{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T22:18:04Z","timestamp":1789942684248,"version":"4.0.1"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,11,17]],"date-time":"2016-11-17T00:00:00Z","timestamp":1479340800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,11,17]],"date-time":"2016-11-17T00:00:00Z","timestamp":1479340800000},"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":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Excessive activation of hepatic stellate cells (HSCs) is a key step in liver fibrogenesis. Here we report that CUG-binding protein 1 (CUGBP1) expression is elevated in HSCs and positively correlates with liver fibrosis severity in human liver biopsies. Transforming growth factor-beta (TGF-\u03b2) selectively increases CUGBP1 expression in cultured HSCs in a p38 mitogen-activated protein kinase (MAPK)-dependent manner. Knockdown of CUGBP1 inhibits alpha smooth muscle actin (\u03b1-SMA) expression and promotes interferon gamma (IFN-\u03b3) production in HSCs\n                    <jats:italic>in vitro<\/jats:italic>\n                    . We further show that CUGBP1 specifically binds to the 3\u2032 untranslated region (UTR) of human IFN-\u03b3 mRNA and promotes its decay. In mice, knockdown of CUGBP1 alleviates, whereas its overexpression exacerbates, bile duct ligation (BDL)-induced hepatic fibrosis. Therefore, CUGBP1-mediated IFN-\u03b3 mRNA decay is a key event for profibrotic TGF-\u03b2-dependent activation of HSCs, and inhibiting CUGBP1 to promote IFN-\u03b3 signalling in activated HSCs could be a novel strategy to treat liver fibrosis.\n                  <\/jats:p>","DOI":"10.1038\/ncomms13498","type":"journal-article","created":{"date-parts":[[2016,11,17]],"date-time":"2016-11-17T04:52:13Z","timestamp":1479358333000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":87,"title":["CUG-binding protein 1 regulates HSC activation and liver fibrogenesis"],"prefix":"10.1038","volume":"7","author":[{"given":"Xingxin","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xudong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxiang","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fenli","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyun","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beicheng","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefeng","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,11,17]]},"reference":[{"key":"BFncomms13498_CR1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1172\/JCI24282","volume":"115","author":"R Bataller","year":"2005","unstructured":"Bataller, R. & Brenner, D. A. Liver fibrosis. J. Clin. Invest. 115, 209\u2013218 (2005).","journal-title":"J. Clin. Invest."},{"key":"BFncomms13498_CR2","doi-asserted-by":"publisher","first-page":"1887","DOI":"10.1172\/JCI66028","volume":"123","author":"D Schuppan","year":"2013","unstructured":"Schuppan, D. & Kim, Y. O. Evolving therapies for liver fibrosis. J. Clin. Invest. 123, 1887\u20131901 (2013).","journal-title":"J. Clin. Invest."},{"key":"BFncomms13498_CR3","doi-asserted-by":"publisher","first-page":"2823","DOI":"10.1038\/ncomms3823","volume":"4","author":"I Mederacke","year":"2013","unstructured":"Mederacke, I. et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat. Commun. 4, 2823 (2013).","journal-title":"Nat. Commun."},{"key":"BFncomms13498_CR4","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1038\/nrgastro.2013.244","volume":"11","author":"K Ray","year":"2014","unstructured":"Ray, K. Liver: hepatic stellate cells hold the key to liver fibrosis. Nat. Rev. Gastroenterol. Hepatol. 