{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:47:40Z","timestamp":1790704060824,"version":"4.1.0"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,2,4]],"date-time":"2021-02-04T00:00:00Z","timestamp":1612396800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,2,4]],"date-time":"2021-02-04T00:00:00Z","timestamp":1612396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Activation of quiescent hepatic stellate cells (HSCs) to myofibroblasts plays a key role in liver fibrosis. We had previously shown that albumin and its derivative, R-III (a retinol-binding protein\u2014albumin domain III fusion protein), inhibited HSC activation by sequestering retinoic acid (RA) and that R-III administration reduced carbon tetrachloride (CCl<jats:sub>4<\/jats:sub>)-induced liver fibrosis. In this study, we aimed to elucidate the mechanism of action of albumin downstream of RA sequestration. Nuclear factor-\u03baB p65 was evenly distributed in the cytoplasm in activated mouse HSCs, whereas albumin expression or R-III treatment (albumin\/R-III) caused the nuclear translocation of p65, probably via RA sequestration, resulting in a dramatic increase in interleukin-1beta (IL-1\u03b2) expression. Albumin\/R-III in turn induced the phosphorylation of Smad3 at the linker region, inhibiting its nuclear import in an IL-1\u03b2-dependent manner. Consistent with the in vitro results, the level of IL-1\u03b2 mRNA expression was higher in CCl<jats:sub>4<\/jats:sub>\/R-III-treated livers than in CCl<jats:sub>4<\/jats:sub>-treated livers. These findings reveal that albumin\/R-III inhibits the transforming growth factor-\u03b2-Smad3 signaling as well as the retinoic acid receptor-mediated pathway, which probably contributes to the inhibition of HSC activation, and suggest that R-III may be an anti-fibrotic drug candidate.<\/jats:p>","DOI":"10.1038\/s41598-021-82758-4","type":"journal-article","created":{"date-parts":[[2021,2,4]],"date-time":"2021-02-04T11:25:08Z","timestamp":1612437908000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Albumin inhibits the nuclear translocation of Smad3 via interleukin-1beta signaling in hepatic stellate cells"],"prefix":"10.1038","volume":"11","author":[{"given":"Ji Hoon","family":"Park","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janghyun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"So-Young","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boram","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jung-Eun","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heekyung","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Wook","family":"Moon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sun-Hwa","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jae Min","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong Sik","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junseo","family":"Oh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,4]]},"reference":[{"key":"82758_CR1","doi-asserted-by":"publisher","first-page":"1247","DOI":"10.1042\/CBI20100321","volume":"34","author":"H Senoo","year":"2010","unstructured":"Senoo, H. et al. Hepatic stellate cell (vitamin A-storing cell) and its relative\u2013past, present and future. Cell Biol. Int. 34, 1247\u20131272. https:\/\/doi.org\/10.1042\/CBI20100321 (2010).","journal-title":"Cell Biol. Int."},{"key":"82758_CR2","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1152\/physrev.00013.2007","volume":"88","author":"SL Friedman","year":"2008","unstructured":"Friedman, S. L. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol. Rev. 88, 125\u2013172. https:\/\/doi.org\/10.1152\/physrev.00013.2007 (2008).","journal-title":"Physiol. Rev."},{"key":"82758_CR3","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1038\/nrgastro.2017.38","volume":"14","author":"T Tsuchida","year":"2017","unstructured":"Tsuchida, T. & Friedman, S. L. Mechanisms of hepatic stellate cell activation. Nat. Rev. Gastroenterol. Hepatol. 14, 397\u2013411. https:\/\/doi.org\/10.1038\/nrgastro.2017.38 (2017).