{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T23:28:40Z","timestamp":1791242920585,"version":"4.1.0"},"reference-count":44,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,10,10]],"date-time":"2016-10-10T00:00:00Z","timestamp":1476057600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,10,10]],"date-time":"2016-10-10T00:00:00Z","timestamp":1476057600000},"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>\n                  <jats:p>\n                    Hepatic fibrosis in nonalcoholic steatohepatitis (NASH) and cirrhosis determines patient prognosis; however, effective treatment for fibrosis has not been established. Oxidative stress and inflammation activate hepatic stellate cells (HSCs) and promote fibrosis. In contrast, cellular senescence inhibits HSCs\u2019 activity and limits fibrosis. The aim of this study was to explore the effect of IGF-I on NASH and cirrhotic models and to clarify the underlying mechanisms. We demonstrate that IGF-I significantly ameliorated steatosis, inflammation, and fibrosis in a NASH model, methionine-choline-deficient diet-fed db\/db mice and ameliorated fibrosis in cirrhotic model, dimethylnitrosamine-treated mice. As the underlying mechanisms, IGF-I improved oxidative stress and mitochondrial function in the liver. In addition, IGF-I receptor was strongly expressed in HSCs and IGF-I induced cellular senescence in HSCs\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Furthermore, in mice lacking the key senescence regulator p53, IGF-I did not induce cellular senescence in HSCs or show any effects on fibrosis. Taken together, these results indicate that IGF-I induces senescence of HSCs, inactivates these cells and limits fibrosis in a p53-dependent manner and that IGF-I may be applied to treat NASH and cirrhosis.\n                  <\/jats:p>","DOI":"10.1038\/srep34605","type":"journal-article","created":{"date-parts":[[2016,10,10]],"date-time":"2016-10-10T05:55:34Z","timestamp":1476078934000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":148,"title":["IGF-I induces senescence of hepatic stellate cells and limits fibrosis in a p53-dependent manner"],"prefix":"10.1038","volume":"6","author":[{"given":"Hitoshi","family":"Nishizawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genzo","family":"Iguchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidenori","family":"Fukuoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiko","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kentaro","family":"Suda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hironori","family":"Bando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryusaku","family":"Matsumoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Yoshida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukiko","family":"Odake","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wataru","family":"Ogawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutaka","family":"Takahashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,10,10]]},"reference":[{"key":"BFsrep34605_CR1","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/S0025-6196(24)00530-5","volume":"55","author":"J Ludwig","year":"1980","unstructured":"Ludwig, J., Viggiano, T. R., McGill, D. B. & Oh, B. J. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 55, 434\u2013438 (1980).","journal-title":"Mayo Clin Proc"},{"key":"BFsrep34605_CR2","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1002\/hep.23521","volume":"51","author":"P Angulo","year":"2010","unstructured":"Angulo, P. Long-term mortality in nonalcoholic fatty liver disease: is liver histology of any prognostic significance? Hepatology 51, 373\u2013375 (2010).","journal-title":"Hepatology"},{"key":"BFsrep34605_CR3","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1016\/S0016-5085(98)70599-2","volume":"114","author":"CP Day","year":"1998","unstructured":"Day, C. P. & James, O. F. Steatohepatitis: a tale