{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:52:39Z","timestamp":1790880759737,"version":"4.1.0"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T00:00:00Z","timestamp":1684800000000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32071186"],"award-info":[{"award-number":["32071186"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,6,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>Alopecia areata (AA) is an autoimmune-related non-cicatricial alopecia, with complete alopecia (AT) or generalized alopecia (AU) as severe forms of AA. However, there are limitations in early identification of AA, and intervention of AA patients who may progress to severe AA will help to improve the incidence rate and prognosis of severe AA.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We obtained two AA-related datasets from the gene expression omnibus database, identified the differentially expressed genes (DEGs), and identified the module genes most related to severe AA through weighted gene co-expression network analysis. Functional enrichment analysis, construction of a protein\u2013protein interaction network and competing endogenous RNA network, and immune cell infiltration analysis were performed to clarify the underlying biological mechanisms of severe AA. Subsequently, pivotal immune monitoring genes (IMGs) were screened through multiple machine-learning algorithms, and the diagnostic effectiveness of the pivotal IMGs was validated by receiver operating characteristic.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>A total of 150 severe AA-related DEGs were identified; the upregulated DEGs were mainly enriched in immune response, while the downregulated DEGs were mainly enriched in pathways related to hair cycle and skin development. Four IMGs (LGR5, SHISA2, HOXC13, and S100A3) with good diagnostic efficiency were obtained. As an important gene of hair follicle stem cells stemness, we verified in vivo that LGR5 downregulation may be an important link leading to severe AA.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Our findings provide a comprehensive understanding of the pathogenesis and underlying biological processes in patients with AA, and identification of four potential IMGs, which is helpful for the early diagnosis of severe AA.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/pcmedi\/pbad009","type":"journal-article","created":{"date-parts":[[2023,5,23]],"date-time":"2023-05-23T11:03:21Z","timestamp":1684839801000},"source":"Crossref","is-referenced-by-count":15,"title":["Construction of regulatory network for alopecia areata progression and identification of immune monitoring genes based on multiple machine-learning algorithms"],"prefix":"10.1093","volume":"6","author":[{"given":"Jiachao","family":"Xiong","sequence":"first","affiliation":[{"name":"Department of Histology and Embryology, Naval Military Medical University , Shanghai 200433 , China"},{"name":"Department of Plastic Surgery, Shanghai East Hospital, Tongji University School of Medicine , Shanghai 200120 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guodong","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Naval Military Medical University , Shanghai 200433 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhixiao","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Naval Military Medical University , Shanghai 200433 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemei","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Plastic Surgery, Shanghai East Hospital, Tongji University School of Medicine , Shanghai 200120 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sha","family":"Xu","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Naval Military Medical University , Shanghai 200433 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Xiong","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Naval Military Medical University , Shanghai 200433 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shizhao","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Burn Surgery, The First Affiliated Hospital of Naval Medical University , Shanghai 200433 