{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T02:01:23Z","timestamp":1773885683459,"version":"3.50.1"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,11,15]],"date-time":"2016-11-15T00:00:00Z","timestamp":1479168000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,11,15]],"date-time":"2016-11-15T00:00:00Z","timestamp":1479168000000},"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>Oral submucous fibrosis (OSF), regarded as a precancerous condition, is characterized by juxta-epithelial inflammatory reaction followed by fibro-elastic change in the lamina properia and epithelial atrophy. The pathologic mechanisms of OSF still need to be further clarified. In the study, we investigated the functional expression of SSEA-4, which is a well-known stemness marker, in myofibroblast activity and the clinical significance in OSF tissues. The expression of SSEA-4 in OSF was evaluated by immunohistochemical staining. Functional analysis of SSEA-4 on myofibroblast activity of OSF was achieved by lentiviral silencing ST3GAL2. Immunohisitochemistry demonstrated that SSEA-4 expression was significantly higher expression in areca quid chewing-associated OSF tissues than those of normal oral mucosa tissues. From flow cytometry analysis, arecoline dose-dependently activated SSEA-4 expression in primary human normal buccal mucosal fibroblasts (BMFs). Sorted SSEA-4-positive cells from fibrotic BMFs (fBMFs) have higher colony-forming unit, collagen gel contraction, and \u03b1-smooth muscle actin (\u03b1-SMA) expression than SSEA-4-negative subset. Knockdown of ST3GAL2 in fBMFs suppressed SSEA-4 expression, collagen contraction, migration, invasiveness, and wound healing capability. Consistently, silencing ST3GAL2 was found to repress arecoline-induced myofibroblast activity in BMFs. The study highlights SSEA-4 as a critical marker for therapeutic intervention to mediate myofibroblast transdifferentiation in areca quid chewing-associated OSF.<\/jats:p>","DOI":"10.1038\/srep37004","type":"journal-article","created":{"date-parts":[[2016,11,15]],"date-time":"2016-11-15T10:20:58Z","timestamp":1479205258000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Aberrant SSEA-4 upregulation mediates myofibroblast activity to promote pre-cancerous oral submucous fibrosis"],"prefix":"10.1038","volume":"6","author":[{"given":"Cheng-Chia","family":"Yu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chuan-Hang","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Chao","family":"Chang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,11,15]]},"reference":[{"key":"BFsrep37004_CR1","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1016\/j.oraloncology.2005.08.005","volume":"42","author":"WM Tilakaratne","year":"2006","unstructured":"Tilakaratne, W. M., K. M. F., Saku Takashi, Peters, T. J. & W. S. Oral submucous fibrosis: Review on aetiology and pathogenesis. Oral oncology 42, 561\u2013568 (2006).","journal-title":"Oral oncology"},{"key":"BFsrep37004_CR2","doi-asserted-by":"publisher","first-page":"1028","DOI":"10.1038\/nm.2807","volume":"18","author":"TA Wynn","year":"2012","unstructured":"Wynn, T. A. & Ramalingam, T. R. Mechanisms of fibrosis: therapeutic translation for fibrotic disease. Nature medicine 18, 1028\u20131040, doi: 10.1038\/nm.2807 (2012).","journal-title":"Nature medicine"},{"key":"BFsrep37004_CR3","doi-asserted-by":"publisher","first-page":"9448","DOI":"10.1073\/pnas.1201840109","volume":"109","author":"T Kisseleva","year":"2012","unstructured":"Kisseleva, T. et al. Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proceedings of the National Academy of Sciences of the United States of America 109, 9448\u20139453, doi: 10.1073\/pnas.1201840109 (2012).