{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:55:12Z","timestamp":1787313312924,"version":"build-2736575974"},"reference-count":71,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2006,6,30]],"date-time":"2006-06-30T00:00:00Z","timestamp":1151625600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>Mercury is widely distributed in the biosphere, and its toxic effects have been associated with human death and several ailments that include cardiovascular diseases, anemia, kidney and liver damage, developmental abnormalities, neurobehavioral disorders, autoimmune diseases, and cancers in experimental animals. At the cellular level, mercury has been shown to interact with sulphydryl groups of proteins and enzymes, to damage DNA, and to modulate cell cycle progression and\/or apoptosis. However, the underlying molecular mechanisms of mercury toxicity remain to be elucidated. Our laboratory has demonstrated that mercury exposure induces cytotoxicity and apoptosis, modulates cell cycle, and transcriptionally activates specific stress genes in human liver carcinoma cells. The liver is one of the few organs capable of regeneration from injury. Dormant genes in the liver are therefore capable of reactivation. In this research, we hypothesize that mercury-induced hepatotoxicity is associated with the modulation of specific gene expressions in liver cells that can lead to several disease states involving immune system dysfunctions. In testing this hypothesis, we used an Affymetrix oligonucleotide microarray with probe sets complementary to more than 20,000 genes to determine whether patterns of gene expressions differ between controls and mercury (1-3\u03bcg\/mL) treated cells. There was a clear separation in gene expression profiles between controls and mercury-treated cells. Hierarchical cluster analysis identified 2,211 target genes that were affected. One hundred and thirty-eight of these genes were up-regulated, among which forty three were significantly over-expressed (p = 0.001) with greater than a two-fold change, and ninety five genes were moderately over-expressed with an increase of more than one fold (p = 0.004). Two thousand and twentythree genes were down-regulated with only forty five of them reaching a statistically significant decline at p = 0.05 according to the Welch\u2019s ANOVA\/Welch\u2019s t-test. Further analyses of affected genes identified genes located on all human chromosomes except chromosome 22 with higher than normal effects on genes found on chromosomes 1-14, 17-20 (sex-determining region Y)-box18SRY, 21 (splicing factor, arginine\/serine-rich 15 and ATP-binding), and X (including BCL6-co-repressor). These genes are categorized as control and regulatory genes for metabolic pathways involving the cell cycle (cyclin-dependent kinases), apoptosis, cytokine expression, Na+\/K+ ATPase, stress responses, G-protein signal transduction, transcription factors, DNA repair as well as metal-regulatory transcription factor 1, MTF1 HGNC, chondroitin sulfate proteoglycan 5 (neuroglycan C), ATPbinding cassette, sub-family G (WHITE), cytochrome b-561 family protein, CDC-like kinase 1 (CLK1 HGNC) (protein tyrosine kinase STY), Na+\/H+ exchanger regulatory factor (NHERF HGNC), potassium voltage-gated channel subfamily H member 2 (KCNH2), putative MAPK activating protein (PM20, PM21), ras homolog gene family, polymerase (DNA directed), \u03b4 regulatory subunit (50kDa), leptin receptor involved in hematopoietin\/interferon-class (D200-domain) cytokine receptor activity and thymidine kinase 2, mitochondrial TK2 HGNC and related genes. Significant alterations in these specific genes provide new directions for deeper mechanistic investigations that would lead to a better understanding of the molecular basis of mercury-induced toxicity and human diseases that may result from disturbances in the immune system.<\/jats:p>","DOI":"10.3390\/ijerph2006030018","type":"journal-article","created":{"date-parts":[[2008,10,25]],"date-time":"2008-10-25T13:52:15Z","timestamp":1224942735000},"page":"141-173","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Microarray Analysis of Mercury-Induced Changes in Gene Expression in Human Liver Carcinoma (HepG2) Cells: Importance in Immune Responses"],"prefix":"10.3390","volume":"3","author":[{"given":"Wellington K.","family":"Ayensu","sequence":"first","affiliation":[{"name":"Cellomics and Toxicogenomics Research Laboratory, NIH-RCMI Center for Environmental Health, College of Science, Engineering and Technology, Jackson State University, Jackson, Mississippi 39217, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3407-6674","authenticated-orcid":false,"given":"Paul