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6734-5618","authenticated-orcid":false,"given":"Minjuan","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Histology and Embryology, Naval Military Medical University , Shanghai 200433 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,5,22]]},"reference":[{"key":"2023061512021632400_bib1","doi-asserted-by":"publisher","first-page":"17011","DOI":"10.1038\/nrdp.2017.11","article-title":"Alopecia areata","volume":"3","author":"Pratt","year":"2017","journal-title":"Nat Rev Dis Primers"},{"key":"2023061512021632400_bib2","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1016\/j.jaad.2019.06.1304","article-title":"Impact of alopecia areata on psychiatric disorders: A retrospective cohort study","volume":"82","author":"Kim","year":"2020","journal-title":"J Am Acad Dermatol"},{"key":"2023061512021632400_bib3","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1016\/j.jaut.2018.12.001","article-title":"Alopecia areata: A multifactorial autoimmune condition","volume":"98","author":"Simakou","year":"2019","journal-title":"J Autoimmun"},{"key":"2023061512021632400_bib4","doi-asserted-by":"publisher","first-page":"120","DOI":"10.3315\/jdcr.2012.1120","article-title":"Alternaria scalp infection in a patient with alopecia areata. Coexistence or causative relationship?","volume":"6","author":"Rudnicka","year":"2012","journal-title":"J Dermatol Case Rep"},{"key":"2023061512021632400_bib5","doi-asserted-by":"publisher","first-page":"5966","DOI":"10.1038\/ncomms6966","article-title":"Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci","volume":"6","author":"Betz","year":"2015","journal-title":"Nat Commun"},{"key":"2023061512021632400_bib6","doi-asserted-by":"publisher","first-page":"1555","DOI":"10.1001\/archderm.139.12.1555","article-title":"Histopathologic features of alopecia areata: A new look","volume":"139","author":"Whiting","year":"2003","journal-title":"Arch Dermatol"},{"key":"2023061512021632400_bib7","doi-asserted-by":"publisher","first-page":"1478","DOI":"10.1016\/j.jaci.2019.08.035","article-title":"Frontiers in alopecia areata pathobiology research","volume":"144","author":"Gilhar","year":"2019","journal-title":"J Allergy Clin Immunol"},{"key":"2023061512021632400_bib8","doi-asserted-by":"publisher","first-page":"13228","DOI":"10.3390\/ijms232113228","article-title":"Ex vivo treatment with allogenic mesenchymal stem cells of a healthy donor on peripheral blood mononuclear cells of patients with severe alopecia areata: Targeting dysregulated T cells and the acquisition of immunotolerance","volume":"23","author":"Kim","year":"2022","journal-title":"Int J Mol Sci"},{"key":"2023061512021632400_bib9","doi-asserted-by":"publisher","first-page":"937886","DOI":"10.3389\/fimmu.2022.937886","article-title":"Identification of immune-associated genes in diagnosing aortic valve calcification with metabolic syndrome by Integrated bioinformatics analysis and machine learning","volume":"13","author":"Zhou","year":"2022","journal-title":"Front Immunol"},{"key":"2023061512021632400_bib10","doi-asserted-by":"publisher","first-page":"782750","DOI":"10.3389\/fgene.2022.782750","article-title":"Comprehensive analysis of LncRNA AC010789.1 delays androgenic alopecia progression by targeting MicroRNA-21 and the wnt\/\u03b2-catenin signaling pathway in hair follicle stem cells","volume":"13","author":"Xiong","year":"2022","journal-title":"Front Genet"},{"key":"2023061512021632400_bib11","doi-asserted-by":"publisher","first-page":"1760","DOI":"10.1101\/gr.135350.111","article-title":"GENCODE: The reference human genome annotation for The ENCODE Project","volume":"22","author":"Harrow","year":"2012","journal-title":"Genome Res"},{"key":"2023061512021632400_bib12","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: An R package for weighted correlation network analysis","volume":"9","author":"Langfelder","year":"2008","journal-title":"BMC Bioinf"},{"key":"2023061512021632400_bib13","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1038\/nmeth.3485","article-title":"miRWalk2.0: a comprehensive atlas of microRNA-target interactions","volume":"12","author":"Dweep","year":"2015","journal-title":"Nat