{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T21:52:57Z","timestamp":1773870777097,"version":"3.50.1"},"reference-count":45,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T00:00:00Z","timestamp":1614816000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T00:00:00Z","timestamp":1614816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Ishidsu Shun Memorial Scholarship, Japan"},{"name":"Tokyo Medical University Research Grant"},{"name":"Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan"},{"name":"a program for the Strategic Research Foundation at Private Universities from the Ministry of Education, Culture, Sports, Science and Technology, Japan"},{"name":"AMED from the Ministry of Education, Culture, Sports, Science and Technology, Japan"},{"name":"Center for Clinical and Translational Research of Kyushu University Hospital"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Among various cytokines, interleukin (IL)-12 family cytokines have very unique characteristics in that they are composed of two distinct subunits and these subunits are shared with each other. IL-23, one of the IL-12 family cytokines, consists of p19 and p40 subunits, is mainly produced by antigen-presenting cells, and plays a critical role in the expansion and maintenance of pathogenic helper CD4<jats:sup>+<\/jats:sup>T (Th)17 cells. Since we initially found that p19 is secreted in the culture supernatant of activated CD4<jats:sup>+<\/jats:sup>T cells, we have further investigated the role of p19. p19 was revealed to associate with CD5 antigen-like (CD5L), which is a repressor of Th17 pathogenicity and is highly expressed in non-pathogenic Th17 cells, to form a composite p19\/CD5L. This p19\/CD5L was shown to activate STAT5 and enhance the differentiation into granulocyte macrophage colony-stimulating factor (GM-CSF)-producing CD4<jats:sup>+<\/jats:sup>T cells. Both CD4<jats:sup>+<\/jats:sup>T cell-specific conditional p19-deficient mice and complete CD5L-deficient mice showed significantly alleviated experimental autoimmune encephalomyelitis (EAE) with reduced frequency of GM-CSF<jats:sup>+<\/jats:sup>CD4<jats:sup>+<\/jats:sup>T cells. During the course of EAE, the serum level of p19\/CD5L, but not CD5L, correlated highly with the clinical symptoms. Thus, the composite p19\/CD5L is a possible novel heterodimeric cytokine that contributes to EAE development with GM-CSF up-regulation.<\/jats:p>","DOI":"10.1038\/s41598-021-84624-9","type":"journal-article","created":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T11:04:29Z","timestamp":1614855869000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["IL-23p19 and CD5 antigen-like form a possible novel heterodimeric cytokine and contribute to experimental autoimmune encephalomyelitis development"],"prefix":"10.1038","volume":"11","author":[{"given":"Hideaki","family":"Hasegawa","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Izuru","family":"Mizoguchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoko","family":"Orii","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinya","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuhiro","family":"Katahira","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshihiko","family":"Yoneto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingli","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toru","family":"Miyazaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takayuki","family":"Yoshimoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,3,4]]},"reference":[{"key":"84624_CR1","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1146\/annurev.immunol.021908.132710","volume":"27","author":"T Korn","year":"2009","unstructured":"Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V. K. IL-17 and Th17 Cells. Ann. Rev. Immunol. 27, 485\u2013517 (2009).","journal-title":"Ann. Rev. Immunol."},{"key":"84624_CR2","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1038\/nri3707","volume":"14","author":"SL Gaffen","year":"2014","unstructured":"Gaffen, S. L., Jain, R., Garg, A. V. & Cua, D. J. The IL-23-IL-17 immune axis: from mechanisms to therapeutic testing. Nat. Rev. Immunol. 