{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T21:57:57Z","timestamp":1787003877546,"version":"build-2736575974"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,4,5]],"date-time":"2017-04-05T00:00:00Z","timestamp":1491350400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,4,5]],"date-time":"2017-04-05T00:00:00Z","timestamp":1491350400000},"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                    Hydrogen sulfide (H\n                    <jats:sub>2<\/jats:sub>\n                    S) exerts synergistic effects with another gaseous signaling molecule nitric oxide (NO) on ion channels and vasculature. However, the mechanism of the synergy is not well understood. Here, we show that the interaction between H\n                    <jats:sub>2<\/jats:sub>\n                    S and NO generates polysulfides (H\n                    <jats:sub>2<\/jats:sub>\n                    S\n                    <jats:sub>n<\/jats:sub>\n                    ), which activate transient receptor potential ankyrin 1 (TRPA1) channels. High performance liquid chromatography with tandem mass spectrometry analysis, along with the imaging of intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    and H\n                    <jats:sub>2<\/jats:sub>\n                    S\n                    <jats:sub>n<\/jats:sub>\n                    , showed that H\n                    <jats:sub>2<\/jats:sub>\n                    S\n                    <jats:sub>n<\/jats:sub>\n                    and their effects were abolished by cyanolysis and by reducing substances such as dithiothreitol (DTT), cysteine, and glutathione (GSH). However, the effects of nitroxyl or nitrosopersulfide, other potential products of H\n                    <jats:sub>2<\/jats:sub>\n                    S and NO interaction, are not affected by cyanolysis or reducing substances. This study demonstrates that H\n                    <jats:sub>2<\/jats:sub>\n                    S\n                    <jats:sub>n<\/jats:sub>\n                    are products of synergy between H\n                    <jats:sub>2<\/jats:sub>\n                    S and NO and provides a new insight into the signaling mechanisms.\n                  <\/jats:p>","DOI":"10.1038\/srep45995","type":"journal-article","created":{"date-parts":[[2017,4,5]],"date-time":"2017-04-05T06:45:12Z","timestamp":1491374712000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":121,"title":["Polysulfides (H2Sn) produced from the interaction of hydrogen sulfide (H2S) and nitric oxide (NO) activate TRPA1 channels"],"prefix":"10.1038","volume":"7","author":[{"given":"Ryo","family":"Miyamoto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin","family":"Koike","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoko","family":"Takano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norihiro","family":"Shibuya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Kimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenjiro","family":"Hanaoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuteru","family":"Urano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Ogasawara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideo","family":"Kimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,4,5]]},"reference":[{"key":"BFsrep45995_CR1","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1523\/JNEUROSCI.16-03-01066.1996","volume":"16","author":"K Abe","year":"1996","unstructured":"Abe, K. & Kimura, H. The possible role of hydrogen sulfide as an endogenous neuromodulator. J. Neurosci. 16, 1066\u20131071 (1996).","journal-title":"J. Neurosci."},{"key":"BFsrep45995_CR2","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1006\/bbrc.1997.6878","volume":"237","author":"R Hosoki","year":"1997","unstructured":"Hosoki, R., Matsuki, N. & Kimura, H. The possible role of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide. Biochem. Biophys. Res. Commun. 237, 527\u2013531 (1997).