Methods"},{"key":"2023061512021632400_bib14","doi-asserted-by":"publisher","first-page":"R1","DOI":"10.1186\/gb-2003-5-1-r1","article-title":"MicroRNA targets in drosophila","volume":"5","author":"Enright","year":"2003","journal-title":"Genome Biol"},{"key":"2023061512021632400_bib15","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1186\/s12938-018-0568-3","article-title":"Machine learning approaches for predicting high cost high need patient expenditures in health care","volume":"17","author":"Yang","year":"2018","journal-title":"Biomed Eng Online"},{"key":"2023061512021632400_bib16","doi-asserted-by":"publisher","first-page":"461","DOI":"10.4037\/ajcc2018525","article-title":"Predicting pressure injury in critical care patients: A machine-learning model","volume":"27","author":"Alderden","year":"2018","journal-title":"Am J Crit Care"},{"key":"2023061512021632400_bib17","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1186\/1471-2105-7-191","article-title":"STEM: A tool for the analysis of short time series gene expression data","volume":"7","author":"Ernst","year":"2006","journal-title":"BMC Bioinf"},{"key":"2023061512021632400_bib18","doi-asserted-by":"publisher","first-page":"pbac020","DOI":"10.1093\/pcmedi\/pbac020","article-title":"JAM-A facilitates hair follicle regeneration in alopecia areata through functioning as ceRNA to protect VCAN expression in dermal papilla cells","volume":"5","author":"Wu","year":"2022","journal-title":"Precis Clin Med"},{"key":"2023061512021632400_bib19","doi-asserted-by":"publisher","first-page":"7135974","DOI":"10.1155\/2019\/7135974","article-title":"Human adipose-derived stem cells promote seawater-immersed wound healing by activating skin stem cells via the EGFR\/MEK\/ERK pathway","volume":"2019","author":"Xiong","year":"2019","journal-title":"Stem Cells Int"},{"key":"2023061512021632400_bib20","doi-asserted-by":"publisher","first-page":"325","DOI":"10.5114\/ceji.2020.101264","article-title":"Immunology of alopecia areata","volume":"45","author":"\u017beberkiewicz","year":"2020","journal-title":"Cent Eur J Immunol"},{"key":"2023061512021632400_bib21","doi-asserted-by":"publisher","first-page":"9104","DOI":"10.1038\/s41598-022-13056-w","article-title":"LGR5 is a conserved marker of hair follicle stem cells in multiple species and is present early and throughout follicle morphogenesis","volume":"12","author":"Polkoff","year":"2022","journal-title":"Sci Rep"},{"key":"2023061512021632400_bib22","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1016\/j.celrep.2018.09.059","article-title":"Single-cell transcriptomics of traced epidermal and hair follicle stem cells reveals rapid adaptations during wound healing","volume":"25","author":"Joost","year":"2018","journal-title":"Cell Rep"},{"key":"2023061512021632400_bib23","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1038\/ng.239","article-title":"Lgr5 marks cycling, yet long-lived, hair follicle stem cells","volume":"40","author":"Jaks","year":"2008","journal-title":"Nat Genet"},{"key":"2023061512021632400_bib24","doi-asserted-by":"publisher","first-page":"165","DOI":"10.4103\/0974-2077.191650","article-title":"Stem cell markers (Cytokeratin 17 and Cytokeratin 19) in scarring and nonscarring alopecia","volume":"9","author":"El\u00a0Sakka","year":"2016","journal-title":"J Cutan Aesthet Surg"},{"key":"2023061512021632400_bib25","doi-asserted-by":"publisher","first-page":"e31","DOI":"10.1590\/s1678-9946202264031","article-title":"Follow-up of patients with COVID-19 by the Delta variant after hospital discharge in Guangzhou, Guandong, China","volume":"64","author":"Wu","year":"2022","journal-title":"Rev Inst Med Trop Sao Paulo"},{"key":"2023061512021632400_bib26","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1080\/14728214.2022.2149735","article-title":"Emerging drugs for the treatment of alopecia areata","volume":"27","author":"Ram\u00edrez-Mar\u00edn","year":"2022","journal-title":"Expert Opin Emerg Drugs"},{"key":"2023061512021632400_bib27","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1159\/000515764","article-title":"Prediction of the risk of Alopecia Areata progressing to Alopecia