{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T05:59:33Z","timestamp":1783576773154,"version":"3.55.0"},"reference-count":49,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,8,31]],"date-time":"2021-08-31T00:00:00Z","timestamp":1630368000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>The function of the immune system extends from defense against external pathogens to the recognition and elimination of mutated or dying cells, aiding elimination of malignant potential and\/or maintaining homeostasis. The many cell types of the immune system secrete a broad range of factors to enable cellular signaling that is vital to physiological processes. Additionally, in the ovary, follicular selection and maturation, as well as ovulation, are directly regulated by the nearby immune cells. Additionally, ovulation and rupture of the follicle have been observed to resemble a local inflammatory response. Cells of the cumulus\u2013oocyte complex (COC) show evolving gene expression profiles throughout the oocytes\u2019 lifespan, including genes associated with immunological processes. Analysis of these genes allows the identification of useful molecular markers, as well as highlighting gene functions and interactions in these cells. Cumulus cells were obtained from hormonally stimulated patients undergoing an in vitro fertilization procedure and studied under long-term culture conditions. The microarray technique made it possible to compare the level of CCs\u2019 gene expression on the 1st, 7th, 15th and 30th day of cultivation. Additionally, RNA microarray analysis was performed to map gene expression in these cells, associated with immunological processes and associated cytokine signaling. Subsequently, the use of DAVID software allowed us to identify the \u201cdefense response to other organism\u201d, \u201cdefense response\u201d, \u201cdefense response to virus\u201d, \u201ccytokine secretion\u201d, \u201ccytokine production\u201d and \u201ccytokine-mediated signaling pathway\u201d GO BP terms, as well as allowing further analysis of the most differentially expressed genes associated with these processes. Of the 122 genes involved, 121 were upregulated and only one was downregulated. The seven most upregulated genes related to the abovementioned terms were ANXA3, IFIT1, HLA-DPA1, MX1, KRT8, HLA-DRA and KRT18. Therefore, genes involved in immunological defense processes are upregulated in CC cultures and could serve as useful molecular markers of growth and development in the COC, as well as the proliferation of granulosa and cumulus cells.<\/jats:p>","DOI":"10.3390\/genes12091369","type":"journal-article","created":{"date-parts":[[2021,8,31]],"date-time":"2021-08-31T08:42:32Z","timestamp":1630399352000},"page":"1369","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Expression Profile of New Gene Markers and Signaling Pathways Involved in Immunological Processes in Human Cumulus-Oophorus Cells"],"prefix":"10.3390","volume":"12","author":[{"given":"B\u0142a\u017cej","family":"Chermu\u0142a","sequence":"first","affiliation":[{"name":"Division of Infertility and Reproductive Endocrinology, Department of Gynecology, Obstetrics and Gynecological Oncology, Poznan University of Medical Sciences, 33 Polna St., 60-535 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Greg","family":"Hutchings","sequence":"additional","affiliation":[{"name":"The School of Medicine, Medical Sciences and Nutrition, Aberdeen University, Aberdeen AB25 2ZD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7518-4834","authenticated-orcid":false,"given":"Wies\u0142awa","family":"Kranc","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Poznan University of Medical Sciences, 6 Swiecickiego St., 60-781 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ma\u0142gorzata","family":"J\u00f3zkowiak","sequence":"additional","affiliation":[{"name":"Department of Toxicology, Poznan University of Medical Sciences, 30 Dojazd St., 60-631 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7399-0303","authenticated-orcid":false,"given":"Karol","family":"Jopek","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Poznan University of Medical Sciences, 6 Swiecickiego St., 60-781 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bogus\u0142awa","family":"Stelmach","sequence":"additional","affiliation":[{"name":"Division of Infertility and Reproductive Endocrinology, Department of Gynecology, Obstetrics and Gynecological Oncology, Poznan University of Medical Sciences, 33 Polna St., 60-535 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1575-3123","authenticated-orcid":false,"given":"Paul","family":"Mozdziak","sequence":"additional","affiliation":[{"name":"Physiology Graduate Program, North Carolina State University, Raleigh, NC 27695, USA"},{"name":"Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leszek","family":"Pawelczyk","sequence":"additional","affiliation":[{"name":"Division of Infertility and Reproductive Endocrinology, Department of Gynecology, Obstetrics and Gynecological Oncology, Poznan