11, 74 (2014).","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"BFncomms13498_CR5","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1007\/s10495-005-1055-4","volume":"10","author":"AM Elsharkawy","year":"2005","unstructured":"Elsharkawy, A. M., Oakley, F. & Mann, D. A. The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis. Apoptosis 10, 927\u2013939 (2005).","journal-title":"Apoptosis"},{"key":"BFncomms13498_CR6","doi-asserted-by":"publisher","first-page":"S73","DOI":"10.1111\/j.1440-1746.2006.04658.x","volume":"22","author":"T Kisseleva","year":"2007","unstructured":"Kisseleva, T. & Brenner, D. A. Role of hepatic stellate cells in fibrogenesis and the reversal of fibrosis. J. Gastroenterol. Hepatol. 22, (Suppl 1) S73\u2013S78 (2007).","journal-title":"J. Gastroenterol. Hepatol."},{"key":"BFncomms13498_CR7","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1157\/13083906","volume":"29","author":"M Sarem","year":"2006","unstructured":"Sarem, M., Znaidak, R., Macias, M. & Rey, R. Hepatic stellate cells: it's role in normal and pathological conditions. Gastroenterol. Hepatol. 29, 93\u2013101 (2006).","journal-title":"Gastroenterol. Hepatol."},{"key":"BFncomms13498_CR8","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 (2008).","journal-title":"Physiol. Rev."},{"key":"BFncomms13498_CR9","doi-asserted-by":"publisher","first-page":"G20","DOI":"10.1152\/ajpgi.00474.2002","volume":"285","author":"J Xu","year":"2003","unstructured":"Xu, J., Fu, Y. & Chen, A. Activation of peroxisome proliferator-activated receptor-gamma contributes to the inhibitory effects of curcumin on rat hepatic stellate cell growth. Am. J. Physiol. Gastrointest. Liver Physiol. 285, G20\u2013G30 (2003).","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"BFncomms13498_CR10","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1002\/ptr.1435","volume":"18","author":"YZ Zhao","year":"2004","unstructured":"Zhao, Y. Z. et al. Tetrandrine induces apoptosis in hepatic stellate cells. Phytother. Res. 18, 306\u2013309 (2004).","journal-title":"Phytother. Res."},{"key":"BFncomms13498_CR11","doi-asserted-by":"publisher","first-page":"902","DOI":"10.1124\/jpet.107.132290","volume":"324","author":"WI Hagens","year":"2008","unstructured":"Hagens, W. I. et al. Cellular targeting of the apoptosis-inducing compound gliotoxin to fibrotic rat livers. J. Pharmacol. Exp. Ther. 324, 902\u2013910 (2008).","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"BFncomms13498_CR12","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1055\/s-2001-17554","volume":"21","author":"M Pinzani","year":"2001","unstructured":"Pinzani, M. & Marra, F. Cytokine receptors and signaling in hepatic stellate cells. Semin. Liver Dis. 21, 397\u2013416 (2001).","journal-title":"Semin. Liver Dis."},{"key":"BFncomms13498_CR13","doi-asserted-by":"publisher","first-page":"4451","DOI":"10.1038\/ncomms5451","volume":"5","author":"I Lopez-Sanchez","year":"2014","unstructured":"Lopez-Sanchez, I. et al. GIV\/Girdin is a central hub for profibrogenic signalling networks during liver fibrosis. Nat. Commun. 5, 4451 (2014).","journal-title":"Nat. Commun."},{"key":"BFncomms13498_CR14","doi-asserted-by":"publisher","first-page":"949","DOI":"10.1016\/j.jhep.2010.02.005","volume":"52","author":"DA Mann","year":"2010","unstructured":"Mann, D. A. & Marra, F. Fibrogenic signalling in hepatic stellate cells. J. Hepatol. 52, 949\u2013950 (2010).","journal-title":"J. Hepatol."},{"key":"BFncomms13498_CR15","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, P. R., Gressner, A. M. & Dooley, S. IFN-gamma abrogates profibrogenic TGF-beta signaling in liver by targeting expression of inhibitory and receptor Smads. J. Hepatol. 46, 295\u2013303 (2007).","journal-title":"J. Hepatol."