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0 | PMC-1310901-05-MATERIALS_AND_METHODS | [
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS__text",
"type": "abstract",
"text": [
"Expression analysis\nTo analyze the IRF-4 transcriptional level, RNA was extracted from cells using the commercial RNAzol-kit (Paesel, Frankfurt, Germany). An aliquot of 1 mug total RNA was used for cDNA synthesis as described previously (27). RNA expression analysis for IRF-4 and the reference gene beta-actin was carried out by semi-quantitative PCR as described previously (3,27). PCR products were verified by automated sequencing. PCR primers and conditions for expression analysis of DNMT or MBP (DNMT1 DNMT3A, DNMT3B, MeCP, MBD1, MBD2 and MBD4) were published elsewhere (28).\nFor analysis of IRF-4 protein expression, a standard immunoblotting assay was performed as described previously (29). Briefly, protein lysates were generated by incubating 1 x 106 cells in 100 microl RIPA buffer (1% NP-40, 0.5% sodiumdesoxycholate, 0.1% SDS, 100 microg/ml phenylmethylsulfonyl fluoride, 10 microl/ml protease-inhibitory-mix, 1 micromol/ml sodiumorthovanadate in phosphate-buffered saline) for 30 min on ice. After centrifugation, protein concentration of the supernatant was determined by BCA-method (Pierce, Rockford, IL) as recommended. Protein lysates (70-100 microg) were electrophoresed on polyacrylamide gels and transferred to a PVDF-membrane (Immobilon P, 0.45 microm; Millipore, Eschborn, Germany). Membranes were blocked with 2.5% blocking reagent (Boehringer Mannheim, Germany) in TBST buffer (4.44 g/l Tris-HCL, 2.65 g/l TrisOH, 8.07 g/l NaCl, 0.2 g/l KCl and 500 microl/l Tween-20 in H2O) and subsequently incubated with primary antibody as indicated and horseradish peroxidase-conjugated secondary antibody, anti-mouse or anti-goat IgG (DAKO, Hamburg, Germany), respectively. The membranes were then developed with an ECL detection kit (Amersham Pharmacia Biotech, Freiburg, Germany). The primary antibodies were goat anti-IRF-4/ICSAT (M-17) (Santa Cruz Biotechnology, Santa Cruz, CA) and mouse anti-beta-actin (AC-74) (Sigma)."
],
"offsets": [
[
0,
1941
]
]
}
] | [
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_T1",
"type": "Protein",
"text": [
"IRF-4"
],
"offsets": [
[
35,
40
]
],
"normalized": []
},
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_T2",
"type": "Protein",
"text": [
"IRF-4"
],
"offsets": [
[
271,
276
]
],
"normalized": []
},
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_T3",
"type": "Protein",
"text": [
"beta-actin"
],
"offsets": [
[
300,
310
]
],
"normalized": []
},
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_T4",
"type": "Protein",
"text": [
"(DNMT1"
],
"offsets": [
[
502,
508
]
],
"normalized": []
},
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_T5",
"type": "Protein",
"text": [
"DNMT3A"
],
"offsets": [
[
509,
515
]
],
"normalized": []
},
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_T6",
"type": "Protein",
"text": [
"DNMT3B"
],
"offsets": [
[
517,
523
]
],
"normalized": []
},
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_T7",
"type": "Protein",
"text": [
"MeCP"
],
"offsets": [
[
525,
529
]
],
"normalized": []
},
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_T8",
"type": "Protein",
"text": [
"MBD1"
],
"offsets": [
[
531,
535
]
],
"normalized": []
},
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_T9",
"type": "Protein",
"text": [
"MBD2"
],
"offsets": [
[
537,
541
]
],
"normalized": []
},
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_T10",
"type": "Protein",
"text": [
"MBD4"
],
"offsets": [
[
546,
550
]
],
"normalized": []
},
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_T11",
"type": "Protein",
"text": [
"IRF-4"
],
"offsets": [
[
599,
604
]
],
"normalized": []
},
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_T12",
"type": "Protein",
"text": [
"IRF-4"
],
"offsets": [
[
1837,
1842
]
],
"normalized": []
},
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_T13",
"type": "Protein",
"text": [
"ICSAT"
],
"offsets": [
[
1843,
1848
]
],
"normalized": []
},
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_T14",
"type": "Protein",
"text": [
"M-17"
],
"offsets": [
[
1850,
1854
]
],
"normalized": []
},
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_T15",
"type": "Protein",
"text": [
"beta-actin"
],
"offsets": [
[
1914,
1924
]
],
"normalized": []
}
] | [
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_E1",
"type": "Transcription",
"trigger": {
"text": [
"transcriptional"
],
"offsets": [
[
41,
56
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-05-MATERIALS_AND_METHODS_T1"
}
]
},
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_E2",
"type": "Transcription",
"trigger": {
"text": [
"RNA expression"
],
"offsets": [
[
243,
257
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-05-MATERIALS_AND_METHODS_T2"
}
]
},
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_E3",
"type": "Transcription",
"trigger": {
"text": [
"RNA expression"
],
"offsets": [
[
243,
257
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-05-MATERIALS_AND_METHODS_T3"
}
]
},
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_E4",
"type": "Gene_expression",
"trigger": {
"text": [
"expression"
],
"offsets": [
[
467,
477
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-05-MATERIALS_AND_METHODS_T4"
}
]
},
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_E5",
"type": "Gene_expression",
"trigger": {
"text": [
"expression"
],
"offsets": [
[
467,
477
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-05-MATERIALS_AND_METHODS_T5"
}
]
},
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_E6",
"type": "Gene_expression",
"trigger": {
"text": [
"expression"
],
"offsets": [
[
467,
477
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-05-MATERIALS_AND_METHODS_T6"
}
]
},
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_E7",
"type": "Gene_expression",
"trigger": {
"text": [
"expression"
],
"offsets": [
[
467,
477
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-05-MATERIALS_AND_METHODS_T7"
}
]
},
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_E8",
"type": "Gene_expression",
"trigger": {
"text": [
"expression"
],
"offsets": [
[
467,
477
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-05-MATERIALS_AND_METHODS_T8"
}
]
},
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_E9",
"type": "Gene_expression",
"trigger": {
"text": [
"expression"
],
"offsets": [
[
467,
477
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-05-MATERIALS_AND_METHODS_T9"
}
]
},
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_E10",
"type": "Gene_expression",
"trigger": {
"text": [
"expression"
],
"offsets": [
[
467,
477
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-05-MATERIALS_AND_METHODS_T10"
}
]
},
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_E11",
"type": "Gene_expression",
"trigger": {
"text": [
"expression"
],
"offsets": [
[
613,
623
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-05-MATERIALS_AND_METHODS_T11"
}
]
}
] | [
{
"id": "PMC-1310901-05-MATERIALS_AND_METHODS_1",
"entity_ids": [
"PMC-1310901-05-MATERIALS_AND_METHODS_T12",
"PMC-1310901-05-MATERIALS_AND_METHODS_T14",
"PMC-1310901-05-MATERIALS_AND_METHODS_T13"
]
}
] | [] |
1 | PMC-2791889-15-Experimental_Procedures | [
{
"id": "PMC-2791889-15-Experimental_Procedures__text",
"type": "abstract",
"text": [
"Immunoblotting\nDifferentiated CD4+ T cells were rested for 5 hr in 1% FCS-containing medium and restimulated as described for specific experiments. Cell lysates were prepared, equal amounts of protein were separated by SDS-PAGE, and phosphorylated or total ERK and actin were detected as described before (Beinke et al., 2004)."
],
"offsets": [
[
0,
327
]
]
}
] | [
{
"id": "PMC-2791889-15-Experimental_Procedures_T1",
"type": "Protein",
"text": [
"CD4"
],
"offsets": [
[
30,
33
]
],
"normalized": []
},
{
"id": "PMC-2791889-15-Experimental_Procedures_T2",
"type": "Protein",
"text": [
"ERK"
],
"offsets": [
[
257,
260
]
],
"normalized": []
},
{
"id": "PMC-2791889-15-Experimental_Procedures_T3",
"type": "Protein",
"text": [
"actin"
],
"offsets": [
[
265,
270
]
],
"normalized": []
}
] | [] | [] | [] |
2 | PMC-2664230-11-RESULTS | [
{
"id": "PMC-2664230-11-RESULTS__text",
"type": "abstract",
"text": [
"PTX upregulates CREB phosphorylation and activation after LPS stimulation\nPhosphorylation of nuclear CREB was used as a marker for CREB activation. LPS stimulation caused a negligible increase in CREB phosphorylation when compared to control (Figure 4A). PTX alone caused a marked increase in CREB phosphorylation (P < 0.01 vs. HBSS). When LPS and PTX exposure occurred simultaneously, CREB phosphorylation was significantly higher than with LPS stimulation alone (543 +/- 92 vs. 100 +/- 0; P < 0.01). In addition, the amount of CREB phosphorylation seen with concomitant LPS and PTX treatment was less than that seen with PTX alone, although this difference was not statistically significant (P = 0.08).\nTo determine if CREB-DNA binding was affected by PTX in a manner similar to CREB phosphorylation, an EMSA was performed. Exposure of LPS-stimulated cells to PTX similarly increased CREB DNA-binding compared to LPS alone (Figure 4B)."
],
"offsets": [
[
0,
937
]
]
}
] | [
{
"id": "PMC-2664230-11-RESULTS_T1",
"type": "Protein",
"text": [
"CREB"
],
"offsets": [
[
886,
890
]
],
"normalized": []
}
] | [
{
"id": "PMC-2664230-11-RESULTS_E1",
"type": "Positive_regulation",
"trigger": {
"text": [
"increased"
],
"offsets": [
[
876,
885
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2664230-11-RESULTS_E2"
}
]
},
{
"id": "PMC-2664230-11-RESULTS_E2",
"type": "Binding",
"trigger": {
"text": [
"binding"
],
"offsets": [
[
895,
902
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2664230-11-RESULTS_T1"
}
]
}
] | [] | [] |
3 | PMC-3245220-07-Results | [
{
"id": "PMC-3245220-07-Results__text",
"type": "abstract",
"text": [
"M-CSF Induces Phosphorylation of NF-kappaB Ser276 in a PKC-dependent Fashion\nSince M-CSF did not regulate NF-kappaB activation by influencing IkappaBalpha, we next sought to determine if M-CSF affected NF-kappaB p65 by post-translational mechanisms. Thus, we examined the phosphorylation of NF-kappaB p65 with specific phospho-NFkappaB p65 (Ser276 and Ser536) antibodies. M-CSF induced the phosphorylation of Ser276 but not Ser536 of NF-kappaB p65 in MDMs. Compared to vehicle, the general PKC inhibitor Ro-31-8220 reduced Ser276 phosphorylation, but not Ser536, phosphorylation in M-CSF-stimulated cells (Figure 5B). Furthermore, M-CSF-stimulated NF-kappaB p65 phosphorylation at residue Ser276 in RAW 264.7 cells was also PKC dependent (Figure 5C). These studies suggested that PKC(s) regulated Ser276 phosphorylation but not Ser536 in both human MDMs and mouse macrophages after M-CSF stimulation.\nWe next performed cellular fractionation to identify the cellular location of phosphorylated NF-kappaB p65 in Raw 264.7 cells. Non-phosphorylated NF-kappaB p65 was located in both cytosolic and nuclear fractions, but phosphorylated Ser276 and Ser536 NF-kappaB p65 was primarily located in nuclear fraction after M-CSF stimulation (Figure 5D). Notably, constitutive phosphorylation of Ser536 NF-kappaB p65 was found in these cells. Importantly, Ro-31-8220 reduced M-CSF-induced Ser276 phosphorylation of NF-kappaB p65 in both the cytosolic and nuclear fractions, while M-CSF-induced NF-kappaB p65 Ser536 phosphorylation was present in the nucleus regardless of PKC inhibition. These observations indicate that M-CSF-induced Ser276 and Ser536 are regulated differently by conventional PKC activation in mononuclear phagocytes. The purity of the cytosol and nuclear cell fractions was confirmed by immunoblotting with GAPDH and Lamin B, respectively (Figure 5D)."
],
"offsets": [
[
0,
1860
]
]
}
] | [
{
"id": "PMC-3245220-07-Results_T1",
"type": "Protein",
"text": [
"IkappaBalpha"
],
"offsets": [
[
142,
154
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T2",
"type": "Protein",
"text": [
"p65"
],
"offsets": [
[
212,
215
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T3",
"type": "Protein",
"text": [
"p65"
],
"offsets": [
[
301,
304
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T4",
"type": "Protein",
"text": [
"p65"
],
"offsets": [
[
444,
447
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T5",
"type": "Protein",
"text": [
"p65"
],
"offsets": [
[
658,
661
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T6",
"type": "Protein",
"text": [
"p65"
],
"offsets": [
[
1004,
1007
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T7",
"type": "Protein",
"text": [
"p65"
],
"offsets": [
[
1057,
1060
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T8",
"type": "Protein",
"text": [
"p65"
],
"offsets": [
[
1161,
1164
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T9",
"type": "Protein",
"text": [
"p65"
],
"offsets": [
[
1302,
1305
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T10",
"type": "Protein",
"text": [
"p65"
],
"offsets": [
[
1414,
1417
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T11",
"type": "Protein",
"text": [
"p65"
],
"offsets": [
[
1493,
1496
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T19",
"type": "Entity",
"text": [
"Ser276"
],
"offsets": [
[
409,
415
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T20",
"type": "Entity",
"text": [
"Ser536"
],
"offsets": [
[
424,
430
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T22",
"type": "Entity",
"text": [
"Ser276"
],
"offsets": [
[
523,
529
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T24",
"type": "Entity",
"text": [
"Ser536"
],
"offsets": [
[
555,
561
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T28",
"type": "Entity",
"text": [
"Ser276"
],
"offsets": [
[
689,
695
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T31",
"type": "Entity",
"text": [
"Ser276"
],
"offsets": [
[
797,
803
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T33",
"type": "Entity",
"text": [
"Ser536"
],
"offsets": [
[
828,
834
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T39",
"type": "Entity",
"text": [
"both cytosolic and nuclear fractions"
],
"offsets": [
[
1076,
1112
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T41",
"type": "Entity",
"text": [
"Ser276"
],
"offsets": [
[
1133,
1139
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T42",
"type": "Entity",
"text": [
"Ser536"
],
"offsets": [
[
1144,
1150
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T44",
"type": "Entity",
"text": [
"nuclear"
],
"offsets": [
[
1190,
1197
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T46",
"type": "Entity",
"text": [
"Ser536"
],
"offsets": [
[
1285,
1291
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T49",
"type": "Entity",
"text": [
"Ser276"
],
"offsets": [
[
1378,
1384
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T52",
"type": "Entity",
"text": [
"Ser536"
],
"offsets": [
[
1497,
1503
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T55",
"type": "Entity",
"text": [
"Ser276"
],
"offsets": [
[
1624,
1630
]
],
"normalized": []
},
{
"id": "PMC-3245220-07-Results_T56",
"type": "Entity",
"text": [
"Ser536"
],
"offsets": [
[
1635,
1641
]
],
"normalized": []
}
] | [
{
"id": "PMC-3245220-07-Results_E1",
"type": "Regulation",
"trigger": {
"text": [
"affected"
],
"offsets": [
[
193,
201
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_E2"
}
]
},
{
"id": "PMC-3245220-07-Results_E2",
"type": "Protein_modification",
"trigger": {
"text": [
"post-translational mechanisms"
],
"offsets": [
[
219,
248
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_T2"
}
]
},
{
"id": "PMC-3245220-07-Results_E3",
"type": "Phosphorylation",
"trigger": {
"text": [
"phosphorylation"
],
"offsets": [
[
272,
287
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_T3"
}
]
},
{
"id": "PMC-3245220-07-Results_E4",
"type": "Positive_regulation",
"trigger": {
"text": [
"induced"
],
"offsets": [
[
378,
385
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_E5"
}
]
},
{
"id": "PMC-3245220-07-Results_E5",
"type": "Phosphorylation",
"trigger": {
"text": [
"phosphorylation"
],
"offsets": [
[
390,
405
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_T4"
},
{
"role": "Site",
"ref_id": "PMC-3245220-07-Results_T19"
}
]
},
{
"id": "PMC-3245220-07-Results_E6",
"type": "Positive_regulation",
"trigger": {
"text": [
"induced"
],
"offsets": [
[
378,
385
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_E7"
}
]
},
{
"id": "PMC-3245220-07-Results_E7",
"type": "Phosphorylation",
"trigger": {
"text": [
"phosphorylation"
],
"offsets": [
[
390,
405
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_T4"
},
{
"role": "Site",
"ref_id": "PMC-3245220-07-Results_T20"
}
]
},
{
"id": "PMC-3245220-07-Results_E8",
"type": "Negative_regulation",
"trigger": {
"text": [
"reduced"
],
"offsets": [
[
515,
522
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_E9"
}
]
},
{
"id": "PMC-3245220-07-Results_E9",
"type": "Phosphorylation",
"trigger": {
"text": [
"phosphorylation"
],
"offsets": [
[
530,
545
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_T4"
},
{
"role": "Site",
"ref_id": "PMC-3245220-07-Results_T22"
}
]
},
{
"id": "PMC-3245220-07-Results_E10",
"type": "Negative_regulation",
"trigger": {
"text": [
"reduced"
],
"offsets": [
[
515,
522
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_E11"
}
]
},
{
"id": "PMC-3245220-07-Results_E11",
"type": "Phosphorylation",
"trigger": {
"text": [
"phosphorylation"
],
"offsets": [
[
563,
578
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_T4"
},
{
"role": "Site",
"ref_id": "PMC-3245220-07-Results_T24"
}
]
},
{
"id": "PMC-3245220-07-Results_E12",
"type": "Positive_regulation",
"trigger": {
"text": [
"stimulated"
],
"offsets": [
[
637,
647
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_E13"
}
]
},
{
"id": "PMC-3245220-07-Results_E13",