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"BFsrep37004_CR4","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1038\/nrcardio.2009.199","volume":"7","author":"SW van den Borne","year":"2010","unstructured":"van den Borne, S. W. et al. Myocardial remodeling after infarction: the role of myofibroblasts. Nature reviews. Cardiology 7, 30\u201337, doi: 10.1038\/nrcardio.2009.199 (2010).","journal-title":"Nature reviews. Cardiology"},{"key":"BFsrep37004_CR5","doi-asserted-by":"publisher","first-page":"1807","DOI":"10.2353\/ajpath.2007.070112","volume":"170","author":"B Hinz","year":"2007","unstructured":"Hinz, B. et al. The myofibroblast: one function, multiple origins. The American journal of pathology 170, 1807\u20131816, doi: 10.2353\/ajpath.2007.070112 (2007).","journal-title":"The American journal of pathology"},{"key":"BFsrep37004_CR6","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1111\/j.1600-0714.2010.00995.x","volume":"40","author":"PV Angadi","year":"2011","unstructured":"Angadi, P. V., Kale, A. D. & Hallikerimath, S. Evaluation of myofibroblasts in oral submucous fibrosis: correlation with disease severity. Journal of oral pathology & medicine: official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 40, 208\u2013213, doi: 10.1111\/j.1600-0714.2010.00995.x (2011).","journal-title":"Journal of oral pathology & medicine: official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology"},{"key":"BFsrep37004_CR7","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1002\/path.3997","volume":"228","author":"M Shi","year":"2012","unstructured":"Shi, M. et al. Glucocorticoid regulation of a novel HPV-E6-p53-miR-145 pathway modulates invasion and therapy resistance of cervical cancer cells. The Journal of pathology 228, 148\u2013157, doi: 10.1002\/path.3997 (2012).","journal-title":"The Journal of pathology"},{"key":"BFsrep37004_CR8","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1002\/path.2786","volume":"223","author":"KA Moutasim","year":"2011","unstructured":"Moutasim, K. A. et al. Betel-derived alkaloid up-regulates keratinocyte alphavbeta6 integrin expression and promotes oral submucous fibrosis. The Journal of pathology 223, 366\u2013377, doi: 10.1002\/path.2786 (2011).","journal-title":"The Journal of pathology"},{"key":"BFsrep37004_CR9","doi-asserted-by":"publisher","first-page":"12137","DOI":"10.18632\/oncotarget.7763","volume":"7","author":"YC Chang","year":"2016","unstructured":"Chang, Y. C. et al. Resveratrol suppresses myofibroblast activity of human buccal mucosal fibroblasts through the epigenetic inhibition of ZEB1 expression. Oncotarget 7, 12137\u201312149, doi: 10.18632\/oncotarget.7763 (2016).","journal-title":"Oncotarget"},{"key":"BFsrep37004_CR10","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1016\/j.jfma.2015.05.009","volume":"115","author":"YH Lee","year":"2016","unstructured":"Lee, Y. H. et al. Elevation of Twist expression by arecoline contributes to the pathogenesis of oral submucous fibrosis. Journal of the Formosan Medical Association\u2009=\u2009Taiwan yi zhi 115, 311\u2013317, doi: 10.1016\/j.jfma.2015.05.009 (2016).","journal-title":"Journal of the Formosan Medical Association\u2009=\u2009Taiwan yi zhi"},{"key":"BFsrep37004_CR11","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1111\/jcmm.12219","volume":"18","author":"YC Chang","year":"2014","unstructured":"Chang, Y. C. et al. Arecoline-induced myofibroblast transdifferentiation from human buccal mucosal fibroblasts is mediated by ZEB1. Journal of cellular and molecular medicine 18, 698\u2013708, doi: 10.1111\/jcmm.12219 (2014).","journal-title":"Journal of cellular and molecular medicine"},{"key":"BFsrep37004_CR12","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1186\/s13058-015-0652-6","volume":"17","author":"A Aloia","year":"2015","unstructured":"Aloia, A. et al. The sialyl-glycolipid stage-specific embryonic antigen 4 marks a subpopulation of chemotherapy-resistant breast cancer cells with mesenchymal features. Breast cancer research: BCR 17, 146, doi: 10.1186\/s13058-015-0652-6 (2015).","journal-title":"Breast cancer research: BCR"},{"key":"BFsrep37004_CR13","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1186\/s13048-016-0221-3","volume":"9","author":"I Virant-Klun","year":"2016","unstructured":"Virant-Klun, I., Kenda-Suster, N. & Smrkolj, S. Small putative NANOG, SOX2, and SSEA-4-positive stem cells resembling very small embryonic-like stem cells in sections of ovarian tissue in