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"BFsrep45995_CR3","doi-asserted-by":"publisher","first-page":"6008","DOI":"10.1093\/emboj\/20.21.6008","volume":"20","author":"W Zhao","year":"2001","unstructured":"Zhao, W., Zhang, J., Lu, Y. & Wang, R. The vasorelaxant effect of H2S as a novel endogenous gaseous KATP channel opener. EMBO J. 20, 6008\u20136016 (2001).","journal-title":"EMBO J"},{"key":"BFsrep45995_CR4","doi-asserted-by":"publisher","first-page":"1165","DOI":"10.1096\/fj.04-1815fje","volume":"18","author":"Y Kimura","year":"2004","unstructured":"Kimura, Y. & Kimura, H. Hydrogen sulfide protects neurons from oxidative stress. FASEB J. 18, 1165\u20131167 (2004).","journal-title":"FASEB J"},{"key":"BFsrep45995_CR5","doi-asserted-by":"publisher","first-page":"2118","DOI":"10.1096\/fj.06-6270fje","volume":"20","author":"RCO Zanardo","year":"2006","unstructured":"Zanardo, R. C. O. et al. Hydrogen sulphide is an endogenous modulator of leukocyte-mediated inflammation. FASEB J. 20, 2118\u20132120 (2006).","journal-title":"FASEB J"},{"key":"BFsrep45995_CR6","doi-asserted-by":"publisher","first-page":"15560","DOI":"10.1073\/pnas.0705891104","volume":"104","author":"JW Elrod","year":"2007","unstructured":"Elrod, J. W. et al. Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function. Proc. Natl. Acad. Sci. USA 104, 15560\u201315565 (2007).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFsrep45995_CR7","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1038\/sj.bjp.0704858","volume":"137","author":"B Teague","year":"2002","unstructured":"Teague, B., Asiedu, S. & Moore, P. K. The smooth muscle relaxant effect of hydrogen sulphide in vitro: Evidence for a physiological role to control intestinal contractility. Br. J. Pharmacol. 137, 139\u2013145 (2002).","journal-title":"Br. J. Pharmacol"},{"key":"BFsrep45995_CR8","doi-asserted-by":"publisher","first-page":"e004093","DOI":"10.1161\/JAHA.112.004093","volume":"1","author":"SC Bir","year":"2012","unstructured":"Bir, S. C. et al. Hydrogen sulfide stimulates ischemic vascular remodeling through nitric oxide synthase and nitrite reduction activity regulating hypoxia-inducible factor-1\u03b1 and vascular endothelial growth factor-dependent angiogenesis. J. Am. Heart Assoc. 1, e004093 (2012).","journal-title":"J. Am. Heart Assoc"},{"key":"BFsrep45995_CR9","doi-asserted-by":"publisher","first-page":"9161","DOI":"10.1073\/pnas.1202916109","volume":"109","author":"C Coletta","year":"2012","unstructured":"Coletta, C. et al. Hydrogen sulfide and nitric oxide are mutually dependent in the regulation of angiogenesis and endothelium-dependent vasorelaxation. Proc. Natl. Acad. Sci. USA 109, 9161\u20139166 (2012).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFsrep45995_CR10","doi-asserted-by":"publisher","first-page":"888","DOI":"10.1161\/CIRCULATIONAHA.108.833491","volume":"120","author":"S Minamishima","year":"2009","unstructured":"Minamishima, S. et al. Hydrogen sulfide improves survival after cardiac arrest and cardiopulmonary resuscitation via a nitric oxide synthase 3-dependent mechanism in mice. Circulation 120, 888\u2013896 (2009).","journal-title":"Circulation"},{"key":"BFsrep45995_CR11","doi-asserted-by":"publisher","first-page":"3182","DOI":"10.1073\/pnas.1321871111","volume":"111","author":"AL King","year":"2014","unstructured":"King, A. L. et al. Hydrogen sulfide cytoprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent. Proc. Natl. Acad. Sci. USA 111, 3182\u20133187 (2014).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFsrep45995_CR12","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1016\/j.bbrc.2006.02.154","volume":"343","author":"M Whiteman","year":"2006","unstructured":"Whiteman, M. et al. Evidence for the formation of a novel nitrosothiol from the gaseous mediators nitric oxide and hydrogen sulphide. Biochem. Biophys. Res. Commun. 343, 303\u2013310 (2006).