"type": "Phosphorylation",
"trigger": {
"text": [
"phosphorylation"
],
"offsets": [
[
662,
677
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_T5"
},
{
"role": "Site",
"ref_id": "PMC-3245220-07-Results_T28"
}
]
},
{
"id": "PMC-3245220-07-Results_E14",
"type": "Regulation",
"trigger": {
"text": [
"dependent"
],
"offsets": [
[
728,
737
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_E12"
}
]
},
{
"id": "PMC-3245220-07-Results_E15",
"type": "Regulation",
"trigger": {
"text": [
"regulated"
],
"offsets": [
[
787,
796
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_E16"
}
]
},
{
"id": "PMC-3245220-07-Results_E16",
"type": "Phosphorylation",
"trigger": {
"text": [
"phosphorylation"
],
"offsets": [
[
804,
819
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_T5"
},
{
"role": "Site",
"ref_id": "PMC-3245220-07-Results_T31"
}
]
},
{
"id": "PMC-3245220-07-Results_E17",
"type": "Regulation",
"trigger": {
"text": [
"regulated"
],
"offsets": [
[
787,
796
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_E18"
}
]
},
{
"id": "PMC-3245220-07-Results_E18",
"type": "Phosphorylation",
"trigger": {
"text": [
"phosphorylation"
],
"offsets": [
[
804,
819
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_T5"
},
{
"role": "Site",
"ref_id": "PMC-3245220-07-Results_T33"
}
]
},
{
"id": "PMC-3245220-07-Results_E19",
"type": "Positive_regulation",
"trigger": {
"text": [
"stimulation"
],
"offsets": [
[
888,
899
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_E15"
}
]
},
{
"id": "PMC-3245220-07-Results_E20",
"type": "Positive_regulation",
"trigger": {
"text": [
"stimulation"
],
"offsets": [
[
888,
899
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_E17"
}
]
},
{
"id": "PMC-3245220-07-Results_E21",
"type": "Localization",
"trigger": {
"text": [
"location"
],
"offsets": [
[
967,
975
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_T6"
}
]
},
{
"id": "PMC-3245220-07-Results_E22",
"type": "Phosphorylation",
"trigger": {
"text": [
"phosphorylated"
],
"offsets": [
[
979,
993
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_T6"
}
]
},
{
"id": "PMC-3245220-07-Results_E23",
"type": "Phosphorylation",
"trigger": {
"text": [
"phosphorylated"
],
"offsets": [
[
1032,
1046
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_T7"
}
]
},
{
"id": "PMC-3245220-07-Results_E24",
"type": "Localization",
"trigger": {
"text": [
"located"
],
"offsets": [
[
1065,
1072
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_T7"
},
{
"role": "ToLoc",
"ref_id": "PMC-3245220-07-Results_T39"
}
]
},
{
"id": "PMC-3245220-07-Results_E25",
"type": "Phosphorylation",
"trigger": {
"text": [
"phosphorylated"
],
"offsets": [
[
1118,
1132
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_T8"
},
{
"role": "Site",
"ref_id": "PMC-3245220-07-Results_T41"
}
]
},
{
"id": "PMC-3245220-07-Results_E26",
"type": "Phosphorylation",
"trigger": {
"text": [
"phosphorylated"
],
"offsets": [
[
1118,
1132
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_T8"
},
{
"role": "Site",
"ref_id": "PMC-3245220-07-Results_T42"
}
]
},
{
"id": "PMC-3245220-07-Results_E27",
"type": "Localization",
"trigger": {
"text": [
"located"
],
"offsets": [
[
1179,
1186
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_T8"
},
{
"role": "ToLoc",
"ref_id": "PMC-3245220-07-Results_T44"
}
]
},
{
"id": "PMC-3245220-07-Results_E28",
"type": "Phosphorylation",
"trigger": {
"text": [
"phosphorylation"
],
"offsets": [
[
1266,
1281
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_T9"
},
{
"role": "Site",
"ref_id": "PMC-3245220-07-Results_T46"
}
]
},
{
"id": "PMC-3245220-07-Results_E29",
"type": "Negative_regulation",
"trigger": {
"text": [
"reduced"
],
"offsets": [
[
1356,
1363
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_E30"
}
]
},
{
"id": "PMC-3245220-07-Results_E30",
"type": "Positive_regulation",
"trigger": {
"text": [
"induced"
],
"offsets": [
[
1370,
1377
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_E31"
}
]
},
{
"id": "PMC-3245220-07-Results_E31",
"type": "Phosphorylation",
"trigger": {
"text": [
"phosphorylation"
],
"offsets": [
[
1385,
1400
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_T10"
},
{
"role": "Site",
"ref_id": "PMC-3245220-07-Results_T49"
}
]
},
{
"id": "PMC-3245220-07-Results_E32",
"type": "Positive_regulation",
"trigger": {
"text": [
"induced"
],
"offsets": [
[
1475,
1482
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_E33"
}
]
},
{
"id": "PMC-3245220-07-Results_E33",
"type": "Phosphorylation",
"trigger": {
"text": [
"phosphorylation"
],
"offsets": [
[
1504,
1519
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_T11"
},
{
"role": "Site",
"ref_id": "PMC-3245220-07-Results_T52"
}
]
},
{
"id": "PMC-3245220-07-Results_E34",
"type": "Regulation",
"trigger": {
"text": [
"regardless"
],
"offsets": [
[
1547,
1557
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_E32"
}
]
},
{
"id": "PMC-3245220-07-Results_E35",
"type": "Positive_regulation",
"trigger": {
"text": [
"induced"
],
"offsets": [
[
1616,
1623
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_T11"
},
{
"role": "Site",
"ref_id": "PMC-3245220-07-Results_T55"
}
]
},
{
"id": "PMC-3245220-07-Results_E36",
"type": "Positive_regulation",
"trigger": {
"text": [
"induced"
],
"offsets": [
[
1616,
1623
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_T11"
},
{
"role": "Site",
"ref_id": "PMC-3245220-07-Results_T56"
}
]
},
{
"id": "PMC-3245220-07-Results_E37",
"type": "Regulation",
"trigger": {
"text": [
"regulated"
],
"offsets": [
[
1646,
1655
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_E36"
}
]
},
{
"id": "PMC-3245220-07-Results_E38",
"type": "Regulation",
"trigger": {
"text": [
"regulated"
],
"offsets": [
[
1646,
1655
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3245220-07-Results_E35"
}
]
}
] | [] | [] |
4 | PMC-3148254-09-Materials_and_Methods | [
{
"id": "PMC-3148254-09-Materials_and_Methods__text",
"type": "abstract",
"text": [
"Somatic cell gene targeting\nThe generation of HOIP-deficient cells was accomplished using a homologous recombination approach described previously [7], [8]. Segments of Rnf31 gene sequence used in the targeting construct (Fig. 1A) were amplified by PCR from A20.2J genomic DNA. The oligonucleotide primers used to generate the 5' flank (1224 bp) were 5'-ttttctagagcggtggcttaagtgaccc-3' and 5'-tattctagatgcagcatctgagaaagcaagc-3'. The 3' flank (6032 bp) primers were 5'-aaaaccggtgtatgcttctttacgggagaaaaatattag-3' and 5'-tataccggtatgaagccaaaggaacactgagag-3'. Restriction endonuclease sites in the oligonucleotide primers allowed insertion of the PCR products into the targeting vector. A20.2J cells were transfected (by electroporation [7]) with the targeting construct and subcloned in medium containing 600 microg/ml G418 sulfate. Homologous recombination in G418-resistant clones was detected by PCR of genomic DNA, as described [7]. Oligonucleotide primers used for screening were 5'-cttcctgatctcagctttaccgtcac-3' (homologous to genomic sequence; approximate position noted in Fig. 1) and 5'-caatccatcttgttcagccat-3' (homologous to sequence in NeoR). Clones in which one copy of Rnf31 had been disrupted were transiently transfected with an expression plasmid encoding Cre, in order to remove NeoR. G418-sensitive subclones were subjected to a second round of targeting to disrupt the remaining copy of Rnf31. G418-resistant clones were tested for homologous recombination by PCR and HOIP protein expression by Western blot."
],
"offsets": [
[
0,
1525
]
]
}
] | [
{
"id": "PMC-3148254-09-Materials_and_Methods_T1",
"type": "Protein",
"text": [
"HOIP"
],
"offsets": [
[
46,
50
]
],
"normalized": []
},
{
"id": "PMC-3148254-09-Materials_and_Methods_T2",
"type": "Protein",
"text": [
"Rnf31"
],
"offsets": [
[
169,
174
]
],
"normalized": []
},
{
"id": "PMC-3148254-09-Materials_and_Methods_T3",
"type": "Protein",
"text": [
"Rnf31"
],
"offsets": [
[
1180,
1185
]
],
"normalized": []
},
{
"id": "PMC-3148254-09-Materials_and_Methods_T4",
"type": "Protein",
"text": [
"Rnf31"
],
"offsets": [
[
1404,
1409
]
],
"normalized": []
},
{
"id": "PMC-3148254-09-Materials_and_Methods_T5",
"type": "Protein",
"text": [
"HOIP"
],
"offsets": [
[
1485,
1489
]
],
"normalized": []
}
] | [
{
"id": "PMC-3148254-09-Materials_and_Methods_E1",
"type": "Negative_regulation",
"trigger": {
"text": [
"deficient"
],
"offsets": [
[
51,
60
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3148254-09-Materials_and_Methods_T1"
}
]
},
{
"id": "PMC-3148254-09-Materials_and_Methods_E2",
"type": "Negative_regulation",
"trigger": {
"text": [
"disrupted"
],
"offsets": [
[
1195,
1204
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3148254-09-Materials_and_Methods_T3"
}
]
},
{
"id": "PMC-3148254-09-Materials_and_Methods_E3",
"type": "Gene_expression",
"trigger": {
"text": [
"expression"
],
"offsets": [
[
1498,
1508
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3148254-09-Materials_and_Methods_T5"
}
]
}
] | [] | [] |
5 | PMC-2626671-06-RESULTS_AND_DISCUSSION | [
{
"id": "PMC-2626671-06-RESULTS_AND_DISCUSSION__text",
"type": "abstract",
"text": [
"Runx3 controls multiple aspects of the CTL differentiation program, in part through induction of Eomes\nBecause Runx3 is highly expressed in peripheral CD8+ T cells, and because of the T-bet-Runx3 cooperation we observed earlier in CD4+ T cells (15), we examined the role of Runx3 in effector CTL differentiation. We isolated CD8+ T cells from Runx3-/- (KO) mice of the outbred ICR background and their WT Runx3+/+ littermates by positive selection with anti-CD8 magnetic beads (Figs. S1 and S2, available at http://www.jem.org/cgi/content/full/jem.20081242/DC1). Strikingly, Runx3-/- CD8+ T cells were strongly impaired in their ability to differentiate into effector CTLs, as judged by expression of perforin, granzyme B, and IFN-gamma (Fig. 3). Compared with WT T cells, perforin mRNA and protein expression were essentially undetectable in Runx3-/- T cells at day 6 of culture (Fig. 3, A and B). Runx3-/- T cells also had no detectable Eomes expression; in contrast, T-bet expression was unimpaired (Fig. 3 A). Furthermore, Runx3 was required for maximal production of IFN-gamma, but not TNF or IL-2, by CD8+ T cells restimulated at day 6 (Fig. 3 C).\nWe previously reported that Th1 cell differentiation was regulated through a feed-forward loop in which T-bet is up-regulated early and induces Runx3, after which T-bet and Runx3 cooperate to induce IFN-gamma and silence IL-4, thus promoting stable differentiation toward the Th1 lineage (15, 22). Because (a) Runx3 appeared necessary for Eomes induction (Fig. 3 A), (b) the kinetics of Eomes expression paralleled those of perforin expression (Fig. 2), and (c) overexpression of Eo-VP16 in either WT or T-bet-deficient T cells led to an increase in both perforin and IFN-gamma expression (Fig. 2, B and D), we asked whether CTL differentiation was also potentially regulated by a feed-forward loop involving these same two classes of Runx and T-box transcription factors. Specifically, we asked whether Runx3, which was necessary for Eomes induction, then cooperated with Eomes to regulate transcription of the effector CTL markers perforin, IFN-gamma, and granzyme B.\nTo test this hypothesis, we used chromatin immunoprecipitation (ChIP) assays to ask whether Eomes and Runx3 bound regulatory regions of the Prf1, Ifng, and Gzmb genes (Fig. 3 D). Both proteins associated with gene regulatory regions in differentiated CTLs. Runx3 bound to the Prf1 and Gzmb transcription start sites (TSS); to a known IL-2 responsive enhancer located near -1 kb of the Prf1 gene (23); to the distal CTL-specific DNase I hypersensitive site 9 in the Prf1 locus (24); to the Ifng promoter near the TSS, as previously reported for Th1 cells (10); and to several DNase I hypersensitive sites in the Ifng locus (Fig. 3 D and not depicted) (25). Eomes bound primarily to the Prf1 TSS and the -1 kb enhancer; this binding was substantially greater than that observed at the promoter of the Il2rb gene, a known direct target of Eomes (8), and comparable to that observed at the Ifng TSS, a known target of T-box proteins in both Th1 and CD8+ T cells (Fig. 3 D) (17).\nTo determine whether Runx3 controlled the expression of CTL effector genes through its induction of Eomes, we retrovirally expressed Runx3 and Eo-VP16 in CD8+ T cells from Runx3-/- mice. Because of the limited number of CD8+ T cells in these mice, and because we saw no difference between Runx3-/- CD8+CD4- SP and CD8+CD4+ DP cells in our previous experiments, we used total Runx3-/- CD8+ T cells without further fractionation as recipients for retroviral transduction. Reconstitution of Runx3-/- CD8+ T cells with Runx3 restored expression of Eomes as well as perforin, granzyme B, and IFN-gamma (Fig. 4, A and B). In addition, Runx3-/- T cells showed a compensatory up-regulation of Runx1, which was suppressed upon reconstitution with Runx3, indicating that Runx1 is a target of repression by Runx3. Notably, Eo-VP16 did not up-regulate perforin expression when expressed in Runx3-/- cells, even though it restored the capacity to induce IFN-gamma expression upon TCR restimulation (Fig. 4, A and B). This result suggests strongly that perforin expression requires Runx3 and Eomes.\nAs expected from their defect in perforin and granzyme B expression, Runx3-/- CD8+ T cells showed defective cytolytic activity in a mixed lymphocyte reaction (12). However, TCR-stimulated Runx3-/- CD8+ cells were as effective as WT cells in killing tumor cells in a redirected CTL assay (12). Furthermore, CD8+ cells from the peritoneal cavity of Runx3-/- mice immunized with certain tumor cells effectively killed these targets (13). Therefore, although activation of the perforin/granzyme B machinery is defective in Runx3-/- CD8+ cells, these cells are not entirely devoid of cytolytic activity and could still effectively kill targets, possibly by alternative mechanisms such as the Fas-Fas ligand pathway."
],
"offsets": [
[
0,
4894
]
]
}
] | [
{
"id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_T1",
"type": "Protein",
"text": [
"Runx3"
],
"offsets": [
[
0,
5
]
],
"normalized": []
},
{
"id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_T2",
"type": "Protein",
"text": [
"Eomes"
],
"offsets": [
[
97,
102
]
],
"normalized": []
},
{
"id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_T3",
"type": "Protein",
"text": [
"Runx3"
],
"offsets": [
[
111,
116
]
],
"normalized": []
},
{
"id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_T4",
"type": "Protein",
"text": [
"CD8"
],
"offsets": [
[
151,
154
]
],
"normalized": []
},
{
"id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_T5",
"type": "Protein",
"text": [
"T-bet"
],
"offsets": [
[
184,
189
]
],
"normalized": []
},
{
"id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_T6",
"type": "Protein",
"text": [
"Runx3"
],
"offsets": [
[
190,
195
]
],
"normalized": []
},
{
"id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_T7",
"type": "Protein",
"text": [
"CD4"
],
"offsets": [
[
231,
234
]
],
"normalized": []
},
{
"id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_T8",
"type": "Protein",
"text": [
"Runx3"
],
"offsets": [
[
274,
279
]
],
"normalized": []
},
{
"id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_T9",
"type": "Protein",
"text": [
"CD8"
],
"offsets": [
[
325,
328
]
],
"normalized": []
},
{
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"id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_E92",
"type": "Positive_regulation",
"trigger": {
"text": [
"activation"
],
"offsets": [
[
4639,
4649
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_T108"
}
]
},
{
"id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_E93",
"type": "Negative_regulation",
"trigger": {
"text": [
"defective"
],
"offsets": [
[
4690,
4699
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_E91"
}
]
},
{
"id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_E94",
"type": "Negative_regulation",
"trigger": {
"text": [
"defective"
],
"offsets": [
[
4690,
4699
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_E92"
}
]
}
] | [] | [
{
"id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_R1",
"type": "Coreference",
"arg1_id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_T113",
"arg2_id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_T48",
"normalized": []
},
{
"id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_R2",
"type": "Coreference",
"arg1_id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_T113",
"arg2_id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_T49",
"normalized": []
},
{
"id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_R3",
"type": "Coreference",
"arg1_id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_T114",
"arg2_id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_T88",
"normalized": []
},
{
"id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_R4",
"type": "Coreference",
"arg1_id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_T115",
"arg2_id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_T92",
"normalized": []
},
{
"id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_R5",
"type": "Coreference",
"arg1_id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_T116",
"arg2_id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_T97",
"normalized": []
},
{
"id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_R6",
"type": "Coreference",
"arg1_id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_T116",
"arg2_id": "PMC-2626671-06-RESULTS_AND_DISCUSSION_T98",
"normalized": []
}
] |
6 | PMC-3279418-11-Materials_and_Methods | [
{
"id": "PMC-3279418-11-Materials_and_Methods__text",
"type": "abstract",
"text": [
"Generation of BMDC\nBMDC were developed as previously reported [54], [55]. Cells were collected after 10-12 days of culture. The cell yield was 2-3x107 cells/mouse with 80-95% BMDC."