of two \u201chits\u201d? Gastroenterology 114, 842\u2013845 (1998).","journal-title":"Gastroenterology"},{"key":"BFsrep34605_CR4","doi-asserted-by":"publisher","first-page":"657","DOI":"10.1016\/j.cell.2008.06.049","volume":"134","author":"V Krizhanovsky","year":"2008","unstructured":"Krizhanovsky, V. et al. Senescence of activated stellate cells limits liver fibrosis. Cell 134, 657\u2013667 (2008).","journal-title":"Cell"},{"key":"BFsrep34605_CR5","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1530\/EJE-12-0252","volume":"167","author":"H Nishizawa","year":"2012","unstructured":"Nishizawa, H. et al. Nonalcoholic fatty liver disease in adult hypopituitary patients with GH deficiency and the impact of GH replacement therapy. Eur J Endocrinol 167, 67\u201374 (2012).","journal-title":"Eur J Endocrinol"},{"key":"BFsrep34605_CR6","doi-asserted-by":"publisher","first-page":"955","DOI":"10.1507\/endocrj.EJ12-0322","volume":"59","author":"Y Takahashi","year":"2012","unstructured":"Takahashi, Y. Essential roles of growth hormone (GH) and insulin-like growth factor-I (IGF-I) in the liver. Endocr J 59, 955\u2013962 (2012).","journal-title":"Endocr J"},{"key":"BFsrep34605_CR7","doi-asserted-by":"publisher","first-page":"7088","DOI":"10.1073\/pnas.96.12.7088","volume":"96","author":"K Sjogren","year":"1999","unstructured":"Sjogren, K. et al. Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice. Proc Natl Acad Sci USA 96, 7088\u20137092 (1999).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep34605_CR8","doi-asserted-by":"publisher","first-page":"1587","DOI":"10.1210\/jc.2011-0179","volume":"96","author":"ME Molitch","year":"2011","unstructured":"Molitch, M. E., Clemmons, D. R., Malozowski, S., Merriam, G. R. & Vance, M. L. Evaluation and treatment of adult growth hormone deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96, 1587\u20131609 (2011).","journal-title":"J Clin Endocrinol Metab"},{"key":"BFsrep34605_CR9","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1016\/j.bbrc.2012.05.115","volume":"423","author":"H Nishizawa","year":"2012","unstructured":"Nishizawa, H. et al. GH-independent IGF-I action is essential to prevent the development of nonalcoholic steatohepatitis in a GH-deficient rat model. Biochem Biophys Res Commun 423, 295\u2013300 (2012).","journal-title":"Biochem Biophys Res Commun"},{"key":"BFsrep34605_CR10","doi-asserted-by":"publisher","first-page":"938","DOI":"10.1053\/j.gastro.2006.12.024","volume":"132","author":"Y Takahashi","year":"2007","unstructured":"Takahashi, Y. et al. Growth hormone reverses nonalcoholic steatohepatitis in a patient with adult growth hormone deficiency. Gastroenterology 132, 938\u2013943 (2007).","journal-title":"Gastroenterology"},{"key":"BFsrep34605_CR11","doi-asserted-by":"publisher","first-page":"E1640","DOI":"10.1210\/jc.2011-1227","volume":"96","author":"F Arturi","year":"2011","unstructured":"Arturi, F. et al. Nonalcoholic fatty liver disease is associated with low circulating levels of insulin-like growth factor-I. J Clin Endocrinol Metab 96, E1640\u2013E1644 (2011).","journal-title":"J Clin Endocrinol Metab"},{"key":"BFsrep34605_CR12","doi-asserted-by":"publisher","first-page":"E304","DOI":"10.1210\/jc.2012-3290","volume":"98","author":"ML Hribal","year":"2013","unstructured":"Hribal, M. L. et al. Insulin-like growth factor-I, inflammatory proteins, and fibrosis in subjects with nonalcoholic fatty liver disease. J Clin Endocrinol Metab 98, E304\u2013E308 (2013).","journal-title":"J Clin Endocrinol Metab"},{"key":"BFsrep34605_CR13","doi-asserted-by":"crossref","unstructured":"Sumida, Y. et al. Lower levels of insulin-like growth factor-1 standard deviation score are associated with histological severity of non-alcoholic fatty liver disease. Hepatol Res (2014).","DOI":"10.1111\/hepr.12408"},{"key":"BFsrep34605_CR14","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1016\/j.jhep.2005.03.025","volume":"43","author":"M