{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:20Z","timestamp":1787028440214,"version":"build-2736575974"},"reference-count":55,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2021,1,13]],"date-time":"2021-01-13T00:00:00Z","timestamp":1610496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003627","name":"Rural Development Administration","doi-asserted-by":"publisher","award":["PJ01384202"],"award-info":[{"award-number":["PJ01384202"]}],"id":[{"id":"10.13039\/501100003627","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002460","name":"Chung-Ang University","doi-asserted-by":"publisher","award":["2020"],"award-info":[{"award-number":["2020"]}],"id":[{"id":"10.13039\/501100002460","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Porcine heart xenotransplantation is a potential treatment for patients with end-stage heart failure. To understand molecular mechanisms of graft rejection after heart transplantation, we transplanted a 31-day-old alpha-1,3-galactosyltransferase knockout (GTKO) porcine heart to a five-year-old cynomolgus monkey. Histological and transcriptome analyses were conducted on xenografted cardiac tissue at rejection (nine days after transplantation). The recipient monkey\u2019s blood parameters were analyzed on days \u22127, \u22123, 1, 4, and 7. Validation was conducted by quantitative real-time PCR (qPCR) with selected genes. A non-transplanted GTKO porcine heart from an age-matched litter was used as a control. The recipient monkey showed systemic inflammatory responses, and the rejected cardiac graft indicated myocardial infarction and cardiac fibrosis. The transplanted heart exhibited a total of 3748 differentially expressed genes compared to the non-transplanted heart transcriptome, with 2443 upregulated and 1305 downregulated genes. Key biological pathways involved at the terminal stage of graft rejection were cardiomyopathies, extracellular interactions, and ion channel activities. The results of qPCR evaluation were in agreement with the transcriptome data. Transcriptome analysis of porcine cardiac tissue at graft rejection reveals dysregulation of the key molecules and signaling pathways, which play relevant roles on structural and functional integrities of the heart.<\/jats:p>","DOI":"10.3390\/ijms22020751","type":"journal-article","created":{"date-parts":[[2021,1,13]],"date-time":"2021-01-13T11:52:32Z","timestamp":1610538752000},"page":"751","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Comprehensive Analysis of Cardiac Xeno-Graft Unveils Rejection Mechanisms"],"prefix":"10.3390","volume":"22","author":[{"given":"Min Young","family":"Park","sequence":"first","affiliation":[{"name":"Department of Animal Science and Technology, College of Biotechnology and Natural Resources, Chung-Ang University, Gyeonggi-do 17546, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5529-418X","authenticated-orcid":false,"given":"Bala Murali","family":"Krishna Vasamsetti","sequence":"additional","affiliation":[{"name":"Animal Biotechnology Division, National Institute of Animal Science, RDA, Jeollabukdo 55365, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7704-5942","authenticated-orcid":false,"given":"Wan Seop","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul 05030, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1249-6181","authenticated-orcid":false,"given":"Hee Jung","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Hallym University College of Medicine, Hallym University Sacred Heart Hospital, Dongan-gu, Anyang 14068, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Do-Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Animal Science and Technology, College of Biotechnology and Natural Resources, Chung-Ang University, Gyeonggi-do 17546, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byeonghwi","family":"Lim","sequence":"additional","affiliation":[{"name":"Department of Animal Science and Technology, College of Biotechnology and Natural Resources, Chung-Ang University, Gyeonggi-do 17546, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kahee","family":"Cho","sequence":"additional","affiliation":[{"name":"Primate Organ Transplantation Centre, Genia Inc., Sungnam 13201, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun Seok","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Thoracic and Cardiovascular Surgery, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul 05030, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyun Keun","family":"Chee","sequence":"additional","affiliation":[{"name":"Department of Thoracic and Cardiovascular Surgery, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul 05030, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8737-0084","authenticated-orcid":false,"given":"Jung Hwan","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul 05030, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7056-3648","authenticated-orcid":false,"given":"Hyun Suk","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul 05030, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harikrishna Reddy","family":"Rallabandi","sequence":"additional","affiliation":[{"name":"Animal Biotechnology