(schema_hint)
+    extractor = create_extractor(llm, tools=[DynamicModel], tool_choice=DynamicModel.__name__)
+    result = extractor.invoke({
+        "messages": [("user", f"Extract data matching this schema from the text.\nSchema: {schema_hint}\n\nText:\n{raw}")]
+    })
+    if result.get("responses"):
+        return result["responses"][0].model_dump_json(indent=2)
+    raise ValueError("TrustCall returned no responses")
+
+
+def _build_model_from_schema(schema_hint: str) -> type:
+    """Build a Pydantic model from a JSON schema hint (e.g. {\"entities\": \"array\", \"key_terms\": \"array\"})."""
+
+
+    try:
+        hint = json.loads(jr_repair(schema_hint, return_objects=False))
+    except Exception:
+        hint = {}
+
+    # Use typing so Pydantic/TrustCall can validate (list -> List[Any], dict -> Dict[str, Any])
+    annotations: Dict[str, type] = {}
+    defaults: Dict[str, Any] = {}
+    for k, v in hint.items():
+        val = str(v).lower()
+        if val in ("list", "array"):
+            annotations[k] = List[Any]
+            defaults[k] = []
+        elif val in ("dict", "object"):
+            annotations[k] = Dict[str, Any]
+            defaults[k] = {}
+        elif val in ("string", "str"):
+            annotations[k] = str
+            defaults[k] = ""
+        elif val in ("int", "integer"):
+            annotations[k] = int
+            defaults[k] = 0
+        elif val in ("float", "number"):
+            annotations[k] = float
+            defaults[k] = 0.0
+        elif val in ("bool", "boolean"):
+            annotations[k] = bool
+            defaults[k] = False
+        else:
+            annotations[k] = Any
+            defaults[k] = None
+    return type("ExtractedData", (BaseModel,), {"__annotations__": annotations, **defaults})
diff --git a/src/utils/postprocessing.py b/src/utils/postprocessing.py
index d1967e3..168cc1d 100644
--- a/src/utils/postprocessing.py
+++ b/src/utils/postprocessing.py
@@ -626,15 +626,24 @@ def _extract_resources_from_raw(raw_result: Dict[str, Any]) -> List[Dict[str, An
     return []
 
 
+def _scalar_str(val: Any) -> str:
+    """Normalize to a single string for scalar fields; handle list from agent output."""
+    if val is None:
+        return ""
+    if isinstance(val, list):
+        return str(val[0]).strip() if val else ""
+    return str(val).strip()
+
+
 def _normalize_resource_for_merge(res: Dict[str, Any]) -> Dict[str, Any]:
     """Normalize a single resource dict from chunk output (name/mentions) to a common shape.
     Includes downstream fields (judge_score, judge_rationale, etc.) when present.
     """
-    name = (res.get("name") or res.get("resource_name") or "").strip()
+    name = _scalar_str(res.get("name") or res.get("resource_name"))
     out = {
         "name": name,
         "description": res.get("description") or "",
-        "type": (res.get("type") or "").strip(),
+        "type": _scalar_str(res.get("type")),
         "category": res.get("category") or "",
         "target": res.get("target") or "",
         "specific_target": res.get("specific_target") or "",
@@ -656,11 +665,22 @@ def _normalize_resource_for_merge(res: Dict[str, Any]) -> Dict[str, Any]:
     return out
 
 
+def _normalize_str_for_key(val: Any) -> str:
+    """Normalize a value to a string for grouping; handle list/non-string from agent output."""
+    if val is None:
+        return ""
+    if isinstance(val, list):
+        if not val:
+            return ""
+        return " ".join(str(x).strip() for x in val if x is not None).strip().lower()
+    return str(val).strip().lower()
+
+
 def _resource_group_key(res: Dict[str, Any]) -> tuple:
     """Key for grouping same resource across chunks (normalized name + type)."""
-    name = (res.get("name") or "").strip().lower()
-    rtype = (res.get("type") or "").strip().lower()
-    return (name or "unknown", rtype or "unknown")
+    name = _normalize_str_for_key(res.get("name")) or "unknown"
+    rtype = _normalize_str_for_key(res.get("type")) or "unknown"
+    return (name, rtype)
 
 
 def _build_mentions_dict(
@@ -734,17 +754,17 @@ def first_non_empty(*vals: Any) -> Any:
                 return v
         return None
 