Conchillo","year":"2005","unstructured":"Conchillo, M. et al. Insulin-like growth factor I (IGF-I) replacement therapy increases albumin concentration in liver cirrhosis: results of a pilot randomized controlled clinical trial. J Hepatol 43, 630\u2013636 (2005).","journal-title":"J Hepatol"},{"key":"BFsrep34605_CR15","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1002\/hep.23412","volume":"51","author":"L Sobrevals","year":"2010","unstructured":"Sobrevals, L. et al. Insulin-like growth factor I gene transfer to cirrhotic liver induces fibrolysis and reduces fibrogenesis leading to cirrhosis reversion in rats. Hepatology 51, 912\u2013921 (2010).","journal-title":"Hepatology"},{"key":"BFsrep34605_CR16","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/1471-230X-5-7","volume":"5","author":"M Garcia-Fernandez","year":"2005","unstructured":"Garcia-Fernandez, M. et al. Antioxidant effects of insulin-like growth factor-I (IGF-I) in rats with advanced liver cirrhosis. BMC Gastroenterol 5, 7 (2005).","journal-title":"BMC Gastroenterol"},{"key":"BFsrep34605_CR17","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/S0925-4439(01)00045-X","volume":"1536","author":"B Muguerza","year":"2001","unstructured":"Muguerza, B. et al. Antifibrogenic effect in vivo of low doses of insulin-like growth factor-I in cirrhotic rats. Biochim Biophys Acta 1536, 185\u2013195 (2001).","journal-title":"Biochim Biophys Acta"},{"key":"BFsrep34605_CR18","doi-asserted-by":"publisher","first-page":"2731","DOI":"10.3748\/wjg.14.2731","volume":"14","author":"R Perez","year":"2008","unstructured":"Perez, R. et al. Mitochondrial protection by low doses of insulin-like growth factor- I in experimental cirrhosis. World J Gastroenterol 14, 2731\u20132739 (2008).","journal-title":"World J Gastroenterol"},{"key":"BFsrep34605_CR19","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/S0168-8278(97)80026-8","volume":"26","author":"A Picardi","year":"1997","unstructured":"Picardi, A. et al. Low doses of insulin-like growth factor-I improve nitrogen retention and food efficiency in rats with early cirrhosis. J Hepatol 26, 191\u2013202 (1997).","journal-title":"J Hepatol"},{"key":"BFsrep34605_CR20","doi-asserted-by":"publisher","first-page":"1306","DOI":"10.1136\/gut.2005.079988","volume":"55","author":"V Lorenzo-Zuniga","year":"2006","unstructured":"Lorenzo-Zuniga, V. et al. Insulin-like growth factor I improves intestinal barrier function in cirrhotic rats. Gut 55, 1306\u20131312 (2006).","journal-title":"Gut"},{"key":"BFsrep34605_CR21","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1089\/scd.2014.0174","volume":"24","author":"EJ Fiore","year":"2015","unstructured":"Fiore, E. J. et al. Mesenchymal stromal cells engineered to produce IGF-I by recombinant adenovirus ameliorate liver fibrosis in mice. Stem Cells Dev 24, 791\u2013801 (2015).","journal-title":"Stem Cells Dev"},{"key":"BFsrep34605_CR22","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1136\/gut.2003.024505","volume":"54","author":"S Sanz","year":"2005","unstructured":"Sanz, S. et al. Expression of insulin-like growth factor I by activated hepatic stellate cells reduces fibrogenesis and enhances regeneration after liver injury. Gut 54, 134\u2013141 (2005).","journal-title":"Gut"},{"key":"BFsrep34605_CR23","doi-asserted-by":"publisher","first-page":"1682","DOI":"10.1053\/gast.1997.v113.pm9352873","volume":"113","author":"I Castilla-Cortazar","year":"1997","unstructured":"Castilla-Cortazar, I. et al. Hepatoprotective effects of insulin-like growth factor I in rats with carbon tetrachloride-induced cirrhosis. Gastroenterology 113, 1682\u20131691 (1997).","journal-title":"Gastroenterology"},{"key":"BFsrep34605_CR24","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1016\/j.bbrc.2012.07.140","volume":"425","author":"AE Handayaningsih","year":"2012","unstructured":"Handayaningsih, A. E. et al. IGF-I enhances cellular