B.","family":"Tchounwou","sequence":"additional","affiliation":[{"name":"Cellomics and Toxicogenomics Research Laboratory, NIH-RCMI Center for Environmental Health, College of Science, Engineering and Technology, Jackson State University, Jackson, Mississippi 39217, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2006,6,30]]},"reference":[{"key":"ref_1","first-page":"85","article-title":"The role of heavy metals in human health","volume":"33","author":"Pier","year":"1975","journal-title":"Texas Rep Biol Med"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7162","DOI":"10.4049\/jimmunol.162.12.7162","article-title":"Protection Against CD95-Mediated Apoptosis by Inorganic Mercury in Jurkat T Cells","volume":"162","author":"Whitekus","year":"1999","journal-title":"The J. Immunol"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1126\/science.281.5381.1305","article-title":"Death receptors: signaling and modulation","volume":"281","author":"Ashkenazi","year":"1998","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1126\/science.281.5381.1305","article-title":"Death Receptors: Signaling and Modulation","volume":"281","author":"Ashkenazi","year":"2002","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/0092-8674(93)90464-2","article-title":"A novel domain within the 55 kD TNF receptor signals cell death","volume":"74","author":"Tartaglia","year":"1993","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1126\/science.7533326","article-title":"The Fas death factor","volume":"276","author":"Nagata","year":"1995","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1126\/science.275.5303.1122","article-title":"Interaction of CED-4 with CED-3 and CED-9, a molecular framework for cell death","volume":"275","author":"Chinnaiyan","year":"1997","journal-title":"Science"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1016\/0167-5699(93)90181-J","article-title":"A possible role for bcl-2 in regulating T cell memory- a \u2018balancing act\u2019 between cell death and survival","volume":"14","author":"Akbar","year":"1993","journal-title":"Immunol Today"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2871","DOI":"10.1182\/blood.V89.8.2871","article-title":"Deficiency of the Fas Apoptosis Pathway Without Fas Gene Mutations in Pediatric Patients With Autoimmunity\/Lymphoproliferation","volume":"89","author":"Dianzani","year":"1997","journal-title":"Blood"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1038\/ni0901-816","article-title":"Regulatory T cells in the control of immune pathology","volume":"2","author":"Maloy","year":"2001","journal-title":"Nat Immunol"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1084\/jem.20022125","article-title":"The programmed Death-1 (PD-1) Pathway Regulates Autoimmune Diabetes in Nonobese Diabetic (NOD) Mice","volume":"198","author":"Ansari","year":"2003","journal-title":"J. Exp Med"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1126\/science.291.5502.319","article-title":"Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice","volume":"291","author":"Nishimura","year":"2001","journal-title":"Science"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/0968-0004(93)90192-P","article-title":"Regulation of src family tyrosine kinases in lymphocytes","volume":"18","author":"Mustelin","year":"1993","journal-title":"Trends in Biochemical Sciences"},{"key":"ref_14","first-page":"1547","article-title":"Apoptotic signaling through CD95 (Fas\/APO-1) activates an acidic sphingomyelinase","volume":"177","author":"Cifone","year":"1993","journal-title":"J Exp Med"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Langston, W. J., and Bebianno, M. J. (1998). Metal Metabolism in Aquatic Environments, Chapman and Hall.","DOI":"10.1007\/978-1-4757-2761-6"},{"key":"ref_16","first-page":"583","article-title":"The Seychelles study of fetal methylmercury exposure and child development: Introduction","volume":"16","author":"Marsh","year":"1995","journal-title":"Neurotoxicol"},{"key":"ref_17","first-page":"639","article-title":"Neurodevelopmental outcomes of Seychellois children sixty-six months after in utero exposure to Methylmercury from a maternal fish diet: pilot study","volume":"16","author":"Myers","year":"1995","journal-title":"Neurotoxicol"},{"key":"ref_18","first-page":"39","article-title":"Environmental Exposure to Mercury and its Toxico-Pathologic Implications to Public Health","volume":"1","author":"Tchounwou","year":"2004","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"ref_19","unstructured":"(1999). Agency for Toxic Substances and Disease Registry, Centers for Disease Control."