University of Medical Sciences, 33 Polna St., 60-535 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Piotrowska-Kempisty","sequence":"additional","affiliation":[{"name":"Department of Toxicology, Poznan University of Medical Sciences, 30 Dojazd St., 60-631 Poznan, Poland"},{"name":"Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 1 Lwowska St., 87-100 Torun, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert Z.","family":"Spaczy\u0144ski","sequence":"additional","affiliation":[{"name":"Division of Infertility and Reproductive Endocrinology, Department of Gynecology, Obstetrics and Gynecological Oncology, Poznan University of Medical Sciences, 33 Polna St., 60-535 Poznan, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bartosz","family":"Kempisty","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Poznan University of Medical Sciences, 6 Swiecickiego St., 60-781 Poznan, Poland"},{"name":"Department of Histology and Embryology, Poznan University of Medical Sciences, 6 Swiecickiego St., 60-781 Poznan, Poland"},{"name":"Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA"},{"name":"Department of Veterinary Surgery, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 1 Lwowska St., 87-100 Torun, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Wigglesworth, K., Lee, K.-B., Emori, C., Sugiura, K., and Eppig, J.J. (2015). Transcriptomic diversification of developing cumulus and mural granulosa cells in mouse ovarian follicles. Biol. Reprod., 92.","DOI":"10.1095\/biolreprod.114.121756"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Chermu\u0142a, B., Kranc, W., Jopek, K., Budna-Tukan, J., Hutchings, G., Dompe, C., Moncrieff, L., Janowicz, K., J\u00f3zkowiak, M., and Jeseta, M. (2020). Human Cumulus Cells in Long-Term In Vitro Culture Reflect Differential Expression Profile of Genes Responsible for Planned Cell Death and Aging-A Study of New Molecular Markers. Cells, 9.","DOI":"10.3390\/cells9051265"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.theriogenology.2016.04.017","article-title":"Driving folliculogenesis by the oocyte-somatic cell dialog: Lessons from genetic models","volume":"86","author":"Monniaux","year":"2016","journal-title":"Theriogenology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1111\/j.1600-0897.2007.00562.x","article-title":"Immune physiology of the mammalian ovary\u2014A review","volume":"59","author":"Bukovsky","year":"2008","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40064-016-2390-3","article-title":"The effect of the immune system on ovarian function and features of ovarian germline stem cells","volume":"5","author":"Ye","year":"2016","journal-title":"Springerplus"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.mce.2019.02.014","article-title":"Human granulosa cells function as innate immune cells executing an inflammatory reaction during ovulation: A microarray analysis","volume":"486","author":"Englund","year":"2019","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1007\/s10815-021-02209-x","article-title":"The time is ripe for oocyte in vitro maturation","volume":"38","author":"Plancha","year":"2021","journal-title":"J. Assist. Reprod. Genet."},{"key":"ref_8","unstructured":"Practice Committees of the American Society for Reproductive Medicine, the Society of Reproductive Biologists and Technologists and the Society for Assisted Reproductive Technology (2021). In vitro maturation: A committee opinion. Fertil. Steril., 115, 298\u2013304."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"60","DOI":"10.2478\/acb-2020-0007","article-title":"New markers of human cumulus oophorus cells cultured in vitro-transcriptomic profile","volume":"8","author":"Brazert","year":"2020","journal-title":"Med. J. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/0003-2697(87)90021-2","article-title":"Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction","volume":"162","author":"Chomczynski","year":"1987","journal-title":"Anal. Biochem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2478\/acb-2021-0001","article-title":"Histone demethylases JHDM1D, PHF2 and PHF8 expression pattern in granulosa cells obtained from patients undergoing IVF procedure during short-term IVC","volume":"9","author":"Bryl","year":"2021","journal-title":"Med. J. Cell Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"8","DOI":"10.2478\/acb-2021-0002","article-title":"Expression of the apoptosis regulatory gene family in the long-term in vitro cultured human cumulus cells","volume":"9","author":"Sibiak","year":"2021","journal-title":"Med. J. Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2912","DOI":"10.1093\/bioinformatics\/btv300","article-title":"GOplot: An R package for visually combining expression data with functional analysis: Fig. 1","volume":"31","author":"Walter","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1830","DOI":"10.1093\/bioinformatics\/btt285","article-title":"Pathview: An R\/Bioconductor package for pathway-based data integration and visualization","volume":"29","author":"Luo","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_15","first-page":"71","article-title":"An improvement of the 2\u02c6(-delta delta CT) method for quantitative real-time polymerase chain reaction data analysis","volume":"3","author":"Rao","year":"2013","journal-title":"Biostat. Bioinforma. Biomath."