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"BFsrep45995_CR13","doi-asserted-by":"publisher","first-page":"12061","DOI":"10.1002\/anie.201305669","volume":"52","author":"JL Miljkovic","year":"2013","unstructured":"Miljkovic, J. L., Kenkel, I., Ivanovic-Burmazovic, I. & Filipovic, M. R. Generation of HNO and HSNO from nitrite by heme-iron-catalyzed metabolism with H2S. Angew. Chem. Int. Ed. 52, 12061\u201312064 (2013).","journal-title":"Angew. Chem. Int. Ed."},{"key":"BFsrep45995_CR14","doi-asserted-by":"publisher","first-page":"4381","DOI":"10.1038\/ncomms5381","volume":"5","author":"M Eberhardt","year":"2014","unstructured":"Eberhardt, M. et al. H2S and NO cooperatively regulate vascular tone by activating a neuroendocrine HNO-TRPA1-CGRP signaling pathway. Nat. Commun. 5, 4381 (2014).","journal-title":"Nat. Commun."},{"key":"BFsrep45995_CR15","doi-asserted-by":"publisher","first-page":"E4651","DOI":"10.1073\/pnas.1509277112","volume":"112","author":"MM Cortese-Krott","year":"2015","unstructured":"Cortese-Krott, M. M. et al. Key bioactive reaction products of the NO\/H2S interaction are S\/N-hybrid species, polysulfides, and nitroxyl. Proc. Natl. Acad. Sci. USA 112, E4651\u20134660 (2015).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFsrep45995_CR16","doi-asserted-by":"publisher","first-page":"1235","DOI":"10.1007\/s00702-016-1600-z","volume":"123","author":"H Kimura","year":"2016","unstructured":"Kimura, H. Hydrogen polysulfide (H2Sn) signaling along with hydrogen sulfide (H2S) and nitric oxide (NO). J. Neural Transm. 123, 1235\u20131245 (2016).","journal-title":"J. Neural Transm."},{"key":"BFsrep45995_CR17","doi-asserted-by":"publisher","first-page":"C894","DOI":"10.1152\/ajpcell.00028.2016","volume":"310","author":"A Moustafa","year":"2016","unstructured":"Moustafa, A. & Habara, Y. Cross talk between polysulfide and nitric oxide in rat peritoneal mast cells. Am. J. Physiol. Cell Physiol. 310, C894\u2013C902 (2016).","journal-title":"Am. J. Physiol. Cell Physiol"},{"key":"BFsrep45995_CR18","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1089\/ars.2008.2253","volume":"11","author":"N Shibuya","year":"2009","unstructured":"Shibuya, N. et al. 3-Mercaptopyruvate sulfurtransferease produces hydrogen sulfide and bound sulfane sulfur in the brain. Antioxid. Redox Signal. 11, 703\u2013714 (2009).","journal-title":"Antioxid. Redox Signal."},{"key":"BFsrep45995_CR19","doi-asserted-by":"publisher","first-page":"1366","DOI":"10.1038\/ncomms2371","volume":"4","author":"N Shibuya","year":"2013","unstructured":"Shibuya, N. et al. A novel pathway for the production of hydrogen sulfide from D-cysteine in mammalian cells. Nat. Commun. 4, 1366 (2013).","journal-title":"Nat. Commun."},{"key":"BFsrep45995_CR20","doi-asserted-by":"publisher","first-page":"14774","DOI":"10.1038\/srep14774","volume":"5","author":"Y Kimura","year":"2015","unstructured":"Kimura, Y. et al. Identification of H2S3 and H2S produced by 3-mercaptopyruvate sulfurtransferase in the brain. Sci Rep 5, 14774 (2015).","journal-title":"Sci Rep"},{"key":"BFsrep45995_CR21","first-page":"200","volume":"100","author":"Y Nagai","year":"2006","unstructured":"Nagai, Y., Tsugane, M., Oka, J.-I. & Kimura, H. Polysulfides induce calcium waves in rat hippocampal astrocytes. J. Pharmacol. Sci. 100, 200 (2006).","journal-title":"J. Pharmacol. Sci."},{"key":"BFsrep45995_CR22","doi-asserted-by":"publisher","first-page":"e109","DOI":"10.1016\/j.neures.2010.07.2052","volume":"685","author":"K Oosumi","year":"2010","unstructured":"Oosumi, K. et al. Polysulfide activates TRP channels and increases intracellular Ca2+ in astrocytes. Neurosci. Res. 685, e109\u2013e222 (2010).","journal-title":"Neurosci. Res."