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/S0031-6997(24)01439-X","article-title":"International Union of Pharmacology. XXII. Nomenclature for Chemokine Receptors","volume":"52","author":"Murphy","year":"2000","journal-title":"Pharmacological Rev"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1091\/mbc.3.1.123","article-title":"Mitogenic pathways regulated by G proteins oncogenes","volume":"3","author":"Gupta","year":"1992","journal-title":"Molecular Biology and Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/S0092-8674(00)81469-5","article-title":"Switching signals on or off by receptor dimerization","volume":"94","author":"Weiss","year":"1998","journal-title":"Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"714","DOI":"10.7326\/0003-4819-100-5-714","article-title":"NIH conference. Systemic lupus erythematosus: insights from animal models","volume":"100","author":"Steinberg","year":"1984","journal-title":"Ann Intern Med"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1084\/jem.20021358","article-title":"Impaired T cell death and lupus-like autoimmunity in T cell-specific adapter protein-deficient mice","volume":"198","author":"Drappa","year":"2003","journal-title":"J. Exp Med"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/0092-8674(91)90636-D","article-title":"Molecular themes in oncogenes","volume":"64","author":"Bishop","year":"1991","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4739","DOI":"10.1093\/nar\/13.13.4739","article-title":"A novel class of human type 1 interferons","volume":"13","author":"Hauptmann","year":"1985","journal-title":"Nuclei Acids Res"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2140","DOI":"10.1084\/jem.157.6.2140","article-title":"Interferon-induced 2\u2032\u20135\u2032 adenylate synthetase in vitro by lymphocytes from systemic lupus erythematosus patients with and without circulating interferon","volume":"157","author":"Preble","year":"1983","journal-title":"J. Exp. Med"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/0042-6822(90)90425-Q","article-title":"Monoclonal antibodies and enzyme immunoassays specific for human interferon IFN\u03c91: evidence that IFN-\u03c9 is a component of human leukocyte IFN","volume":"175","author":"Adolf","year":"1990","journal-title":"Virology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1006\/jaut.1998.0215","article-title":"Patients with systemic lupus erythematosus have reduced numbers for circulating natural interferon-alpha-producing cells","volume":"11","author":"Cederblad","year":"1998","journal-title":"J. Autoimmunol"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Blomberg, S., Eloranta, M. L., and Cederblad, B. (2001). Presence of cutaneous interferon-\u03b1 producing cells in patients with systemic lupus erythematosus. Lupus, 10484\u2013490.","DOI":"10.1191\/096120301678416042"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1136\/ard.45.3.220","article-title":"2\u2032 5\u2032Oligoadenylate synthetase induction in lymphocytes of patients with connective tissue diseases","volume":"45","author":"Hylton","year":"1986","journal-title":"Ann. Rheum. Dis"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"178","DOI":"10.7326\/0003-4819-115-3-178","article-title":"Autoimmunity after alpha-interferon therapy for malignant carcinoid tumor","volume":"115","author":"Ronnblom","year":"1991","journal-title":"Ann. Intern. Med"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1002\/art.1780250407","article-title":"Serum interferon levels in patients with systemic lupus erythematosus","volume":"25","author":"Ytterberg","year":"1982","journal-title":"Arthritis Rheum"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1111\/j.1365-2796.1990.tb00144.x","article-title":"Possible induction of systemic lupus erythematosus by interferon-\u03b1 treatment in-patient with a malignant carcinoid tumor","volume":"227","author":"Ronnblom","year":"1990","journal-title":"J. Intern. Med"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1084\/jem.189.3.521","article-title":"Type I interferon keep activated T cells alive","volume":"189","author":"Marrack","year":"1999","journal-title":"J. Exp. Med"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6317","DOI":"10.4049\/jimmunol.162.11.6317","article-title":"Inhibition of B cell receptor-mediated apoptosis by IFN","volume":"162","author":"Su","year":"1999","journal-title":"J. Immunol"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1126\/science.1064890","article-title":"Induction of dendritic cell differentiation by IFN-\u03b1 in systemic lupus erythymatosus","volume":"294","author":"Blanco","year":"2001","journal-title":"Science"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1016\/S1471-4906(01)01955-X","article-title":"An etiopathogenic role for the type I IFN system in