],
"offsets": [
[
0,
180
]
]
}
] | [] | [] | [] | [] |
7 | PMC-2889865-15-Materials_and_methods | [
{
"id": "PMC-2889865-15-Materials_and_methods__text",
"type": "abstract",
"text": [
"Reverse transcription quantitative PCR (RT-qPCR)\nRT-qPCR was used to determine gene expression levels of il-6 and cxcl8 in response to PMA following inhibition of NF-kappaB, JNK and PKC. The following primer sequences were used, il-6: forward- TGTGAAAGCAGCAAAGAGGCACTG, reverse- ACAGCTCTGGCTTGTTCCTCACTA; cxcl8: forward- ACCACACTGCGCCAACACAGAAAT, reverse- AAACTTCTCCACAACCCTCTGCAC. Thermocycling conditions for CYBR Green (Quanta, USA) consisted of a denaturation step for 10 min at 95 degreesC followed by 60 cycles of 95degreesC for 1s and 60degreesC for 30s. Gene expression was analysed using Stratagene (Mx3000p(TM)) (AH diagnostics). The obtained Ct values were normalized against 18S. Initially, all measured 18S Ct values were used to calculate a mean Ct value that was used to determine the deltaCt values for each sample. Gene expression patterns for il-6 and cxcl8 were then normalized with regard to the samples 18S deltaCt."
],
"offsets": [
[
0,
936
]
]
}
] | [
{
"id": "PMC-2889865-15-Materials_and_methods_T1",
"type": "Protein",
"text": [
"il-6"
],
"offsets": [
[
105,
109
]
],
"normalized": []
},
{
"id": "PMC-2889865-15-Materials_and_methods_T2",
"type": "Protein",
"text": [
"cxcl8"
],
"offsets": [
[
114,
119
]
],
"normalized": []
},
{
"id": "PMC-2889865-15-Materials_and_methods_T3",
"type": "Protein",
"text": [
"il-6"
],
"offsets": [
[
229,
233
]
],
"normalized": []
},
{
"id": "PMC-2889865-15-Materials_and_methods_T4",
"type": "Protein",
"text": [
"cxcl8"
],
"offsets": [
[
305,
310
]
],
"normalized": []
},
{
"id": "PMC-2889865-15-Materials_and_methods_T5",
"type": "Protein",
"text": [
"il-6"
],
"offsets": [
[
861,
865
]
],
"normalized": []
},
{
"id": "PMC-2889865-15-Materials_and_methods_T6",
"type": "Protein",
"text": [
"cxcl8"
],
"offsets": [
[
870,
875
]
],
"normalized": []
}
] | [
{
"id": "PMC-2889865-15-Materials_and_methods_E1",
"type": "Gene_expression",
"trigger": {
"text": [
"expression"
],
"offsets": [
[
84,
94
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2889865-15-Materials_and_methods_T1"
}
]
},
{
"id": "PMC-2889865-15-Materials_and_methods_E2",
"type": "Gene_expression",
"trigger": {
"text": [
"expression"
],
"offsets": [
[
84,
94
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2889865-15-Materials_and_methods_T2"
}
]
},
{
"id": "PMC-2889865-15-Materials_and_methods_E3",
"type": "Positive_regulation",
"trigger": {
"text": [
"in response to"
],
"offsets": [
[
120,
134
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2889865-15-Materials_and_methods_E1"
}
]
},
{
"id": "PMC-2889865-15-Materials_and_methods_E4",
"type": "Positive_regulation",
"trigger": {
"text": [
"in response to"
],
"offsets": [
[
120,
134
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2889865-15-Materials_and_methods_E2"
}
]
},
{
"id": "PMC-2889865-15-Materials_and_methods_E5",
"type": "Positive_regulation",
"trigger": {
"text": [
"following"
],
"offsets": [
[
139,
148
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2889865-15-Materials_and_methods_E3"
}
]
},
{
"id": "PMC-2889865-15-Materials_and_methods_E6",
"type": "Positive_regulation",
"trigger": {
"text": [
"following"
],
"offsets": [
[
139,
148
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2889865-15-Materials_and_methods_E4"
}
]
},
{
"id": "PMC-2889865-15-Materials_and_methods_E7",
"type": "Gene_expression",
"trigger": {
"text": [
"expression"
],
"offsets": [
[
837,
847
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2889865-15-Materials_and_methods_T5"
}
]
},
{
"id": "PMC-2889865-15-Materials_and_methods_E8",
"type": "Gene_expression",
"trigger": {
"text": [
"expression"
],
"offsets": [
[
837,
847
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2889865-15-Materials_and_methods_T6"
}
]
}
] | [] | [] |
8 | PMC-3148254-00-TIAB | [
{
"id": "PMC-3148254-00-TIAB__text",
"type": "abstract",
"text": [
"HOIL-1L Interacting Protein (HOIP) Is Essential for CD40 Signaling\nCD40 is a cell surface receptor important in the activation of antigen-presenting cells during immune responses. In macrophages and dendritic cells, engagement of CD40 by its ligand CD154 provides signals critical for anti-microbial and T cell-mediated immune responses, respectively. In B cells, CD40 signaling has a major role in regulating cell proliferation, antibody production, and memory B cell development. CD40 engagement results in the formation of a receptor-associated complex that mediates activation of NF-kappaB, stress-activated protein kinases, and other signaling molecules. However, the mechanisms that link CD40 to these signaling events have been only partially characterized. Known components of the CD40 signaling complex include members of the TNF receptor-associated factor (TRAF) family of proteins. We previously showed that the TRAF family member TRAF2 mediates recruitment of HOIL-1L-interacting protein (HOIP) to the cytoplasmic domain of CD40, suggesting that HOIP has a role in the CD40 signaling pathway. To determine the role of HOIP in CD40 signaling, we used somatic cell gene targeting to generate mouse B cell lines deficient in HOIP. We found that the CD40-induced upregulation of CD80 and activation of germline immunoglobulin epsilon transcription were defective in HOIP-deficient cells. We also found that the CD40-mediated activation of NF-kappaB and c-Jun kinase was impaired. Recruitment of IkappaB kinase proteins to the CD40 signaling complex was undetectable in HOIP-deficient cells, potentially explaining the defect in NF-kappaB activation. Restoration of HOIP expression reversed the defects in cellular activation and signaling. These results reveal HOIP as a key component of the CD40 signaling pathway."
],
"offsets": [
[
0,
1823
]
]
}
] | [
{
"id": "PMC-3148254-00-TIAB_T1",
"type": "Protein",
"text": [
"HOIL-1L Interacting Protein"
],
"offsets": [
[
0,
27
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T2",
"type": "Protein",
"text": [
"HOIP"
],
"offsets": [
[
29,
33
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T3",
"type": "Protein",
"text": [
"CD40"
],
"offsets": [
[
52,
56
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T4",
"type": "Protein",
"text": [
"CD40"
],
"offsets": [
[
67,
71
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T5",
"type": "Protein",
"text": [
"CD40"
],
"offsets": [
[
230,
234
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T6",
"type": "Protein",
"text": [
"ligand"
],
"offsets": [
[
242,
248
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T7",
"type": "Protein",
"text": [
"CD154"
],
"offsets": [
[
249,
254
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T8",
"type": "Protein",
"text": [
"CD40"
],
"offsets": [
[
364,
368
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T9",
"type": "Protein",
"text": [
"CD40"
],
"offsets": [
[
482,
486
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T10",
"type": "Protein",
"text": [
"CD40"
],
"offsets": [
[
694,
698
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T11",
"type": "Protein",
"text": [
"TRAF2"
],
"offsets": [
[
942,
947
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T12",
"type": "Protein",
"text": [
"HOIL-1L-interacting protein"
],
"offsets": [
[
972,
999
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T13",
"type": "Protein",
"text": [
"HOIP"
],
"offsets": [
[
1001,
1005
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T14",
"type": "Protein",
"text": [
"CD40"
],
"offsets": [
[
1036,
1040
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T15",
"type": "Protein",
"text": [
"HOIP"
],
"offsets": [
[
1058,
1062
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T16",
"type": "Protein",
"text": [
"CD40"
],
"offsets": [
[
1081,
1085
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T17",
"type": "Protein",
"text": [
"HOIP"
],
"offsets": [
[
1130,
1134
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T18",
"type": "Protein",
"text": [
"CD40"
],
"offsets": [
[
1138,
1142
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T19",
"type": "Protein",
"text": [
"HOIP"
],
"offsets": [
[
1234,
1238
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T20",
"type": "Protein",
"text": [
"CD40"
],
"offsets": [
[
1258,
1262
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T21",
"type": "Protein",
"text": [
"CD80"
],
"offsets": [
[
1287,
1291
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T22",
"type": "Protein",
"text": [
"HOIP"
],
"offsets": [
[
1374,
1378
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T23",
"type": "Protein",
"text": [
"CD40"
],
"offsets": [
[
1419,
1423
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T24",
"type": "Protein",
"text": [
"HOIP"
],
"offsets": [
[
1577,
1581
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T25",
"type": "Protein",
"text": [
"HOIP"
],
"offsets": [
[
1673,
1677
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T26",
"type": "Protein",
"text": [
"HOIP"
],
"offsets": [
[
1769,
1773
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T27",
"type": "Protein",
"text": [
"CD40"
],
"offsets": [
[
1800,
1804
]
],
"normalized": []
},
{
"id": "PMC-3148254-00-TIAB_T32",
"type": "Entity",
"text": [
"cytoplasmic domain"
],
"offsets": [
[
1014,
1032
]
],
"normalized": []
}
] | [
{
"id": "PMC-3148254-00-TIAB_E1",
"type": "Binding",
"trigger": {
"text": [
"engagement"
],
"offsets": [
[
216,
226
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3148254-00-TIAB_T5"
},
{
"role": "Theme2",
"ref_id": "PMC-3148254-00-TIAB_T7"
}
]
},
{
"id": "PMC-3148254-00-TIAB_E2",
"type": "Binding",
"trigger": {
"text": [
"engagement"
],
"offsets": [
[
487,
497
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3148254-00-TIAB_T9"
}
]
},
{
"id": "PMC-3148254-00-TIAB_E3",
"type": "Positive_regulation",
"trigger": {
"text": [
"mediates"
],
"offsets": [
[
948,
956
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3148254-00-TIAB_E4"
},
{
"role": "Cause",
"ref_id": "PMC-3148254-00-TIAB_T11"
}
]
},
{
"id": "PMC-3148254-00-TIAB_E4",
"type": "Binding",
"trigger": {
"text": [
"recruitment"
],
"offsets": [
[
957,
968
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3148254-00-TIAB_T12"
},
{
"role": "Theme2",
"ref_id": "PMC-3148254-00-TIAB_T14"
},
{
"role": "Site2",
"ref_id": "PMC-3148254-00-TIAB_T32"
}
]
},
{
"id": "PMC-3148254-00-TIAB_E5",
"type": "Negative_regulation",
"trigger": {
"text": [
"deficient"
],
"offsets": [
[
1221,
1230
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3148254-00-TIAB_T19"
}
]
},
{
"id": "PMC-3148254-00-TIAB_E6",
"type": "Positive_regulation",
"trigger": {
"text": [
"induced"
],
"offsets": [
[
1263,
1270
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3148254-00-TIAB_E7"
},
{
"role": "Cause",
"ref_id": "PMC-3148254-00-TIAB_T20"
}
]
},
{
"id": "PMC-3148254-00-TIAB_E7",
"type": "Positive_regulation",
"trigger": {
"text": [
"upregulation"
],
"offsets": [
[
1271,
1283
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3148254-00-TIAB_T21"
}
]
},
{
"id": "PMC-3148254-00-TIAB_E8",
"type": "Negative_regulation",
"trigger": {
"text": [
"defective"
],
"offsets": [
[
1361,
1370
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3148254-00-TIAB_E6"
}
]
},
{
"id": "PMC-3148254-00-TIAB_E9",
"type": "Negative_regulation",
"trigger": {
"text": [
"deficient"
],
"offsets": [
[
1379,
1388
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3148254-00-TIAB_T22"
}
]
},
{
"id": "PMC-3148254-00-TIAB_E10",
"type": "Negative_regulation",
"trigger": {
"text": [
"deficient"
],
"offsets": [
[
1582,
1591
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3148254-00-TIAB_T24"
}
]
},
{
"id": "PMC-3148254-00-TIAB_E11",
"type": "Positive_regulation",
"trigger": {
"text": [
"Restoration"
],
"offsets": [
[
1658,
1669
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3148254-00-TIAB_E12"
}
]
},
{
"id": "PMC-3148254-00-TIAB_E12",
"type": "Gene_expression",
"trigger": {
"text": [
"expression"
],
"offsets": [
[
1678,
1688
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3148254-00-TIAB_T25"
}
]
}
] | [
{
"id": "PMC-3148254-00-TIAB_1",
"entity_ids": [
"PMC-3148254-00-TIAB_T1",
"PMC-3148254-00-TIAB_T2"
]
},
{
"id": "PMC-3148254-00-TIAB_2",
"entity_ids": [
"PMC-3148254-00-TIAB_T12",
"PMC-3148254-00-TIAB_T13"
]
}
] | [] |
9 | PMC-3245220-32-Caption-Figure_8 | [
{
"id": "PMC-3245220-32-Caption-Figure_8__text",
"type": "abstract",
"text": [
"NF-kappaB p65 Ser276 is essential in regulating NF-kappaB activity.\n(A) Raw 264.7 cell line was transiently transfected with pNF-kappaB-SEAP along with empty vector or plasmid encoding either NF-kappaB p65 WT or NF-kappaB p65 276S/A. The cells were transfected for 18-24 hours, serum starved for 4 hours, and then incubated with 10 microM of Ro-31-8220 for 30 minutes prior to treatment with 100 ng/ml of M-CSF for 2 hours and SEAP secretion in the medium was measured. (B) NF-kappaB p65-/- cell line was transiently transfected with pNF-kappaB-SEAP along with empty vector or plasmid encoding either NF-kappaB p65 WT, NF-kappaB p65 276S/A, or NF-kappaB p65 536S/A. The cells were cultured for 24 hours and then serum starved for 4 hours. Cells were then incubated in fresh DMEM medium for 2 hours and SEAP secretion in the medium was measured. The results shown are fold change over empty vector + pTAL-SEAP. (C) NF-kappaB p65-/- cell line was transiently transfected with pNF-kappaB-SEAP with either empty vector or plasmid encoding either NF-kappaB p65 WT or NF-kappaB p65 276S/A. The cells were transfected for 24 hours and serum starved for 4 hours, and then incubated with 10 microM of Ro-31-8220 for 30 minutes prior to treatment with 10 ng/ml of TNFalpha. The supernatant were collected after 2 hours of treatment and SEAP secretion in the medium was measured. The results shown are the fold change over empty vector + pNF-kappaB-SEAP. Data shown are mean +/- S.E.M for at least three independent experiments performed in duplicate."
],
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] | [] | [] |
10 | PMC-2065877-06-Results | [
{
"id": "PMC-2065877-06-Results__text",
"type": "abstract",
"text": [
"LMP1 Upregulates IL10 and Constitutively Activates Stat3\nTo identify cytokines that may contribute to the increased survival and growth of lymphomas, the expression levels of a panel of cytokines were screened on CD19+ MACS-purified B cells, using an RPA probe set for IL4, IL5, IL10, IL13, IL15, IL9, IL2, IL6, and IFNgamma. Expression levels were quantified with a phosphorimager and normalized to the ribosomal housekeeping gene L32. None of the tested cytokines were detected in wild-type lymphocytes, therefore cytokine:L32 ratios were set to 1 in the mouse B cell lymphoma line 967. Transcription of IL10, IL15, and IFNgamma were reproducibly detected in LMP1 transgenic lymphocytes and lymphoma cells and was higher than in the B cell lymphoma cell lines 967 and K46mu (Figure 5A). There was no significant difference in the expression of IL15 and IFNgamma between LMP1 transgenic lymphocytes and lymphoma cells, suggesting that upregulation of IL15 and IFNgamma is induced by LMP1 expression in healthy lymphocytes but is not a unique property of malignant lymphocytes. Strikingly, IL10, a B lymphocyte stimulatory cytokine, was increased 1.5- to 5-fold in the wild-type and LMP1 transgenic lymphoma cells compared to LMP1 transgenic lymphocytes (Figure 5A). Production of IL15 and IFNgamma has been associated with induction of cytotoxic effector responses in cells latently infected with EBV [33,34]. However, transformation and growth properties induced by EBV are associated with the upregulation of IL10 [35-38]; hence, the effects of IL10 upregulation on the growth properties of the lymphoma cells were further examined. Immunoblot analysis indicated that LMP1 transgenic lymphocytes and wild-type and LMP1 transgenic lymphoma cells had corresponding increased levels of phosphorylated alpha and beta isoforms of activated Stat3, a target of the IL10 receptor (Figure 5B). However, when comparing the same lymphomas, there was no correlation between the levels of IL10 induction and the levels of Stat3 activation. This suggests that the activation of Stat3 is not solely induced by IL10 or that Stat3 activation may be constitutive. Additionally, there was no correlation between the levels of LMP1 expression and the levels of IL10 induction (Figures 1A and 5A). This indicates that the induction of IL10 is a general property associated with enhanced survival and may only be indirectly affected by LMP1. Neutralizing antibodies to IL10 did not affect the survival of lymphoma cells as determined by the MTS assay (unpublished data), suggesting constitutive activation of Stat3. This was confirmed by immunoblot analysis such that in the presence of anti-IL10 neutralizing antibodies, pStat3 levels remained activated in lymphoma cells isolated from wild-type and LMP1 transgenic lymphomas (Figure 5C). Exogenous addition of IL10 enhanced pStat3 activation above constitutive levels, indicating that lymphoma cells are responsive to IL10 treatment (Figure 5C). This means that although the lymphoma cells have constitutive Stat3 activation, it may be further enhanced by IL10 induction. The neutralizing effect of the anti-IL10 antibody was confirmed by pre-incubation of IL10 with anti-IL10 antibody compared to a rat IgG1 isotype control (Figure 5C).\nNuclear translocation of pStat3 is a consequence of activation, and nuclear pStat3 was not detected by immunohistochemistry staining of spleen sections from control mice. However, nuclear pStat3 was detectable in LMP1 transgenic mice and wild-type lymphomas and was detected more homogeneously in LMP1 transgenic lymphomas (Figure 5D). The constitutive activation of pStat3 and abundant nuclear Stat3 suggests that Stat3 signaling contributes to LMP1-mediated lymphoma development."