},{"key":"BFncomms13498_CR16","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1038\/labinvest.2013.135","volume":"94","author":"H Motoyama","year":"2014","unstructured":"Motoyama, H. et al. Cytoglobin is expressed in hepatic stellate cells, but not in myofibroblasts, in normal and fibrotic human liver. Lab Invest. 94, 192\u2013207 (2014).","journal-title":"Lab Invest."},{"key":"BFncomms13498_CR17","doi-asserted-by":"crossref","first-page":"3193","DOI":"10.1242\/jcs.115.15.3193","volume":"115","author":"AV Bakin","year":"2002","unstructured":"Bakin, A. V., Rinehart, C., Tomlinson, A. K. & Arteaga, C. L. p38 mitogen-activated protein kinase is required for TGF beta-mediated fibroblastic transdifferentiation and cell migration. J. Cell Sci. 115, 3193\u20133206 (2002).","journal-title":"J. Cell Sci."},{"key":"BFncomms13498_CR18","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/j.canlet.2006.12.016","volume":"252","author":"E-S Kim","year":"2007","unstructured":"Kim, E.-S., Sohn, Y.-W. & Moon, A. TGF-beta-induced transcriptional activation of MMP-2 is mediated by activating transcription factor (ATF)2 in human breast epithelial cells. Cancer Lett. 252, 147\u2013156 (2007).","journal-title":"Cancer Lett."},{"key":"BFncomms13498_CR19","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.1002\/hep.510230538","volume":"23","author":"GS Baroni","year":"1996","unstructured":"Baroni, G. S. et al. Interferon gamma decreases hepatic stellate cell activation and extracellular matrix deposition in rat liver fibrosis. Hepatology 23, 1189\u20131199 (1996).","journal-title":"Hepatology"},{"key":"BFncomms13498_CR20","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/S0016-5085(03)00666-8","volume":"125","author":"S Dooley","year":"2003","unstructured":"Dooley, S. et al. Smad7 prevents activation of hepatic stellate cells and liver fibrosis in rats. Gastroenterology 125, 178\u2013191 (2003).","journal-title":"Gastroenterology"},{"key":"BFncomms13498_CR21","doi-asserted-by":"publisher","first-page":"201","DOI":"10.4161\/rna.7056","volume":"5","author":"IA Vlasova","year":"2008","unstructured":"Vlasova, I. A. & Bohjanen, P. R. Posttranscriptional regulation of gene networks by GU-rich elements and CELF proteins. RNA Biol. 5, 201\u2013207 (2008).","journal-title":"RNA Biol."},{"key":"BFncomms13498_CR22","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1016\/S0168-8278(02)00050-8","volume":"36","author":"D Kobold","year":"2002","unstructured":"Kobold, D. et al. Expression of reelin in hepatic stellate cells and during hepatic tissue repair: a novel marker for the differentiation of HSC from other liver myofibroblasts. J. Hepatol. 36, 607\u2013613 (2002).","journal-title":"J. Hepatol."},{"key":"BFncomms13498_CR23","doi-asserted-by":"publisher","first-page":"1539","DOI":"10.1093\/hmg\/ddi162","volume":"14","author":"TH Ho","year":"2005","unstructured":"Ho, T. H., Bundman, D., Armstrong, D. L. & Cooper, T. A. Transgenic mice expressing CUG-BP1 reproduce splicing mis-regulation observed in myotonic dystrophy. Hum. Mol. Genet. 14, 1539\u20131547 (2005).","journal-title":"Hum. Mol. Genet."},{"key":"BFncomms13498_CR24","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1126\/science.280.5364.737","volume":"280","author":"AV Philips","year":"1998","unstructured":"Philips, A. V., Timchenko, L. T. & Cooper, T. A. Disruption of splicing regulated by a CUG-binding protein in myotonic dystrophy. Science 280, 737\u2013741 (1998).","journal-title":"Science"},{"key":"BFncomms13498_CR25","doi-asserted-by":"publisher","first-page":"4517","DOI":"10.1093\/nar\/27.22.4517","volume":"27","author":"NA Timchenko","year":"1999","unstructured":"Timchenko, N. A., Welm, A. L., Lu, X. & Timchenko, L. T. CUG repeat binding protein (CUGBP1) interacts with the 5' region of C\/EBPbeta mRNA and regulates translation of C\/EBPbeta isoforms. Nucleic Acids Res. 27, 4517\u20134525 (1999).","journal-title":"Nucleic Acids Res."