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2478\/acb-2019-0001","article-title":"Genes regulating programmed cell death are significantly upregulated in porcine immature oocytes","volume":"7","author":"Antosik","year":"2019","journal-title":"Med. J. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"91","DOI":"10.2478\/acb-2018-0015","article-title":"Response to abiotic and organic substances stimulation belongs to ontologic groups significantly up-regulated in porcine immature oocytes","volume":"6","author":"Kranc","year":"2018","journal-title":"Med. J. Cell Biol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Singh, A.K., Dutta, M., Chattopadhyay, R., Chakravarty, B., and Chaudhury, K. (2016). Intrafollicular interleukin-8, interleukin-12, and adrenomedullin are the promising prognostic markers of oocyte and embryo quality in women with endometriosis. J. Assist. Reprod. Genet., 33.","DOI":"10.1007\/s10815-016-0782-5"},{"key":"ref_19","unstructured":"Lee, K.S., Joo, B.S., Na, Y.J., Yoon, M.S., Choi, O.H., and Kim, W.W. (2000). Relationships Between Concentrations of Tumor Necrosis Factor-\u03b1 and Nitric Oxide in Follicular Fluid and Oocyte Quality. J. Assist. Reprod. Genet., 17."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1080\/00016340500501715","article-title":"Increased ENA-78 in the follicular fluid of patients with endometriosis","volume":"85","author":"Wunder","year":"2006","journal-title":"Acta Obstet. Gynecol. Scand."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1016\/j.bbrc.2005.10.004","article-title":"Annexin A3 is a potential angiogenic mediator","volume":"337","author":"Park","year":"2005","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41419-017-0143-z","article-title":"Downregulation of annexin A3 inhibits tumor metastasis and decreases drug resistance in breast cancer","volume":"9","author":"Du","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Huang, P., Zhou, Y., Liu, Z., and Zhang, P. (2016). Interaction between ANXA1 and GATA-3 in Immunosuppression of CD4+ T Cells. Mediators Inflamm., 2016.","DOI":"10.1155\/2016\/1701059"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1111\/imm.13239","article-title":"Annexin A3 in sepsis: Novel perspectives from an exploration of public transcriptome data","volume":"161","author":"Toufiq","year":"2020","journal-title":"Immunology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"10535","DOI":"10.1002\/jcp.27717","article-title":"Annexin A3 gene silencing promotes myocardial cell repair through activation of the PI3K\/Akt signaling pathway in rats with acute myocardial infarction","volume":"234","author":"Meng","year":"2019","journal-title":"J. Cell. Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1016\/j.theriogenology.2009.07.005","article-title":"Molecules involved in sperm-oviduct adhesion and release","volume":"73","author":"Talevi","year":"2010","journal-title":"Theriogenology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1042\/bj3030481","article-title":"Annexin 3 is associated with cytoplasmic granules in neutrophils and monocytes and translocates to the plasma membrane in activated cells","volume":"303","year":"1994","journal-title":"Biochem. J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7554\/eLife.14228","article-title":"Evolution-guided functional analyses reveal diverse antiviral specificities encoded by ifit1 genes in mammals","volume":"5","author":"Daugherty","year":"2016","journal-title":"eLife"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.coviro.2014.03.006","article-title":"Interferon-stimulated genes: Roles in viral pathogenesis","volume":"6","author":"Schoggins","year":"2014","journal-title":"Curr. Opin. Virol."},{"key":"ref_30","unstructured":"Nakaranurack, C., Puttilerpong, C., and Suwanpimolkul, G. (2016). Advance Publication by J-STAGE. J. Reprod. Dev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.meegid.2016.03.034","article-title":"Protective effects of HLA-DPA1\/DPB1 variants against Hepatitis B virus infection in an Indonesian population","volume":"41","author":"Wasityastuti","year":"2016","journal-title":"Infect. Genet. Evol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"482","DOI":"10.21451\/1984-3143-AR990","article-title":"In vitro production of bovine embryos: Cumulus\/granulosa cell gene expression patterns point to early atresia as beneficial for oocyte competence","volume":"14","author":"Mazzoni","year":"2017","journal-title":"Anim. Reprod."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13048-016-0217-z","article-title":"Molecular manipulation of keratin 8\/18 intermediate filaments: Modulators of FAS-mediated death signaling in human ovarian granulosa tumor cells","volume":"9","author":"Trisdale","year":"2016","journal-title":"J. Ovarian Res."