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"82758_CR4","doi-asserted-by":"publisher","first-page":"1473","DOI":"10.1002\/cphy.c120035","volume":"3","author":"JE Puche","year":"2013","unstructured":"Puche, J. E., Saiman, Y. & Friedman, S. L. Hepatic stellate cells and liver fibrosis. Compreh. Physiol. 3, 1473\u20131492. https:\/\/doi.org\/10.1002\/cphy.c120035 (2013).","journal-title":"Compreh. Physiol."},{"key":"82758_CR5","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1136\/gut.43.1.128","volume":"43","author":"MV Apte","year":"1998","unstructured":"Apte, M. V. et al. Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut 43, 128\u2013133 (1998).","journal-title":"Gut"},{"key":"82758_CR6","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1136\/gutjnl-2011-301220","volume":"61","author":"M Erkan","year":"2012","unstructured":"Erkan, M. et al. StellaTUM: current consensus and discussion on pancreatic stellate cell research. Gut 61, 172\u2013178. https:\/\/doi.org\/10.1136\/gutjnl-2011-301220 (2012).","journal-title":"Gut"},{"key":"82758_CR7","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1007\/s00535-008-2180-y","volume":"43","author":"JT Li","year":"2008","unstructured":"Li, J. T., Liao, Z. X., Ping, J., Xu, D. & Wang, H. Molecular mechanism of hepatic stellate cell activation and antifibrotic therapeutic strategies. J. Gastroenterol. 43, 419\u2013428. https:\/\/doi.org\/10.1007\/s00535-008-2180-y (2008).","journal-title":"J. Gastroenterol."},{"key":"82758_CR8","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1586\/17474124.2.6.803","volume":"2","author":"Z Ghiassi-Nejad","year":"2008","unstructured":"Ghiassi-Nejad, Z. & Friedman, S. L. Advances in antifibrotic therapy. Expert. Rev. Gastroenterol. Hepatol. 2, 803\u2013816. https:\/\/doi.org\/10.1586\/17474124.2.6.803 (2008).","journal-title":"Expert. Rev. Gastroenterol. Hepatol."},{"key":"82758_CR9","volume-title":"The Retinoids: biology, chemistry, and medicine","author":"MB Sporn","year":"1994","unstructured":"Sporn, M. B., Roberts, A. B. & Goodman, D. S. The Retinoids: biology, chemistry, and medicine 2nd edn. (Raven Press, New York, 1994).","edition":"2"},{"key":"82758_CR10","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1021\/cr400161b","volume":"114","author":"P Huang","year":"2014","unstructured":"Huang, P., Chandra, V. & Rastinejad, F. Retinoic acid actions through mammalian nuclear receptors. Chem. Rev. 114, 233\u2013254. https:\/\/doi.org\/10.1021\/cr400161b (2014).","journal-title":"Chem. Rev."},{"key":"82758_CR11","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1126\/science.1136244","volume":"315","author":"R Kawaguchi","year":"2007","unstructured":"Kawaguchi, R. et al. A membrane receptor for retinol binding protein mediates cellular uptake of vitamin A. Science 315, 820\u2013825. https:\/\/doi.org\/10.1126\/science.1136244 (2007).","journal-title":"Science"},{"key":"82758_CR12","doi-asserted-by":"publisher","first-page":"e24993","DOI":"10.1371\/journal.pone.0024993","volume":"6","author":"DN D'Ambrosio","year":"2011","unstructured":"D\u2019Ambrosio, D. N. et al. Distinct populations of hepatic stellate cells in the mouse liver have different capacities for retinoid and lipid storage. PLoS ONE 6, e24993. https:\/\/doi.org\/10.1371\/journal.pone.0024993 (2011).","journal-title":"PLoS ONE"},{"key":"82758_CR13","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1016\/S0168-8278(99)80262-1","volume":"30","author":"M Okuno","year":"1999","unstructured":"Okuno, M. et al. Increased 9,13-di-cis-retinoic acid in rat hepatic fibrosis: implication for a potential link between retinoid loss and TGF-beta mediated fibrogenesis in vivo. J. Hepatol. 30, 1073\u20131080 (1999).","journal-title":"J. Hepatol."