Division, National Institute of Animal Science, RDA, Jeollabukdo 55365, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun A.","family":"Ock","sequence":"additional","affiliation":[{"name":"Animal Biotechnology Division, National Institute of Animal Science, RDA, Jeollabukdo 55365, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mi-Ryung","family":"Park","sequence":"additional","affiliation":[{"name":"Animal Biotechnology Division, National Institute of Animal Science, RDA, Jeollabukdo 55365, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heasun","family":"Lee","sequence":"additional","affiliation":[{"name":"Animal Biotechnology Division, National Institute of Animal Science, RDA, Jeollabukdo 55365, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2949-3075","authenticated-orcid":false,"given":"In-Sul","family":"Hwang","sequence":"additional","affiliation":[{"name":"Animal Biotechnology Division, National Institute of Animal Science, RDA, Jeollabukdo 55365, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6934-398X","authenticated-orcid":false,"given":"Jun-Mo","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Animal Science and Technology, College of Biotechnology and Natural Resources, Chung-Ang University, Gyeonggi-do 17546, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0651-0306","authenticated-orcid":false,"given":"Keon Bong","family":"Oh","sequence":"additional","affiliation":[{"name":"Animal Biotechnology Division, National Institute of Animal Science, RDA, Jeollabukdo 55365, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ik Jin","family":"Yun","sequence":"additional","affiliation":[{"name":"Department of Surgery, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul 05030, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1016\/j.healun.2019.01.1317","article-title":"Molecular assessment of rejection and injury in lung transplant biopsies","volume":"38","author":"Halloran","year":"2019","journal-title":"J. Heart Lung Transpl."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1080\/14737159.2016.1239530","article-title":"Advances in diagnostics for transplant rejection","volume":"16","author":"Nasr","year":"2016","journal-title":"Expert Rev. Mol. Diagn."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1038\/s41586-018-0765-z","article-title":"Consistent success in life-supporting porcine cardiac xenotransplantation","volume":"564","author":"Langin","year":"2018","journal-title":"Nature"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"11138","DOI":"10.1038\/ncomms11138","article-title":"Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO. hCD46. hTBM pig-to-primate cardiac xenograft","volume":"7","author":"Mohiuddin","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1007\/s12265-015-9612-x","article-title":"Cardiac allograft vasculopathy: A donor or recipient induced pathology?","volume":"8","author":"Huibers","year":"2015","journal-title":"J. Cardiovasc. Transl. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1053\/j.gastro.2010.10.059","article-title":"Immunologic basis of graft rejection and tolerance following transplantation of liver or other solid organs","volume":"140","author":"Strom","year":"2011","journal-title":"Gastroenterology"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Herrer, I., Rosello-Lleti, E., Ortega, A., Tarazon, E., Molina-Navarro, M.M., Trivino, J.C., Martinez-Dolz, L., Almenar, L., Lago, F., and Sanchez-Lazaro, I. (2015). Gene expression network analysis reveals new transcriptional regulators as novel factors in human ischemic cardiomyopathy. BMC Med. Genom., 8.","DOI":"10.1186\/s12920-015-0088-y"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Sweet, M.E., Cocciolo, A., Slavov, D., Jones, K.L., Sweet, J.R., Graw, S.L., Reece, T.B., Ambardekar, A.V., Bristow, M.R., and Mestroni, L. (2018). Transcriptome analysis of human heart failure reveals dysregulated cell adhesion in dilated cardiomyopathy and activated immune pathways in ischemic heart failure. BMC Genom., 19.","DOI":"10.1186\/s12864-018-5213-9"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1016\/j.theriogenology.2010.11.001","article-title":"Resurrection of an alpha-1,3-galactosyltransferase gene-targeted miniature pig by recloning using postmortem ear skin fibroblasts","volume":"75","author":"Ahn","year":"2011","journal-title":"Theriogenology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1111\/j.1432-2277.1998.tb00818.x","article-title":"C-reactive protein in the monitoring of acute rejection after heart transplantation","volume":"11","author":"Balk","year":"1998","journal-title":"Transpl. Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1111\/ajt.13940","article-title":"The Role of Neutrophils in Transplanted Organs","volume":"17","author":"Scozzi","year":"2017","journal-title":"Am. J. Transpl."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2569","DOI":"10.1016\/j.transproceed.2006.09.002","article-title":"Diagnostic usefulness of inflammatory markers in acute cellular rejection after heart transplantation","volume":"38","author":"Almenar","year":"2006","journal-title":"Transpl. Proc."