},{"key":"BFsrep45995_CR23","doi-asserted-by":"publisher","first-page":"2451","DOI":"10.1096\/fj.12-226415","volume":"27","author":"Y Kimura","year":"2013","unstructured":"Kimura, Y. et al. Polysulfides are possible H2S-derived signaling molecules in rat brain. FASEB J. 27, 2451\u20132457 (2013).","journal-title":"FASEB J"},{"key":"BFsrep45995_CR24","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1186\/s12990-015-0023-4","volume":"11","author":"Y Hatakeyama","year":"2015","unstructured":"Hatakeyama, Y., Takahashi, K., Tominaga, M., Kimura, H. & Ohta, T. Polysulfide evokes acute pain through the activation of nociceptive TRPA1 in mouse sensory neurons. Mol. Pain 11:24 (2015).","journal-title":"Mol. Pain"},{"key":"BFsrep45995_CR25","doi-asserted-by":"publisher","first-page":"3548","DOI":"10.1016\/j.febslet.2013.09.013","volume":"587","author":"S Koike","year":"2013","unstructured":"Koike, S., Ogasawara, Y., Shibuya, N., Kimura, H. & Ishii, K. Polysulfide exerts a protective effect against cytotoxicity cuased by t-buthylhydroperoxide through Nrf2 signaling in neuroblastoma cells. FEBS lett 587, 3548\u20133555 (2013).","journal-title":"FEBS lett"},{"key":"BFsrep45995_CR26","doi-asserted-by":"publisher","first-page":"1749","DOI":"10.1089\/ars.2012.5041","volume":"19","author":"R Greiner","year":"2013","unstructured":"Greiner, R. et al. Polysulfides link H2S to protein thiol oxidation. Antioxid. Redox Signal. 19, 1749\u20131765 (2013).","journal-title":"Antioxid. Redox Signal."},{"key":"BFsrep45995_CR27","doi-asserted-by":"publisher","first-page":"1344","DOI":"10.1161\/HYPERTENSIONAHA.114.04281","volume":"64","author":"D Stubbert","year":"2014","unstructured":"Stubbert, D. et al. Protein kinase G I\u03b1 oxidation paradoxically underlies blood pressure lowering by the reductant hydrogen sulfide. Hypertension 64, 1344\u20131351 (2014).","journal-title":"Hypertension"},{"key":"BFsrep45995_CR28","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1016\/j.freeradbiomed.2015.09.007","volume":"89","author":"AP Jarosz","year":"2015","unstructured":"Jarosz, A. P. et al. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is inactivated by S-sulfuration in vitro . Free Rad. Biol. Med. 89, 512\u2013521 (2015).","journal-title":"Free Rad. Biol. Med"},{"key":"BFsrep45995_CR29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ab.2011.01.044","volume":"413","author":"JI Toohey","year":"2011","unstructured":"Toohey, J. I. Sulfur signaling: Is the agent sulfide or sulfane? Anal Biochem 413, 1\u20137 (2011).","journal-title":"Anal Biochem"},{"key":"BFsrep45995_CR30","doi-asserted-by":"publisher","first-page":"1355","DOI":"10.1016\/j.bbapap.2014.01.002","volume":"1844","author":"O Kabil","year":"2014","unstructured":"Kabil, O., Motl, N. & Banerjee, R. H2S and its role in redox signaling. Biochim. Biophys. Acta 1844, 1355\u20131366 (2014).","journal-title":"Biochim. Biophys. Acta"},{"key":"BFsrep45995_CR31","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1038\/nchembio.1834","volume":"11","author":"TV Mishanina","year":"2015","unstructured":"Mishanina, T. V., Libiad, M. & Banerjee, R. Biogenesis of reactive sulfur species for signaling by hydrogen sulfide oxidation pathways. Nat. Chem. Biol. 11, 457\u2013464 (2015).","journal-title":"Nat. Chem. Biol."},{"issue":"6","key":"BFsrep45995_CR32","doi-asserted-by":"publisher","first-page":"1064","DOI":"10.1039\/C6CC08372B","volume":"53","author":"Yoko Takano","year":"2017","unstructured":"Takano, Y. et al. Development of a reversible fluorescent probe for reactive sulfur species, sulfane sulfur, and its biological application. Chem. Commun. 53, 1064\u20131067 (2017).","journal-title":"Chemical Communications"},{"key":"BFsrep45995_CR33","doi-asserted-by":"publisher","first-page":"2485","DOI":"10.1523\/JNEUROSCI.5369-07.2008","volume":"28","author":"DA Andersson","year":"2008","unstructured":"Andersson, D. A., Gentry, C., Moss, S. & Bevan, S. Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress. J. Neurosci. 28, 2485\u20132494 (2008).","journal-title":"J. Neurosci."},{"key":"BFsrep45995_CR34","doi-asserted-by":"crossref","unstructured":"Keefer, L. K., Nims, R. W., Davies, K. M. & Wink, D. A. \u201cNONOates\u201d (1-substituted diazen-1-ium-1,2-diolates) as nitric oxide donors: convenient nitric oxide dosage forms. Methods Enzym. 