{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T20:47:54Z","timestamp":1793998074376,"version":"4.8.0"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T00:00:00Z","timestamp":1648771200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T00:00:00Z","timestamp":1648771200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31970830"],"award-info":[{"award-number":["31970830"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31700768"],"award-info":[{"award-number":["31700768"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32000615"],"award-info":[{"award-number":["32000615"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31900657"],"award-info":[{"award-number":["31900657"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["31830021"],"award-info":[{"award-number":["31830021"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81771957"],"award-info":[{"award-number":["81771957"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Liver fibrosis represents a severe stage of liver damage, with hallmarks of inflammation, hepatic stellate cell activation, and extracellular matrix accumulation. Although previous studies demonstrated \u03b3\u03b4 T cells are involved in liver fibrosis, the precise role and mechanisms of \u03b3\u03b4 T cells migrating to fibrotic liver have not been elucidated. Here, we aim to investigate the functional subsets of \u03b3\u03b4 T cells in hepatic fibrosis and to further explore the underlying causes and drivers of migration. In this study, we observed that \u03b3\u03b4 T cells accumulate in fibrotic liver. Adoptive transfer of \u03b3\u03b4 T, especially V\u03b34 \u03b3\u03b4 T subset, can significantly alleviate liver fibrosis. In addition, CCl<jats:sub>4<\/jats:sub> treatment also leads to activation of mTOR signaling in \u03b3\u03b4 T cells. Genetic deletion of the Rictor gene, but not Raptor, in \u03b3\u03b4 T cells markedly exacerbated liver fibrosis. Mechanistically, CCl<jats:sub>4<\/jats:sub>-induced liver injury causes macrophage accumulation in the liver, and IL-1\u03b2 produced by macrophages promotes mTORC2 signaling activation in \u03b3\u03b4 T cells, which upregulates T-bet expression and eventually promotes CXCR3 transcription to drive \u03b3\u03b4 T cell migration. Moreover, hepatic \u03b3\u03b4 T cells ameliorated liver fibrosis by cytotoxicity against activated hepatic stellate cells in FasL-dependent manner, and secrete IFN-\u03b3 to inhibit the differentiation of pro-fibrotic Th17 cells. Thus, IL-1\u03b2-activated mTORC2 signaling in \u03b3\u03b4 T cells upregulates CXCR3 expression, which is critical for IFN-\u03b3<jats:sup>+<\/jats:sup> \u03b3\u03b4 T cells migration into the liver and amelioration of liver fibrosis. Our findings indicate that targeting the mTORC2 or CXCR3 in \u03b3\u03b4 T cells could be considered as a promising approach for \u03b3\u03b4 T cell immunotherapy against liver fibrosis.<\/jats:p>","DOI":"10.1038\/s41419-022-04739-3","type":"journal-article","created":{"date-parts":[[2022,4,1]],"date-time":"2022-04-01T03:18:16Z","timestamp":1648783096000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["IL-1\u03b2-activated mTORC2 promotes accumulation of IFN-\u03b3+ \u03b3\u03b4 T cells by upregulating CXCR3 to restrict hepatic fibrosis"],"prefix":"10.1038","volume":"13","author":[{"given":"Qihui","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quanli","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zengfeng","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanfang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaomiao","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiliang","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zonghua","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zerong","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-yong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guodong","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiong","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenhua","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kebing","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaosong","family":"Ben","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanchun","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueshi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6524-8777","authenticated-orcid":false,"given":"Zhinan","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4600-3082","authenticated-orcid":false,"given":"Jianlei","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ligong","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,4,1]]},"reference":[{"key":"4739_CR1","doi-asserted-by":"publisher","first-page":"1028","DOI":"10.1038\/nm.2807","volume":"18","author":"TA Wynn","year":"2012","unstructured":"Wynn TA, Ramalingam TR. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nat Med. 2012;18:1028\u201340.","journal-title":"Nat Med"},{"key":"4739_CR2","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1038\/nri3623","volume":"14","author":"A Pellicoro","year":"2014","unstructured":"Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA. Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol. 2014;14:181\u201394.","journal-title":"Nat Rev Immunol"},{"key":"4739_CR3","doi-asserted-by":"publisher","first-page":"1728","DOI":"10.1053\/j.gastro.2020.01.027","volume":"158","author":"X Liu","year":"2020","unstructured":"Liu X, Xu J, Rosenthal S, Zhang LJ, McCubbin R, Meshgin N, et al. Identification of lineage-specific transcription factors that prevent activation of hepatic stellate cells and promote fibrosis resolution. Gastroenterology. 2020;158:1728\u201344. e14.","journal-title":"Gastroenterology"},{"key":"4739_CR4","doi-asserted-by":"publisher","first-page":"1971","DOI":"10.1053\/j.gastro.2018.09.010","volume":"155","author":"X Luo","year":"2018","unstructured":"Luo X, Li H, Ma L, Zhou J, Guo X, Woo SL, et al. Expression of STING is increased in liver tissues from patients with NAFLD and promotes macrophage-mediated hepatic inflammation and fibrosis in mice. Gastroenterology. 2018;155:1971\u201384. e4.","journal-title":"Gastroenterology."},{"key":"4739_CR5","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1016\/j.jcmgh.2018.01.003","volume":"5","author":"Z Zhou","year":"2018","unstructured":"Zhou Z, Xu MJ, Cai Y, Wang W, Jiang JX, Varga ZV, et al. Neutrophil-hepatic stellate cell interactions promote fibrosis in experimental steatohepatitis. Cell Mol Gastroenterol Hepatol. 2018;5:399\u2013413.","journal-title":"Cell Mol Gastroenterol Hepatol"},{"key":"4739_CR6","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12464-3","volume":"10","author":"PA Szabo","year":"2019","unstructured":"Szabo PA, Levitin HM, Miron M, Snyder ME, Senda T, Yuan J, et al. Single-cell transcriptomics of human T cells reveals tissue and activation signatures in health and disease. Nat Commun. 2019;10:4706.","journal-title":"Nat Commun"},{"key":"4739_CR7","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1038\/nri797","volume":"2","author":"SR Carding","year":"2002","unstructured":"Carding SR, Egan PJ. Gammadelta T cells: functional plasticity and heterogeneity. Nat Rev Immunol. 2002;2:336\u201345.","journal-title":"Nat Rev Immunol"},{"key":"4739_CR8","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1084\/jem.20030584","volume":"198","author":"Y Gao","year":"2003","unstructured":"Gao Y, Yang W, Pan M, Scully E, Girardi M, Augenlicht LH, et al. Gamma delta T cells provide an early source of interferon gamma in tumor immunity. J Exp Med. 2003;198:433\u201342.","journal-title":"J Exp Med"},{"key":"4739_CR9","doi-asserted-by":"publisher","first-page":"477","DOI":"10.3389\/fimmu.2019.00477","volume":"10","author":"M Liu","year":"2019","unstructured":"Liu M, Hu Y, Yuan Y, Tian Z, Zhang C. \u03b3\u03b4T cells suppress liver fibrosis via strong cytolysis and enhanced NK cell-mediated cytotoxicity against hepatic stellate cells. Front Immunol. 2019;10:477.","journal-title":"Front Immunol"},{"key":"4739_CR10","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1111\/imr.12845","volume":"295","author":"H Huang","year":"2020","unstructured":"Huang H, Long L, Zhou P, Chapman NM, Chi H. mTOR signaling at the crossroads of environmental signals and T-cell fate decisions. Immunological Rev. 2020;295:15\u201338.","journal-title":"Immunological Rev"},{"key":"4739_CR11","doi-asserted-by":"publisher","first-page":"2248","DOI":"10.1038\/s41418-020-0500-9","volume":"27","author":"Q Yang","year":"2020","unstructured":"Yang Q, Liu X, Liu Q, Guan Z, Luo J, Cao G, et al. Roles of mTORC1 and mTORC2 in controlling \u03b3\u03b4 T1 and \u03b3\u03b4 T17 differentiation and function. Cell Death Differ. 2020;27:2248\u201362.","journal-title":"Cell Death Differ"},{"key":"4739_CR12","doi-asserted-by":"publisher","first-page":"6231","DOI":"10.7150\/thno.45219","volume":"10","author":"J Jin","year":"2020","unstructured":"Jin J, Zhao Q. Emerging role of mTOR in tumor immune contexture: impact on chemokine-related immune cells migration. Theranostics. 2020;10:6231\u201344.","journal-title":"Theranostics."