},{"key":"BFncomms13498_CR26","doi-asserted-by":"publisher","first-page":"7820","DOI":"10.1074\/jbc.M005960200","volume":"276","author":"NA Timchenko","year":"2001","unstructured":"Timchenko, N. A. et al. RNA CUG repeats sequester CUGBP1 and alter protein levels and activity of CUGBP1. J. Biol. Chem. 276, 7820\u20137826 (2001).","journal-title":"J. Biol. Chem."},{"key":"BFncomms13498_CR27","doi-asserted-by":"publisher","first-page":"3970","DOI":"10.1128\/MCB.00624-10","volume":"30","author":"B Rattenbacher","year":"2010","unstructured":"Rattenbacher, B. et al. Analysis of CUGBP1 targets identifies GU-repeat sequences that mediate rapid mRNA decay. Mol. Cell Biol. 30, 3970\u20133980 (2010).","journal-title":"Mol. Cell Biol."},{"key":"BFncomms13498_CR28","doi-asserted-by":"publisher","first-page":"32806","DOI":"10.1074\/jbc.M605701200","volume":"281","author":"LT Timchenko","year":"2006","unstructured":"Timchenko, L. T. et al. Age-specific CUGBP1-eIF2 complex increases translation of CCAAT\/enhancer-binding protein beta in old liver. J. Biol. Chem. 281, 32806\u201332819 (2006).","journal-title":"J. Biol. Chem."},{"key":"BFncomms13498_CR29","doi-asserted-by":"publisher","first-page":"E10","DOI":"10.25011\/cim.v37i1.20864","volume":"37","author":"Y Liu","year":"2014","unstructured":"Liu, Y. et al. Suppression of CUGBP1 inhibits growth of hepatocellular carcinoma cells. Clin. Invest. Med. 37, E10\u2013E18 (2014).","journal-title":"Clin. Invest. Med."},{"key":"BFncomms13498_CR30","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.1074\/jbc.M113.526780","volume":"289","author":"IH Hong","year":"2014","unstructured":"Hong, I. H. et al. Age-associated change of C\/EBP family proteins causes severe liver injury and acceleration of liver proliferation after CCl4 treatments. J. Biol. Chem. 289, 1106\u20131118 (2014).","journal-title":"J. Biol. Chem."},{"key":"BFncomms13498_CR31","doi-asserted-by":"publisher","first-page":"3005","DOI":"10.1128\/MCB.00421-15","volume":"35","author":"M Breaux","year":"2015","unstructured":"Breaux, M. et al. p300 Regulates Liver Functions by Controlling p53 and C\/EBP Family Proteins through Multiple Signaling Pathways. Mol. Cell Biol. 35, 3005\u20133016 (2015).","journal-title":"Mol. Cell Biol."},{"key":"BFncomms13498_CR32","doi-asserted-by":"publisher","first-page":"819","DOI":"10.1016\/S1542-3565(05)00404-0","volume":"3","author":"HL Weng","year":"2005","unstructured":"Weng, H. L. et al. Effect of interferon-gamma on hepatic fibrosis in chronic hepatitis B virus infection: a randomized controlled study. Clin. Gastroenterol. Hepatol. 3, 819\u2013828 (2005).","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"BFncomms13498_CR33","doi-asserted-by":"publisher","first-page":"1044","DOI":"10.1002\/hep.27137","volume":"60","author":"HS Yi","year":"2014","unstructured":"Yi, H. S. et al. Alcohol dehydrogenase III exacerbates liver fibrosis by enhancing stellate cell activation and suppressing natural killer cells in mice. Hepatology 60, 1044\u20131053 (2014).","journal-title":"Hepatology"},{"key":"BFncomms13498_CR34","doi-asserted-by":"publisher","first-page":"3497","DOI":"10.4049\/jimmunol.1201006","volume":"189","author":"X Wu","year":"2012","unstructured":"Wu, X. et al. Selective sequestration of STAT1 in the cytoplasm via phosphorylated SHP-2 ameliorates murine experimental colitis. J. Immunol. 189, 3497\u20133507 (2012).","journal-title":"J. Immunol."