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"trigger": {
"text": [
"activation"
],
"offsets": [
[
3323,
3333
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2065877-06-Results_T60"
}
]
},
{
"id": "PMC-2065877-06-Results_E55",
"type": "Localization",
"trigger": {
"text": [
"detected"
],
"offsets": [
[
3362,
3370
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2065877-06-Results_T61"
},
{
"role": "ToLoc",
"ref_id": "PMC-2065877-06-Results_T110"
}
]
},
{
"id": "PMC-2065877-06-Results_E56",
"type": "Localization",
"trigger": {
"text": [
"detectable"
],
"offsets": [
[
3470,
3480
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2065877-06-Results_T62"
},
{
"role": "ToLoc",
"ref_id": "PMC-2065877-06-Results_T112"
}
]
},
{
"id": "PMC-2065877-06-Results_E57",
"type": "Localization",
"trigger": {
"text": [
"detected"
],
"offsets": [
[
3537,
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]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2065877-06-Results_T62"
},
{
"role": "ToLoc",
"ref_id": "PMC-2065877-06-Results_T112"
}
]
},
{
"id": "PMC-2065877-06-Results_E58",
"type": "Positive_regulation",
"trigger": {
"text": [
"activation"
],
"offsets": [
[
3624,
3634
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2065877-06-Results_T65"
}
]
},
{
"id": "PMC-2065877-06-Results_E59",
"type": "Positive_regulation",
"trigger": {
"text": [
"activation"
],
"offsets": [
[
3624,
3634
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2065877-06-Results_T66"
}
]
}
] | [] | [
{
"id": "PMC-2065877-06-Results_R1",
"type": "Coreference",
"arg1_id": "PMC-2065877-06-Results_T69",
"arg2_id": "PMC-2065877-06-Results_T5",
"normalized": []
},
{
"id": "PMC-2065877-06-Results_R2",
"type": "Coreference",
"arg1_id": "PMC-2065877-06-Results_T69",
"arg2_id": "PMC-2065877-06-Results_T6",
"normalized": []
},
{
"id": "PMC-2065877-06-Results_R3",
"type": "Coreference",
"arg1_id": "PMC-2065877-06-Results_T69",
"arg2_id": "PMC-2065877-06-Results_T7",
"normalized": []
},
{
"id": "PMC-2065877-06-Results_R4",
"type": "Coreference",
"arg1_id": "PMC-2065877-06-Results_T69",
"arg2_id": "PMC-2065877-06-Results_T8",
"normalized": []
},
{
"id": "PMC-2065877-06-Results_R5",
"type": "Coreference",
"arg1_id": "PMC-2065877-06-Results_T69",
"arg2_id": "PMC-2065877-06-Results_T9",
"normalized": []
},
{
"id": "PMC-2065877-06-Results_R6",
"type": "Coreference",
"arg1_id": "PMC-2065877-06-Results_T69",
"arg2_id": "PMC-2065877-06-Results_T10",
"normalized": []
},
{
"id": "PMC-2065877-06-Results_R7",
"type": "Coreference",
"arg1_id": "PMC-2065877-06-Results_T69",
"arg2_id": "PMC-2065877-06-Results_T11",
"normalized": []
},
{
"id": "PMC-2065877-06-Results_R8",
"type": "Coreference",
"arg1_id": "PMC-2065877-06-Results_T69",
"arg2_id": "PMC-2065877-06-Results_T12",
"normalized": []
},
{
"id": "PMC-2065877-06-Results_R9",
"type": "Coreference",
"arg1_id": "PMC-2065877-06-Results_T69",
"arg2_id": "PMC-2065877-06-Results_T13",
"normalized": []
}
] |
11 | PMC-2626671-15-MATERIALS_AND_METHODS | [
{
"id": "PMC-2626671-15-MATERIALS_AND_METHODS__text",
"type": "abstract",
"text": [
"Northern and Western blot analyses.\nRNA isolation and Northern blot analysis was performed as previously described (29). In brief, 10 mug of total RNA was loaded per lane and transferred to positively charged nylon membranes (Hybond-N+; GE Healthcare), which was confirmed by ethidium bromide staining of ribosomal RNA species on the membrane. Membranes were hybridized with 1 ng/ml alpha-[32P]dCTP-labeled trichloroacetic acid precipitable probe in ExpressHyb hybridization buffer (Clontech Laboratories, Inc.). All cDNA probes were confirmed to have the appropriate single-copy specificity under these conditions using genomic Southern blot analysis. Band intensities were acquired by phosphorimaging analysis.\nFor Western analysis, whole-cell protein lysates were obtained from CD8+ T cells at the time points indicated in the figures during clonal expansion in 100 U/ml IL-2 with lysis buffer (50 mM Tris [pH 7.5], 150 mM NaCl, 10% glycerol, 5 mM EDTA, 1% NP-40) by resuspending samples in 10 mul per 106 cells and incubating on ice for 30 min in the presence of protease inhibitors. Immunoblot analysis was performed with the antibodies indicated in the figures after SDS-PAGE (10-30 mug of total protein was loaded per well). Quantification of detected protein was performed with an Intelligent Dark Box unit (LAS-3000; Fujifilm) and normalized for loading with the amount of RNA Pol-II detected in each lane."
],
"offsets": [
[
0,
1415
]
]
}
] | [
{
"id": "PMC-2626671-15-MATERIALS_AND_METHODS_T1",
"type": "Protein",
"text": [
"CD8"
],
"offsets": [
[
781,
784
]
],
"normalized": []
},
{
"id": "PMC-2626671-15-MATERIALS_AND_METHODS_T2",
"type": "Protein",
"text": [
"IL-2"
],
"offsets": [
[
874,
878
]
],
"normalized": []
}
] | [] | [] | [] |
12 | PMC-1447668-05-Results | [
{
"id": "PMC-1447668-05-Results__text",
"type": "abstract",
"text": [
"The Transactivation Functions of HTLV-I Tax Are Suppressed by Foxp3\nPrevious studies by Bettelli and colleagues have demonstrated that Foxp3 can repress both the basal levels of NF-kappaB activation as well as tumor necrosis factor-alpha-stimulated NF-kappaB activation [15]. Our next step was to determine whether Foxp3 could also suppress the activation of NF-kappaB caused by a strong viral transactivator protein. HTLV-I encodes a multifunctional transactivator protein, Tax, capable of activating both the NF-kappaB and CREB pathways [24-29]. Since the HTLV-I Tax protein can function at multiple levels in both the cytoplasm and the nucleus to stimulate activation of NF-kappaB [28,29], we hypothesized that overexpression of Foxp3 may interfere with this process. However, since Tax-dependent HTLV-I gene expression is independent of NF-kappaB [18], we also hypothesized that Foxp3 would not affect Tax-dependent activation of the HTLV-I LTR. To test these hypotheses, we overexpressed HTLV-I Tax, full-length Foxp3, and/or deltaFKH in HEK 293T cells cotransfected with an HTLV-I LTR or NF-kappaB reporter vector. As shown in Figure 4A, HTLV-I Tax strongly up-regulated NF-kappaB-dependent transcriptional activation (~60-fold). Interestingly, overexpression of Foxp3, but not deltaFKH, suppressed Tax-mediated activation of NF-kappaB-dependent transcription. These observations further suggest that the carboxyl-terminal FKH domain is required for inhibiting activation of NF-kappaB in the presence of Tax in HEK 293T cells, strikingly similar to the requirements of Foxp3 inhibition of basal NF-kappaB activation shown in Figure 2B. Transactivation of the HTLV-I LTR was stimulated about 55-fold by overexpression of Tax (Figure 4B), while transfection of Foxp3 suppressed Tax-dependent HTLV-I LTR activation, although HTLV-I LTR activation in the presence or absence of Tax is independent of NF-kappaB or NF-AT (another transcriptional activator known to interact with Foxp3). Furthermore, overexpression of deltaFKH also led to suppression of HTLV-I transactivation by Tax to a similar extent as full-length Foxp3 (Figure 4B). The suppressive effects shown in Figure 4A and 4B were not the result of Foxp3 down-regulating the expression of the transfected Tax plasmid as determined by real-time RT-PCR (Figure 4C). These results strongly suggest that Foxp3 interacts with transcriptional regulators in addition to NF-kappaB and NF-AT, and that the carboxyl-terminal FKH domain, and therefore localization to the nucleus, are not required for inhibition of Tax-mediated HTLV-I LTR activation (even in HEK 293T cells).\nTo determine whether Foxp3 inhibited the transactivation functions of Tax by directly associating with this viral protein, we generated an expression vector in which HTLV-I Tax was fused in-frame to the carboxyl terminus of the Gal4 DNA-binding domain (Gal4-BD). This Gal4-BD-Tax fusion protein activated transcription of a synthetic promoter containing five Gal4 binding sites, while Gal4-BD was insufficient to stimulate transcription by itself (Figure 4D). Transactivation of the Gal4-resposive promoter by Gal4-BD-Tax remained relatively unaffected by overexpression of either EGFP (control), Foxp3, or deltaFKH, suggesting that Foxp3 does not repress Tax transactivation by directly interfacing with the HTLV-I Tax protein. To confirm that Foxp3 had a direct effect on HTLV-I replication, we transfected HEK 293T cells with a well-characterized HTLV-I infectious molecular clone (termed ACH) [30] in the presence of full-length Foxp3, deltaFKH, or control vector. ACH has been previously shown to direct the expression of viral antigens, produce infectious virus, and transform CD4+ T cells both in vitro and in vivo [31,32]. After 24 h, the amount of viral antigen expression, in this case Tax mRNA, was detected by a sensitive real-time RT-PCR assay. As illustrated in Figure 5, the level of Tax mRNA synthesized from ACH was down-regulated in the presence of Foxp3 compared to the level produced in the presence of the control vector. deltaFKH did not have a discernable affect on Tax expression. These data indicate that Foxp3 is capable of repressing the expression of Tax from an infectious HTLV-I molecular clone."
],
"offsets": [
[
0,
4253
]
]
}
] | [
{
"id": "PMC-1447668-05-Results_T1",
"type": "Protein",
"text": [
"Tax"
],
"offsets": [
[
40,
43
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T2",
"type": "Protein",
"text": [
"Foxp3"
],
"offsets": [
[
62,
67
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T3",
"type": "Protein",
"text": [
"Foxp3"
],
"offsets": [
[
135,
140
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T4",
"type": "Protein",
"text": [
"tumor necrosis factor-alpha"
],
"offsets": [
[
210,
237
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T5",
"type": "Protein",
"text": [
"Foxp3"
],
"offsets": [
[
315,
320
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T6",
"type": "Protein",
"text": [
"Tax"
],
"offsets": [
[
475,
478
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T7",
"type": "Protein",
"text": [
"Tax"
],
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[
565,
568
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T8",
"type": "Protein",
"text": [
"Foxp3"
],
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[
732,
737
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T9",
"type": "Protein",
"text": [
"Tax"
],
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[
786,
789
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T10",
"type": "Protein",
"text": [
"Foxp3"
],
"offsets": [
[
883,
888
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T11",
"type": "Protein",
"text": [
"Tax"
],
"offsets": [
[
906,
909
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T12",
"type": "Protein",
"text": [
"Tax"
],
"offsets": [
[
1000,
1003
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T13",
"type": "Protein",
"text": [
"Foxp3"
],
"offsets": [
[
1017,
1022
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T14",
"type": "Protein",
"text": [
"deltaFKH"
],
"offsets": [
[
1031,
1039
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T15",
"type": "Protein",
"text": [
"Tax"
],
"offsets": [
[
1151,
1154
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T16",
"type": "Protein",
"text": [
"Foxp3"
],
"offsets": [
[
1269,
1274
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T17",
"type": "Protein",
"text": [
"deltaFKH"
],
"offsets": [
[
1284,
1292
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T18",
"type": "Protein",
"text": [
"Tax"
],
"offsets": [
[
1305,
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]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T19",
"type": "Protein",
"text": [
"Tax"
],
"offsets": [
[
1510,
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]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T20",
"type": "Protein",
"text": [
"Foxp3"
],
"offsets": [
[
1575,
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]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T21",
"type": "Protein",
"text": [
"Tax"
],
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[
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]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T22",
"type": "Protein",
"text": [
"Foxp3"
],
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[
1765,
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]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T23",
"type": "Protein",
"text": [
"Tax"
],
"offsets": [
[
1782,
1785
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T24",
"type": "Protein",
"text": [
"Tax"
],
"offsets": [
[
1880,
1883
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T25",
"type": "Protein",
"text": [
"Foxp3"
],
"offsets": [
[
1979,
1984
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T26",
"type": "Protein",
"text": [
"deltaFKH"
],
"offsets": [
[
2018,
2026
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T27",
"type": "Protein",
"text": [
"Tax"
],
"offsets": [
[
2080,
2083
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T28",
"type": "Protein",
"text": [
"Foxp3"
],
"offsets": [
[
2119,
2124
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T29",
"type": "Protein",
"text": [
"Foxp3"
],
"offsets": [
[
2211,
2216
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T30",
"type": "Protein",
"text": [
"Tax"
],
"offsets": [
[
2267,
2270
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T31",
"type": "Protein",
"text": [
"Foxp3"
],
"offsets": [
[
2362,
2367
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T32",
"type": "Protein",
"text": [
"Tax"
],
"offsets": [
[
2567,
2570
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T33",
"type": "Protein",
"text": [
"Foxp3"
],
"offsets": [
[
2649,
2654
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T34",
"type": "Protein",
"text": [
"Tax"
],
"offsets": [
[
2698,
2701
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T35",
"type": "Protein",
"text": [
"Tax"
],
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[
2801,
2804
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T36",
"type": "Protein",
"text": [
"Gal4"
],
"offsets": [
[
2856,
2860
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T37",
"type": "Protein",
"text": [
"Gal4"
],
"offsets": [
[
2881,
2885
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T38",
"type": "Protein",
"text": [
"Gal4-BD-Tax"
],
"offsets": [
[
2896,
2907
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T39",
"type": "Protein",
"text": [
"Gal4"
],
"offsets": [
[
3013,
3017
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T40",
"type": "Protein",
"text": [
"Gal4-BD-Tax"
],
"offsets": [
[
3138,
3149
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T41",
"type": "Protein",
"text": [
"Foxp3"
],
"offsets": [
[
3225,
3230
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T42",
"type": "Protein",
"text": [
"deltaFKH"
],
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[
3235,
3243
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T43",
"type": "Protein",
"text": [
"Foxp3"
],
"offsets": [
[
3261,
3266
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T44",
"type": "Protein",
"text": [
"Tax"
],
"offsets": [
[
3284,
3287
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T45",
"type": "Protein",
"text": [
"Tax"
],
"offsets": [
[
3344,
3347
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T46",
"type": "Protein",
"text": [
"Foxp3"
],
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[
3373,
3378
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T47",
"type": "Protein",
"text": [
"Foxp3"
],
"offsets": [
[
3561,
3566
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T48",
"type": "Protein",
"text": [
"deltaFKH"
],
"offsets": [
[
3568,
3576
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T49",
"type": "Protein",
"text": [
"CD4"
],
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[
3711,
3714
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T50",
"type": "Protein",
"text": [
"Tax"
],
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[
3824,
3827
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T51",
"type": "Protein",
"text": [
"Tax"
],
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[
3927,
3930
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T52",
"type": "Protein",
"text": [
"Foxp3"
],
"offsets": [
[
3995,
4000
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T53",
"type": "Protein",
"text": [
"deltaFKH"
],
"offsets": [
[
4071,
4079
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T54",
"type": "Protein",
"text": [
"Tax"
],
"offsets": [
[
4117,
4120
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T55",
"type": "Protein",
"text": [
"Foxp3"
],
"offsets": [
[
4158,
4163
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T56",
"type": "Protein",
"text": [
"Tax"
],
"offsets": [
[
4207,
4210
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T70",
"type": "Entity",
"text": [
"nucleus"
],
"offsets": [
[
2523,
2530
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T57",
"type": "Anaphora",
"text": [
"this viral protein"
],
"offsets": [
[
2731,
2749
]
],
"normalized": []
},
{
"id": "PMC-1447668-05-Results_T58",
"type": "Anaphora",
"text": [
"viral antigen"
],
"offsets": [
[
3785,
3798
]
],
"normalized": []
}
] | [
{
"id": "PMC-1447668-05-Results_E1",
"type": "Positive_regulation",
"trigger": {
"text": [
"overexpression"
],
"offsets": [
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]
]
},
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{
"role": "Theme",
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}
]
},
{
"id": "PMC-1447668-05-Results_E2",
"type": "Positive_regulation",
"trigger": {
"text": [
"overexpressed"
],
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[
979,
992
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1447668-05-Results_T12"
}
]
},
{
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"text": [
"overexpressed"
],
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[
979,
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]
]
},
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{
"role": "Theme",
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}
]
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"text": [
"overexpressed"
],
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979,
992
]
]
},
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{
"role": "Theme",
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}
]
},
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"overexpression"
],
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1251,
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]
]
},
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{
"role": "Theme",
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}
]
},
{
"id": "PMC-1447668-05-Results_E6",
"type": "Gene_expression",
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"text": [
"overexpression"
],
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[
1251,
1265
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1447668-05-Results_T17"
}
]
},
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"text": [
"overexpression"
],
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1708,
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]
]
},
"arguments": [
{
"role": "Theme",
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}
]
},
{
"id": "PMC-1447668-05-Results_E8",
"type": "Gene_expression",
"trigger": {
"text": [
"transfection"
],
"offsets": [
[
1749,
1761
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1447668-05-Results_T22"
}
]
},
{
"id": "PMC-1447668-05-Results_E9",
"type": "Binding",
"trigger": {
"text": [
"interact"
],
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[
1965,
1973
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1447668-05-Results_T25"
}
]
},
{
"id": "PMC-1447668-05-Results_E10",
"type": "Positive_regulation",
"trigger": {
"text": [
"overexpression"
],
"offsets": [
[
2000,
2014
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1447668-05-Results_T26"
}
]
},
{
"id": "PMC-1447668-05-Results_E11",
"type": "Negative_regulation",
"trigger": {
"text": [
"down-regulating"
],
"offsets": [
[
2217,
2232
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1447668-05-Results_E12"
},
{
"role": "Cause",
"ref_id": "PMC-1447668-05-Results_T29"
}
]
},
{
"id": "PMC-1447668-05-Results_E12",
"type": "Gene_expression",
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"text": [
"expression"
],
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2237,
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]
]
},
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{
"role": "Theme",
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}
]
},
{
"id": "PMC-1447668-05-Results_E13",
"type": "Binding",
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"text": [
"interacts"
],
"offsets": [
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2368,
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]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1447668-05-Results_T31"
}
]
},
{
"id": "PMC-1447668-05-Results_E14",
"type": "Localization",
"trigger": {
"text": [
"localization"
],
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2503,
2515
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1447668-05-Results_T31"
},
{
"role": "ToLoc",
"ref_id": "PMC-1447668-05-Results_T70"
}
]
},
{
"id": "PMC-1447668-05-Results_E15",
"type": "Binding",
"trigger": {
"text": [
"associating"
],
"offsets": [
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2714,
2725
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1447668-05-Results_T33"
},
{
"role": "Theme2",
"ref_id": "PMC-1447668-05-Results_T34"
}
]
},
{
"id": "PMC-1447668-05-Results_E16",
"type": "Positive_regulation",
"trigger": {
"text": [
"overexpression"
],
"offsets": [
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3184,
3198
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1447668-05-Results_T41"
}
]
},
{
"id": "PMC-1447668-05-Results_E17",
"type": "Positive_regulation",
"trigger": {
"text": [
"overexpression"
],
"offsets": [
[
3184,
3198
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1447668-05-Results_T42"
}
]
},
{
"id": "PMC-1447668-05-Results_E18",
"type": "Negative_regulation",
"trigger": {
"text": [
"interfacing"
],
"offsets": [
[
3316,
3327
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1447668-05-Results_T45"
},
{
"role": "Cause",
"ref_id": "PMC-1447668-05-Results_T43"
}
]
},
{
"id": "PMC-1447668-05-Results_E19",
"type": "Transcription",
"trigger": {
"text": [
"expression"
],
"offsets": [
[
3799,
3809
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1447668-05-Results_T50"
}
]
},
{
"id": "PMC-1447668-05-Results_E20",
"type": "Transcription",
"trigger": {
"text": [
"synthesized"
],
"offsets": [
[
3936,
3947
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1447668-05-Results_T51"
}
]
},
{
"id": "PMC-1447668-05-Results_E21",
"type": "Negative_regulation",
"trigger": {
"text": [
"down-regulated"
],
"offsets": [
[
3961,
3975
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1447668-05-Results_E20"
},
{
"role": "Cause",
"ref_id": "PMC-1447668-05-Results_T52"
}
]
},
{
"id": "PMC-1447668-05-Results_E22",
"type": "Transcription",
"trigger": {
"text": [
"produced"
],
"offsets": [
[
4023,
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]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1447668-05-Results_T51"
}
]
},
{
"id": "PMC-1447668-05-Results_E23",
"type": "Regulation",
"trigger": {
"text": [
"affect"
],
"offsets": [
[
4107,
4113
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1447668-05-Results_E24"
},
{
"role": "Cause",
"ref_id": "PMC-1447668-05-Results_T53"
}
]
},
{
"id": "PMC-1447668-05-Results_E24",
"type": "Gene_expression",
"trigger": {
"text": [
"expression"
],
"offsets": [
[
4121,
4131
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1447668-05-Results_T54"
}
]
},
{
"id": "PMC-1447668-05-Results_E25",
"type": "Negative_regulation",
"trigger": {
"text": [
"repressing"
],
"offsets": [
[
4178,
4188
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1447668-05-Results_E26"
},
{
"role": "Cause",
"ref_id": "PMC-1447668-05-Results_T55"
}
]
},
{
"id": "PMC-1447668-05-Results_E26",
"type": "Gene_expression",
"trigger": {
"text": [
"expression"
],
"offsets": [
[
4193,
4203
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1447668-05-Results_T56"
}
]
}
] | [] | [
{
"id": "PMC-1447668-05-Results_R1",
"type": "Coreference",
"arg1_id": "PMC-1447668-05-Results_T57",
"arg2_id": "PMC-1447668-05-Results_T34",
"normalized": []
},
{
"id": "PMC-1447668-05-Results_R2",
"type": "Coreference",
"arg1_id": "PMC-1447668-05-Results_T58",
"arg2_id": "PMC-1447668-05-Results_T50",
"normalized": []
}
] |
13 | PMC-3245220-20-Materials_and_Methods | [
{
"id": "PMC-3245220-20-Materials_and_Methods__text",
"type": "abstract",
"text": [
"Western Blot Analysis\nCells were washed with PBS and resuspended in cell lysis buffer. (Cell Signaling Technology) and incubated for 10 minutes on ice then centrifuged to remove the insoluble fraction. The protein concentration was determined by the BCA protein assay (Bio-Rad, Hercules, CA). Cell lysates were separated by SDS-PAGE on 10% polyacrylamide gels and then transferred onto nitrocellulose membranes and subjected to Western blotting. The immunoblotted proteins were detected by ECL reagent (GE Healthcare Bio-Sciences Corp., Piscataway, NJ)."