},{"key":"4739_CR13","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1002\/hep.26697","volume":"59","author":"L Hammerich","year":"2014","unstructured":"Hammerich L, Bangen JM, Govaere O, Zimmermann HW, Gassler N, Huss S, et al. Chemokine receptor CCR6-dependent accumulation of \u03b3\u03b4 T cells in injured liver restricts hepatic inflammation and fibrosis. Hepatology. 2014;59:630\u201342.","journal-title":"Hepatology."},{"key":"4739_CR14","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.ctrv.2017.11.007","volume":"63","author":"R Tokunaga","year":"2018","unstructured":"Tokunaga R, Zhang W, Naseem M, Puccini A, Berger MD, Soni S, et al. CXCL9, CXCL10, CXCL11\/CXCR3 axis for immune activation \u2013 a target for novel cancer therapy. Cancer Treat Rev. 2018;63:40\u20137.","journal-title":"Cancer Treat Rev"},{"key":"4739_CR15","doi-asserted-by":"crossref","unstructured":"Pandey V, Fleming-Martinez A, Bastea L, Doeppler HR, Eisenhauer J, Le T, et al. CXCL10\/CXCR3 signaling contributes to an inflammatory microenvironment and its blockade enhances progression of murine pancreatic precancerous lesions. eLife. 2021;10:e60646.","DOI":"10.7554\/eLife.60646"},{"key":"4739_CR16","doi-asserted-by":"publisher","first-page":"1410","DOI":"10.1189\/jlb.0308173","volume":"84","author":"MP Holt","year":"2008","unstructured":"Holt MP, Cheng L, Ju C. Identification and characterization of infiltrating macrophages in acetaminophen-induced liver injury. J Leukoc Biol. 2008;84:1410\u201321.","journal-title":"J Leukoc Biol"},{"key":"4739_CR17","doi-asserted-by":"publisher","DOI":"10.1186\/s12967-017-1378-2","volume":"16","author":"Y Zhao","year":"2018","unstructured":"Zhao Y, Niu C, Cui J. Gamma-delta (\u03b3\u03b4) T cells: friend or foe in cancer development? J Transl Med. 2018;16:3.","journal-title":"J Transl Med"},{"key":"4739_CR18","doi-asserted-by":"publisher","first-page":"126","DOI":"10.4049\/jimmunol.0903767","volume":"185","author":"W He","year":"2010","unstructured":"He W, Hao J, Dong S, Gao Y, Tao J, Chi H, et al. Naturally activated V gamma 4 gamma delta T cells play a protective role in tumor immunity through expression of eomesodermin. J Immunol. 2010;185:126\u201333.","journal-title":"J Immunol"},{"key":"4739_CR19","doi-asserted-by":"publisher","first-page":"3432","DOI":"10.1182\/blood-2005-04-1393","volume":"106","author":"GM Lord","year":"2005","unstructured":"Lord GM, Rao RM, Choe H, Sullivan BM, Lichtman AH, Luscinskas FW, et al. T-bet is required for optimal proinflammatory CD4+ T-cell trafficking. Blood. 2005;106:3432\u20139.","journal-title":"Blood."},{"key":"4739_CR20","doi-asserted-by":"publisher","first-page":"3034","DOI":"10.1016\/j.celrep.2019.05.019","volume":"27","author":"Y Cai","year":"2019","unstructured":"Cai Y, Xue F, Qin H, Chen X, Liu N, Fleming C, et al. Differential roles of the mTOR-STAT3 signaling in dermal \u03b3\u03b4 T cell effector function in skin inflammation. Cell Rep. 2019;27:3034\u201348. e5","journal-title":"Cell Rep."},{"key":"4739_CR21","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1172\/JCI88881","volume":"127","author":"Y Koyama","year":"2017","unstructured":"Koyama Y, Brenner DA. Liver inflammation and fibrosis. J Clin Investig. 2017;127:55\u201364.","journal-title":"J Clin Investig"},{"key":"4739_CR22","doi-asserted-by":"crossref","unstructured":"Huang E, Peng N, Xiao F, Hu D, Wang X, Lu L. The roles of immune cells in the pathogenesis of fibrosis. Int J Mol Sci. 2020;21:5203.","DOI":"10.3390\/ijms21155203"},{"key":"4739_CR23","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1016\/S1542-3565(05)00404-0","volume":"3","author":"HL Weng","year":"2005","unstructured":"Weng HL, Wang BE, Jia JD, Wu WF, Xian JZ, Mertens PR, et al. Effect of interferon-gamma on hepatic fibrosis in chronic hepatitis B virus infection: a randomized controlled study. Clin Gastroenterol Hepatology. 2005;3:819\u201328.","journal-title":"Clin Gastroenterol Hepatology"},{"key":"4739_CR24","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/j.jhep.2006.09.014","volume":"46","author":"H Weng","year":"2007","unstructured":"Weng H, Mertens PR, Gressner AM, Dooley S. IFN-gamma abrogates profibrogenic TGF-beta signaling in liver by targeting expression of inhibitory and receptor Smads. J Hepatol. 