{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T02:54:51Z","timestamp":1791860091208,"version":"4.3.4"},"reference-count":45,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,11,10]],"date-time":"2015-11-10T00:00:00Z","timestamp":1447113600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,11,10]],"date-time":"2015-11-10T00:00:00Z","timestamp":1447113600000},"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>Proliferative vitreoretinopathy (PVR) is a serious complication of retinal detachment and ocular trauma and its recurrence may lead to irreversible vision loss. Epithelial to mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells is a critical step in the pathogenesis of PVR, which is characterized by fibrotic membrane formation and traction retinal detachment. In this study, we investigated the potential impact of resveratrol (RESV) on EMT and the fibrotic process in cultured RPE cells and further examined the preventive effect of RESV on PVR development using a rabbit model of PVR. We found that RESV induces mesenchymal to epithelial transition (MET) and inhibits transforming growth factor-\u03b22(TGF-\u03b22)-induced EMT of RPE cells by deacetylating SMAD4. The effect of RESV on MET was dependent on sirtuin1 activation. RESV suppressed proliferation, migration and fibronectin synthesis induced by platelet-derived growth factor-BB or TGF-\u03b22. <jats:italic>In vivo<\/jats:italic>, RESV inhibited the progression of experimental PVR in rabbit eyes. Histological findings showed that RESV reduced fibrotic membrane formation and decreased \u03b1-SMA expression in the epiretinal membranes. These results suggest the potential use of RESV as a therapeutic agent to prevent the development of PVR by targeting EMT of RPE.<\/jats:p>","DOI":"10.1038\/srep16386","type":"journal-article","created":{"date-parts":[[2015,11,10]],"date-time":"2015-11-10T10:34:28Z","timestamp":1447151668000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":69,"title":["Resveratrol inhibits epithelial-mesenchymal transition of retinal pigment epithelium and development of proliferative vitreoretinopathy"],"prefix":"10.1038","volume":"5","author":[{"given":"Keijiro","family":"Ishikawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shikun","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroto","family":"Terasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hossein","family":"Nazari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiming","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Spee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ram","family":"Kannan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R","family":"Hinton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,11,10]]},"reference":[{"key":"BFsrep16386_CR1","doi-asserted-by":"publisher","first-page":"188","DOI":"10.1016\/S0002-9394(14)75004-4","volume":"100","author":"SJ Ryan","year":"1985","unstructured":"Ryan, S. J. The pathophysiology of proliferative vitreoretinopathy in its management. Am J Ophthalmol 100, 188\u2013193 (1985).","journal-title":"Am J Ophthalmol"},{"key":"BFsrep16386_CR2","doi-asserted-by":"publisher","first-page":"1806","DOI":"10.1016\/B978-1-4557-0737-9.00107-7","volume":"Vol. 3","author":"IJ Constable","year":"2013","unstructured":"Constable I. J. & Nagpal M. In Retina 5th edn, Vol. 3 (eds Ryan, S. J. et al.) Ch. 107, p. 1806\u20131825 (Elsevier, 2013).","journal-title":"Retina 5th edn"},{"key":"BFsrep16386_CR3","doi-asserted-by":"publisher","first-page":"1577","DOI":"10.1002\/jcp.24606","volume":"229","author":"GM Tosi","year":"2014","unstructured":"Tosi, G. M., Marigliani, D., Romeo, N. & Toti, P. Disease pathways in proliferative vitreoretinopathy: an ongoing challenge. J Cell Physiol 229, 1577\u20131583 (2014).","journal-title":"J Cell Physiol"},{"key":"BFsrep16386_CR4","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/S1350-9462(98)00024-X","volume":"18","author":"P Hiscott","year":"1999","unstructured":"Hiscott, P., Sheridan, C., Magee, R. M. & Grierson, I. Matrix and the retinal pigment epithelium in proliferative retinal disease. Prog Retin Eye Res 18, 167\u2013190 (1999).","journal-title":"Prog Retin Eye Res"},{"key":"BFsrep16386_CR5","doi-asserted-by":"publisher","first-page":"845","DOI":"10.1152\/physrev.00021.2004","volume":"85","author":"O Strauss","year":"2005","unstructured":"Strauss, O. The retinal pigment epithelium in visual function. Physiol. Rev. 85, 845\u2013881 (2005).","journal-title":"Physiol. Rev."