14, 585\u2013600 (2014).","journal-title":"Nat. Rev. Immunol."},{"key":"84624_CR3","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1038\/nature04753","volume":"441","author":"E Bettelli","year":"2006","unstructured":"Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235\u2013238 (2006).","journal-title":"Nature"},{"key":"84624_CR4","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1038\/nature04754","volume":"441","author":"PR Mangan","year":"2006","unstructured":"Mangan, P. R. et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature 441, 231\u2013234 (2006).","journal-title":"Nature"},{"key":"84624_CR5","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/j.immuni.2006.01.001","volume":"24","author":"M Veldhoen","year":"2006","unstructured":"Veldhoen, M., Hocking, R. J., Atkins, C. J., Locksley, R. M. & Stockinger, B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179\u2013189 (2006).","journal-title":"Immunity"},{"key":"84624_CR6","doi-asserted-by":"publisher","first-page":"967","DOI":"10.1038\/ni1488","volume":"8","author":"L Zhou","year":"2007","unstructured":"Zhou, L. et al. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat. Immunol. 8, 967\u2013974 (2007).","journal-title":"Nat. Immunol."},{"key":"84624_CR7","doi-asserted-by":"publisher","first-page":"1390","DOI":"10.1038\/ni1539","volume":"8","author":"MJ McGeachy","year":"2007","unstructured":"McGeachy, M. J. et al. TGF-beta and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain T(H)-17 cell-mediated pathology. Nat. Immunol. 8, 1390\u20131397 (2007).","journal-title":"Nat. Immunol."},{"key":"84624_CR8","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1038\/ni.2416","volume":"13","author":"Y Lee","year":"2012","unstructured":"Lee, Y. et al. Induction and molecular signature of pathogenic TH17 cells. Nat. Immunol. 13, 991\u2013999 (2012).","journal-title":"Nat. Immunol."},{"key":"84624_CR9","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1038\/ni.3632","volume":"18","author":"S Heink","year":"2017","unstructured":"Heink, S. et al. Trans-presentation of IL-6 by dendritic cells is required for the priming of pathogenic TH17 cells. Nat. Immunol. 18, 74\u201385 (2017).","journal-title":"Nat. Immunol."},{"key":"84624_CR10","doi-asserted-by":"publisher","first-page":"1400","DOI":"10.1016\/j.cell.2015.11.009","volume":"163","author":"JT Gaublomme","year":"2015","unstructured":"Gaublomme, J. T. et al. Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity. Cell 163, 1400\u20131412 (2015).","journal-title":"Cell"},{"key":"84624_CR11","doi-asserted-by":"publisher","first-page":"1413","DOI":"10.1016\/j.cell.2015.10.068","volume":"163","author":"C Wang","year":"2015","unstructured":"Wang, C. et al. CD5L\/AIM Regulates Lipid Biosynthesis and Restrains Th17 Cell Pathogenicity. Cell 163, 1413\u20131427 (2015).","journal-title":"Cell"},{"key":"84624_CR12","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1016\/j.immuni.2016.10.026","volume":"45","author":"B Becher","year":"2016","unstructured":"Becher, B., Tugues, S. & Greter, M. GM-CSF: from growth factor to central mediator of tissue inflammation. Immunity 45, 963\u2013973 (2016).","journal-title":"Immunity"},{"key":"84624_CR13","doi-asserted-by":"publisher","first-page":"568543","DOI":"10.1155\/2015\/568543","volume":"2015","author":"A Shiomi","year":"2015","unstructured":"Shiomi, A. & Usui, T. Pivotal roles of GM-CSF in autoimmunity and inflammation. Mediators Inflamm. 2015, 568543 (2015).","journal-title":"Mediators Inflamm."},{"key":"84624_CR14","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1038\/cr.2014.154","volume":"24","author":"W Sheng","year":"2014","unstructured":"Sheng, W. et al. STAT5 programs a distinct subset of GM-CSF-producing T helper cells that is essential for autoimmune neuroinflammation. Cell Res. 24, 1387\u20131402 (2014).","journal-title":"Cell Res."},{"key":"84624_CR15","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1126\/scitranslmed.3008706","volume":"6","author":"R Noster","year":"2014","unstructured":"Noster, R. et al. IL-17 and GM-CSF expression are antagonistically regulated by human T helper cells. Sci. Transl. Med. 6, 241\u2013280 (2014).","journal-title":"Sci. Transl. Med."