Totalis and Alopecia Universalis: Biomarker development with bioinformatics analysis and machine learning","volume":"238","author":"Zhang","year":"2022","journal-title":"Dermatology"},{"key":"2023061512021632400_bib28","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.1111\/bjd.16808","article-title":"Alopecia areata: A review of disease pathogenesis","volume":"179","author":"Rajabi","year":"2018","journal-title":"Br J Dermatol"},{"key":"2023061512021632400_bib29","first-page":"40","article-title":"Differential expression of CXCL1, CXCL9, CXCL10 and CXCL12 chemokines in alopecia areata","volume":"10","author":"Zainodini","year":"2013","journal-title":"Iran J Immunol"},{"key":"2023061512021632400_bib30","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1111\/pcmr.12559","article-title":"Differential expression of CXCL9, CXCL10, and IFN-\u03b3 in vitiligo and alopecia areata patients","volume":"30","author":"Maouia","year":"2017","journal-title":"Pigment Cell Melanoma Res"},{"key":"2023061512021632400_bib31","doi-asserted-by":"publisher","first-page":"260","DOI":"10.3109\/09546634.2015.1093591","article-title":"Serum cytokine and chemokine profiles in patients with alopecia areata","volume":"27","author":"Bilgic","year":"2016","journal-title":"J Dermatolog Treat"},{"key":"2023061512021632400_bib32","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1126\/science.aaz8658","article-title":"The CD8\u03b1-pilr\u03b1 interaction maintains CD8(+) T cell quiescence","volume":"376","author":"Zheng","year":"2022","journal-title":"Science"},{"issue":"17","key":"2023061512021632400_bib33","doi-asserted-by":"publisher","first-page":"e159402","DOI":"10.1172\/JCI159402","article-title":"Multidimensional single-cell analysis identifies a role for CD2-CD58 interactions in clinical antitumor T cell responses","volume":"132","author":"Romain","year":"2022","journal-title":"J Clin Invest"},{"key":"2023061512021632400_bib34","doi-asserted-by":"publisher","first-page":"3385","DOI":"10.1002\/1878-0261.13104","article-title":"Human intestinal and circulating invariant natural killer T\u2009cells are cytotoxic against colorectal cancer cells via the perforin-granzyme pathway","volume":"15","author":"D\u00edaz-Basabe","year":"2021","journal-title":"Mol Oncol"},{"key":"2023061512021632400_bib35","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1111\/exd.13284","article-title":"Granzyme A potentiates chemokine production in IL-17-stimulated keratinocytes","volume":"26","author":"Cheuk","year":"2017","journal-title":"Exp Dermatol"},{"key":"2023061512021632400_bib36","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1016\/j.immuni.2008.12.020","article-title":"Lymphocyte crawling and transendothelial migration require chemokine triggering of high-affinity LFA-1 integrin","volume":"30","author":"Shulman","year":"2009","journal-title":"Immunity"},{"key":"2023061512021632400_bib37","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1038\/jid.2012.344","article-title":"Endogenous retinoids in the pathogenesis of alopecia areata","volume":"133","author":"Duncan","year":"2013","journal-title":"J Invest Dermatol"},{"key":"2023061512021632400_bib38","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1111\/j.1432-0436.1986.tb00562.x","article-title":"The complement of native alpha-keratin polypeptides of hair-forming cells: A subset of eight polypeptides that differ from epithelial cytokeratins","volume":"32","author":"Heid","year":"1986","journal-title":"Differentiation"},{"key":"2023061512021632400_bib39","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1111\/j.0022-202X.2005.23692.x","article-title":"Transfer of CD8(+) cells induces localized hair loss whereas CD4(+)\/CD25(-) cells promote systemic alopecia areata and CD4(+)\/CD25(+) cells blockade disease onset in the C3H\/HeJ mouse model","volume":"124","author":"McElwee","year":"2005","journal-title":"J Invest Dermatol"},{"key":"2023061512021632400_bib40","doi-asserted-by":"publisher","first-page":"177","DOI":"10.1016\/j.jdermsci.2021.04.009","article-title":"Induction of alopecia areata in C3H\/HeJ mice using cryopreserved