},{"key":"BFsrep16386_CR6","doi-asserted-by":"publisher","first-page":"2755","DOI":"10.1167\/iovs.09-4725","volume":"51","author":"S Tamiya","year":"2010","unstructured":"Tamiya, S., Liu, L. & Kaplan, H. J. Epithelial-mesenchymal transition and proliferation of retinal pigment epithelial cells initiated upon loss of cell-cell contact. Invest Ophthalmol Vis Sci 51, 2755\u20132763 (2010).","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"BFsrep16386_CR7","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/j.preteyeres.2013.12.006","volume":"40","author":"S Pennock","year":"2014","unstructured":"Pennock, S., Haddock, L. J., Eliott, D., Mukai, S. & Kazlauskas, A. Is neutralizing vitreal growth factors a viable strategy to prevent proliferative vitreoretinopathy? Prog Retin Eye Res 40, 16\u201334 (2014)","journal-title":"Prog Retin Eye Res"},{"key":"BFsrep16386_CR8","doi-asserted-by":"publisher","first-page":"4060","DOI":"10.1074\/jbc.M109.056523","volume":"285","author":"E Takahashi","year":"2010","unstructured":"Takahashi E. et al. Tumor necrosis factor-\u03b1 regulates transforming growth factor-\u03b2-dependent epithelial-mesenchymal transition by promoting hyaluron-CD44-moesin interaction. J Biol Chem 285, 4060\u20134073 (2010)","journal-title":"J Biol Chem"},{"key":"BFsrep16386_CR9","doi-asserted-by":"publisher","first-page":"1975","DOI":"10.1096\/fj.03-0168rev","volume":"17","author":"S Pervaiz","year":"2003","unstructured":"Pervaiz, S. Resveratrol: from grapevines to mammalian biology. Faseb J 17, 1975\u20131985 (2003).","journal-title":"Faseb J"},{"key":"BFsrep16386_CR10","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1007\/978-3-642-38007-5_10","volume":"159","author":"A Borriello","year":"2014","unstructured":"Borriello, A. et al. Resveratrol: from basic studies to bedside. Cancer Treat. Res. 159, 167\u2013184 (2014).","journal-title":"Cancer Treat. Res."},{"key":"BFsrep16386_CR11","doi-asserted-by":"publisher","first-page":"768","DOI":"10.1038\/nrc1189","volume":"3","author":"YJ Surh","year":"2003","unstructured":"Surh, Y. J. Cancer chemoprevention with dietary phytochemicals. Nat. Rev. Cancer 3, 768\u2013780 (2003).","journal-title":"Nat. Rev. Cancer"},{"key":"BFsrep16386_CR12","doi-asserted-by":"publisher","first-page":"17187","DOI":"10.1074\/jbc.M501250200","volume":"280","author":"MT Borra","year":"2005","unstructured":"Borra, M. T., Smith, B. C. & Denu, J. M. Mechanism of human SIRT1 activation by resveratrol. J Biol Chem 280, 17187\u201317195 (2005).","journal-title":"J Biol Chem"},{"key":"BFsrep16386_CR13","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1038\/nature08197","volume":"460","author":"T Finkel","year":"2009","unstructured":"Finkel, T., Deng, C. X. & Mostoslavsky, R. Recent progress in the biology and physiology of sirtuins. Nature 460, 587\u2013591 (2009).","journal-title":"Nature"},{"key":"BFsrep16386_CR14","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1007\/s00417-014-2604-8","volume":"252","author":"C Bola","year":"2014","unstructured":"Bola, C., Bartlett, H. & Eperjesi, F. Resveratrol and the eye: activity and molecular mechanisms. Graefes Arch Clin Exp Ophthalmol 252, 699\u2013713 (2014).","journal-title":"Graefes Arch Clin Exp Ophthalmol"},{"key":"BFsrep16386_CR15","doi-asserted-by":"publisher","first-page":"1218","DOI":"10.1016\/j.jnutbio.2014.05.015","volume":"25","author":"N Nagai","year":"2014","unstructured":"Nagai, N., Kubota, S., Tsubota, K. & Ozawa, Y. Resveratrol prevents the development of choroidal neovascularization by modulating AMP-activated protein kinase in macrophages and other cell types. J. Nutr. Biochem. 