},{"key":"82758_CR14","doi-asserted-by":"publisher","first-page":"548","DOI":"10.1002\/hep.24047","volume":"53","author":"H He","year":"2011","unstructured":"He, H., Mennone, A., Boyer, J. L. & Cai, S. Y. Combination of retinoic acid and ursodeoxycholic acid attenuates liver injury in bile duct-ligated rats and human hepatic cells. Hepatology (Baltimore, MD) 53, 548\u2013557. https:\/\/doi.org\/10.1002\/hep.24047 (2011).","journal-title":"Hepatology (Baltimore, MD)"},{"key":"82758_CR15","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.bbadis.2006.08.009","volume":"1772","author":"L Wang","year":"2007","unstructured":"Wang, L. et al. Effects of retinoic acid on the development of liver fibrosis produced by carbon tetrachloride in mice. Biochem. Biophys. Acta. 1772, 66\u201371. https:\/\/doi.org\/10.1016\/j.bbadis.2006.08.009 (2007).","journal-title":"Biochem. Biophys. Acta."},{"key":"82758_CR16","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1053\/jhep.1997.v26.pm0009328313","volume":"26","author":"M Okuno","year":"1997","unstructured":"Okuno, M. et al. Retinoids exacerbate rat liver fibrosis by inducing the activation of latent TGF-beta in liver stellate cells. Hepatology (Baltimore, MD) 26, 913\u2013921. https:\/\/doi.org\/10.1053\/jhep.1997.v26.pm0009328313 (1997).","journal-title":"Hepatology (Baltimore, MD)"},{"key":"82758_CR17","doi-asserted-by":"publisher","first-page":"d204","DOI":"10.2741\/A775","volume":"7","author":"M Okuno","year":"2002","unstructured":"Okuno, M. et al. Retinoids in liver fibrosis and cancer. Front. Biosci. 7, d204-218 (2002).","journal-title":"Front. Biosci."},{"key":"82758_CR18","doi-asserted-by":"publisher","first-page":"819","DOI":"10.15252\/emmm.201404527","volume":"7","author":"H Lee","year":"2015","unstructured":"Lee, H. et al. Fusion protein of retinol-binding protein and albumin domain III reduces liver fibrosis. EMBO Mol. Med. 7, 819\u2013830. https:\/\/doi.org\/10.15252\/emmm.201404527 (2015).","journal-title":"EMBO Mol. Med."},{"issue":"Suppl 5","key":"82758_CR19","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1046\/j.1365-2036.16.s5.2.x","volume":"16","author":"TW Evans","year":"2002","unstructured":"Evans, T. W. Review article: albumin as a drug\u2013biological effects of albumin unrelated to oncotic pressure. Aliment Pharmacol. Ther. 16(Suppl 5), 6\u201311 (2002).","journal-title":"Aliment Pharmacol. Ther."},{"key":"82758_CR20","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1038\/1869","volume":"5","author":"S Curry","year":"1998","unstructured":"Curry, S., Mandelkow, H., Brick, P. & Franks, N. Crystal structure of human serum albumin complexed with fatty acid reveals an asymmetric distribution of binding sites. Nat. Struct. Biol. 5, 827\u2013835. https:\/\/doi.org\/10.1038\/1869 (1998).","journal-title":"Nat. Struct. Biol."},{"key":"82758_CR21","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1016\/j.ejmech.2011.12.002","volume":"48","author":"A Belatik","year":"2012","unstructured":"Belatik, A., Hotchandani, S., Bariyanga, J. & Tajmir-Riahi, H. A. Binding sites of retinol and retinoic acid with serum albumins. Eur. J. Med. Chem. 48, 114\u2013123. https:\/\/doi.org\/10.1016\/j.ejmech.2011.12.002 (2012).","journal-title":"Eur. J. Med. Chem."},{"key":"82758_CR22","doi-asserted-by":"publisher","first-page":"1382","DOI":"10.1136\/gut.2008.170233","volume":"58","author":"N Kim","year":"2009","unstructured":"Kim, N. et al. Formation of vitamin A lipid droplets in pancreatic stellate cells requires albumin. Gut 58, 1382\u20131390. https:\/\/doi.org\/10.1136\/gut.2008.170233 (2009).","journal-title":"Gut"},{"key":"82758_CR23","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/j.bbrc.2012.01.012","volume":"418","author":"S Choi","year":"2012","unstructured":"Choi, S. et al. Recombinant fusion protein of albumin-retinol binding protein inactivates stellate cells. Biochem. Biophys. Res. Commun. 418, 191\u2013197. https:\/\/doi.org\/10.1016\/j.bbrc.2012.01.012 (2012).