],
"offsets": [
[
0,
553
]
]
}
] | [] | [] | [] | [] |
14 | PMC-2065877-10-Materials_and_Methods | [
{
"id": "PMC-2065877-10-Materials_and_Methods__text",
"type": "abstract",
"text": [
"Transgenic mice.\nGeneration of LMP1 mice under the Ig heavy chain promoter and enhancer have been described previously and were maintained as heterozygotes on a Balbc background [26]. LMP1 mice were genotyped by Southern blot and PCR analysis of tail DNA as described previously [26]. Spleen and liver sections were fixed in 4% paraformaldehyde and embedded in paraffin, and 5-mum sections were stained with hematoxylin and eosin for histopathological analysis. Lymphomas were passaged by intraperitoneal injection of 1 x 108 splenocytes into SCID mice and sacrificed upon development of an extended abdomen. Animals were housed in the Association for Assessment and Accreditation for Animal Care-approved animal facility at the University of North Carolina at Chapel Hill. All protocols were approved by the Institutional Animal Care and Use Committee."
],
"offsets": [
[
0,
853
]
]
}
] | [
{
"id": "PMC-2065877-10-Materials_and_Methods_T1",
"type": "Protein",
"text": [
"LMP1"
],
"offsets": [
[
31,
35
]
],
"normalized": []
},
{
"id": "PMC-2065877-10-Materials_and_Methods_T2",
"type": "Protein",
"text": [
"LMP1"
],
"offsets": [
[
184,
188
]
],
"normalized": []
}
] | [] | [] | [] |
15 | PMC-2065877-24-Caption-Figure_6 | [
{
"id": "PMC-2065877-24-Caption-Figure_6__text",
"type": "abstract",
"text": [
"LMP1 Activates Akt Signaling and Deregulates the Rb Cell Cycle Pathway\n(A and B) Immunoblot analysis of purified B cells (CD19+) from the spleens of WT and LMP1 transgenic mice for Akt signaling, probing for (A) activated pAkt and downstream targets, including inactivated pGSK3alpha/beta, and (B) activated p-mTOR, and total levels of FoxO1. Arrows indicate the positions of alpha and beta isoforms of GSK3. The white line indicates that intervening lanes have been spliced out.\n(C) Immunoblot analysis for cell cycle proteins regulating the Rb pathway, probing for activated pRb, and total levels of Cdk2 and the Cdk inhibitor p27. Actin was used as a loading control."
],
"offsets": [
[
0,
670
]
]
}
] | [
{
"id": "PMC-2065877-24-Caption-Figure_6_T1",
"type": "Protein",
"text": [
"LMP1"
],
"offsets": [
[
0,
4
]
],
"normalized": []
},
{
"id": "PMC-2065877-24-Caption-Figure_6_T2",
"type": "Protein",
"text": [
"Akt"
],
"offsets": [
[
15,
18
]
],
"normalized": []
},
{
"id": "PMC-2065877-24-Caption-Figure_6_T3",
"type": "Protein",
"text": [
"Rb"
],
"offsets": [
[
49,
51
]
],
"normalized": []
},
{
"id": "PMC-2065877-24-Caption-Figure_6_T4",
"type": "Protein",
"text": [
"CD19"
],
"offsets": [
[
122,
126
]
],
"normalized": []
},
{
"id": "PMC-2065877-24-Caption-Figure_6_T5",
"type": "Protein",
"text": [
"LMP1"
],
"offsets": [
[
156,
160
]
],
"normalized": []
},
{
"id": "PMC-2065877-24-Caption-Figure_6_T6",
"type": "Protein",
"text": [
"Akt"
],
"offsets": [
[
181,
184
]
],
"normalized": []
},
{
"id": "PMC-2065877-24-Caption-Figure_6_T7",
"type": "Protein",
"text": [
"pAkt"
],
"offsets": [
[
222,
226
]
],
"normalized": []
},
{
"id": "PMC-2065877-24-Caption-Figure_6_T8",
"type": "Protein",
"text": [
"pGSK3alpha"
],
"offsets": [
[
273,
283
]
],
"normalized": []
},
{
"id": "PMC-2065877-24-Caption-Figure_6_T9",
"type": "Protein",
"text": [
"beta"
],
"offsets": [
[
284,
288
]
],
"normalized": []
},
{
"id": "PMC-2065877-24-Caption-Figure_6_T10",
"type": "Protein",
"text": [
"p-mTOR"
],
"offsets": [
[
308,
314
]
],
"normalized": []
},
{
"id": "PMC-2065877-24-Caption-Figure_6_T11",
"type": "Protein",
"text": [
"FoxO1"
],
"offsets": [
[
336,
341
]
],
"normalized": []
},
{
"id": "PMC-2065877-24-Caption-Figure_6_T12",
"type": "Protein",
"text": [
"GSK3"
],
"offsets": [
[
403,
407
]
],
"normalized": []
},
{
"id": "PMC-2065877-24-Caption-Figure_6_T13",
"type": "Protein",
"text": [
"Rb"
],
"offsets": [
[
543,
545
]
],
"normalized": []
},
{
"id": "PMC-2065877-24-Caption-Figure_6_T14",
"type": "Protein",
"text": [
"pRb"
],
"offsets": [
[
577,
580
]
],
"normalized": []
},
{
"id": "PMC-2065877-24-Caption-Figure_6_T15",
"type": "Protein",
"text": [
"Cdk2"
],
"offsets": [
[
602,
606
]
],
"normalized": []
},
{
"id": "PMC-2065877-24-Caption-Figure_6_T16",
"type": "Protein",
"text": [
"p27"
],
"offsets": [
[
629,
632
]
],
"normalized": []
}
] | [
{
"id": "PMC-2065877-24-Caption-Figure_6_E1",
"type": "Regulation",
"trigger": {
"text": [
"targets"
],
"offsets": [
[
242,
249
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2065877-24-Caption-Figure_6_T8"
}
]
},
{
"id": "PMC-2065877-24-Caption-Figure_6_E2",
"type": "Regulation",
"trigger": {
"text": [
"targets"
],
"offsets": [
[
242,
249
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2065877-24-Caption-Figure_6_T9"
}
]
},
{
"id": "PMC-2065877-24-Caption-Figure_6_E3",
"type": "Positive_regulation",
"trigger": {
"text": [
"inactivated"
],
"offsets": [
[
261,
272
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2065877-24-Caption-Figure_6_T8"
}
]
},
{
"id": "PMC-2065877-24-Caption-Figure_6_E4",
"type": "Positive_regulation",
"trigger": {
"text": [
"inactivated"
],
"offsets": [
[
261,
272
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2065877-24-Caption-Figure_6_T9"
}
]
},
{
"id": "PMC-2065877-24-Caption-Figure_6_E5",
"type": "Positive_regulation",
"trigger": {
"text": [
"activated"
],
"offsets": [
[
298,
307
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2065877-24-Caption-Figure_6_T10"
}
]
},
{
"id": "PMC-2065877-24-Caption-Figure_6_E6",
"type": "Positive_regulation",
"trigger": {
"text": [
"activated"
],
"offsets": [
[
567,
576
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2065877-24-Caption-Figure_6_T14"
}
]
}
] | [] | [] |
16 | PMC-2065877-00-TIAB | [
{
"id": "PMC-2065877-00-TIAB__text",
"type": "abstract",
"text": [
"EBV Latent Membrane Protein 1 Activates Akt, NFkappaB, and Stat3 in B Cell Lymphomas\nLatent membrane protein 1 (LMP1) is the major oncoprotein of Epstein-Barr virus (EBV). In transgenic mice, LMP1 promotes increased lymphoma development by 12 mo of age. This study reveals that lymphoma develops in B-1a lymphocytes, a population that is associated with transformation in older mice. The lymphoma cells have deregulated cell cycle markers, and inhibitors of Akt, NFkappaB, and Stat3 block the enhanced viability of LMP1 transgenic lymphocytes and lymphoma cells in vitro. Lymphoma cells are independent of IL4/Stat6 signaling for survival and proliferation, but have constitutively activated Stat3 signaling. These same targets are also deregulated in wild-type B-1a lymphomas that arise spontaneously through age predisposition. These results suggest that Akt, NFkappaB, and Stat3 pathways may serve as effective targets in the treatment of EBV-associated B cell lymphomas."
],
"offsets": [
[
0,
974
]
]
}
] | [
{
"id": "PMC-2065877-00-TIAB_T1",
"type": "Protein",
"text": [
"Latent Membrane Protein 1"
],
"offsets": [
[
4,
29
]
],
"normalized": []
},
{
"id": "PMC-2065877-00-TIAB_T2",
"type": "Protein",
"text": [
"Akt"
],
"offsets": [
[
40,
43
]
],
"normalized": []
},
{
"id": "PMC-2065877-00-TIAB_T3",
"type": "Protein",
"text": [
"Stat3"
],
"offsets": [
[
59,
64
]
],
"normalized": []
},
{
"id": "PMC-2065877-00-TIAB_T4",
"type": "Protein",
"text": [
"Latent membrane protein 1"
],
"offsets": [
[
85,
110
]
],
"normalized": []
},
{
"id": "PMC-2065877-00-TIAB_T5",
"type": "Protein",
"text": [
"LMP1"
],
"offsets": [
[
112,
116
]
],
"normalized": []
},
{
"id": "PMC-2065877-00-TIAB_T6",
"type": "Protein",
"text": [
"LMP1"
],
"offsets": [
[
192,
196
]
],
"normalized": []
},
{
"id": "PMC-2065877-00-TIAB_T7",
"type": "Protein",
"text": [
"Akt"
],
"offsets": [
[
458,
461
]
],
"normalized": []
},
{
"id": "PMC-2065877-00-TIAB_T8",
"type": "Protein",
"text": [
"Stat3"
],
"offsets": [
[
477,
482
]
],
"normalized": []
},
{
"id": "PMC-2065877-00-TIAB_T9",
"type": "Protein",
"text": [
"LMP1"
],
"offsets": [
[
515,
519
]
],
"normalized": []
},
{
"id": "PMC-2065877-00-TIAB_T10",
"type": "Protein",
"text": [
"IL4"
],
"offsets": [
[
606,
609
]
],
"normalized": []
},
{
"id": "PMC-2065877-00-TIAB_T11",
"type": "Protein",
"text": [
"Stat6"
],
"offsets": [
[
610,
615
]
],
"normalized": []
},
{
"id": "PMC-2065877-00-TIAB_T12",
"type": "Protein",
"text": [
"Stat3"
],
"offsets": [
[
692,
697
]
],
"normalized": []
},
{
"id": "PMC-2065877-00-TIAB_T13",
"type": "Protein",
"text": [
"Akt"
],
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"These same targets"
],
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}
] | [
{
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}
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"role": "Theme",
"ref_id": "PMC-2065877-00-TIAB_T3"
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}
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}
] |
17 | PMC-2791889-05-Results | [
{
"id": "PMC-2791889-05-Results__text",
"type": "abstract",
"text": [
"IL-10 Production Is Maintained by High TCR Signal Strength and IL-12\nWe next investigated whether repeated strong TCR activation is a compensatory signal for IL-12-induced STAT4 signaling in the induction of IL-10 in Th1 cells. For this, CD4+ T cells were differentiated for 2 consecutive weeks with high antigen doses in the presence or absence of IL-12 throughout (Figures 4A-4D). High antigen dose and IL-12 cooperated to induce maximal IL-10 production (Figures 4A and 4B), given that this combination resulted in the highest numbers of IL-10-producing Th1 cells. Repeated high antigen dose stimulation in the absence of exogenously added IL-12 resulted in the production of IL-10 by Th1 cells, suggesting that repeated strong TCR triggering may overcome the need for IL-12 for IL-10 induction (Figures 4C and 4D). However, IL-10 induction under these conditions was abrogated when IL-12p40-deficient DCs were used as APCs (Figure 4E). Thus, IL-12 is essential during both primary and secondary antigenic stimulation for production of IL-10 by Th1 cells.\nTo determine the requirements for stability of the IL-10-producing Th1 cells, we differentiated CD4+ T cells for 1 week with high antigen doses with or without IL-12 (Figures 4A and 4C), washed them, and then restimulated them for an additional week with a low antigen dose, in the absence or presence of IL-12 (Figure 4F). Th1 cells induced in the first week to produce IL-10 by culture with high antigen doses and IL-12 lost their ability to express IL-10 when recultured with low doses of OVA, which could be compensated for, to some extent, by addition of IL-12 to the secondary cultures (Figure 4F), again suggesting that antigen dose and IL-12 signals cooperate for the induction of IL-10. Finally, DO11.10 CD4+ cells that were exposed to low doses of antigen and IL-12 during the primary differentiation phase produced high amounts of IFN-gamma but little IL-10, but they could be induced to produce IL-10 when both high antigen dose and IL-12 were present during the recall phase (Figure S4). Thus, high antigen dose and IL-12 are required for sustaining the induction of IL-10 production by Th1 cells."