25, 1218\u20131225 (2014).","journal-title":"J. Nutr. Biochem."},{"key":"BFsrep16386_CR16","first-page":"88","volume":"5","author":"CN Nagineni","year":"2014","unstructured":"Nagineni, C. N. et al. Resveratrol Suppresses Expression of VEGF by Human Retinal Pigment Epithelial Cells: Potential Nutraceutical for Age-related Macular Degeneration. Aging and disease 5, 88\u2013100 (2014).","journal-title":"Aging and disease"},{"key":"BFsrep16386_CR17","doi-asserted-by":"publisher","first-page":"1725","DOI":"10.2353\/ajpath.2010.100098","volume":"177","author":"S Kubota","year":"2010","unstructured":"Kubota, S. et al. Resveratrol prevents light-induced retinal degeneration via suppressing activator protein-1 activation. Am J Pathol 177, 1725\u20131731 (2010).","journal-title":"Am J Pathol"},{"key":"BFsrep16386_CR18","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1016\/j.clnu.2014.08.014","volume":"34","author":"YQ Zhang","year":"2014","unstructured":"Zhang, Y. Q. et al. Resveratrol ameliorates lipopolysaccharide-induced epithelial mesenchymal transition and pulmonary fibrosis through suppression of oxidative stress and transforming growth factor-beta1 signaling. Clin Nutr. 34, 752\u2013760 (2014).","journal-title":"Clin Nutr."},{"key":"BFsrep16386_CR19","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1016\/j.bcp.2014.09.002","volume":"92","author":"Y Bai","year":"2014","unstructured":"Bai, Y. et al. Resveratrol inhibits epithelial-mesenchymal transition and renal fibrosis by antagonizing the hedgehog signaling pathway. Biochem. Pharmacol. 92, 484\u2013493 (2014).","journal-title":"Biochem. Pharmacol."},{"key":"BFsrep16386_CR20","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.2353\/ajpath.2010.090923","volume":"177","author":"J Li","year":"2010","unstructured":"Li, J., Qu, X., Ricardo, S. D., Bertram, J. F. & Nikolic-Paterson, D. J. Resveratrol inhibits renal fibrosis in the obstructed kidney: potential role in deacetylation of Smad3. Am J Pathol 177, 1065\u20131071 (2010).","journal-title":"Am J Pathol"},{"key":"BFsrep16386_CR21","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1006\/exer.1994.1114","volume":"59","author":"BA Pfeffer","year":"1994","unstructured":"Pfeffer, B. A., Flanders, K. C., Guerin, C. J., Danielpour, D. & Anderson, D. H. Transforming growth factor beta 2 is the predominant isoform in the neural retina, retinal pigment epithelium-choroid and vitreous of the monkey eye. Exp Eye Res 59, 323\u2013333 (1994).","journal-title":"Exp Eye Res"},{"key":"BFsrep16386_CR22","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1006\/excr.1997.3873","volume":"239","author":"DR Hinton","year":"1998","unstructured":"Hinton, D. R. et al. Mitogen-activated protein kinase activation mediates PDGF-directed migration of RPE cells. Exp Cell Res 239, 11\u201315 (1998).","journal-title":"Exp Cell Res"},{"key":"BFsrep16386_CR23","first-page":"4324","volume":"41","author":"M Jin","year":"2000","unstructured":"Jin, M., He, S., W\u00f6rpel, V., Ryan, S. J. & Hinton, D. R. Promotion of adhesion and migration of RPE cells to provisional extracellular matrices by TNF-alpha. Invest Ophthalmol Vis Sci 41, 4324\u20134332 (2000).","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"BFsrep16386_CR24","first-page":"747","volume":"9","author":"D Kent","year":"2003","unstructured":"Kent, D. & Sheridan, C. Choroidal neovascularization: a wound healing perspective. Mol Vis 9, 747\u2013755 (2003).","journal-title":"Mol Vis"},{"key":"BFsrep16386_CR25","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1038\/nprot.2007.4","volume":"2","author":"RN Agrawal","year":"2007","unstructured":"Agrawal, R. N. et al. In vivo models of proliferative vitreoretinopathy. Nat Protoc 2, 67\u201377 (2007).","journal-title":"Nat Protoc"},{"key":"BFsrep16386_CR26","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1016\/S0002-9394(14)75946-X","volume":"85","author":"R