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"82758_CR24","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines8100431","author":"JJ Cha","year":"2020","unstructured":"Cha, J. J. et al. Inhibition of renal stellate cell activation reduces renal fibrosis. Biomedicines https:\/\/doi.org\/10.3390\/biomedicines8100431 (2020).","journal-title":"Biomedicines"},{"key":"82758_CR25","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1002\/glia.20153","volume":"50","author":"ST Dheen","year":"2005","unstructured":"Dheen, S. T., Jun, Y., Yan, Z., Tay, S. S. & Ling, E. A. Retinoic acid inhibits expression of TNF-alpha and iNOS in activated rat microglia. Glia 50, 21\u201331. https:\/\/doi.org\/10.1002\/glia.20153 (2005).","journal-title":"Glia"},{"key":"82758_CR26","doi-asserted-by":"publisher","first-page":"22532","DOI":"10.1074\/jbc.M115.662908","volume":"290","author":"R Wang","year":"2015","unstructured":"Wang, R. et al. All-trans-retinoic acid reduces BACE1 expression under inflammatory conditions via modulation of nuclear factor kappaB (NFkappaB) signaling. J. Biol. Chem. 290, 22532\u201322542. https:\/\/doi.org\/10.1074\/jbc.M115.662908 (2015).","journal-title":"J. Biol. Chem."},{"key":"82758_CR27","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1002\/hep.27332","volume":"61","author":"E Seki","year":"2015","unstructured":"Seki, E. & Schwabe, R. F. Hepatic inflammation and fibrosis: functional links and key pathways. Hepatology (Baltimore, MD) 61, 1066\u20131079. https:\/\/doi.org\/10.1002\/hep.27332 (2015).","journal-title":"Hepatology (Baltimore, MD)"},{"key":"82758_CR28","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1080\/03008200802148355","volume":"49","author":"JP Pujol","year":"2008","unstructured":"Pujol, J. P. et al. Interleukin-1 and transforming growth factor-beta 1 as crucial factors in osteoarthritic cartilage metabolism. Connect Tissue Res. 49, 293\u2013297. https:\/\/doi.org\/10.1080\/03008200802148355 (2008).","journal-title":"Connect Tissue Res."},{"key":"82758_CR29","doi-asserted-by":"publisher","first-page":"3020","DOI":"10.1002\/art.22840","volume":"56","author":"C Bauge","year":"2007","unstructured":"Bauge, C. et al. Interleukin-1beta impairment of transforming growth factor beta1 signaling by down-regulation of transforming growth factor beta receptor type II and up-regulation of Smad7 in human articular chondrocytes. Arthritis Rheum 56, 3020\u20133032. https:\/\/doi.org\/10.1002\/art.22840 (2007).","journal-title":"Arthritis Rheum"},{"key":"82758_CR30","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1016\/j.cellsig.2017.09.010","volume":"40","author":"GG van den Akker","year":"2017","unstructured":"van den Akker, G. G. et al. Interleukin 1 beta-induced SMAD2\/3 linker modifications are TAK1 dependent and delay TGFbeta signaling in primary human mesenchymal stem cells. Cell Signal 40, 190\u2013199. https:\/\/doi.org\/10.1016\/j.cellsig.2017.09.010 (2017).","journal-title":"Cell Signal"},{"key":"82758_CR31","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1083\/jcb.200703106","volume":"178","author":"L Xu","year":"2007","unstructured":"Xu, L. et al. Msk is required for nuclear import of TGF-{beta}\/BMP-activated Smads. J. Cell. Biol. 178, 981\u2013994. https:\/\/doi.org\/10.1083\/jcb.200703106 (2007).","journal-title":"J. Cell. Biol."},{"key":"82758_CR32","doi-asserted-by":"publisher","first-page":"2017","DOI":"10.1016\/j.cellsig.2013.06.001","volume":"25","author":"D Kamato","year":"2013","unstructured":"Kamato, D. et al. Transforming growth factor-beta signalling: role and consequences of Smad linker region phosphorylation. Cell Signal 25, 2017\u20132024. https:\/\/doi.org\/10.1016\/j.cellsig.2013.06.001 (2013).","journal-title":"Cell Signal"},{"key":"82758_CR33","doi-asserted-by":"publisher","first-page":"27271","DOI":"10.1074\/jbc.M503368200","volume":"280","author":"A Hoffmann","year":"2005","unstructured":"Hoffmann, A. et al. Transforming growth factor-beta-activated kinase-1 (TAK1), a MAP3K, interacts with Smad proteins and interferes with osteogenesis in murine mesenchymal progenitors. J. Biol. Chem. 280, 27271\u201327283. https:\/\/doi.org\/10.1074\/jbc.M503368200 (2005).","journal-title":"J. Biol. Chem."