},{"key":"84624_CR16","doi-asserted-by":"publisher","first-page":"1289","DOI":"10.1016\/j.immuni.2019.04.006","volume":"50","author":"J Komuczki","year":"2019","unstructured":"Komuczki, J. et al. Fate-Mapping of GM-CSF Expression Identifies a Discrete Subset of Inflammation-Driving T Helper Cells Regulated by Cytokines IL-23 and IL-1beta. Immunity 50, 1289\u20131304 (2019).","journal-title":"Immunity"},{"key":"84624_CR17","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1038\/ni.2366","volume":"13","author":"DA Vignali","year":"2012","unstructured":"Vignali, D. A. & Kuchroo, V. K. IL-12 family cytokines: immunological playmakers. Nat. Immunol. 13, 722\u2013728 (2012).","journal-title":"Nat. Immunol."},{"key":"84624_CR18","doi-asserted-by":"publisher","first-page":"719","DOI":"10.1038\/nm.3895","volume":"21","author":"MW Teng","year":"2015","unstructured":"Teng, M. W. et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat. Med. 21, 719\u2013729 (2015).","journal-title":"Nat. Med."},{"key":"84624_CR19","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1038\/nature01355","volume":"421","author":"DJ Cua","year":"2003","unstructured":"Cua, D. J. et al. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain. Nature 421, 744\u2013748 (2003).","journal-title":"Nature"},{"key":"84624_CR20","doi-asserted-by":"publisher","first-page":"2589","DOI":"10.4049\/jimmunol.178.4.2589","volume":"178","author":"P Thakker","year":"2007","unstructured":"Thakker, P. et al. IL-23 is critical in the induction but not in the effector phase of experimental autoimmune encephalomyelitis. J. Immunol. 178, 2589\u20132598 (2007).","journal-title":"J. Immunol."},{"key":"84624_CR21","doi-asserted-by":"publisher","first-page":"6028","DOI":"10.4049\/jimmunol.1400159","volume":"192","author":"K Abdi","year":"2014","unstructured":"Abdi, K. et al. Free IL-12p40 monomer is a polyfunctional adaptor for generating novel IL-12-like heterodimers extracellularly. J. Immunol. 192, 6028\u20136036 (2014).","journal-title":"J. Immunol."},{"key":"84624_CR22","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1016\/j.jmb.2008.07.051","volume":"382","author":"PJ Lupardus","year":"2008","unstructured":"Lupardus, P. J. & Garcia, K. C. The structure of interleukin-23 reveals the molecular basis of p40 subunit sharing with interleukin-12. J. Mol. Biol. 382, 931\u2013941 (2008).","journal-title":"J. Mol. Biol."},{"key":"84624_CR23","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1016\/j.jmb.2008.08.001","volume":"382","author":"BM Beyer","year":"2008","unstructured":"Beyer, B. M. et al. Crystal structures of the pro-inflammatory cytokine interleukin-23 and its complex with a high-affinity neutralizing antibody. J. Mol. Biol. 382, 942\u2013955 (2008).","journal-title":"J. Mol. Biol."},{"key":"84624_CR24","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1016\/S1074-7613(00)00070-4","volume":"13","author":"B Oppmann","year":"2000","unstructured":"Oppmann, B. et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 13, 715\u2013725 (2000).","journal-title":"Immunity"},{"key":"84624_CR25","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1146\/annurev-immunol-032414-112134","volume":"33","author":"H Yoshida","year":"2015","unstructured":"Yoshida, H. & Hunter, C. A. The immunobiology of interleukin-27. Annu. Rev. Immunol. 33, 417\u2013443 (2015).","journal-title":"Annu. Rev. Immunol."},{"key":"84624_CR26","doi-asserted-by":"publisher","first-page":"479","DOI":"10.3389\/fimmu.2016.00479","volume":"7","author":"H Hasegawa","year":"2016","unstructured":"Hasegawa, H. et al. Expanding Diversity in Molecular Structures and Functions of the IL-6\/IL-12 Heterodimeric Cytokine Family. Front Immunol. 7, 479 (2016).","journal-title":"Front Immunol."},{"key":"84624_CR27","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1016\/j.bcp.2019.03.026","volume":"165","author":"S Detry","year":"2019","unstructured":"Detry, S., Skladanowska, K., Vuylsteke, M., Savvides, S. N. & Bloch, Y. Revisiting the combinatorial potential of cytokine subunits in the IL-12 family. Biochem. Pharmacol. 