2007;46:295\u2013303.","journal-title":"J Hepatol"},{"key":"4739_CR25","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1189\/jlb.68.4.568","volume":"68","author":"J Yamamoto","year":"2000","unstructured":"Yamamoto J, Adachi Y, Onoue Y, Adachi YS, Okabe Y, Itazawa T, et al. Differential expression of the chemokine receptors by the Th1- and Th2-type effector populations within circulating CD4+ T cells. J Leukoc Biol. 2000;68:568\u201374.","journal-title":"J Leukoc Biol"},{"key":"4739_CR26","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1002\/immu.200310023","volume":"33","author":"A Langenkamp","year":"2003","unstructured":"Langenkamp A, Nagata K, Murphy K, Wu L, Lanzavecchia A, Sallusto F. Kinetics and expression patterns of chemokine receptors in human CD4+ T lymphocytes primed by myeloid or plasmacytoid dendritic cells. Eur J Immunol. 2003;33:474\u201382.","journal-title":"Eur J Immunol"},{"key":"4739_CR27","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1053\/j.gastro.2009.03.053","volume":"137","author":"HE Wasmuth","year":"2009","unstructured":"Wasmuth HE, Lammert F, Zaldivar MM, Weiskirchen R, Hellerbrand C, Scholten D, et al. Antifibrotic effects of CXCL9 and its receptor CXCR3 in livers of mice and humans. Gastroenterology. 2009;137:309\u201319. 19.e1-3.","journal-title":"Gastroenterology."},{"key":"4739_CR28","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1038\/nri3198","volume":"12","author":"H Chi","year":"2012","unstructured":"Chi H. Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol. 2012;12:325\u201338.","journal-title":"Nat Rev Immunol"},{"key":"4739_CR29","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1038\/ni.2005","volume":"12","author":"GM Delgoffe","year":"2011","unstructured":"Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ, Horton MR, et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol. 2011;12:295\u2013303.","journal-title":"Nat Immunol"},{"key":"4739_CR30","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1016\/j.immuni.2017.04.028","volume":"46","author":"RG Jones","year":"2017","unstructured":"Jones RG, Pearce EJ. MenTORing immunity: mTOR signaling in the development and function of tissue-resident immune cells. Immunity. 2017;46:730\u201342.","journal-title":"Immunity."},{"key":"4739_CR31","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1016\/j.immuni.2017.11.008","volume":"47","author":"K Essig","year":"2017","unstructured":"Essig K, Hu D, Guimaraes JC, Alterauge D, Edelmann S, Raj T, et al. Roquin suppresses the PI3K-mTOR signaling pathway to inhibit T helper cell differentiation and conversion of Treg to Tfr cells. Immunity 2017;47:1067\u201382. e12","journal-title":"Immunity"},{"key":"4739_CR32","doi-asserted-by":"publisher","first-page":"1122","DOI":"10.1038\/ncb1183","volume":"6","author":"E Jacinto","year":"2004","unstructured":"Jacinto E, Loewith R, Schmidt A, Lin S, R\u00fcegg MA, Hall A, et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol. 2004;6:1122\u20138.","journal-title":"Nat Cell Biol"},{"key":"4739_CR33","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1182\/blood-2012-06-439786","volume":"121","author":"B Kellersch","year":"2013","unstructured":"Kellersch B, Brocker T. Langerhans cell homeostasis in mice is dependent on mTORC1 but not mTORC2 function. Blood. 2013;121:298\u2013307.","journal-title":"Blood."},{"key":"4739_CR34","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1038\/s41423-020-0515-7","volume":"18","author":"Y Xu","year":"2021","unstructured":"Xu Y, Xiang Z, Alnaggar M, Kouakanou L, Li J, He J, et al. Allogeneic V\u03b39V\u03b42 T-cell immunotherapy exhibits promising clinical safety and prolongs the survival of patients with late-stage lung or liver cancer. Cell Mol Immunol. 2021;18:427\u201339.","journal-title":"Cell Mol Immunol"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-022-04739-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-022-04739-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-022-04739-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,24]],"date-time":"2022-11-24T14:57:07Z","timestamp":1669301827000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-022-04739-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,1]]},"references-count":34,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["4739"],"URL":"https:\/\/doi.org\/10.1038\/s41419-022-04739-3","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,1]]},"assertion":[{"value":"5 July 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 February 2022","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 March 2022","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 April 2022","order":4,"name":"first_online","label":"First Online","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":"289"}}