},{"key":"82758_CR34","doi-asserted-by":"publisher","first-page":"2846","DOI":"10.4049\/jimmunol.1302537","volume":"192","author":"M Gu","year":"2014","unstructured":"Gu, M. et al. Phosphatase holoenzyme PP1\/GADD34 negatively regulates TLR response by inhibiting TAK1 serine 412 phosphorylation. J. Immunol. 192, 2846\u20132856. https:\/\/doi.org\/10.4049\/jimmunol.1302537 (2014).","journal-title":"J. Immunol."},{"key":"82758_CR35","doi-asserted-by":"publisher","first-page":"G1324","DOI":"10.1152\/ajpgi.90564.2008","volume":"296","author":"RG Gieling","year":"2009","unstructured":"Gieling, R. G., Wallace, K. & Han, Y. P. Interleukin-1 participates in the progression from liver injury to fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G1324-1331. https:\/\/doi.org\/10.1152\/ajpgi.90564.2008 (2009).","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"82758_CR36","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.abb.2015.10.014","volume":"590","author":"E Di Muzio","year":"2016","unstructured":"Di Muzio, E. et al. All-trans-retinoic acid and retinol binding to the FA1 site of human serum albumin competitively inhibits heme-Fe(III) association. Arch. Biochem. Biophys. 590, 56\u201363. https:\/\/doi.org\/10.1016\/j.abb.2015.10.014 (2016).","journal-title":"Arch. Biochem. Biophys."},{"key":"82758_CR37","doi-asserted-by":"publisher","first-page":"226","DOI":"10.3390\/ijms14010226","volume":"14","author":"TB Zhou","year":"2012","unstructured":"Zhou, T. B., Drummen, G. P. & Qin, Y. H. The controversial role of retinoic acid in fibrotic diseases: analysis of involved signaling pathways. Int. J. Mol. Sci. 14, 226\u2013243. https:\/\/doi.org\/10.3390\/ijms14010226 (2012).","journal-title":"Int. J. Mol. Sci."},{"key":"82758_CR38","doi-asserted-by":"publisher","first-page":"e91559","DOI":"10.1371\/journal.pone.0091559","volume":"9","author":"MM Mia","year":"2014","unstructured":"Mia, M. M., Boersema, M. & Bank, R. A. Interleukin-1beta attenuates myofibroblast formation and extracellular matrix production in dermal and lung fibroblasts exposed to transforming growth factor-beta1. PLoS ONE 9, e91559. https:\/\/doi.org\/10.1371\/journal.pone.0091559 (2014).","journal-title":"PLoS ONE"},{"key":"82758_CR39","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20061295","author":"RPH Meier","year":"2019","unstructured":"Meier, R. P. H. et al. Interleukin-1 receptor antagonist modulates liver inflammation and fibrosis in mice in a model-dependent manner. Int. J. Mol. Sci. https:\/\/doi.org\/10.3390\/ijms20061295 (2019).","journal-title":"Int. J. Mol. Sci."},{"key":"82758_CR40","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1016\/S0022-2275(20)37232-1","volume":"38","author":"NE Nagy","year":"1997","unstructured":"Nagy, N. E. et al. Storage of vitamin A in extrahepatic stellate cells in normal rats. J. Lipid Res. 38, 645\u2013658 (1997).","journal-title":"J. Lipid Res."},{"key":"82758_CR41","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1038\/nprot.2015.017","volume":"10","author":"I Mederacke","year":"2015","unstructured":"Mederacke, I., Dapito, D. H., Affo, S., Uchinami, H. & Schwabe, R. F. High-yield and high-purity isolation of hepatic stellate cells from normal and fibrotic mouse livers. Nat. Protoc. 10, 305\u2013315. https:\/\/doi.org\/10.1038\/nprot.2015.017 (2015).","journal-title":"Nat. Protoc."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-82758-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-82758-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-82758-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T03:11:28Z","timestamp":1670037088000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-82758-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,4]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["82758"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-82758-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,4]]},"assertion":[{"value":"29 August 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 January 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 February 2021","order":3,"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":"3196"}}