patients with ovarian cancer. Journal of ovarian research 9, 12, doi: 10.1186\/s13048-016-0221-3 (2016).","journal-title":"Journal of ovarian research"},{"key":"BFsrep37004_CR14","doi-asserted-by":"publisher","first-page":"1743","DOI":"10.1182\/blood-2005-11-010504","volume":"109","author":"EJ Gang","year":"2007","unstructured":"Gang, E. J., Bosnakovski, D., Figueiredo, C. A., Visser, J. W. & Perlingeiro, R. C. SSEA-4 identifies mesenchymal stem cells from bone marrow. Blood 109, 1743\u20131751, doi: 10.1182\/blood-2005-11-010504 (2007).","journal-title":"Blood"},{"key":"BFsrep37004_CR15","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1016\/j.oraloncology.2013.04.012","volume":"49","author":"Z Noto","year":"2013","unstructured":"Noto, Z. et al. CD44 and SSEA-4 positive cells in an oral cancer cell line HSC-4 possess cancer stem-like cell characteristics. Oral oncology 49, 787\u2013795, doi: 10.1016\/j.oraloncology.2013.04.012 (2013).","journal-title":"Oral oncology"},{"key":"BFsrep37004_CR16","doi-asserted-by":"publisher","first-page":"902","DOI":"10.1093\/glycob\/cwv032","volume":"25","author":"K Sivasubramaniyan","year":"2015","unstructured":"Sivasubramaniyan, K. et al. Expression of stage-specific embryonic antigen-4 (SSEA-4) defines spontaneous loss of epithelial phenotype in human solid tumor cells. Glycobiology 25, 902\u2013917, doi: 10.1093\/glycob\/cwv032 (2015).","journal-title":"Glycobiology"},{"key":"BFsrep37004_CR17","doi-asserted-by":"publisher","first-page":"2482","DOI":"10.1073\/pnas.1400283111","volume":"111","author":"YW Lou","year":"2014","unstructured":"Lou, Y. W. et al. Stage-specific embryonic antigen-4 as a potential therapeutic target in glioblastoma multiforme and other cancers. Proceedings of the National Academy of Sciences of the United States of America 111, 2482\u20132487, doi: 10.1073\/pnas.1400283111 (2014).","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"BFsrep37004_CR18","doi-asserted-by":"publisher","first-page":"1369","DOI":"10.1016\/j.ajpath.2014.01.012","volume":"184","author":"H Xia","year":"2014","unstructured":"Xia, H. et al. Identification of a cell-of-origin for fibroblasts comprising the fibrotic reticulum in idiopathic pulmonary fibrosis. The American journal of pathology 184, 1369\u20131383, doi: 10.1016\/j.ajpath.2014.01.012 (2014).","journal-title":"The American journal of pathology"},{"key":"BFsrep37004_CR19","doi-asserted-by":"publisher","first-page":"e55122","DOI":"10.1371\/journal.pone.0055122","volume":"8","author":"CC Yu","year":"2013","unstructured":"Yu, C. C., Tsai, C. H., Hsu, H. I. & Chang, Y. C. Elevation of S100A4 expression in buccal mucosal fibroblasts by arecoline: involvement in the pathogenesis of oral submucous fibrosis. PloS one 8, e55122, doi: 10.1371\/journal.pone.0055122 (2013).","journal-title":"PloS one"},{"key":"BFsrep37004_CR20","doi-asserted-by":"crossref","first-page":"24002","DOI":"10.18632\/oncotarget.4365","volume":"6","author":"YC Chang","year":"2015","unstructured":"Chang, Y. C. et al. Activation of microRNA-494-targeting Bmi1 and ADAM10 by silibinin ablates cancer stemness and predicts favourable prognostic value in head and neck squamous cell carcinomas. Oncotarget 6, 24002\u201324016 (2015).","journal-title":"Oncotarget"},{"key":"BFsrep37004_CR21","doi-asserted-by":"publisher","first-page":"20180","DOI":"10.18632\/oncotarget.7745","volume":"7","author":"CC Yu","year":"2016","unstructured":"Yu, C. C., Chen, P. N., Peng, C. Y., Yu, C. H. & Chou, M. Y. Suppression of miR-204 enables oral squamous cell carcinomas to promote cancer stemness, EMT traits, and lymph node metastasis. Oncotarget 7, 20180\u201320192, doi: 10.18632\/oncotarget.7745 (2016).","journal-title":"Oncotarget"},{"key":"BFsrep37004_CR22","doi-asserted-by":"publisher","first-page":"2650","DOI":"10.1091\/mbc.E14-01-0044","volume":"25","author":"R Du","year":"2014","unstructured":"Du, R. et al. Hypoxia-induced Bmi1 promotes renal tubular epithelial cell-mesenchymal transition and renal fibrosis via PI3K\/Akt signal. Molecular biology of the cell 25, 2650\u20132659, doi: 10.1091\/mbc.E14-01-0044 (2014).","journal-title":"Molecular biology of the cell"},{"key":"BFsrep37004_CR23","doi-asserted-by":"publisher","first-page":"768","DOI":"10.3324\/haematol.2014.118463","volume":"100","author":"I Triviai","year":"2015","unstructured":"Triviai, I. et al. CD133 marks a stem cell population that drives human primary myelofibrosis. Haematologica 100, 768\u2013779, doi: 10.3324\/haematol.2014.118463 (2015).","journal-title":"Haematologica"},{"key":"BFsrep37004_CR24","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1002\/art.38276","volume":"66","author":"S Liu","year":"2014","unstructured":"Liu, S., Herault, Y., Pavlovic, G. & Leask, A. Skin progenitor cells contribute to bleomycin-induced skin fibrosis. Arthritis Rheumatol 66, 707\u2013713, doi: 10.1002\/art.38276 (2014).","journal-title":"Arthritis Rheumatol"},{"key":"BFsrep37004_CR25","doi-asserted-by":"publisher","first-page":"e7798","DOI":"10.1371\/journal.pone.0007798","volume":"4","author":"Q Zhang","year":"2009","unstructured":"Zhang, Q. et al. Tumor-like stem cells derived from human keloid are governed by the inflammatory niche driven by IL-17\/IL-6 axis. PloS one 4, e7798, doi: 10.1371\/journal.pone.0007798 (2009).","journal-title":"PloS one"},{"key":"BFsrep37004_CR26","doi-asserted-by":"publisher","first-page":"e0129252","DOI":"10.1371\/journal.pone.0129252","volume":"10","author":"I Pant","year":"2015","unstructured":"Pant, I., Kumar, N., Khan, I., Rao, S. G. & Kondaiah, P. Role of Areca Nut Induced TGF-beta and Epithelial-Mesenchymal Interaction in the Pathogenesis of Oral Submucous Fibrosis. PloS one 10, e0129252, doi: 10.1371\/journal.pone.0129252 (2015).","journal-title":"PloS one"},{"key":"BFsrep37004_CR27","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1016\/j.yexmp.2013.08.006","volume":"95","author":"RK Das","year":"2013","unstructured":"Das, R. K. et al. Epithelio-mesenchymal transitional attributes in oral sub-mucous fibrosis. Experimental and molecular pathology 95, 259\u2013269, doi: 10.1016\/j.yexmp.2013.08.006 (2013).","journal-title":"Experimental and molecular pathology"},{"key":"BFsrep37004_CR28","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1016\/S1368-8375(02)00123-9","volume":"39","author":"SF Yang","year":"2003","unstructured":"Yang, S. F., H. Y., Tsai, C. H., Chou, M. Y. & Chang, Y. C. The upregulation of type I plasminogen activator inhibitor in oral submucous fibrosis. Oral oncology 39, 367\u2013372 (2003).","journal-title":"Oral oncology"},{"key":"BFsrep37004_CR29","doi-asserted-by":"publisher","first-page":"940","DOI":"10.1016\/j.oraloncology.2005.05.006","volume":"41","author":"CH Tsai","year":"2005","unstructured":"Tsai, C. H., Yang, S. F., Chen, Y. J., Chou, M. Y. & Chang, Y. C. The upregulation of insulin-like growth factor-1 in oral submucous fibrosis. Oral oncology 41, 940\u2013946, doi: 10.1016\/j.oraloncology.2005.05.006 (2005).","journal-title":"Oral oncology"},{"key":"BFsrep37004_CR30","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1016\/j.oraloncology.2006.06.007","volume":"43","author":"WF Ni","year":"2007","unstructured":"Ni, W. F., T. C., Yang, S. F. & Chang, Y. C. Elevated expression of NF-kB in oral submucous fibrosis-evidence for NF-kB induction by safrole in human buccal mucosal fibroblasts. Oral oncology 43, 557\u2013562 (2007).","journal-title":"Oral oncology"},{"key":"BFsrep37004_CR31","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1016\/S1368-8375(01)00083-5","volume":"38","author":"YC Chang","year":"2002","unstructured":"Chang, Y. C., T. C., Tai, K. W., Yang, S. H., Chou, M. Y. & Lii, C. K. Elevated vimentin expression in buccal mucosal fibroblasts by arecoline in vitro as a possible pathogenesis for oral submucous fibrosis. Oral oncology 38, 425\u2013430 (2002).","journal-title":"Oral oncology"},{"key":"BFsrep37004_CR32","doi-asserted-by":"publisher","first-page":"G950","DOI":"10.1152\/ajpgi.00132.2011","volume":"301","author":"TN Wight","year":"2011","unstructured":"Wight, T. N. & Potter-Perigo, S. The extracellular matrix: an active or passive player in fibrosis? American journal of