senescence via the reactive oxygen species-p53 pathway. Biochem Biophys Res Commun 425, 478\u2013484 (2012).","journal-title":"Biochem Biophys Res Commun"},{"key":"BFsrep34605_CR25","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1136\/gut.2004.042127","volume":"54","author":"L Xu","year":"2005","unstructured":"Xu, L. et al. Human hepatic stellate cell lines, LX-1 and LX-2: new tools for analysis of hepatic fibrosis. Gut 54, 142\u2013151 (2005).","journal-title":"Gut"},{"key":"BFsrep34605_CR26","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1016\/j.cell.2007.07.003","volume":"130","author":"M Collado","year":"2007","unstructured":"Collado, M., Blasco, M. A. & Serrano, M. Cellular senescence in cancer and aging. Cell 130, 223\u2013233 (2007).","journal-title":"Cell"},{"key":"BFsrep34605_CR27","doi-asserted-by":"publisher","first-page":"e0140189","DOI":"10.1371\/journal.pone.0140189","volume":"10","author":"R Matsumoto","year":"2015","unstructured":"Matsumoto, R. et al. Accelerated Telomere Shortening in Acromegaly; IGF-I Induces Telomere Shortening and Cellular Senescence. PLoS One 10, e0140189 (2015).","journal-title":"PLoS One"},{"key":"BFsrep34605_CR28","doi-asserted-by":"publisher","first-page":"1000","DOI":"10.1002\/hep.28379","volume":"63","author":"D Dibra","year":"2016","unstructured":"Dibra, D. et al. Mutant p53 in concert with an interleukin-27 receptor alpha deficiency causes spontaneous liver inflammation, fibrosis, and steatosis in mice. Hepatology 63, 1000\u20131012 (2016).","journal-title":"Hepatology"},{"key":"BFsrep34605_CR29","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1038\/nrendo.2011.72","volume":"7","author":"BW Smith","year":"2011","unstructured":"Smith, B. W. & Adams, L. A. Nonalcoholic fatty liver disease and diabetes mellitus: pathogenesis and treatment. Nat Rev Endocrinol 7, 456\u2013465 (2011).","journal-title":"Nat Rev Endocrinol"},{"key":"BFsrep34605_CR30","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1111\/j.1365-2036.2011.04912.x","volume":"35","author":"E Boettcher","year":"2012","unstructured":"Boettcher, E., Csako, G., Pucino, F., Wesley, R. & Loomba, R. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 35, 66\u201375 (2012).","journal-title":"Aliment Pharmacol Ther"},{"key":"BFsrep34605_CR31","doi-asserted-by":"publisher","first-page":"1675","DOI":"10.1056\/NEJMoa0907929","volume":"362","author":"AJ Sanyal","year":"2010","unstructured":"Sanyal, A. J. et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 362, 1675\u20131685 (2010).","journal-title":"N Engl J Med"},{"key":"BFsrep34605_CR32","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/nrendo.2010.171","volume":"7","author":"PE Clayton","year":"2011","unstructured":"Clayton, P. E., Banerjee, I., Murray, P. G. & Renehan, A. G. Growth hormone, the insulin-like growth factor axis, insulin and cancer risk. Nat Rev Endocrinol 7, 11\u201324 (2011).","journal-title":"Nat Rev Endocrinol"},{"key":"BFsrep34605_CR33","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/1756-8722-4-30","volume":"4","author":"J Wu","year":"2011","unstructured":"Wu, J. & Zhu, A. X. Targeting insulin-like growth factor axis in hepatocellular carcinoma. J Hematol Oncol 4, 30 (2011).","journal-title":"J Hematol Oncol"},{"key":"BFsrep34605_CR34","doi-asserted-by":"publisher","first-page":"97","DOI":"10.3109\/10408363.2011.596521","volume":"48","author":"BW Smith","year":"2011","unstructured":"Smith, B. W. & Adams, L. A. Non-alcoholic fatty liver disease. Crit Rev Clin Lab Sci 48, 97\u2013113 (2011).","journal-title":"Crit Rev Clin Lab Sci"},{"key":"BFsrep34605_CR35","first-page":"3313","volume":"8","author":"T, Tsukada","year":"1993","unstructured":"Tsukada, T., Tomooka, Y. et al. Enhanced proliferative potential in culture of cells from p53-deficient mice. Oncogene 8(12), 3313\u20133322 (1993).","journal-title":"Oncogene"},{"key":"BFsrep34605_CR36","doi-asserted-by":"publisher","first-page":"1760","DOI":"10.1002\/hep.510290640","volume":"29","author":"K