268 (1996).","DOI":"10.1016\/S0076-6879(96)68030-6"},{"key":"BFsrep45995_CR35","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1002\/jbt.2570040409","volume":"4","author":"R Jarabak","year":"1989","unstructured":"Jarabak, R. & Westley, J. The sulfur-cyanolysis sites of serum albumin: metabolite competition studies. J. Biochem. Toxicol. 4, 255\u2013261 (1989).","journal-title":"J. Biochem. Toxicol."},{"key":"BFsrep45995_CR36","doi-asserted-by":"publisher","first-page":"12016","DOI":"10.1021\/ja3009693","volume":"134","author":"MR Filipoovic","year":"2012","unstructured":"Filipoovic, M. R. et al. Chemical characterization of the smallest S-nitrosothiol, HSNO; cellular cross-talk of H2S and S-nitrosothiols. J. Am. Chem. Soc. 134, 12016\u201312027 (2012).","journal-title":"J. Am. Chem. Soc."},{"key":"BFsrep45995_CR37","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1016\/j.redox.2013.12.031","volume":"2","author":"MM Cortese-Krott","year":"2014","unstructured":"Cortese-Krott, M. M. et al. Nitrosopersulfide (SSNO\u2212) accounts for sustained NO bioactivity of S-nitrosothiols following reaction with sulfide. Redox Biol. 2, 234\u2013244 (2014).","journal-title":"Redox Biol"},{"key":"BFsrep45995_CR38","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1007\/s004180050286","volume":"110","author":"N Nagahara","year":"1998","unstructured":"Nagahara, N., Ito, T., Kitamura, H. & Nishino, T. Tissue and subcellular distribution of mercaptopyruvate sulfurtransferase in the rat: confocal laser fluorescence and immunoelectron microscopic studies combined with biochemical analysis. Histochem. Cell. Biol. 110, 243\u2013250 (1998).","journal-title":"Histochem. Cell. Biol"},{"key":"BFsrep45995_CR39","doi-asserted-by":"publisher","first-page":"1854","DOI":"10.1096\/fj.05-3724fje","volume":"19","author":"Y Enokido","year":"2005","unstructured":"Enokido, Y. et al. Cystathionine beta-synthase, a key enzyme for homocysteine metabolism, is preferentially expressed in the radial glia\/astrocyte lineage of developing mouse CNS. FASEB J. 19, 1854\u20131856 (2005).","journal-title":"FASEB J"},{"key":"BFsrep45995_CR40","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1093\/jb\/mvp111","volume":"146","author":"N Shibuya","year":"2009","unstructured":"Shibuya, N., Mikam, i. Y., Kimura, Y., Nagahara, N. & Kimura, H. Vascular endothelium exresses 3-mercaptopyruvate sulfurtransferase and produces hydrogen sulfide. J. Biochem. 146, 623\u2013626 (2009).","journal-title":"J. Biochem."},{"key":"BFsrep45995_CR41","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1089\/ars.2010.3525","volume":"15","author":"MD Levitt","year":"2011","unstructured":"Levitt, M. D., Abdel-Rehim, M. S. & Furne, J. Free and acid-labile hydrogen sulfide concentrations in mouse tissues:Anomalously high free hydrogen sulfide in aortic tissue. Antioxid. Redox Signal. 15, 373\u2013378 (2011).","journal-title":"Antioxid. Redox Signal."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep45995.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep45995","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/doifinder\/10.1038\/srep45995","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/www.nature.com\/articles\/srep45995.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T18:33:06Z","timestamp":1671820386000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep45995"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,5]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,5,31]]}},"alternative-id":["BFsrep45995"],"URL":"https:\/\/doi.org\/10.1038\/srep45995","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,5]]},"assertion":[{"value":"29 December 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 March 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 April 2017","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":"45995"}}