165, 240\u2013248 (2019).","journal-title":"Biochem. Pharmacol."},{"key":"84624_CR28","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1016\/0167-5699(95)80035-2","volume":"16","author":"T Germann","year":"1995","unstructured":"Germann, T., Rude, E., Mattner, F. & Gately, M. K. The IL-12 p40 homodimer as a specific antagonist of the IL-12 heterodimer. Immunol. Today 16, 500\u2013501 (1995).","journal-title":"Immunol. Today"},{"key":"84624_CR29","doi-asserted-by":"publisher","first-page":"192","DOI":"10.18632\/aging.100296","volume":"3","author":"LS Steelman","year":"2011","unstructured":"Steelman, L. S. et al. Roles of the Raf\/MEK\/ERK and PI3K\/PTEN\/Akt\/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging. Aging (Albany NY) 3, 192\u2013222 (2011).","journal-title":"Aging (Albany NY)"},{"key":"84624_CR30","doi-asserted-by":"publisher","first-page":"1510","DOI":"10.1038\/s41467-017-01771-2","volume":"8","author":"MH Al-Mossawi","year":"2017","unstructured":"Al-Mossawi, M. H. et al. Unique transcriptome signatures and GM-CSF expression in lymphocytes from patients with spondyloarthritis. Nat. Commun. 8, 1510 (2017).","journal-title":"Nat. Commun."},{"key":"84624_CR31","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1189\/jlb.3RU0215-074R","volume":"98","author":"L Sanjurjo","year":"2015","unstructured":"Sanjurjo, L., Aran, G., Roher, N., Valledor, A. F. & Sarrias, M. R. AIM\/CD5L: a key protein in the control of immune homeostasis and inflammatory disease. J. Leukoc Biol. 98, 173\u2013184 (2015).","journal-title":"J. Leukoc Biol."},{"key":"84624_CR32","doi-asserted-by":"publisher","first-page":"567","DOI":"10.1007\/s00281-018-0717-6","volume":"40","author":"S Arai","year":"2018","unstructured":"Arai, S. & Miyazaki, T. A scavenging system against internal pathogens promoted by the circulating protein apoptosis inhibitor of macrophage (AIM). Semin. Immunopathol. 40, 567\u2013575 (2018).","journal-title":"Semin. Immunopathol."},{"key":"84624_CR33","doi-asserted-by":"publisher","first-page":"6923","DOI":"10.1038\/s41598-019-43356-7","volume":"9","author":"KAO Gandy","year":"2019","unstructured":"Gandy, K. A. O., Zhang, J., Nagarkatti, P. & Nagarkatti, M. The role of gut microbiota in shaping the relapse-remitting and chronic-progressive forms of multiple sclerosis in mouse models. Sci. Rep. 9, 6923 (2019).","journal-title":"Sci. Rep."},{"key":"84624_CR34","doi-asserted-by":"publisher","first-page":"15183","DOI":"10.1038\/s41598-020-72197-y","volume":"10","author":"DM Johanson 2nd","year":"2020","unstructured":"Johanson, D. M. 2nd. et al. Experimental autoimmune encephalomyelitis is associated with changes of the microbiota composition in the gastrointestinal tract. Sci. Rep. 10, 15183 (2020).","journal-title":"Sci. Rep."},{"key":"84624_CR35","doi-asserted-by":"publisher","first-page":"ra28","DOI":"10.1126\/scisignal.aad2357","volume":"9","author":"G Espigol-Frigole","year":"2016","unstructured":"Espigol-Frigole, G. et al. Identification of IL-23p19 as an endothelial proinflammatory peptide that promotes gp130-STAT3 signaling. Sci. Signal 9, ra28 (2016).","journal-title":"Sci. Signal"},{"key":"84624_CR36","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1111\/cei.12840","volume":"186","author":"X Wang","year":"2016","unstructured":"Wang, X. et al. Interleukin (IL)-39 [IL-23p19\/Epstein-Barr virus-induced 3 (Ebi3)] induces differentiation\/expansion of neutrophils in lupus-prone mice. Clin. Exp. Immunol. 186, 144\u2013156 (2016).","journal-title":"Clin. Exp. Immunol."},{"key":"84624_CR37","doi-asserted-by":"publisher","first-page":"1343","DOI":"10.1002\/eji.201546095","volume":"46","author":"X Wang","year":"2016","unstructured":"Wang, X. et al. A novel IL-23p19\/Ebi3 (IL-39) cytokine mediates inflammation in Lupus-like mice. Eur. J. Immunol. 46, 1343\u20131350 (2016).","journal-title":"Eur. J. Immunol."