],
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}
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},
{
"id": "PMC-2791889-05-Results_E23",
"type": "Positive_regulation",
"trigger": {
"text": [
"cooperate"
],
"offsets": [
[
1717,
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]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2791889-05-Results_E24"
}
]
},
{
"id": "PMC-2791889-05-Results_E24",
"type": "Gene_expression",
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"text": [
"induction"
],
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1735,
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]
]
},
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{
"role": "Theme",
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}
]
},
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"text": [
"produced"
],
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]
]
},
"arguments": [
{
"role": "Theme",
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}
]
},
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"id": "PMC-2791889-05-Results_E26",
"type": "Gene_expression",
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"text": [
"produced"
],
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1876,
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]
]
},
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{
"role": "Theme",
"ref_id": "PMC-2791889-05-Results_T33"
}
]
},
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"type": "Positive_regulation",
"trigger": {
"text": [
"induced"
],
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[
1947,
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]
]
},
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{
"role": "Theme",
"ref_id": "PMC-2791889-05-Results_E28"
},
{
"role": "Cause",
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}
]
},
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"text": [
"produce"
],
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]
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"role": "Theme",
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}
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},
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"induction"
],
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2126,
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]
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{
"role": "Theme",
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},
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}
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},
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"id": "PMC-2791889-05-Results_E30",
"type": "Gene_expression",
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"production"
],
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},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2791889-05-Results_T37"
}
]
}
] | [] | [] |
18 | PMC-2626671-17-Caption-Figure_1 | [
{
"id": "PMC-2626671-17-Caption-Figure_1__text",
"type": "abstract",
"text": [
"Kinetics of gene expression during CD8+ T cell differentiation. (A) Kinetics of Prf1, Gzmb, Tbx21 (T-bet), and Eomes mRNA expression in differentiating P14 CD8+ T cells analyzed by Northern blotting. RNA from day 7 Th1 cells was used as a control. Sizes of mRNA transcripts are indicated. (B) Quantification of relative mRNA amounts by phosphorimager analysis. (C) Kinetics of protein expression in differentiating P14 CD8+ T cells analyzed by immunoblotting. Sizes of protein bands are indicated. (D) Relative protein amounts quantified from the Western blots. (E) Intracellular staining for granzyme B, IFN-gamma, and TNF. Granzyme B staining was specific relative to an isotype control (not depicted). Cells were restimulated with PMA and ionomycin for 4 h. (F) FACS-based assay to measure cytolytic activity of P14 CD8+ T cells against EL4 targets loaded with 0 (-) or 1 (+) muM Gp33 peptide (effector-to-target ratio = 5:1). Percentage of Annexin V+ (apoptotic) target cells in the CD8-negative EL4 target population (dot plots) was determined (histograms). Cytolytic activity was blocked by incubation with 2 mM EGTA (not depicted), confirming involvement of the granule exocytosis (perforin-granzyme B) pathway. Data are representative of at least five (A-E) or three (F) independent experiments."
],
"offsets": [
[
0,
1303
]
]
}
] | [
{
"id": "PMC-2626671-17-Caption-Figure_1_T1",
"type": "Protein",
"text": [
"CD8"
],
"offsets": [
[
35,
38
]
],
"normalized": []
},
{
"id": "PMC-2626671-17-Caption-Figure_1_T2",
"type": "Protein",
"text": [
"Prf1"
],
"offsets": [
[
80,
84
]
],
"normalized": []
},
{
"id": "PMC-2626671-17-Caption-Figure_1_T3",
"type": "Protein",
"text": [
"Gzmb"
],
"offsets": [
[
86,
90
]
],
"normalized": []
},
{
"id": "PMC-2626671-17-Caption-Figure_1_T4",
"type": "Protein",
"text": [
"Tbx21"
],
"offsets": [
[
92,
97
]
],
"normalized": []
},
{
"id": "PMC-2626671-17-Caption-Figure_1_T5",
"type": "Protein",
"text": [
"T-bet"
],
"offsets": [
[
99,
104
]
],
"normalized": []
},
{
"id": "PMC-2626671-17-Caption-Figure_1_T6",
"type": "Protein",
"text": [
"Eomes"
],
"offsets": [
[
111,
116
]
],
"normalized": []
},
{
"id": "PMC-2626671-17-Caption-Figure_1_T7",
"type": "Protein",
"text": [
"CD8"
],
"offsets": [
[
156,
159
]
],
"normalized": []
},
{
"id": "PMC-2626671-17-Caption-Figure_1_T8",
"type": "Protein",
"text": [
"CD8"
],
"offsets": [
[
419,
422
]
],
"normalized": []
},
{
"id": "PMC-2626671-17-Caption-Figure_1_T9",
"type": "Protein",
"text": [
"granzyme B"
],
"offsets": [
[
593,
603
]
],
"normalized": []
},
{
"id": "PMC-2626671-17-Caption-Figure_1_T10",
"type": "Protein",
"text": [
"IFN-gamma"
],
"offsets": [
[
605,
614
]
],
"normalized": []
},
{
"id": "PMC-2626671-17-Caption-Figure_1_T11",
"type": "Protein",
"text": [
"TNF"
],
"offsets": [
[
620,
623
]
],
"normalized": []
},
{
"id": "PMC-2626671-17-Caption-Figure_1_T12",
"type": "Protein",
"text": [
"Granzyme B"
],
"offsets": [
[
625,
635
]
],
"normalized": []
},
{
"id": "PMC-2626671-17-Caption-Figure_1_T13",
"type": "Protein",
"text": [
"CD8"
],
"offsets": [
[
819,
822
]
],
"normalized": []
},
{
"id": "PMC-2626671-17-Caption-Figure_1_T14",
"type": "Protein",
"text": [
"Annexin V"
],
"offsets": [
[
944,
953
]
],
"normalized": []
},
{
"id": "PMC-2626671-17-Caption-Figure_1_T15",
"type": "Protein",
"text": [
"CD8"
],
"offsets": [
[
987,
990
]
],
"normalized": []
},
{
"id": "PMC-2626671-17-Caption-Figure_1_T16",
"type": "Protein",
"text": [
"perforin"
],
"offsets": [
[
1189,
1197
]
],
"normalized": []
},
{
"id": "PMC-2626671-17-Caption-Figure_1_T17",
"type": "Protein",
"text": [
"granzyme B"
],
"offsets": [
[
1198,
1208
]
],
"normalized": []
}
] | [
{
"id": "PMC-2626671-17-Caption-Figure_1_E1",
"type": "Transcription",
"trigger": {
"text": [
"mRNA expression"
],
"offsets": [
[
117,
132
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2626671-17-Caption-Figure_1_T2"
}
]
},
{
"id": "PMC-2626671-17-Caption-Figure_1_E2",
"type": "Transcription",
"trigger": {
"text": [
"mRNA expression"
],
"offsets": [
[
117,
132
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2626671-17-Caption-Figure_1_T3"
}
]
},
{
"id": "PMC-2626671-17-Caption-Figure_1_E3",
"type": "Transcription",
"trigger": {
"text": [
"mRNA expression"
],
"offsets": [
[
117,
132
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2626671-17-Caption-Figure_1_T4"
}
]
},
{
"id": "PMC-2626671-17-Caption-Figure_1_E4",
"type": "Transcription",
"trigger": {
"text": [
"mRNA expression"
],
"offsets": [
[
117,
132
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2626671-17-Caption-Figure_1_T6"
}
]
},
{
"id": "PMC-2626671-17-Caption-Figure_1_E5",
"type": "Gene_expression",
"trigger": {
"text": [
"staining"
],
"offsets": [
[
580,
588
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2626671-17-Caption-Figure_1_T9"
}
]
},
{
"id": "PMC-2626671-17-Caption-Figure_1_E6",
"type": "Gene_expression",
"trigger": {
"text": [
"staining"
],
"offsets": [
[
580,
588
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2626671-17-Caption-Figure_1_T10"
}
]
},
{
"id": "PMC-2626671-17-Caption-Figure_1_E7",
"type": "Gene_expression",
"trigger": {
"text": [
"staining"
],
"offsets": [
[
580,
588
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2626671-17-Caption-Figure_1_T11"
}
]
},
{
"id": "PMC-2626671-17-Caption-Figure_1_E8",
"type": "Gene_expression",
"trigger": {
"text": [
"staining"
],
"offsets": [
[
636,
644
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2626671-17-Caption-Figure_1_T12"
}
]
}
] | [
{
"id": "PMC-2626671-17-Caption-Figure_1_1",
"entity_ids": [
"PMC-2626671-17-Caption-Figure_1_T4",
"PMC-2626671-17-Caption-Figure_1_T5"
]
}
] | [] |
19 | PMC-3148254-10-Materials_and_Methods | [
{
"id": "PMC-3148254-10-Materials_and_Methods__text",
"type": "abstract",
"text": [
"Retroviral transduction\nA retroviral vector (pMIP) was used for the stable transduction of cells with HOIP and IKKgamma cDNA constructs. pMIP was constructed by replacing the IRES and GFP encoding sequences in pMIG [31] with the IRES and puromycin resistance gene from pIRESpuro2 (Clontech). FLAG-tagged mouse HOIP cDNA was inserted into the multiple cloning site of pMIP. A pMIP construct encoding mouse IKKgamma with an amino terminal birch profilin peptide (BP)-tag was also prepared. Retroviral particles were generated by transient transfection of 293T cells with pMIP, pMIP-HOIP, or pMIP-IKKgamma and the packaging vector pCL-Eco [32]. Two days after transfection, culture supernatants were harvested and filtered. A20.2J or HOIP-deficient cells were added to 24-well plates (2.5x105 cells/well) with 1 ml virus-containing supernatant and 8 microg/ml polybrene. Plates were centrifuged at 500 x g for 2 hrs at room temperature. Cells were cultured in B cell culture medium for 48 hrs, after which the transduced cells were selected in 3 microg/ml puromycin."
],
"offsets": [
[
0,
1063
]
]
}
] | [
{
"id": "PMC-3148254-10-Materials_and_Methods_T1",
"type": "Protein",
"text": [
"HOIP"
],
"offsets": [
[
102,
106
]
],
"normalized": []
},
{
"id": "PMC-3148254-10-Materials_and_Methods_T2",
"type": "Protein",
"text": [
"IKKgamma"
],
"offsets": [
[
111,
119
]
],
"normalized": []
},
{
"id": "PMC-3148254-10-Materials_and_Methods_T3",
"type": "Protein",
"text": [
"HOIP"
],
"offsets": [
[
310,
314
]
],
"normalized": []
},
{
"id": "PMC-3148254-10-Materials_and_Methods_T4",
"type": "Protein",
"text": [
"IKKgamma"
],
"offsets": [
[
405,
413
]
],
"normalized": []
},
{
"id": "PMC-3148254-10-Materials_and_Methods_T5",
"type": "Protein",
"text": [
"HOIP"
],
"offsets": [
[
580,
584
]
],
"normalized": []
},
{
"id": "PMC-3148254-10-Materials_and_Methods_T6",
"type": "Protein",
"text": [
"IKKgamma"
],
"offsets": [
[
594,
602
]
],
"normalized": []
},
{
"id": "PMC-3148254-10-Materials_and_Methods_T7",
"type": "Protein",
"text": [
"HOIP"
],
"offsets": [
[
731,
735
]
],
"normalized": []
}
] | [
{
"id": "PMC-3148254-10-Materials_and_Methods_E1",
"type": "Negative_regulation",
"trigger": {
"text": [
"deficient"
],
"offsets": [
[
736,
745
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-3148254-10-Materials_and_Methods_T7"
}
]
}
] | [] | [] |
20 | PMC-2664230-05-MATERIALS_AND_METHODS | [
{
"id": "PMC-2664230-05-MATERIALS_AND_METHODS__text",
"type": "abstract",
"text": [
"SDS-PAGE and Immunoblotting (I-kappaBalpha, NF-kappaB p65, and CREB)\nFollowing stimulation, PBMCs were washed with ice-cold PBS and centrifuged to collect a cell pellet. The pellet was resuspended in ice-cold SDS sample buffer supplemented with 100 mM dithiothreitol. Cytoplasmic and nuclear extracts were isolated with NE-PER nuclear and cytoplasmic extraction reagents with 1x Halt Protease Inhibitor Cocktail according to the manufacturer's instructions. Protein concentrations were determined with the BCA protein reagent kit for each sample according to a standardized curve for albumin. Cell lysates were collected by boiling the samples in a 100degreesC water bath for 5 minutes. Ten mug of protein per sample was separated by SDS-polyacrylamide gel electrophoresis through 8-16% tris-glycine polyacrylamide gradient gels and transferred to nitrocellulose membranes. The membranes were blocked with 5% milk in Tris-buffered saline/Tween 20 (Fischer Scientific, Pittsburgh, PA) for 1 hour. Cytoplasmic extracts were incubated with phosphorylated I-kappaBalpha antibody (1:200), while nuclear extracts were incubated with either phosphorylated NF-kappaB p65 antibody (1:500) or phosphorylated CREB antibody (1:500) overnight at 4degreesC in separate experiments. The membranes were washed with Tris-buffered saline/Tween 20 and incubated for 1 hour at room temperature with the secondary antibody, horseradish peroxidase-linked anti-rabbit IgG diluted 1:2000 in blocking solution. After repeated washing of the membrane, the Supersignal West Pico Chemiluminescent Kit was applied for antibody detection per the manufacturer's instructions.\nWestern blot data is presented as a percentage of LPS stimulation. The percentage of LPS stimulation was calculated by dividing the mean band pixel total for each treatment arm divided by the mean pixel total of samples stimulated with LPS and multiplying by 100. Thus, LPS stimulation is reported as 100% and each of the treatment arms is reported as a percent of LPS stimulation."
],
"offsets": [
[
0,
2026
]
]
}
] | [
{
"id": "PMC-2664230-05-MATERIALS_AND_METHODS_T1",
"type": "Protein",
"text": [
"I-kappaBalpha"
],
"offsets": [
[
29,
42
]
],
"normalized": []
},
{
"id": "PMC-2664230-05-MATERIALS_AND_METHODS_T2",
"type": "Protein",
"text": [
"p65"
],
"offsets": [
[
54,
57
]
],
"normalized": []
},
{
"id": "PMC-2664230-05-MATERIALS_AND_METHODS_T3",
"type": "Protein",
"text": [
"CREB"
],
"offsets": [
[
63,
67
]
],
"normalized": []
},
{
"id": "PMC-2664230-05-MATERIALS_AND_METHODS_T4",
"type": "Protein",
"text": [
"I-kappaBalpha"
],
"offsets": [
[
1052,
1065
]
],
"normalized": []
},
{
"id": "PMC-2664230-05-MATERIALS_AND_METHODS_T5",
"type": "Protein",
"text": [
"p65"
],
"offsets": [
[
1159,
1162
]
],
"normalized": []
}
] | [
{
"id": "PMC-2664230-05-MATERIALS_AND_METHODS_E1",
"type": "Phosphorylation",
"trigger": {
"text": [
"phosphorylated"
],
"offsets": [
[
1037,
1051
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2664230-05-MATERIALS_AND_METHODS_T4"
}
]
},
{
"id": "PMC-2664230-05-MATERIALS_AND_METHODS_E2",
"type": "Phosphorylation",
"trigger": {
"text": [
"phosphorylated"
],
"offsets": [
[
1134,
1148
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2664230-05-MATERIALS_AND_METHODS_T5"
}
]
}
] | [] | [] |
21 | PMC-3245220-19-Materials_and_Methods | [
{
"id": "PMC-3245220-19-Materials_and_Methods__text",
"type": "abstract",
"text": [
"Annexin V/PI Apoptosis Assay\nCell apoptosis assay was performed as described previously [51] using the Annexin V-FITC apoptosis detection kit (BD PharMingen, San Diego, CA). Briefly, human monocytes (5x106) were incubated with inhibitors for 30 minutes in X-vivo medium and restimulated with 100 ng/ml M-CSF overnight. The cells were removed from the culture dish using Accutase (eBioscience, San Diego, CA) and stained with Annexin V-FITC and PI and analyzed by flow cytometry (FACSCalibur; BD PharMingen). Annexin V-FITC and PI double negative cells were considered non-apoptotic cells for statistical analysis."
],
"offsets": [
[
0,
613
]
]
}
] | [
{
"id": "PMC-3245220-19-Materials_and_Methods_T1",
"type": "Protein",
"text": [
"Annexin V"
],
"offsets": [
[
0,
9
]
],
"normalized": []
},
{
"id": "PMC-3245220-19-Materials_and_Methods_T2",
"type": "Protein",
"text": [
"Annexin V"
],
"offsets": [
[
103,
112
]
],
"normalized": []
},
{
"id": "PMC-3245220-19-Materials_and_Methods_T3",
"type": "Protein",
"text": [
"Annexin V"
],
"offsets": [
[
425,
434
]
],
"normalized": []
},
{
"id": "PMC-3245220-19-Materials_and_Methods_T4",
"type": "Protein",
"text": [
"Annexin V"
],
"offsets": [
[
508,
517
]
],
"normalized": []
}
] | [] | [] | [] |
22 | PMC-2065877-20-Caption-Figure_2 | [
{
"id": "PMC-2065877-20-Caption-Figure_2__text",
"type": "abstract",
"text": [
"LMP1 Promotes B-1a Lymphomas That Can Escape Allelic Exclusion\n(A) Flow cytometry analysis of splenocytes from a WT or LMP1 transgenic lymphoma for the pan-B cell (CD19), B-1a cell (CD5), and Ig heavy chain (IgM and IgD) and light chain (kappa and lambda) markers. Shown are the results from WT lymphoma 1 and LMP1 transgenic lymphoma 4. This analysis was repeated on four other LMP1 transgenic lymphomas (1, 2, 3, and 6) showing a similar B-1a phenotype, of which lymphomas 2 and 4 were also doubly positive for kappa and lambda light chains.\n(B) Flow cytometry analysis of WT or LMP1 transgenic splenocytes for B-1a (CD19+CD5+) and B-1b or B2 subsets (CD19+CD5-). Percentages of B-1a and B-1b or B2 subsets are shown in each quadrant. This analysis was repeated on three other WT and two other LMP1 transgenic mice with similar results.\n(C) Immunoblot analysis for kappa and lambda light chains of B cells (CD19+) purified from WT and LMP1 transgenic mice. Actin was used as a loading control."