Ikeda","year":"1999","unstructured":"Ikeda, K. et al. In vitro migratory potential of rat quiescent hepatic stellate cells and its augmentation by cell activation. Hepatology 29, 1760\u20131767 (1999).","journal-title":"Hepatology"},{"key":"BFsrep34605_CR37","doi-asserted-by":"publisher","first-page":"1494","DOI":"10.1172\/JCI26498","volume":"116","author":"H Kanda","year":"2006","unstructured":"Kanda, H. et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 116, 1494\u20131505 (2006).","journal-title":"J Clin Invest"},{"key":"BFsrep34605_CR38","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1016\/S0092-8674(00)81902-9","volume":"88","author":"M Serrano","year":"1997","unstructured":"Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593\u2013602 (1997).","journal-title":"Cell"},{"key":"BFsrep34605_CR39","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1006\/excr.2000.4875","volume":"257","author":"J Severino","year":"2000","unstructured":"Severino, J., Allen, R. G., Balin, S., Balin, A. & Cristofalo, V. J. Is beta-galactosidase staining a marker of senescence in vitro and in vivo? Exp Cell Res 257, 162\u2013171 (2000).","journal-title":"Exp Cell Res"},{"key":"BFsrep34605_CR40","doi-asserted-by":"publisher","first-page":"2467","DOI":"10.1111\/j.1572-0241.1999.01377.x","volume":"94","author":"EM Brunt","year":"1999","unstructured":"Brunt, E. M., Janney, C. G., Di Bisceglie, A. M., Neuschwander-Tetri, B. A. & Bacon, B. R. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol 94, 2467\u20132474 (1999).","journal-title":"Am J Gastroenterol"},{"key":"BFsrep34605_CR41","doi-asserted-by":"publisher","first-page":"1313","DOI":"10.1002\/hep.20701","volume":"41","author":"DE Kleiner","year":"2005","unstructured":"Kleiner, D. E. et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41, 1313\u20131321 (2005).","journal-title":"Hepatology"},{"key":"BFsrep34605_CR42","doi-asserted-by":"publisher","first-page":"282","DOI":"10.1053\/j.gastro.2006.10.014","volume":"132","author":"T Ota","year":"2007","unstructured":"Ota, T. et al. Insulin resistance accelerates a dietary rat model of nonalcoholic steatohepatitis. Gastroenterology 132, 282\u2013293 (2007).","journal-title":"Gastroenterology"},{"key":"BFsrep34605_CR43","doi-asserted-by":"publisher","first-page":"1730","DOI":"10.1053\/j.gastro.2010.07.046","volume":"139","author":"RK Soon Jr.","year":"2010","unstructured":"Soon, R. K., Jr., Yan, J. S., Grenert, J. P. & Maher, J. J. Stress signaling in the methionine-choline-deficient model of murine fatty liver disease. Gastroenterology 139, 1730\u20131739, 1739 e1731 (2010).","journal-title":"Gastroenterology"},{"key":"BFsrep34605_CR44","doi-asserted-by":"publisher","first-page":"e110","DOI":"10.1371\/journal.pbio.0050110","volume":"5","author":"JF Passos","year":"2007","unstructured":"Passos, J. F. et al. Mitochondrial dysfunction accounts for the stochastic heterogeneity in telomere-dependent senescence. PLoS Biol 5, e110 (2007).","journal-title":"PLoS Biol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep34605.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep34605","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep34605.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T00:26:51Z","timestamp":1749601611000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep34605"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,10,10]]},"references-count":44,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,12,16]]}},"alternative-id":["BFsrep34605"],"URL":"https:\/\/doi.org\/10.1038\/srep34605","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,10,10]]},"assertion":[{"value":"21 April 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 September 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 October 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":"34605"}}