},{"key":"BFncomms13498_CR35","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1136\/gut.2005.084475","volume":"55","author":"RA Standish","year":"2006","unstructured":"Standish, R. A., Cholongitas, E., Dhillon, A., Burroughs, A. K. & Dhillon, A. P. An appraisal of the histopathological assessment of liver fibrosis. Gut 55, 569\u2013578 (2006).","journal-title":"Gut"},{"key":"BFncomms13498_CR36","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 (2015).","journal-title":"Nat. Protoc."},{"key":"BFncomms13498_CR37","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1016\/j.bcp.2012.08.006","volume":"84","author":"XX Wu","year":"2012","unstructured":"Wu, X. X. et al. Rebuilding the balance of STAT1 and STAT3 signalings by fusaruside, a cerebroside compound, for the treatment of T-cell-mediated fulminant hepatitis in mice. Biochem. Pharmacol. 84, 1164\u20131173 (2012).","journal-title":"Biochem. Pharmacol."},{"key":"BFncomms13498_CR38","doi-asserted-by":"publisher","first-page":"1717","DOI":"10.1016\/j.bcp.2009.03.002","volume":"77","author":"Y Sun","year":"2009","unstructured":"Sun, Y. et al. Selective triggering of apoptosis of concanavalin A-activated T cells by fraxinellone for the treatment of T-cell-dependent hepatitis in mice. Biochem. Pharmacol. 77, 1717\u20131724 (2009).","journal-title":"Biochem. Pharmacol."},{"key":"BFncomms13498_CR39","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1038\/nbt1396","volume":"26","author":"Y Sato","year":"2008","unstructured":"Sato, Y. et al. Resolution of liver cirrhosis using vitamin A-coupled liposomes to deliver siRNA against a collagen-specific chaperone. Nat. Biotechnol. 26, 431\u2013442 (2008).","journal-title":"Nat. Biotechnol."},{"key":"BFncomms13498_CR40","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1053\/gast.1996.v110.pm8536857","volume":"110","author":"C Gartung","year":"1996","unstructured":"Gartung, C. et al. Down-regulation of expression and function of the rat liver Na+\/bile acid cotransporter in extrahepatic cholestasis. Gastroenterology 110, 199\u2013209 (1996).","journal-title":"Gastroenterology"},{"key":"BFncomms13498_CR41","doi-asserted-by":"publisher","first-page":"67","DOI":"10.3109\/01902149509031745","volume":"21","author":"W Malkusch","year":"1995","unstructured":"Malkusch, W., Rehn, B. & Bruch, J. Advantages of Sirius Red staining for quantitative morphometric collagen measurements in lungs. Exp. Lung Res. 21, 67\u201377 (1995).","journal-title":"Exp. Lung Res."},{"key":"BFncomms13498_CR42","doi-asserted-by":"crossref","first-page":"1735","DOI":"10.1093\/clinchem\/40.9.1735","volume":"40","author":"M Lange","year":"1994","unstructured":"Lange, M. & Malyusz, M. Improved determination of small amounts of free hydroxyproline in biological fluids. Clin. Chem. 40, 1735\u20131738 (1994).","journal-title":"Clin. Chem."}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/ncomms13498.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms13498","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms13498.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T04:40:14Z","timestamp":1672807214000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/ncomms13498"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,11,17]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,12,23]]}},"alternative-id":["BFncomms13498"],"URL":"https:\/\/doi.org\/10.1038\/ncomms13498","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,11,17]]},"assertion":[{"value":"23 July 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 October 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 November 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"13498"}}