],
"offsets": [
[
0,
995
]
]
}
] | [
{
"id": "PMC-2065877-20-Caption-Figure_2_T1",
"type": "Protein",
"text": [
"LMP1"
],
"offsets": [
[
0,
4
]
],
"normalized": []
},
{
"id": "PMC-2065877-20-Caption-Figure_2_T2",
"type": "Protein",
"text": [
"LMP1"
],
"offsets": [
[
119,
123
]
],
"normalized": []
},
{
"id": "PMC-2065877-20-Caption-Figure_2_T3",
"type": "Protein",
"text": [
"CD19"
],
"offsets": [
[
164,
168
]
],
"normalized": []
},
{
"id": "PMC-2065877-20-Caption-Figure_2_T4",
"type": "Protein",
"text": [
"CD5"
],
"offsets": [
[
182,
185
]
],
"normalized": []
},
{
"id": "PMC-2065877-20-Caption-Figure_2_T5",
"type": "Protein",
"text": [
"LMP1"
],
"offsets": [
[
310,
314
]
],
"normalized": []
},
{
"id": "PMC-2065877-20-Caption-Figure_2_T6",
"type": "Protein",
"text": [
"LMP1"
],
"offsets": [
[
379,
383
]
],
"normalized": []
},
{
"id": "PMC-2065877-20-Caption-Figure_2_T7",
"type": "Protein",
"text": [
"LMP1"
],
"offsets": [
[
581,
585
]
],
"normalized": []
},
{
"id": "PMC-2065877-20-Caption-Figure_2_T8",
"type": "Protein",
"text": [
"CD19"
],
"offsets": [
[
619,
623
]
],
"normalized": []
},
{
"id": "PMC-2065877-20-Caption-Figure_2_T9",
"type": "Protein",
"text": [
"CD5"
],
"offsets": [
[
624,
627
]
],
"normalized": []
},
{
"id": "PMC-2065877-20-Caption-Figure_2_T10",
"type": "Protein",
"text": [
"CD19"
],
"offsets": [
[
654,
658
]
],
"normalized": []
},
{
"id": "PMC-2065877-20-Caption-Figure_2_T11",
"type": "Protein",
"text": [
"CD5"
],
"offsets": [
[
659,
662
]
],
"normalized": []
},
{
"id": "PMC-2065877-20-Caption-Figure_2_T12",
"type": "Protein",
"text": [
"LMP1"
],
"offsets": [
[
796,
800
]
],
"normalized": []
},
{
"id": "PMC-2065877-20-Caption-Figure_2_T13",
"type": "Protein",
"text": [
"CD19"
],
"offsets": [
[
909,
913
]
],
"normalized": []
},
{
"id": "PMC-2065877-20-Caption-Figure_2_T14",
"type": "Protein",
"text": [
"LMP1"
],
"offsets": [
[
937,
941
]
],
"normalized": []
}
] | [] | [] | [] |
23 | PMC-1447668-17-Materials_and_Methods | [
{
"id": "PMC-1447668-17-Materials_and_Methods__text",
"type": "abstract",
"text": [
"Western blot analysis.\nHEK 293T cells were plated at a density of 5 x 105 cells/well in six-well culture plates (BD Biosciences) 1 d prior to transfection with the appropriate plasmid DNA (2 mug total) using FuGene 6 transfection reagent (Roche). Cells were harvested 24 h posttransfection for whole-cell lysates in RIPA buffer (50 mM Tris-HCl [pH 7.4], 150 mM NaCl, 1% Igepal (NP-40), 0.5% sodium deoxycholate, 1 mM EDTA, 1 mM DTT, 1 mM PMSF, and 1x Complete Mini Protease Inhibitor [Roche]). Protein concentration was determined by Lowry assay (Bio-Rad, Hercules, California, United States) and colorimetric reactions were read using a VersaMax microplate reader (Molecular Devices, Sunnyvale, California, United States) at an absorbance of 750 nm. Size fractionation was performed on 20 mug of protein/sample by SDS-PAGE, and the protein was transferred to nitrocellulose or PVDF membranes and subjected to immunoblotting using the indicated antibodies. Foxp3 was detected using rabbit anti-human Foxp3 polyclonal antibody (ab4728 or ab10563; Abcam, Cambridge, United Kingdom) and anti-rabbit IgG-HRP secondary antibody (Cell Signaling Technology, Beverly, Massachusetts, United States). NF-kappaB p65 and CREB-1 were detected using rabbit anti-human polyclonal (p65) or monoclonal antibody (CREB-1; 48H2) (Cell Signaling Technology). Beta-actin was detected using a mouse monoclonal antibody (AC-15; Sigma, St. Louis, Missouri, United States). For coimmunoprecipitation analysis, cell lysates were precleared with 30 mul of protein A/G plus-agarose beads (Santa Cruz Biotechnology, Santa Cruz, California, United States) and then incubated with mouse monoclonal anti-HA antibody (6E2; 1:100; Cell Signaling Technology) and 30 mul of protein A/G plus-agarose beads overnight. The immunoprecipitates were washed four times with RIPA buffer, resuspended in SDS sample buffer, and heated at 95 degreesC for 5 min. Proteins were then treated as described for Western blot analysis."
],
"offsets": [
[
0,
1980
]
]
}
] | [
{
"id": "PMC-1447668-17-Materials_and_Methods_T1",
"type": "Protein",
"text": [
"Foxp3"
],
"offsets": [
[
957,
962
]
],
"normalized": []
},
{
"id": "PMC-1447668-17-Materials_and_Methods_T2",
"type": "Protein",
"text": [
"Foxp3"
],
"offsets": [
[
1000,
1005
]
],
"normalized": []
},
{
"id": "PMC-1447668-17-Materials_and_Methods_T3",
"type": "Protein",
"text": [
"p65"
],
"offsets": [
[
1201,
1204
]
],
"normalized": []
},
{
"id": "PMC-1447668-17-Materials_and_Methods_T4",
"type": "Protein",
"text": [
"CREB-1"
],
"offsets": [
[
1209,
1215
]
],
"normalized": []
},
{
"id": "PMC-1447668-17-Materials_and_Methods_T5",
"type": "Protein",
"text": [
"p65"
],
"offsets": [
[
1266,
1269
]
],
"normalized": []
},
{
"id": "PMC-1447668-17-Materials_and_Methods_T6",
"type": "Protein",
"text": [
"CREB-1"
],
"offsets": [
[
1295,
1301
]
],
"normalized": []
},
{
"id": "PMC-1447668-17-Materials_and_Methods_T7",
"type": "Protein",
"text": [
"Beta-actin"
],
"offsets": [
[
1338,
1348
]
],
"normalized": []
}
] | [] | [] | [] |
24 | PMC-1310901-11-RESULTS | [
{
"id": "PMC-1310901-11-RESULTS__text",
"type": "abstract",
"text": [
"Methylation-sensitive enzymes do not cut specific sites in the IRF-4 promoter in hematopoietic cells\nTo further investigate promoter methylation as a regulatory mechanism of IRF-4 gene expression, restriction-PCR-assays were performed (20,24), where only methylated DNA would not be cut enabling subsequent PCR amplification and vice versa. Genomic DNA from leukemic cells Jurkat, CML-T1, U-937, K-562, EM-2 and BV-173 was digested with the methylation-sensitive enzymes HpaII, Bsh1236I and HaeII-isochizomer Bsp143II. EcoRI, which has no recognition site within the IRF-4 promoter, and the methylation-resistant enzyme MspI served as controls. Two separate amplification reactions were performed, generating two fragments, F1 and F2 (Figure 3A). After digestion with HpaII and Bsp143II a sufficient PCR amplification of F1 and F2 was detected in DNA from IRF-4-negative Jurkat, CML-T1, U-937, K-562 and EM-2 cells, suggesting a promoter methylation (and restriction protection) at the respective recognition sites (Figure 3B and C). Notably, in IRF-4-positive SD-1 cells digestion with the methylation-sensitive enzymes completely inhibited amplification of F1 and F2. In IRF-4-positive BV-173 cells a HpaII, but not a Bsh1236I digestion, significantly reduced the amplifiable DNA message of F2 (Figure 3C), whereas amplification of F1 was not affected (Figure 3B). This implied that IRF-4 transcription in SD-1 and BV-173 cells is associated with less promoter methylation (in BV-173 especially at HpaII sites) as compared with the tested IRF-4-negative cells."
],
"offsets": [
[
0,
1562
]
]
}
] | [
{
"id": "PMC-1310901-11-RESULTS_T1",
"type": "Protein",
"text": [
"IRF-4"
],
"offsets": [
[
63,
68
]
],
"normalized": []
},
{
"id": "PMC-1310901-11-RESULTS_T2",
"type": "Protein",
"text": [
"IRF-4"
],
"offsets": [
[
174,
179
]
],
"normalized": []
},
{
"id": "PMC-1310901-11-RESULTS_T3",
"type": "Protein",
"text": [
"IRF-4"
],
"offsets": [
[
567,
572
]
],
"normalized": []
},
{
"id": "PMC-1310901-11-RESULTS_T4",
"type": "Protein",
"text": [
"IRF-4"
],
"offsets": [
[
856,
861
]
],
"normalized": []
},
{
"id": "PMC-1310901-11-RESULTS_T5",
"type": "Protein",
"text": [
"IRF-4"
],
"offsets": [
[
1046,
1051
]
],
"normalized": []
},
{
"id": "PMC-1310901-11-RESULTS_T6",
"type": "Protein",
"text": [
"IRF-4"
],
"offsets": [
[
1173,
1178
]
],
"normalized": []
},
{
"id": "PMC-1310901-11-RESULTS_T7",
"type": "Protein",
"text": [
"IRF-4"
],
"offsets": [
[
1385,
1390
]
],
"normalized": []
},
{
"id": "PMC-1310901-11-RESULTS_T8",
"type": "Protein",
"text": [
"IRF-4"
],
"offsets": [
[
1541,
1546
]
],
"normalized": []
}
] | [
{
"id": "PMC-1310901-11-RESULTS_E1",
"type": "Gene_expression",
"trigger": {
"text": [
"expression"
],
"offsets": [
[
185,
195
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-11-RESULTS_T2"
}
]
},
{
"id": "PMC-1310901-11-RESULTS_E2",
"type": "Gene_expression",
"trigger": {
"text": [
"negative"
],
"offsets": [
[
862,
870
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-11-RESULTS_T4"
}
]
},
{
"id": "PMC-1310901-11-RESULTS_E3",
"type": "Gene_expression",
"trigger": {
"text": [
"positive"
],
"offsets": [
[
1052,
1060
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-11-RESULTS_T5"
}
]
},
{
"id": "PMC-1310901-11-RESULTS_E4",
"type": "Gene_expression",
"trigger": {
"text": [
"positive"
],
"offsets": [
[
1179,
1187
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-11-RESULTS_T6"
}
]
},
{
"id": "PMC-1310901-11-RESULTS_E5",
"type": "Transcription",
"trigger": {
"text": [
"transcription"
],
"offsets": [
[
1391,
1404
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-11-RESULTS_T7"
}
]
},
{
"id": "PMC-1310901-11-RESULTS_E6",
"type": "Gene_expression",
"trigger": {
"text": [
"negative"
],
"offsets": [
[
1547,
1555
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-11-RESULTS_T8"
}
]
}
] | [] | [] |
25 | PMC-2889865-03-Results | [
{
"id": "PMC-2889865-03-Results__text",
"type": "abstract",
"text": [
"Induction of inflammatory responses\nThe ability of PMA and HK E. coli to induce an inflammatory response in Jurkat T-cells was evaluated using a multiplex cytokine assay following 24 h stimulation. The cytokine profile revealed an enhanced induction of the pro-inflammatory cytokines IL-2, IL-6, TNF and the chemokine CXCL8. The levels of the anti-inflammatory cytokine IL-10 were unaffected by PMA but were significantly decreased by HK E. coli (Table 1). These results confirmed that PMA and HK E. coli induced an inflammatory response in the Jurkat T-cells. It is interesting to note that PMA was 120-fold more effective at inducing CXCL8 than HK E. coli. PMA-dependent induction of AP-1 and down-regulation of NF-kappaB suggests an involvement of AP-1 in CXCL8 regulation. Determination of the time course of cytokine induction in response to PMA showed that CXCL8 was already released between 2-6 h, while TNF and IL-6 were released between 6-24 h (figure 3). These results indicated that the cytokines were differentially regulated and that the release was not associated with the early transient induction of NF-kappaB. The temporal induction of AP-1 correlated to the CXCL8 levels and preceded the TNF and IL-6 release. This suggests an association between CXCL8 release and AP-1 signalling."
],
"offsets": [
[
0,
1299
]
]
}
] | [
{
"id": "PMC-2889865-03-Results_T1",
"type": "Protein",
"text": [
"IL-2"
],
"offsets": [
[
284,
288
]
],
"normalized": []
},
{
"id": "PMC-2889865-03-Results_T2",
"type": "Protein",
"text": [
"IL-6"
],
"offsets": [
[
290,
294
]
],
"normalized": []
},
{
"id": "PMC-2889865-03-Results_T3",
"type": "Protein",
"text": [
"CXCL8"
],
"offsets": [
[
318,
323
]
],
"normalized": []
},
{
"id": "PMC-2889865-03-Results_T4",
"type": "Protein",
"text": [
"IL-10"
],
"offsets": [
[
370,
375
]
],
"normalized": []
},
{
"id": "PMC-2889865-03-Results_T5",
"type": "Protein",
"text": [
"CXCL8"
],
"offsets": [
[
636,
641
]
],
"normalized": []
},
{
"id": "PMC-2889865-03-Results_T6",
"type": "Protein",
"text": [
"CXCL8"
],
"offsets": [
[
759,
764
]
],
"normalized": []
},
{
"id": "PMC-2889865-03-Results_T7",
"type": "Protein",
"text": [
"CXCL8"
],
"offsets": [
[
863,
868
]
],
"normalized": []
},
{
"id": "PMC-2889865-03-Results_T8",
"type": "Protein",
"text": [
"IL-6"
],
"offsets": [
[
919,
923
]
],
"normalized": []
},
{
"id": "PMC-2889865-03-Results_T9",
"type": "Protein",
"text": [
"CXCL8"
],
"offsets": [
[
1176,
1181
]
],
"normalized": []
},
{
"id": "PMC-2889865-03-Results_T10",
"type": "Protein",
"text": [
"IL-6"
],
"offsets": [
[
1214,
1218
]
],
"normalized": []
},
{
"id": "PMC-2889865-03-Results_T11",
"type": "Protein",
"text": [
"CXCL8"
],
"offsets": [
[
1265,
1270
]
],
"normalized": []
},
{
"id": "PMC-2889865-03-Results_T12",
"type": "Anaphora",
"text": [
"the cytokines"
],
"offsets": [
[
994,
1007
]
],
"normalized": []
}
] | [
{
"id": "PMC-2889865-03-Results_E1",
"type": "Positive_regulation",
"trigger": {
"text": [
"enhanced"
],
"offsets": [
[
231,
239
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2889865-03-Results_E2"
}
]
},
{
"id": "PMC-2889865-03-Results_E2",
"type": "Positive_regulation",
"trigger": {
"text": [
"induction"
],
"offsets": [
[
240,
249
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2889865-03-Results_T3"
}
]
},
{
"id": "PMC-2889865-03-Results_E3",
"type": "Regulation",
"trigger": {
"text": [
"unaffected"
],
"offsets": [
[
381,
391
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2889865-03-Results_T4"
}
]
},
{
"id": "PMC-2889865-03-Results_E4",
"type": "Negative_regulation",
"trigger": {
"text": [
"decreased"
],
"offsets": [
[
422,
431
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2889865-03-Results_T4"
}
]
},
{
"id": "PMC-2889865-03-Results_E5",
"type": "Positive_regulation",
"trigger": {
"text": [
"effective"
],
"offsets": [
[
614,
623
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2889865-03-Results_E6"
}
]
},
{
"id": "PMC-2889865-03-Results_E6",
"type": "Positive_regulation",
"trigger": {
"text": [
"inducing"
],
"offsets": [
[
627,
635
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2889865-03-Results_T5"
}
]
},
{
"id": "PMC-2889865-03-Results_E7",
"type": "Regulation",
"trigger": {
"text": [
"involvement"
],
"offsets": [
[
736,
747
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2889865-03-Results_E8"
}
]
},
{
"id": "PMC-2889865-03-Results_E8",
"type": "Regulation",
"trigger": {
"text": [
"regulation"
],
"offsets": [
[
765,
775
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2889865-03-Results_T6"
}
]
},
{
"id": "PMC-2889865-03-Results_E9",
"type": "Localization",
"trigger": {
"text": [
"released"
],
"offsets": [
[
881,
889
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2889865-03-Results_T7"
}
]
},
{
"id": "PMC-2889865-03-Results_E10",
"type": "Localization",
"trigger": {
"text": [
"released"
],
"offsets": [
[
929,
937
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2889865-03-Results_T8"
}
]
},
{
"id": "PMC-2889865-03-Results_E11",
"type": "Regulation",
"trigger": {
"text": [
"regulated"
],
"offsets": [
[
1028,
1037
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2889865-03-Results_T7"
}
]
},
{
"id": "PMC-2889865-03-Results_E12",
"type": "Regulation",
"trigger": {
"text": [
"regulated"
],
"offsets": [
[
1028,
1037
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2889865-03-Results_T8"
}
]
},
{
"id": "PMC-2889865-03-Results_E13",
"type": "Localization",
"trigger": {
"text": [
"release"
],
"offsets": [
[
1219,
1226
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2889865-03-Results_T10"
}
]
},
{
"id": "PMC-2889865-03-Results_E14",
"type": "Localization",
"trigger": {
"text": [
"release"
],
"offsets": [
[
1271,
1278
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2889865-03-Results_T11"
}
]
}
] | [] | [
{
"id": "PMC-2889865-03-Results_R1",
"type": "Coreference",
"arg1_id": "PMC-2889865-03-Results_T12",
"arg2_id": "PMC-2889865-03-Results_T7",
"normalized": []
},
{
"id": "PMC-2889865-03-Results_R2",
"type": "Coreference",
"arg1_id": "PMC-2889865-03-Results_T12",
"arg2_id": "PMC-2889865-03-Results_T8",
"normalized": []
}
] |
26 | PMC-2065877-18-Materials_and_Methods | [
{
"id": "PMC-2065877-18-Materials_and_Methods__text",
"type": "abstract",
"text": [
"Antibodies.\nFITC-conjugated goat anti-mouse IgM, rat IgG2akappa anti-mouse IgD (clone 11-26), rat IgG1kappa anti-mouse kappa (clone 187.1), rat IgG2bkappa anti-mouse lambda (clone JC5-1); PE-conjugated goat anti-mouse IgG; un-conjugated goat anti-mouse kappa and anti-mouse lambda were purchased from Southern Biotech. APC-conjugated rat IgG2akappa anti-mouse CD19 (clone 6D5), PE-conjugated mouse IgG2akappa anti-LMP1 (clone S12), un-conjugated mouse IgG2a anti-Rb (clone 2), and anti-Cdk2 (clone 55) were purchased from BD Bioscience. PE-conjugated rat IgG2akappa anti-mouse CD5 (clone 53-7.3) was purchased from eBioscience. Rat anti-LMP1 (clones 8G3, 1G6, 7E10, and 7G8) was purchased from Ascenion. Rabbit anti-pAkt (Ser473), anti-pGSK3alpha/beta (Ser21/9), anti-pStat3 (Tyr705), anti-pStat6 (Tyr641), anti-pmTOR (Ser2448), anti-Stat6, anti-Akt, anti-FoxO1, and anti-p27 were purchased from Cell Signaling. Rabbit anti-Stat3 (H-190), anti-IkappaBalpha (C-21), and goat anti-beta actin (I-19) were purchased from Santa Cruz Biotechnology. Mouse IgG1kappa anti-GSK3 was purchased from Upstate Biotechnology. Rabbit anti-pRb (Thr373) was purchased from EMD Biosciences."