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Sarapik, A., Velthut, A., Haller-Kikkatalo, K., Faure, G.C., B\u00e9n\u00e9, M.C., De Carvalho Bittencourt, M., Massin, F., Uibo, R., and Salumets, A. (2012). Follicular proinflammatory cytokines and chemokines as markers of IVF success. Clin. Dev. Immunol., 2012.","DOI":"10.1155\/2012\/606459"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1093\/humrep\/14.1.162","article-title":"Cytokines in the follicular fluid of stimulated and non-stimulated human ovaries; Is ovulation a suppressed inflammatory reaction?","volume":"14","author":"Chen","year":"1999","journal-title":"Hum. Reprod."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1477-7827-1-95","article-title":"Multiple roles of TNF super family members in corpus luteum function","volume":"1","author":"Okuda","year":"2003","journal-title":"Reprod. Biol. Endocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1095\/biolreprod48.4.707","article-title":"Tumor necrosis factor-\u03b1 gene expression in mouse oocytes and follicular cells","volume":"48","author":"Chen","year":"1993","journal-title":"Biol. Reprod."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1210\/jcem-71-5-1096","article-title":"Immunological evidence for a human ovarian tumor necrosis factor-\u03b1","volume":"71","author":"Roby","year":"1990","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1016\/S0015-0282(16)55438-7","article-title":"Tumor necrosis factor \u03b1 in the human ovary: Presence in follicular fluid and effects on cell proliferation and prostaglandin production","volume":"58","author":"Wang","year":"1992","journal-title":"Fertil. Steril."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1262\/jrd.50.39","article-title":"Possible actions of tumor necrosis factor-\u03b1 in ovarian function","volume":"50","author":"Sakumoto","year":"2004","journal-title":"J. Reprod. Dev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1530\/REP-17-0053","article-title":"Follicular expression of pro-inflammatory cytokines tumour necrosis factor-\u03b1 (TNF\u03b1), interleukin 6 (IL6) and their receptors in cattle: TNF\u03b1 IL6 and macrophages suppress thecal androgen production in vitro","volume":"154","author":"Samir","year":"2017","journal-title":"Reproduction"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1471-2164-15-72","article-title":"The global effect of follicle-stimulating hormone and tumour necrosis factor \u03b1 on gene expression in cultured bovine ovarian granulosa cells","volume":"15","author":"Glister","year":"2014","journal-title":"BMC Genom."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1111\/j.1439-0531.2008.01172.x","article-title":"Role of Cell Death Ligand and Receptor System on Regulation of Follicular Atresia in Pig Ovaries","volume":"43","author":"Manabe","year":"2008","journal-title":"Reprod. Domest. Anim."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1017\/S0967199420000222","article-title":"Interleukin-1\u03b2 and TNF-\u03b1 systems in ovarian follicles and their roles during follicular development, oocyte maturation and ovulation","volume":"28","author":"Silva","year":"2020","journal-title":"Zygote"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Naz, R.K., Zhu, X., and Menge, A.C. (1997). Expression of Tumor Necrosis Factor-\u03b1 and Its Receptors Type I and Type II in Human Oocytes, Wiley-Liss, Inc.","DOI":"10.1002\/(SICI)1098-2795(199706)47:2<127::AID-MRD1>3.0.CO;2-O"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0739-7240(96)00094-X","article-title":"Potential roles of tumor necrosis factor-\u03b1 in follicular development, ovulation, and the life span of the corpus luteum","volume":"14","author":"Terranova","year":"1997","journal-title":"Domest. Anim. Endocrinol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.18632\/aging.101507","article-title":"Cumulus cell-released tumor necrosis factor (TNF)-a promotes post-ovulatory aging of mouse oocytes","volume":"10","author":"Kong","year":"2018","journal-title":"Aging"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1007\/s12016-016-8596-x","article-title":"Tumor Necrosis Factor-Alpha and Pregnancy: Focus on Biologics. An Updated and Comprehensive Review","volume":"53","author":"Llurba","year":"2017","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/S2305-0500(13)60092-5","article-title":"LIF and TNF alpha concentrations in embryo culture media are predictive for embryo implantation in IVF","volume":"1","author":"Zollner","year":"2012","journal-title":"Asian Pac. J. Reprod."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/9\/1369\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:53:14Z","timestamp":1760165594000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/12\/9\/1369"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,31]]},"references-count":49,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["genes12091369"],"URL":"https:\/\/doi.org\/10.3390\/genes12091369","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,31]]}}}