-    type_ = first_non_empty(*(r.get("type") for r in group)) or ""
-    category = first_non_empty(*(r.get("category") for r in group)) or ""
-    target = first_non_empty(*(r.get("target") for r in group)) or ""
-    specific_target = first_non_empty(*(r.get("specific_target") for r in group)) or "N/A"
+    type_ = _scalar_str(first_non_empty(*(r.get("type") for r in group)) or "")
+    category = _scalar_str(first_non_empty(*(r.get("category") for r in group)) or "")
+    target = _scalar_str(first_non_empty(*(r.get("target") for r in group)) or "")
+    specific_target = _scalar_str(first_non_empty(*(r.get("specific_target") for r in group)) or "N/A")
     url = first_non_empty(*(r.get("url") for r in group))
-    performance = first_non_empty(*(r.get("performance") for r in group)) or ""
-    model_architecture = first_non_empty(*(r.get("model_architecture") for r in group)) or ""
+    performance = _scalar_str(first_non_empty(*(r.get("performance") for r in group)) or "")
+    model_architecture = _scalar_str(first_non_empty(*(r.get("model_architecture") for r in group)) or "")
 
-    # Longest description
-    description = max((r.get("description") or "" for r in group), key=len)
-    name = best.get("name") or ""
+    # Longest description (handle list from agent)
+    description = max((_scalar_str(r.get("description")) or "" for r in group), key=len)
+    name = _scalar_str(best.get("name"))
 
     # Merge key_features and mapped_* (dedupe; prefer tool-backed entries with real ontology IDs over N/A)
     def _has_real_id(d: Any) -> bool:
@@ -1014,6 +1034,25 @@ def _merge_single_resource_group_with_provenance(
     return merged
 
 
+def _flatten_resource_items(container: Any) -> List[Dict[str, Any]]:
+    """Flatten container to a list of resource dicts; handle dict-of-lists, list, or nested lists from agent output."""
+    out: List[Dict[str, Any]] = []
+    if container is None:
+        return out
+    if isinstance(container, dict):
+        for _k, v in container.items():
+            out.extend(_flatten_resource_items(v))
+        return out
+    if isinstance(container, list):
+        for x in container:
+            if isinstance(x, dict):
+                out.append(x)
+            elif isinstance(x, list):
+                out.extend(_flatten_resource_items(x))
+        return out
+    return out
+
+
 def merge_downstream_chunk_results_with_provenance(
     chunk_results: List[Dict[str, Any]],
     container_key: str,
@@ -1032,26 +1071,25 @@ def merge_downstream_chunk_results_with_provenance(
         if not isinstance(result, dict):
             continue
         container = result.get(container_key)
-        if container is None:
-            continue
-        if isinstance(container, dict):
-            for _k, v in container.items():
-                if isinstance(v, list):
-                    all_items.extend(v)
-                elif isinstance(v, dict):
-                    all_items.append(v)
-        elif isinstance(container, list):
-            all_items.extend(container)
+        all_items.extend(_flatten_resource_items(container))
 
     if not all_items:
-        return {container_key: {} if isinstance(chunk_results[0].get(container_key), dict) else []}
+        first = chunk_results[0] if chunk_results else {}
+        return {container_key: {} if isinstance(first.get(container_key), dict) else []}
 
-    # Group by resource identity (name + type)
+    # Group by resource identity (name + type); skip items that break grouping
     groups: Dict[tuple, List[Dict[str, Any]]] = defaultdict(list)
     for item in all_items:
-        if isinstance(item, dict):
+        if not isinstance(item, dict):
+            continue
+        try:
             key = _resource_group_key(item)
             groups[key].append(item)
+        except (AttributeError, TypeError, KeyError) as e:
+            logger.warning(
+                "Skipping resource item for grouping due to unexpected shape: %s", e
+            )
+            continue
 