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.ygeno.2014.12.002","article-title":"RNA-Seq identifies novel myocardial gene expression signatures of heart failure","volume":"105","author":"Liu","year":"2015","journal-title":"Genomics"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Li, X., Liu, C.Y., Li, Y.S., Xu, J., Li, D.G., Li, X., and Han, D. (2016). Deep RNA sequencing elucidates microRNA-regulated molecular pathways in ischemic cardiomyopathy and nonischemic cardiomyopathy. Genet. Mol. Res., 15.","DOI":"10.4238\/gmr.15027465"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1186\/1479-5876-9-174","article-title":"Gene expression profiling in acute allograft rejection: Challenging the immunologic constant of rejection hypothesis","volume":"9","author":"Spivey","year":"2011","journal-title":"J. Transl. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1126\/science.285.5430.1028","article-title":"Integrin signaling","volume":"285","author":"Giancotti","year":"1999","journal-title":"Science"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.yjmcc.2013.10.006","article-title":"Dynamic cell\u2013cell and cell\u2013ECM interactions in the heart","volume":"70","author":"Howard","year":"2014","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1161\/CIRCRESAHA.119.311148","article-title":"The Extracellular Matrix in Ischemic and Nonischemic Heart Failure","volume":"125","author":"Frangogiannis","year":"2019","journal-title":"Circ. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1016\/j.jacc.2015.01.029","article-title":"RNA sequencing analysis identifies new human collagen genes involved in cardiac remodeling","volume":"65","author":"Rivera","year":"2015","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3133","DOI":"10.1007\/s00018-011-0779-2","article-title":"Emerging functions of matricellular proteins","volume":"68","author":"Roberts","year":"2011","journal-title":"Cell Mol. Life Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1161\/HYPERTENSIONAHA.111.175323","article-title":"Endogenous thrombospondin 1 protects the pressure-overloaded myocardium by modulating fibroblast phenotype and matrix metabolism","volume":"58","author":"Xia","year":"2011","journal-title":"Hypertension"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1161\/CIRCRESAHA.113.302593","article-title":"Thrombospondin-1 induction in the diabetic myocardium stabilizes the cardiac matrix in addition to promoting vascular rarefaction through angiopoietin-2 upregulation","volume":"113","author":"Cavalera","year":"2013","journal-title":"Circ. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1177\/153537020523000904","article-title":"Thrombospondin-1 is induced in rat myocardial infarction and its induction is accelerated by ischemia\/reperfusion","volume":"230","author":"Sezaki","year":"2005","journal-title":"Exp. Biol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2363","DOI":"10.1096\/fj.11-190728","article-title":"Thrombospondin-4 regulates fibrosis and remodeling of the myocardium in response to pressure overload","volume":"26","author":"Frolova","year":"2012","journal-title":"FASEB J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1016\/j.cell.2012.03.050","article-title":"A thrombospondin-dependent pathway for a protective ER stress response","volume":"149","author":"Lynch","year":"2012","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"S143","DOI":"10.1016\/j.cardfail.2009.07.199","article-title":"Tenascin-C Regulates Fibrosis, Inflammation and Immunological Response","volume":"15","author":"Hiroe","year":"2009","journal-title":"J. Card. Fail."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"H1072","DOI":"10.1152\/ajpheart.00255.2009","article-title":"Tenascin-C may aggravate left ventricular remodeling and function after myocardial infarction in mice","volume":"298","author":"Nishioka","year":"2010","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_28","first-page":"283","article-title":"Tenascin-C and mechanotransduction in the development and diseases of cardiovascular system","volume":"5","author":"Aoki","year":"2014","journal-title":"Front. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.1161\/CIRCRESAHA.116.304937","article-title":"Mechanotransduction in cardiac hypertrophy and failure","volume":"116","author":"Lyon","year":"2015","journal-title":"Circ. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1161\/CIRCULATIONAHA.106.174287","article-title":"Contemporary definitions and classification of the cardiomyopathies: An American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention","volume":"113","author":"Maron","year":"2006","journal-title":"Circulation"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"478","DOI":"10.4330\/wjc.v6.i6.478","article-title":"Cardiomyopathies: Evolution of pathogenesis concepts and potential for new therapies","volume":"6","author":"Sisakian","year":"2014","journal-title":"World J. Cardiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1136\/bmj.1.5219.69","article-title":"Clinical aspects of cardiomyopathy","volume":"1","author":"Goodwin","year":"1961","journal-title":"Br. Med. J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1161\/CIRCRESAHA.113.301651","article-title":"Mechanisms of altered Ca2\u207a handling in heart failure","volume":"113","author":"Luo","year":"2013","journal-title":"Circ. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1161\/CIRCRESAHA.118.311403","article-title":"G-Protein-Coupled Receptors in Heart Disease","volume":"123","author":"Wang","year":"2018","journal-title":"Circ. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"904","DOI":"10.3389\/fphar.2018.00904","article-title":"New Insights in Cardiac beta-Adrenergic Signaling During Heart Failure and Aging","volume":"9","author":"Eguchi","year":"2018","journal-title":"Front. Pharm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1172\/JCI22811","article-title":"Alpha1-adrenergic receptors prevent a maladaptive cardiac response to pressure overload","volume":"116","author":"Swigart","year":"2006","journal-title":"J. Clin. Invest."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1161\/CIRCRESAHA.117.310230","article-title":"Calcium and excitation-contraction coupling in the heart","volume":"121","author":"Eisner","year":"2017","journal-title":"Circ. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1007\/s12551-018-0442-3","article-title":"Role of ion channels in heart failure and channelopathies","volume":"10","author":"Rahm","year":"2018","journal-title":"Biophys. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1710","DOI":"10.1016\/j.healun.2005.03.019","article-title":"Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection","volume":"24","author":"Stewart","year":"2005","journal-title":"J. Heart Lung Transpl."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1111\/ajt.13643","article-title":"Inflammatory Cytokines, Endothelial Function, and Chronic Allograft Vasculopathy in Children: An Investigation of the Donor and Recipient Vasculature After Heart Transplantation","volume":"16","author":"Fenton","year":"2016","journal-title":"Am. J. Transpl."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3815","DOI":"10.1161\/01.CIR.0000150539.72783.BF","article-title":"Detection of cardiac allograft rejection and response to immunosuppressive therapy with peripheral blood gene expression","volume":"110","author":"Horwitz","year":"2004","journal-title":"Circulation"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Chih, S., Chruscinski, A., Ross, H.J., Tinckam, K., Butany, J., and Rao, V. (2012). Antibody-Mediated Rejection: An Evolving Entity in Heart Transplantation. J. Transpl., 210210.","DOI":"10.1155\/2012\/210210"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1016\/j.healun.2017.07.003","article-title":"SERCA2a: A potential non-invasive biomarker of cardiac allograft rejection","volume":"36","author":"Ortega","year":"2017","journal-title":"J. Heart Lung Transpl."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1186\/s12967-016-1083-6","article-title":"Targeted myocardial gene expression in failing hearts by RNA sequencing","volume":"14","author":"Dhar","year":"2016","journal-title":"J. Transl. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"25","DOI":"10.4285\/jkstn.2017.31.1.25","article-title":"Non-invasive myocardial strain imaging to evaluate graft rejection in the cardiac xenotransplantation","volume":"31","author":"Yang","year":"2017","journal-title":"J. Korean Soc. Transpl."},{"key":"ref_46","unstructured":"Andrews, S. (2010). FastQC: A Quality Control Tool for High Throughput Sequence Data, Babraham Bioinformatics, Babraham Institute."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: A flexible trimmer for Illumina sequence data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/nmeth.3317","article-title":"HISAT: A fast spliced aligner with low memory requirements","volume":"12","author":"Kim","year":"2015","journal-title":"Nat. Methods"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: An efficient general purpose program for assigning sequence reads to genomic features","volume":"30","author":"Liao","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"R25","DOI":"10.1186\/gb-2010-11-3-r25","article-title":"A scaling normalization method for differential expression analysis of RNA-seq data","volume":"11","author":"Robinson","year":"2010","journal-title":"Genome Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"W169","DOI":"10.1093\/nar\/gkm415","article-title":"DAVID Bioinformatics Resources: Expanded annotation database and novel algorithms to better extract biology from large gene lists","volume":"35","author":"Huang","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"D258","DOI":"10.1093\/nar\/gkh036","article-title":"The Gene Ontology (GO) database and informatics resource","volume":"32","author":"Consortium","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/2\/751\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:10:46Z","timestamp":1760159446000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/2\/751"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,13]]},"references-count":55,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["ijms22020751"],"URL":"https:\/\/doi.org\/10.3390\/ijms22020751","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,13]]}}}