Machemer","year":"1978","unstructured":"Machemer, R., van Horn, D. & Aaberg, T. M. Pigment epithelial proliferation in human retinal detachment with massive periretinal proliferation. Am J Ophthalmol 85, 181\u2013191 (1978).","journal-title":"Am J Ophthalmol"},{"key":"BFsrep16386_CR27","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/0002-9394(75)90137-3","volume":"80","author":"MS Mandelcorn","year":"1975","unstructured":"Mandelcorn, M. S., Machemer, R., Fineberg, E. & Hersch, S. B. Proliferation and metaplasia of intravitreal retinal pigment epithelium cell autotransplants. Am J Ophthalmol 80, 227\u2013237 (1975).","journal-title":"Am J Ophthalmol"},{"key":"BFsrep16386_CR28","doi-asserted-by":"publisher","first-page":"1420","DOI":"10.1172\/JCI39104","volume":"119","author":"R Kalluri","year":"2009","unstructured":"Kalluri, R. & Weinberg, R. A. The basics of epithelial-mesenchymal transition. J Clin Invest 119, 1420\u20131428 (2009).","journal-title":"J Clin Invest"},{"key":"BFsrep16386_CR29","doi-asserted-by":"crossref","unstructured":"Ishikawa, K., Kannan, R. & Hinton, D. R. Molecular mechanisms of subretinal fibrosis in age-related macular degeneration. Exp Eye Res, 10.1016\/j.exer.2015.03.009 (2015).","DOI":"10.1016\/j.exer.2015.03.009"},{"key":"BFsrep16386_CR30","doi-asserted-by":"publisher","first-page":"525","DOI":"10.5483\/BMBRep.2015.48.9.140","volume":"48","author":"JH Kim","year":"2015","unstructured":"Kim, J. H., Park, S., Chung, H. & Oh, S. Wnt5a attenuates the pathogenic effects of the Wnt\/beta-catenin pathway in human retinal pigment epithelial cells via down-regulating beta-catenin and Snail. BMB Rep 48, 525\u2013530 (2015).","journal-title":"BMB Rep"},{"key":"BFsrep16386_CR31","doi-asserted-by":"publisher","first-page":"e23322","DOI":"10.1371\/journal.pone.0023322","volume":"6","author":"H Li","year":"2011","unstructured":"Li, H., Wang, H., Wang, F., Gu, Q. & Xu, X. Snail involves in the transforming growth factor beta1-mediated epithelial-mesenchymal transition of retinal pigment epithelial cells. PLoS One 6, e23322 (2011).","journal-title":"PLoS One"},{"key":"BFsrep16386_CR32","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1002\/jcp.24165","volume":"228","author":"JP Palma-Nicolas","year":"2013","unstructured":"Palma-Nicolas, J. P. & Lopez-Colome, A. M. Thrombin induces slug-mediated E-cadherin transcriptional repression and the parallel up-regulation of N-cadherin by a transcription-independent mechanism in RPE cells. J Cell Physiol 228, 581\u2013589 (2013).","journal-title":"J Cell Physiol"},{"key":"BFsrep16386_CR33","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1038\/nature01960","volume":"425","author":"KT Howitz","year":"2003","unstructured":"Howitz, K. T. et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191\u2013196 (2003).","journal-title":"Nature"},{"key":"BFsrep16386_CR34","first-page":"166","volume":"64","author":"C Canto","year":"2012","unstructured":"Canto, C. & Auwerx, J. Targeting sirtuin 1 to improve metabolism: all you need is NAD(+)? Pharmacol. Rev. 64, 166\u2013187 (2012).","journal-title":"Targeting sirtuin 1 to improve metabolism: all you need is NAD(+)? Pharmacol. Rev"},{"key":"BFsrep16386_CR35","doi-asserted-by":"publisher","first-page":"1175","DOI":"10.1016\/j.celrep.2013.03.019","volume":"3","author":"P Simic","year":"2013","unstructured":"Simic, P. et al. SIRT1 suppresses the epithelial-to-mesenchymal transition in cancer metastasis and organ fibrosis. Cell Rep. 3, 1175\u20131186 (2013).","journal-title":"Cell Rep"},{"key":"BFsrep16386_CR36","doi-asserted-by":"publisher","first-page":"e56819","DOI":"10.1371\/journal.pone.0056819","volume":"8","author":"CM Chan","year":"2013","unstructured":"Chan, C. M., Chang, H. H., Wang, V. C., Huang, C. L. & Hung, C. F. Inhibitory effects of resveratrol on PDGF-BB-induced retinal pigment epithelial cell migration via PDGFRbeta, PI3K\/Akt and MAPK pathways. PLoS ONE 8, e56819 (2013).","journal-title":"PLoS ONE"},{"key":"BFsrep16386_CR37","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1002\/jat.1249","volume":"28","author":"E Ch\u00e1vez","year":"2008","unstructured":"Ch\u00e1vez, E. et al. Resveratrol prevents fibrosis, NF-kappaB activation and TGF-beta increases induced by chronic CCl4 treatment in rats. J. Appl. Toxicol. 