SLE","volume":"22","author":"Ronnblom","year":"2001","journal-title":"Trends Immunol"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"299","DOI":"10.4049\/jimmunol.134.1.299","article-title":"Stimulation of in vitro immunoglobulin production by interferon-\u03b1","volume":"134","author":"Neubauer","year":"1985","journal-title":"J. Immunol"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1126\/science.285.5425.260","article-title":"member of the tumor necrosis factor family and B lymphocyte stimulator","volume":"285","author":"Moore","year":"1999","journal-title":"Science"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1177\/00220345980770060601","article-title":"Activation of the immune system and systemic immune-complex deposits in Brown Norway rats with dental amalgam restorations","volume":"77","author":"Hultman","year":"1998","journal-title":"J. Dent. Res"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/0090-1229(92)90212-7","article-title":"Murine susceptibility to mercury. I. Autoantibody profiles and systemic immune deposits in inbred, congenic and intra-H-2 recombinant strains","volume":"65","author":"Hultman","year":"1992","journal-title":"Clin. Immunol. Immuno-Pathol"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1006\/clin.1993.1088","article-title":"Murine susceptibility to mercury. II. Autoantibody profiles and renal immune deposits in hybrid, backcross, and H-2d congenic mice","volume":"68","author":"Hultman","year":"1993","journal-title":"Clin. Immunol. Immuno. Pathol"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"234","DOI":"10.4049\/jimmunol.161.1.234","article-title":"The prototypic Th2 autoimmunity induced by mercury is dependent on IFN- \u03b3 and not TH1\/TH2 imbalance","volume":"161","author":"Kono","year":"1998","journal-title":"J. Immunol"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1006\/clin.1997.4405","article-title":"Class II haplotype differentially regulates immune response in HgCl2-treated mice","volume":"84","author":"Hanley","year":"1997","journal-title":"Clin Immunol Immunopathol"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.4049\/jimmunol.161.4.1778","article-title":"Resistance to HgCl2-induced autoimmunity in haplotype-heterozygous mice is an intrinsic property of B cells","volume":"161","author":"Hanley","year":"2002","journal-title":"J. Immunol"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3272","DOI":"10.4049\/jimmunol.136.9.3272","article-title":"Autoimmunity induced by HgCl2 in Brown-Norway rats I. Production of monoclonal antibodies","volume":"36","author":"Hirsch","year":"1986","journal-title":"J. Immunol"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1038\/sj.gene.6363975","article-title":"Discovery of distinctive gene expression profiles in rheumatoid synovium using cDNA microarray technology: evidence for the existence of multiple pathways of tissue destruction and repair","volume":"4","author":"Huizinga","year":"2003","journal-title":"Genes and Immunity"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1038\/35090591","article-title":"Haematopoietic cell specific CDM family protein DOCK2 is essential for lymphocyte migration","volume":"412","author":"Fukui","year":"2001","journal-title":"Nature"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1002\/1529-0131(199904)42:4<609::AID-ANR3>3.0.CO;2-I","article-title":"Signal transduction and transcription factors in rheumatic disease","volume":"42","author":"Firestein","year":"1999","journal-title":"Arthritis Rheum"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1084\/jem.20010955","article-title":"Genetic Dissection of SLE. SLE1 and FAS Impact Alternate Pathways Leading to Lymphoproliferative Autoimmunity","volume":"196","author":"Shi","year":"2002","journal-title":"J. Exp. Med"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"5501","DOI":"10.4049\/jimmunol.158.11.5501","article-title":"High susceptibility to collagen-induced arthritis in mice lacking IFN- \u03b3 receptors","volume":"158","author":"Chiocchia","year":"1997","journal-title":"J. Immunol"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"5507","DOI":"10.4049\/jimmunol.158.11.5507","article-title":"Accelerated collagen-induced arthritis in IFN-\u03b3 receptor-deficient mice","volume":"158","author":"Vermeire","year":"1997","journal-title":"J. Immunol"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"197","DOI":"10.4049\/jimmunol.160.1.197","article-title":"Characterization and mapping to human chromosome 8q24.3 of Ly-6-related gene 9804 encoding an apparent homologue of mouse TSA-1","volume":"160","author":"Shan","year":"1998","journal-title":"J. Immunol"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2260","DOI":"10.1073\/pnas.93.6.2260","article-title":"Checkpoints