],
"offsets": [
[
0,
1171
]
]
}
] | [
{
"id": "PMC-2065877-18-Materials_and_Methods_T1",
"type": "Protein",
"text": [
"CD19"
],
"offsets": [
[
360,
364
]
],
"normalized": []
},
{
"id": "PMC-2065877-18-Materials_and_Methods_T2",
"type": "Protein",
"text": [
"LMP1"
],
"offsets": [
[
414,
418
]
],
"normalized": []
},
{
"id": "PMC-2065877-18-Materials_and_Methods_T3",
"type": "Protein",
"text": [
"Rb"
],
"offsets": [
[
463,
465
]
],
"normalized": []
},
{
"id": "PMC-2065877-18-Materials_and_Methods_T4",
"type": "Protein",
"text": [
"Cdk2"
],
"offsets": [
[
486,
490
]
],
"normalized": []
},
{
"id": "PMC-2065877-18-Materials_and_Methods_T5",
"type": "Protein",
"text": [
"CD5"
],
"offsets": [
[
577,
580
]
],
"normalized": []
},
{
"id": "PMC-2065877-18-Materials_and_Methods_T6",
"type": "Protein",
"text": [
"LMP1"
],
"offsets": [
[
637,
641
]
],
"normalized": []
},
{
"id": "PMC-2065877-18-Materials_and_Methods_T7",
"type": "Protein",
"text": [
"pAkt"
],
"offsets": [
[
716,
720
]
],
"normalized": []
},
{
"id": "PMC-2065877-18-Materials_and_Methods_T8",
"type": "Protein",
"text": [
"pGSK3alpha"
],
"offsets": [
[
736,
746
]
],
"normalized": []
},
{
"id": "PMC-2065877-18-Materials_and_Methods_T9",
"type": "Protein",
"text": [
"beta"
],
"offsets": [
[
747,
751
]
],
"normalized": []
},
{
"id": "PMC-2065877-18-Materials_and_Methods_T10",
"type": "Protein",
"text": [
"pStat3"
],
"offsets": [
[
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774
]
],
"normalized": []
},
{
"id": "PMC-2065877-18-Materials_and_Methods_T11",
"type": "Protein",
"text": [
"pStat6"
],
"offsets": [
[
790,
796
]
],
"normalized": []
},
{
"id": "PMC-2065877-18-Materials_and_Methods_T12",
"type": "Protein",
"text": [
"pmTOR"
],
"offsets": [
[
812,
817
]
],
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},
{
"id": "PMC-2065877-18-Materials_and_Methods_T13",
"type": "Protein",
"text": [
"Stat6"
],
"offsets": [
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]
],
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},
{
"id": "PMC-2065877-18-Materials_and_Methods_T14",
"type": "Protein",
"text": [
"Akt"
],
"offsets": [
[
846,
849
]
],
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},
{
"id": "PMC-2065877-18-Materials_and_Methods_T15",
"type": "Protein",
"text": [
"FoxO1"
],
"offsets": [
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856,
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]
],
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},
{
"id": "PMC-2065877-18-Materials_and_Methods_T16",
"type": "Protein",
"text": [
"p27"
],
"offsets": [
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872,
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]
],
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},
{
"id": "PMC-2065877-18-Materials_and_Methods_T17",
"type": "Protein",
"text": [
"Stat3"
],
"offsets": [
[
924,
929
]
],
"normalized": []
},
{
"id": "PMC-2065877-18-Materials_and_Methods_T18",
"type": "Protein",
"text": [
"IkappaBalpha"
],
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944,
956
]
],
"normalized": []
},
{
"id": "PMC-2065877-18-Materials_and_Methods_T19",
"type": "Protein",
"text": [
"beta actin"
],
"offsets": [
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]
],
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},
{
"id": "PMC-2065877-18-Materials_and_Methods_T20",
"type": "Protein",
"text": [
"GSK3"
],
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1064,
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]
],
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},
{
"id": "PMC-2065877-18-Materials_and_Methods_T21",
"type": "Protein",
"text": [
"pRb"
],
"offsets": [
[
1123,
1126
]
],
"normalized": []
}
] | [] | [] | [] |
27 | PMC-2889865-17-Caption-Figure_1 | [
{
"id": "PMC-2889865-17-Caption-Figure_1__text",
"type": "abstract",
"text": [
"AP-1 activation following long-term exposure of Jurkat T-cells to PMA. Jurkat T-cells were transfected with luciferase reporter plasmids containing the AP-1 cis-elements. (A) Time-dependent AP-1 activation in response to PMA. (B) HK E. coli does not activate AP-1. (C) Dose-dependent activation of AP-1 were performed using PMA alone (grey bars) and in combination with calcium ionophore (CaI 955 muM, black bars). (D) TCR-/- deficient cells responded to PMA (162 nM) by up-regulating AP-1 activity. Statistical significance from the control was determined using Student's t-test. (n = 4). Controls were arbitrarily set to 1."
],
"offsets": [
[
0,
625
]
]
}
] | [
{
"id": "PMC-2889865-17-Caption-Figure_1_T1",
"type": "Protein",
"text": [
"luciferase"
],
"offsets": [
[
108,
118
]
],
"normalized": []
}
] | [] | [] | [] |
28 | PMC-1310901-00-TIAB | [
{
"id": "PMC-1310901-00-TIAB__text",
"type": "abstract",
"text": [
"Down-regulation of interferon regulatory factor 4 gene expression in leukemic cells due to hypermethylation of CpG motifs in the promoter region\nAlthough the bcr-abl translocation has been shown to be the causative genetic aberration in chronic myeloid leukemia (CML), there is mounting evidence that the deregulation of other genes, such as the transcription factor interferon regulatory factor 4 (IRF-4), is also implicated in the pathogenesis of CML. Promoter methylation of CpG target sites or direct deletions/insertions of genes are mechanisms of a reversible or permanent silencing of gene expression, respectively. Therefore, we investigated whether IRF-4 promoter methylation or mutation may be involved in the regulation of IRF-4 expression in leukemia cells. Whereas promoter mutations or structural rearrangements could be excluded as a cause of altered IRF-4 expression in hematopoietic cells, the IRF-4 promoter methylation status was found to significantly influence IRF-4 transcription. First, treatment of IRF-4-negative lymphoid, myeloid and monocytic cell lines with the methylation-inhibitor 5-aza-2-deoxycytidine resulted in a time- and concentration-dependent increase of IRF-4 mRNA and protein levels. Second, using a restriction-PCR-assay and bisulfite-sequencing we identified specifically methylated CpG sites in IRF-4-negative but not in IRF-4-positive cells. Third, we clearly determined promoter methylation as a mechanism for IRF-4 down-regulation via reporter gene assays, but did not detect an association of methylational status and mRNA expression of DNA methyltransferases or methyl-CpG-binding proteins. Together, these data suggest CpG site-specific IRF-4 promoter methylation as a putative mechanism of down-regulated IRF-4 expression in leukemia."
],
"offsets": [
[
0,
1785
]
]
}
] | [
{
"id": "PMC-1310901-00-TIAB_T1",
"type": "Protein",
"text": [
"interferon regulatory factor 4"
],
"offsets": [
[
19,
49
]
],
"normalized": []
},
{
"id": "PMC-1310901-00-TIAB_T2",
"type": "Protein",
"text": [
"bcr"
],
"offsets": [
[
158,
161
]
],
"normalized": []
},
{
"id": "PMC-1310901-00-TIAB_T3",
"type": "Protein",
"text": [
"abl"
],
"offsets": [
[
162,
165
]
],
"normalized": []
},
{
"id": "PMC-1310901-00-TIAB_T4",
"type": "Protein",
"text": [
"interferon regulatory factor 4"
],
"offsets": [
[
367,
397
]
],
"normalized": []
},
{
"id": "PMC-1310901-00-TIAB_T5",
"type": "Protein",
"text": [
"IRF-4"
],
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[
399,
404
]
],
"normalized": []
},
{
"id": "PMC-1310901-00-TIAB_T6",
"type": "Protein",
"text": [
"IRF-4"
],
"offsets": [
[
658,
663
]
],
"normalized": []
},
{
"id": "PMC-1310901-00-TIAB_T7",
"type": "Protein",
"text": [
"IRF-4"
],
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734,
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]
],
"normalized": []
},
{
"id": "PMC-1310901-00-TIAB_T8",
"type": "Protein",
"text": [
"IRF-4"
],
"offsets": [
[
866,
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]
],
"normalized": []
},
{
"id": "PMC-1310901-00-TIAB_T9",
"type": "Protein",
"text": [
"IRF-4"
],
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911,
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]
],
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},
{
"id": "PMC-1310901-00-TIAB_T10",
"type": "Protein",
"text": [
"IRF-4"
],
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]
],
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},
{
"id": "PMC-1310901-00-TIAB_T11",
"type": "Protein",
"text": [
"IRF-4"
],
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]
],
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},
{
"id": "PMC-1310901-00-TIAB_T12",
"type": "Protein",
"text": [
"IRF-4"
],
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1194,
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]
],
"normalized": []
},
{
"id": "PMC-1310901-00-TIAB_T13",
"type": "Protein",
"text": [
"IRF-4"
],
"offsets": [
[
1339,
1344
]
],
"normalized": []
},
{
"id": "PMC-1310901-00-TIAB_T14",
"type": "Protein",
"text": [
"IRF-4"
],
"offsets": [
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1365,
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]
],
"normalized": []
},
{
"id": "PMC-1310901-00-TIAB_T15",
"type": "Protein",
"text": [
"IRF-4"
],
"offsets": [
[
1456,
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]
],
"normalized": []
},
{
"id": "PMC-1310901-00-TIAB_T16",
"type": "Protein",
"text": [
"IRF-4"
],
"offsets": [
[
1687,
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]
],
"normalized": []
},
{
"id": "PMC-1310901-00-TIAB_T17",
"type": "Protein",
"text": [
"IRF-4"
],
"offsets": [
[
1756,
1761
]
],
"normalized": []
},
{
"id": "PMC-1310901-00-TIAB_T18",
"type": "Anaphora",
"text": [
"other genes"
],
"offsets": [
[
321,
332
]
],
"normalized": []
}
] | [
{
"id": "PMC-1310901-00-TIAB_E1",
"type": "Negative_regulation",
"trigger": {
"text": [
"Down-regulation"
],
"offsets": [
[
0,
15
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-00-TIAB_E2"
}
]
},
{
"id": "PMC-1310901-00-TIAB_E2",
"type": "Gene_expression",
"trigger": {
"text": [
"expression"
],
"offsets": [
[
55,
65
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-00-TIAB_T1"
}
]
},
{
"id": "PMC-1310901-00-TIAB_E3",
"type": "Regulation",
"trigger": {
"text": [
"deregulation"
],
"offsets": [
[
305,
317
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-00-TIAB_T4"
}
]
},
{
"id": "PMC-1310901-00-TIAB_E4",
"type": "Regulation",
"trigger": {
"text": [
"regulation"
],
"offsets": [
[
720,
730
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-00-TIAB_E5"
}
]
},
{
"id": "PMC-1310901-00-TIAB_E5",
"type": "Gene_expression",
"trigger": {
"text": [
"expression"
],
"offsets": [
[
740,
750
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-00-TIAB_T7"
}
]
},
{
"id": "PMC-1310901-00-TIAB_E6",
"type": "Regulation",
"trigger": {
"text": [
"altered"
],
"offsets": [
[
858,
865
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-00-TIAB_E7"
}
]
},
{
"id": "PMC-1310901-00-TIAB_E7",
"type": "Gene_expression",
"trigger": {
"text": [
"expression"
],
"offsets": [
[
872,
882
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-00-TIAB_T8"
}
]
},
{
"id": "PMC-1310901-00-TIAB_E8",
"type": "Regulation",
"trigger": {
"text": [
"influence"
],
"offsets": [
[
972,
981
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-00-TIAB_E9"
}
]
},
{
"id": "PMC-1310901-00-TIAB_E9",
"type": "Transcription",
"trigger": {
"text": [
"transcription"
],
"offsets": [
[
988,
1001
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-00-TIAB_T10"
}
]
},
{
"id": "PMC-1310901-00-TIAB_E10",
"type": "Gene_expression",
"trigger": {
"text": [
"negative"
],
"offsets": [
[
1029,
1037
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-00-TIAB_T11"
}
]
},
{
"id": "PMC-1310901-00-TIAB_E11",
"type": "Positive_regulation",
"trigger": {
"text": [
"resulted"
],
"offsets": [
[
1134,
1142
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-00-TIAB_E12"
}
]
},
{
"id": "PMC-1310901-00-TIAB_E12",
"type": "Positive_regulation",
"trigger": {
"text": [
"increase"
],
"offsets": [
[
1182,
1190
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-00-TIAB_T12"
}
]
},
{
"id": "PMC-1310901-00-TIAB_E13",
"type": "Gene_expression",
"trigger": {
"text": [
"negative"
],
"offsets": [
[
1345,
1353
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-00-TIAB_T13"
}
]
},
{
"id": "PMC-1310901-00-TIAB_E14",
"type": "Gene_expression",
"trigger": {
"text": [
"positive"
],
"offsets": [
[
1371,
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]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-00-TIAB_T14"
}
]
},
{
"id": "PMC-1310901-00-TIAB_E15",
"type": "Negative_regulation",
"trigger": {
"text": [
"down-regulation"
],
"offsets": [
[
1462,
1477
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-00-TIAB_T15"
}
]
},
{
"id": "PMC-1310901-00-TIAB_E16",
"type": "Negative_regulation",
"trigger": {
"text": [
"down-regulated"
],
"offsets": [
[
1741,
1755
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-00-TIAB_E17"
}
]
},
{
"id": "PMC-1310901-00-TIAB_E17",
"type": "Gene_expression",
"trigger": {
"text": [
"expression"
],
"offsets": [
[
1762,
1772
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-1310901-00-TIAB_T17"
}
]
}
] | [
{
"id": "PMC-1310901-00-TIAB_1",
"entity_ids": [
"PMC-1310901-00-TIAB_T4",
"PMC-1310901-00-TIAB_T5"
]
}
] | [
{
"id": "PMC-1310901-00-TIAB_R1",
"type": "Coreference",
"arg1_id": "PMC-1310901-00-TIAB_T18",
"arg2_id": "PMC-1310901-00-TIAB_T4",
"normalized": []
}
] |
29 | PMC-2065877-27-Caption-Table_1 | [
{
"id": "PMC-2065877-27-Caption-Table_1__text",
"type": "abstract",
"text": [
"Summary of Analysis Performed on Wild-Type and LMP1 Transgenic Lymphomas"
],
"offsets": [
[
0,
72
]
]
}
] | [
{
"id": "PMC-2065877-27-Caption-Table_1_T1",
"type": "Protein",
"text": [
"LMP1"
],
"offsets": [
[
47,
51
]
],
"normalized": []
}
] | [
{
"id": "PMC-2065877-27-Caption-Table_1_E1",
"type": "Gene_expression",
"trigger": {
"text": [
"Transgenic"
],
"offsets": [
[
52,
62
]
]
},
"arguments": [
{
"role": "Theme",
"ref_id": "PMC-2065877-27-Caption-Table_1_T1"
}
]
}
] | [] | [] |
30 | PMC-3245220-15-Materials_and_Methods | [
{
"id": "PMC-3245220-15-Materials_and_Methods__text",
"type": "abstract",
"text": [
"Electrophoresis of the Mobility Shift Analysis (EMSA)\nNuclear extracts were isolated from MDMs by using a nuclear extraction kit according to the manufacturer's instruction from Active Motif (Carlsbad, CA). Briefly, MDMs were lysed in hypotonic lysis buffer (20 mM Hepes, pH 7.5; 5 mM NaF, 10 microM Na2MoO4 0.5% NP-40 and 0.1 mM EDTA), and then nuclei were resuspended in lysis buffer supplemented with 0.5 mM DTT and 0.2 mM PMSF. The NF-kappaB consensus oligonucleotides (sense: AGTTGAGGGGACTTTCCCAGGC; antisense: GCCTGGGAAAGTCCCCTCAACT) labeled with 32P by T4 polynucleokinase (Promega, Madison, WI) were incubated with nuclear extracts in binding buffer (10 mM Tris pH 7.6, 1 mM DTT, 0.5 mM EDTA, 2 microg polydI-dC and 10% Glycerol) at 30degreesC for 30 minutes. The free DNA and DNA-protein mixtures were resolved in 5% native polyacrylamide gels in 0.5x TBE buffer (45 mM Tris, 45 mM boric acid and 1 mM EDTA, pH 8.3) by electrophoresis. The gel was dried and subjected to autoradiography analysis."
],
"offsets": [
[
0,
1005
]
]
}
] | [] | [] | [] | [] |
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Dataset Card for BioNLP 2013 GE
The BioNLP-ST GE task has been promoting development of fine-grained information extraction (IE) from biomedical documents, since 2009. Particularly, it has focused on the domain of NFkB as a model domain of Biomedical IE
Citation Information
@inproceedings{kim-etal-2013-genia,
title = "The {G}enia Event Extraction Shared Task, 2013 Edition - Overview",
author = "Kim, Jin-Dong and
Wang, Yue and
Yasunori, Yamamoto",
booktitle = "Proceedings of the {B}io{NLP} Shared Task 2013 Workshop",
month = aug,
year = "2013",
address = "Sofia, Bulgaria",
publisher = "Association for Computational Linguistics",
url = "https://aclanthology.org/W13-2002",
pages = "8--15",
}
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