},{"key":"84624_CR38","doi-asserted-by":"publisher","first-page":"1551","DOI":"10.1056\/NEJMoa1607017","volume":"376","author":"KA Papp","year":"2017","unstructured":"Papp, K. A. et al. Risankizumab versus Ustekinumab for Moderate-to-Severe Plaque Psoriasis. N. Engl. J. Med. 376, 1551\u20131560 (2017).","journal-title":"N. Engl. J. Med."},{"key":"84624_CR39","doi-asserted-by":"publisher","first-page":"13466","DOI":"10.1038\/ncomms13466","volume":"7","author":"P Kulig","year":"2016","unstructured":"Kulig, P. et al. IL-12 protects from psoriasiform skin inflammation. Nat. Commun. 7, 13466 (2016).","journal-title":"Nat. Commun."},{"key":"84624_CR40","doi-asserted-by":"publisher","first-page":"2313","DOI":"10.1002\/j.1460-2075.1993.tb05885.x","volume":"12","author":"VK Tsiagbe","year":"1993","unstructured":"Tsiagbe, V. K. et al. Linkage of superantigen-like stimulation of syngeneic T cells in a mouse model of follicular center B cell lymphoma to transcription of endogenous mammary tumor virus. EMBO J. 12, 2313\u20132320 (1993).","journal-title":"EMBO J."},{"key":"84624_CR41","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/0092-8674(82)90020-4","volume":"30","author":"SM Hedrick","year":"1982","unstructured":"Hedrick, S. M. et al. The fine specificity of antigen and Ia determinant recognition by T cell hybridoma clones specific for pigeon cytochrome c. Cell 30, 141\u2013152 (1982).","journal-title":"Cell"},{"key":"84624_CR42","doi-asserted-by":"publisher","first-page":"e107990","DOI":"10.1371\/journal.pone.0107990","volume":"9","author":"S Aparicio-Siegmund","year":"2014","unstructured":"Aparicio-Siegmund, S. et al. Recombinant p35 from bacteria can form Interleukin (IL-)12, but Not IL-35. PLoS ONE 9, e107990 (2014).","journal-title":"PLoS ONE"},{"key":"84624_CR43","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1016\/0378-1119(91)90434-D","volume":"108","author":"H Niwa","year":"1991","unstructured":"Niwa, H., Yamamura, K. & Miyazaki, J. Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 108, 193\u2013199 (1991).","journal-title":"Gene"},{"key":"84624_CR44","doi-asserted-by":"publisher","first-page":"2903","DOI":"10.4049\/jimmunol.180.5.2903","volume":"180","author":"T Owaki","year":"2008","unstructured":"Owaki, T. et al. STAT3 is indispensable to IL-27-mediated cell proliferation but not to IL-27-induced Th1 differentiation and suppression of proinflammatory cytokine production. J. Immunol. 180, 2903\u20132911 (2008).","journal-title":"J. Immunol."},{"key":"84624_CR45","doi-asserted-by":"crossref","first-page":"5500","DOI":"10.4049\/jimmunol.160.11.5500","volume":"160","author":"T Yoshimoto","year":"1998","unstructured":"Yoshimoto, T. et al. A pathogenic role of IL-12 in blood-stage murine malaria lethal strain Plasmodium berghei NK65 infection. J. Immunol. 160, 5500\u20135505 (1998).","journal-title":"J. Immunol."}],"updated-by":[{"DOI":"10.1038\/s41598-021-01575-x","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2021,11,3]],"date-time":"2021-11-03T00:00:00Z","timestamp":1635897600000}}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-84624-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-84624-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-84624-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,22]],"date-time":"2023-10-22T11:11:36Z","timestamp":1697973096000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-84624-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,4]]},"references-count":45,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["84624"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-84624-9","relation":{"correction":[{"id-type":"doi","id":"10.1038\/s41598-021-01575-x","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,4]]},"assertion":[{"value":"24 September 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 February 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 March 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 November 2021","order":4,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":5,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":6,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1038\/s41598-021-01575-x","URL":"https:\/\/doi.org\/10.1038\/s41598-021-01575-x","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"5266"}}