in the progression of autoimmune disease: lessons from diabetes models","volume":"93","author":"Andre","year":"1996","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"812","DOI":"10.2337\/diab.45.6.812","article-title":"Genetic absence of gamma-interferon delays but does not prevent diabetes in NOD mice","volume":"45","author":"Hultgren","year":"1996","journal-title":"Diabetes"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/0955-0674(93)90114-6","article-title":"Ras-related proteins","volume":"5","author":"Hall","year":"1993","journal-title":"Current Opinion in Cellular Biology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1146\/annurev.bi.62.070193.004223","article-title":"Function and regulation of Ras","volume":"62","author":"Lowy","year":"1993","journal-title":"Annual Review of Biochemistry"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"39","DOI":"10.3390\/ijerph2004010039","article-title":"Molecular and Cellular Mechanisms Associated with Autoimmune Diseases","volume":"1","author":"Ayensu","year":"2004","journal-title":"Int. J. Environ. Res. Public Health"},{"key":"ref_60","unstructured":"(2002). Affymetrix manual: Affymetrix Technical Gene Chip manual version 5.0."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1172\/JCI119217","article-title":"Evidence for linkage of a candidate chromosome 1 region to human systemic lupus erythematosus","volume":"99","author":"Tsao","year":"1997","journal-title":"J. Clin Invest"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"10483","DOI":"10.1073\/pnas.97.19.10483","article-title":"Complex promoter and coding region beta 2-adrenergic receptor haplotypes alter receptor expression and predict in vivo responsiveness","volume":"97","author":"Drysdale","year":"2000","journal-title":"Proc Natl Acad Sci USA"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"4988","DOI":"10.1093\/emboj\/18.18.4988","article-title":"Implication of calpain in caspase activation during B cell clonal deletion","volume":"18","year":"1999","journal-title":"EMBO J"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"5015","DOI":"10.1128\/MCB.16.9.5015","article-title":"Inhibition of NF-\u03baB\/Rel induces apoptosis of murine B cells","volume":"16","author":"Wu","year":"1996","journal-title":"Mol. Cell Biol"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.1093\/emboj\/19.8.1745","article-title":"Transcriptional control by the TGF-\u03b2\/Smad signaling system","volume":"19","author":"Wotton","year":"2000","journal-title":"EMBO J"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/S0968-0004(99)01519-4","article-title":"Signalling input converge on nuclear effectors in TGF-\u03b2 signaling","volume":"25","author":"Miyazono","year":"2000","journal-title":"Trends Biochem. Sci"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/S0962-8924(99)01579-2","article-title":"Regulation of Smad signalling by protein associations and signalling crosstalk","volume":"9","author":"Zhang","year":"1999","journal-title":"Trends Cell Biol"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/S1074-7613(01)00201-1","article-title":"Delineating the genetic basis of systemic lupus erythematosus","volume":"15","author":"Wakeland","year":"2001","journal-title":"Immunity"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"14869","DOI":"10.1073\/pnas.95.25.14869","article-title":"Genome scan of human systemic lupus erythematosus: Evidence for linkage on chromosome 1q in African-American pedigrees","volume":"95","author":"Moser","year":"1998","journal-title":"Proc. Nat. Acad. Sci. USA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1002\/art.1780350310","article-title":"A revised estimate of twin concordance in systemic lupus erythematosus","volume":"35","author":"Deapen","year":"1992","journal-title":"Arthritis Rheum"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1086\/302767","article-title":"Genome screening in human systemic lupus erythematosus: results from a second Minnesota cohort and combined analyses of sib-pair families","volume":"66","author":"Gaffney","year":"2000","journal-title":"Am J Human Genet"}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/3\/2\/141\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T22:25:00Z","timestamp":1760221500000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/3\/2\/141"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,6,30]]},"references-count":71,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2006,6]]}},"alternative-id":["ijerph2006030018"],"URL":"https:\/\/doi.org\/10.3390\/ijerph2006030018","relation":{},"ISSN":["1660-4601"],"issn-type":[{"value":"1660-4601","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,6,30]]}}}