     # Merge each group and add provenance
     merged_list = [
@@ -1498,13 +1536,40 @@ def normalize_final_result_for_output(final: Dict[str, Any], task_type: str) ->
         allowed |= {"entities", "key_terms"}
         for key in INTERMEDIATE_CONTAINER_KEYS_NER:
             final.pop(key, None)
-        # If entities/key_terms missing but judge_ner_terms present, flatten
+        # If entities/key_terms missing, promote from judge_ner_terms or any container (hardcoded or root-level dicts).
+        # Check hardcoded pipeline placeholder keys first, then any other key in final whose value is a dict with entities/key_terms.
         if not final.get("entities") and not final.get("key_terms"):
             jn = final.get("judge_ner_terms")
             if jn and isinstance(jn, dict):
                 entities = _flatten_container_to_list(jn)
                 final["entities"] = entities
                 final["key_terms"] = final.get("key_terms") or []
+            else:
+                hardcoded = (
+                    "judged_structured_information_with_human_feedback",
+                    "aligned_structured_information",
+                    "extracted_structured_information",
+                )
+                # Also check any root-level key whose value is a dict with entities/key_terms (not only hardcoded names)
+                container_keys = list(hardcoded)
+                for k, v in final.items():
+                    if k not in hardcoded and isinstance(v, dict) and ("entities" in v or "key_terms" in v):
+                        container_keys.append(k)
+                for container_key in container_keys:
+                    container = final.get(container_key)
+                    if container is None:
+                        continue
+                    if isinstance(container, dict) and ("entities" in container or "key_terms" in container):
+                        final["entities"] = container.get("entities") or []
+                        final["key_terms"] = container.get("key_terms") or final.get("key_terms") or []
+                        break
+                    flattened = _flatten_container_to_list(container)
+                    if flattened:
+                        final["entities"] = flattened
+                        final["key_terms"] = final.get("key_terms") or (
+                            container.get("key_terms") if isinstance(container, dict) else []
+                        )
+                        break
         final.pop("judge_ner_terms", None)
         for key in list(final):
             if key not in allowed:
diff --git a/src/utils/task_tools.py b/src/utils/task_tools.py
index 34d1001..d16ad01 100644
--- a/src/utils/task_tools.py
+++ b/src/utils/task_tools.py
@@ -42,10 +42,10 @@
 # Tools that apply to ALL task types for this agent. Combined with task-specific
 # tools when resolving; order is generic first, then task-specific (deduped by name).
 GENERIC_TOOLS_BY_STAGE: Dict[str, List[str]] = {
-    "extractor_agent": [],
-    "alignment_agent": ["concept_mapping_tool"],
-    "judge_agent": [],
-    "human_feedback": [],
+    "extractor_agent": ["repair_json"],
+    "alignment_agent": ["concept_mapping_tool", "repair_json"],
+    "judge_agent": ["repair_json"],
+    "human_feedback": ["repair_json"],
 }
 
 # ----------------------------
@@ -83,6 +83,7 @@ def _resolve_tool(
     task_config: Optional[Dict[str, Any]] = None,
     agent_key: Optional[str] = None,
     task_key: Optional[str] = None,
+    task_type: Optional[str] = None,
 ) -> Any:
     """Resolve a tool name to a CrewAI tool instance (lazy import).
 
@@ -91,6 +92,7 @@ def _resolve_tool(
     extractor agent's role, goal, and task description for LLM-based NER.
     Otherwise returns the default (ML-only) NER tool. For ``concept_mapping_tool``,
     returns :class:`.conceptmappingtool.ConceptMappingTool` (requires BIOPORTAL_API_KEY).
+    For ``repair_json``, sets LLM context and default schema from task_type when provided.
 
     Parameters
     ----------
@@ -104,6 +106,8 @@ def _resolve_tool(
         Agent key (e.g. ``extractor_agent``); used to read role/goal from agent_config.
     task_key : str, optional
         Task key (e.g. ``extraction_task``); used to read description from task_config.
+    task_type : str, optional
+        Task type (e.g. ``ner``, ``resource``); used to set default schema for repair_json.
 
     Returns
     -------
@@ -148,6 +152,28 @@ def _resolve_tool(
                 logger.warning(f"ConceptMappingTool not registered (missing BIOPORTAL_API_KEY): {e}")
                 return None
         return _TOOL_REGISTRY.get(name)
+    if name == "repair_json":
+        from .json_repair_tool import (
+            get_default_schema_for_task_type,
+            repair_json_tool,
+            set_repair_json_default_schema,
+            set_repair_json_llm_context,
+        )
+        if agent_config and agent_key:
+            agent_cfg = agent_config.get(agent_key) or {}
+            llm_config = agent_cfg.get("llm") or {}
+            api_key = (
+                llm_config.get("api_key")
+                or os.environ.get("OPENROUTER_API_KEY")
+                or os.environ.get("OPENAI_API_KEY")
+                or ""
+            )
+            set_repair_json_llm_context(llm_config=llm_config, api_key=api_key)
+        if task_type:
+            set_repair_json_default_schema(get_default_schema_for_task_type(task_type))
+        if name not in _TOOL_REGISTRY:
+            _TOOL_REGISTRY[name] = repair_json_tool
+        return _TOOL_REGISTRY.get(name)
     if name not in _TOOL_REGISTRY:
         logger.warning(f"Unknown tool name '{name}', skipping")
         return None
@@ -266,6 +292,7 @@ def get_tools_for_agent(
             task_config=task_config,
             agent_key=agent_key,
             task_key=task_key,
+            task_type=task_type,
         )
         if t is not None:
             tools.append(t)