physiology. Gastrointestinal and liver physiology 301, G950\u2013G955, doi: 10.1152\/ajpgi.00132.2011 (2011).","journal-title":"American journal of physiology. Gastrointestinal and liver physiology"},{"key":"BFsrep37004_CR33","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1177\/0022034516634288","volume":"95","author":"WH Yang","year":"2016","unstructured":"Yang, W. H., Deng, Y. T., Hsieh, Y. P., Wu, K. J. & Kuo, M. Y. Thrombin Activates Latent TGFbeta1 via Integrin alphavbeta1 in Gingival Fibroblasts. Journal of dental research 95, 939\u2013945, doi: 10.1177\/0022034516634288 (2016).","journal-title":"Journal of dental research"},{"key":"BFsrep37004_CR34","doi-asserted-by":"publisher","first-page":"976","DOI":"10.1177\/0022034515580986","volume":"94","author":"WH Yang","year":"2015","unstructured":"Yang, W. H., Deng, Y. T., Hsieh, Y. P., Wu, K. J. & Kuo, M. Y. NADPH Oxidase 4 Mediates TGFbeta1-induced CCN2 in Gingival Fibroblasts. Journal of dental research 94, 976\u2013982, doi: 10.1177\/0022034515580986 (2015).","journal-title":"Journal of dental research"},{"key":"BFsrep37004_CR35","doi-asserted-by":"publisher","first-page":"27610","DOI":"10.1038\/srep27610","volume":"6","author":"Q Liu","year":"2016","unstructured":"Liu, Q. et al. Salvianolic Acid B Attenuates Experimental Pulmonary Fibrosis through Inhibition of the TGF-beta Signaling Pathway. Scientific Reports 6, 27610, doi: 10.1038\/srep27610 (2016).","journal-title":"Scientific Reports"},{"key":"BFsrep37004_CR36","doi-asserted-by":"publisher","first-page":"16552","DOI":"10.1038\/srep16552","volume":"5","author":"HY Li","year":"2015","unstructured":"Li, H. Y. et al. Activation of TGF-beta1-CD147 positive feedback loop in hepatic stellate cells promotes liver fibrosis. Scientific Reports 5, 16552, doi: 10.1038\/srep16552 (2015).","journal-title":"Scientific Reports"},{"key":"BFsrep37004_CR37","doi-asserted-by":"publisher","first-page":"e51806","DOI":"10.1371\/journal.pone.0051806","volume":"7","author":"I Khan","year":"2012","unstructured":"Khan, I., Kumar, N., Pant, I., Narra, S. & Kondaiah, P. Activation of TGF-beta pathway by areca nut constituents: a possible cause of oral submucous fibrosis. PloS one 7, e51806, doi: 10.1371\/journal.pone.0051806 (2012).","journal-title":"PloS one"},{"key":"BFsrep37004_CR38","doi-asserted-by":"publisher","first-page":"4085","DOI":"10.1158\/1078-0432.CCR-07-4404","volume":"14","author":"SH Chiou","year":"2008","unstructured":"Chiou, S. H. et al. Positive correlations of Oct-4 and Nanog in oral cancer stem-like cells and high-grade oral squamous cell carcinoma. Clinical cancer research: an official journal of the American Association for Cancer Research 14, 4085\u20134095, doi: 10.1158\/1078-0432.CCR-07-4404 (2008).","journal-title":"Clinical cancer research: an official journal of the American Association for Cancer Research"},{"key":"BFsrep37004_CR39","doi-asserted-by":"publisher","first-page":"3425","DOI":"10.1158\/0008-5472.CAN-12-3840","volume":"73","author":"CC Yu","year":"2013","unstructured":"Yu, C. C. et al. miR145 targets the SOX9\/ADAM17 axis to inhibit tumor-initiating cells and IL-6-mediated paracrine effects in head and neck cancer. Cancer research 73, 3425\u20133440, doi: 10.1158\/0008-5472.CAN-12-3840 (2013).","journal-title":"Cancer research"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep37004.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep37004","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep37004.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T02:58:10Z","timestamp":1672887490000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep37004"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,11,15]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,12,23]]}},"alternative-id":["BFsrep37004"],"URL":"https:\/\/doi.org\/10.1038\/srep37004","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,11,15]]},"assertion":[{"value":"3 August 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 October 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 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":"37004"}}