lymphocytes","volume":"102","author":"Hashimoto","year":"2021","journal-title":"J Dermatol Sci"},{"key":"2023061512021632400_bib41","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.1111\/jocd.13131","article-title":"Evaluation of complete blood cell and inflammatory parameters in patients with alopecia areata: Their association with disease severity","volume":"19","author":"\u0130slamo\u011flu","year":"2020","journal-title":"J Cosmet Dermatol"},{"key":"2023061512021632400_bib42","doi-asserted-by":"publisher","first-page":"4048","DOI":"10.1111\/jocd.14048","article-title":"Investigation of the relationship between alopecia areata and inflammatory blood parameters","volume":"20","author":"Dere","year":"2021","journal-title":"J Cosmet Dermatol"},{"key":"2023061512021632400_bib43","doi-asserted-by":"publisher","first-page":"102711","DOI":"10.1016\/j.jaut.2021.102711","article-title":"Resident human dermal \u03b3\u03b4t-cells operate as stress-sentinels: Lessons from the hair follicle","volume":"124","author":"Uchida","year":"2021","journal-title":"J Autoimmun"},{"key":"2023061512021632400_bib44","doi-asserted-by":"publisher","first-page":"106544","DOI":"10.1016\/j.intimp.2020.106544","article-title":"Identification and verification of EOMEs regulated network in Alopecia areata","volume":"84","author":"Yuan","year":"2020","journal-title":"Int Immunopharmacol"},{"key":"2023061512021632400_bib45","doi-asserted-by":"publisher","first-page":"e94260","DOI":"10.1371\/journal.pone.0094260","article-title":"Abnormal interactions between perifollicular mast cells and CD8+ T-cells may contribute to the pathogenesis of alopecia areata","volume":"9","author":"Bertolini","year":"2014","journal-title":"PLoS One"},{"key":"2023061512021632400_bib46","doi-asserted-by":"publisher","first-page":"828","DOI":"10.1038\/jid.2010.391","article-title":"The nude mutant gene Foxn1 is a HOXC13 regulatory target during hair follicle and nail differentiation","volume":"131","author":"Potter","year":"2011","journal-title":"J Invest Dermatol"},{"key":"2023061512021632400_bib47","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1007\/s00441-015-2312-7","article-title":"Hoxc13 is a crucial regulator of murine hair cycle","volume":"364","author":"Qiu","year":"2016","journal-title":"Cell Tissue Res"},{"key":"2023061512021632400_bib48","doi-asserted-by":"publisher","first-page":"13532","DOI":"10.4238\/2015.October.28.14","article-title":"Blockade of S100A3 activity inhibits murine hair growth","volume":"14","author":"Guan","year":"2015","journal-title":"Genet Mol Res"},{"key":"2023061512021632400_bib49","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1016\/j.cell.2017.03.038","article-title":"Epithelial-mesenchymal micro-niches govern stem cell lineage choices","volume":"169","author":"Yang","year":"2017","journal-title":"Cell"},{"key":"2023061512021632400_bib50","doi-asserted-by":"publisher","first-page":"14091","DOI":"10.1038\/ncomms14091","article-title":"Macrophages induce AKT\/\u03b2-catenin-dependent Lgr5(+) stem cell activation and hair follicle regeneration through TNF","volume":"8","author":"Wang","year":"2017","journal-title":"Nat Commun"}],"container-title":["Precision Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/pcm\/advance-article-pdf\/doi\/10.1093\/pcmedi\/pbad009\/50537761\/pbad009.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/pcm\/article-pdf\/6\/2\/pbad009\/50615554\/pbad009.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/pcm\/article-pdf\/6\/2\/pbad009\/50615554\/pbad009.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,15]],"date-time":"2023-06-15T12:03:05Z","timestamp":1686830585000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/pcm\/article\/doi\/10.1093\/pcmedi\/pbad009\/7176078"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,22]]},"references-count":50,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2023,6,8]]}},"URL":"https:\/\/doi.org\/10.1093\/pcmedi\/pbad009","relation":{},"ISSN":["2096-5303","2516-1571"],"issn-type":[{"value":"2096-5303","type":"print"},{"value":"2516-1571","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,6]]},"published":{"date-parts":[[2023,5,22]]},"article-number":"pbad009"}}