28, 35\u201343 (2008).","journal-title":"J. Appl. Toxicol."},{"key":"BFsrep16386_CR38","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1016\/j.cbi.2004.11.003","volume":"151","author":"RE King","year":"2005","unstructured":"King, R. E., Kent, K. D. & Bomser, J. A. Resveratrol reduces oxidation and proliferation of human retinal pigment epithelial cells via extracellular signal-regulated kinase inhibition. Chem. Biol. Interact. 151, 143\u2013149 (2005).","journal-title":"Chem. Biol. Interact."},{"key":"BFsrep16386_CR39","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1002\/jcb.23431","volume":"113","author":"W Yu","year":"2012","unstructured":"Yu, W., Fu, Y. C. & Wang, W. Cellular and molecular effects of resveratrol in health and disease. J Cell Biochem 113, 752\u2013759 (2012).","journal-title":"J Cell Biochem"},{"key":"BFsrep16386_CR40","first-page":"2783","volume":"24","author":"BB Aggarwal","year":"2004","unstructured":"Aggarwal, B. B. et al. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res 24, 2783\u20132840 (2004).","journal-title":"Anticancer Res"},{"key":"BFsrep16386_CR41","doi-asserted-by":"crossref","unstructured":"Zhang, H., He, S., Spee, C., Ishikawa, K. & Hinton, D. R. SIRT1 mediated inhibition of VEGF\/VEGFR2 signaling by Resveratrol and its relevance to choroidal neovascularization. Cytokine, 10.1016\/j.cyto.2015.06.019. (2015).","DOI":"10.1016\/j.cyto.2015.06.019"},{"key":"BFsrep16386_CR42","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1038\/nprot.2009.33","volume":"4","author":"S Sonoda","year":"2009","unstructured":"Sonoda, S. et al. A protocol for the culture and differentiation of highly polarized human retinal pigment epithelial cells. Nat Protoc 4, 662\u2013673 (2009).","journal-title":"Nat Protoc"},{"key":"BFsrep16386_CR43","doi-asserted-by":"publisher","first-page":"3398","DOI":"10.1182\/blood-2009-01-197095","volume":"115","author":"S Kase","year":"2010","unstructured":"Kase, S. et al. alphaB-crystallin regulation of angiogenesis by modulation of VEGF. Blood 115, 3398\u20133406 (2010).","journal-title":"Blood"},{"key":"BFsrep16386_CR44","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1096\/fj.13-229740","volume":"28","author":"K Ishikawa","year":"2014","unstructured":"Ishikawa, K. et al. Periostin promotes the generation of fibrous membranes in proliferative vitreoretinopathy. Faseb J 28, 131\u2013142 (2014).","journal-title":"Faseb J"},{"key":"BFsrep16386_CR45","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1016\/S0002-9394(14)77370-2","volume":"93","author":"DM Fastenberg","year":"1982","unstructured":"Fastenberg, D. M., Diddie, K. R., Dorey, K. & Ryan, S. J. The role of cellular proliferation in an experimental model of massive periretinal proliferation. Am J Ophthalmol 93, 565\u2013572 (1982).","journal-title":"Am J Ophthalmol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep16386","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep16386.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep16386.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T13:07:49Z","timestamp":1672924069000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep16386"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,11,10]]},"references-count":45,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,12,21]]}},"alternative-id":["BFsrep16386"],"URL":"https:\/\/doi.org\/10.1038\/srep16386","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,11,10]]},"assertion":[{"value":"17 July 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 October 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 November 2015","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":"16386"}}