{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T15:38:41Z","timestamp":1790869121020,"version":"4.1.0"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2018,3,16]],"date-time":"2018-03-16T00:00:00Z","timestamp":1521158400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,3,16]],"date-time":"2018-03-16T00:00:00Z","timestamp":1521158400000},"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":["Int J Oral Sci"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The hyphal development of\n                    <jats:italic>Candida albicans<\/jats:italic>\n                    (\n                    <jats:italic>C. albicans<\/jats:italic>\n                    ) has been considered as an essential virulent factor for host cell damage. However, the missing link between hyphae and virulence of\n                    <jats:italic>C. albicans<\/jats:italic>\n                    is also been discovered. Here, we identified that the null mutants of\n                    <jats:italic>ERG3<\/jats:italic>\n                    and\n                    <jats:italic>ERG11<\/jats:italic>\n                    , two key genes in ergosterol biosynthesis pathway, can form typical hyphae but failed to cause the oral mucosal infection in vitro and in vivo for the first time. In particular, the\n                    <jats:italic>erg3\u0394\/\u0394<\/jats:italic>\n                    and\n                    <jats:italic>erg11\u0394\/\u0394<\/jats:italic>\n                    strains co-cultured with epithelial cells significantly reduced the adhesion, damage, and cytokine (interleukin-1\u03b1 (IL-1\u03b1)) production, whereas the invasion was not affected in vitro. Importantly, they were incapable of extensive hyphal invasion, formation of micro-abscesses, and tongue epithelium damage compared to wild type due to the decrease of the colonization and epithelial infection area in a murine oropharyngeal candidiasis model. The fluconazole (FLC), an antifungal targeted at ergosterol biosynthesis, relieved the epithelial infection of\n                    <jats:italic>C. albicans<\/jats:italic>\n                    in vitro and in vivo even under non-growth inhibitory dosage confirming the virulent contribution of ergosterol biosynthesis pathway. The\n                    <jats:italic>erg3\u0394\/\u0394<\/jats:italic>\n                    and\n                    <jats:italic>erg11\u0394\/\u0394<\/jats:italic>\n                    strains were cleared by macrophages similar to wild type, whereas their virulence factors including agglutinin-like sequence 1 (Als1), secreted aspartyl proteinase 6 (Sap6), and hyphal wall protein-1 (Hwp1) were significantly reduced indicated that the non-toxicity might not result from the change on immune tolerance but the defective virulence. The incapacity of\n                    <jats:italic>erg3\u0394\/\u0394<\/jats:italic>\n                    and\n                    <jats:italic>erg11\u0394\/\u0394<\/jats:italic>\n                    in epithelial infection highlights the contribution of ergosterol biosynthesis pathway to\n                    <jats:italic>C. albicans<\/jats:italic>\n                    pathogenesis and fluconazole can not only eliminate the fungal pathogens but also reduced their virulence even at low dosage.\n                  <\/jats:p>","DOI":"10.1038\/s41368-018-0013-2","type":"journal-article","created":{"date-parts":[[2018,4,3]],"date-time":"2018-04-03T21:57:52Z","timestamp":1522792672000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":59,"title":["ERG3 and ERG11 genes are critical for the pathogenesis of Candida albicans during the oral mucosal infection"],"prefix":"10.1038","volume":"10","author":[{"given":"Yujie","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengguang","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingye","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biao","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuedong","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,3,16]]},"reference":[{"key":"13_CR1","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1007\/s00520-010-0892-z","volume":"18","author":"RV Lalla","year":"2010","unstructured":"Lalla, R. V. et al. A systematic review of oral fungal infections in patients receiving cancer therapy. Support Care Cancer 18, 985\u2013992 (2010).","journal-title":"Support Care Cancer"},{"key":"13_CR2","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1136\/pmj.78.922.455","volume":"78","author":"A Akpan","year":"2002","unstructured":"Akpan, A. & Morgan, R. Oral candidiasis. Postgrad. Med. J. 78, 455\u2013459 (2002).","journal-title":"Postgrad. Med. J."},{"issue":"Suppl 1","key":"13_CR3","first-page":"77","volume":"51","author":"T Daniluk","year":"2006","unstructured":"Daniluk, T. et al. Occurrence rate of oral Candida albicans in denture wearer patients. Adv. Med. Sci. 51(Suppl 1), 77\u201380 (2006).","journal-title":"Adv. Med. Sci."},{"key":"13_CR4","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1016\/0002-9343(94)90300-X","volume":"97","author":"JA Sangeorzan","year":"1994","unstructured":"Sangeorzan, J. A. et al. Epidemiology of oral candidiasis in HIV-infected patients: colonization, infection, treatment, and emergence of fluconazole resistance. Am. J. Med. 97, 339\u2013346 (1994).","journal-title":"Am. J. Med."},{"key":"13_CR5","doi-asserted-by":"publisher","first-page":"e1000713","DOI":"10.1371\/journal.ppat.1000713","volume":"6","author":"MA Ghannoum","year":"2010","unstructured":"Ghannoum, M. A. et al. Characterization of the oral fungal microbiome (mycobiome) in healthy individuals. PLoS Pathog. 6, e1000713 (2010).","journal-title":"PLoS Pathog."},{"key":"13_CR6","doi-asserted-by":"publisher","first-page":"e1005867","DOI":"10.1371\/journal.ppat.1005867","volume":"12","author":"D Wilson","year":"2016","unstructured":"Wilson, D., Naglik, J. R. & Hube, B. The missing link between Candida albicans hyphal morphogenesis and host cell damage. PLoS Pathog. 12, e1005867 (2016).","journal-title":"PLoS Pathog."},{"key":"13_CR7","doi-asserted-by":"publisher","first-page":"3689","DOI":"10.1128\/IAI.70.7.3689-3700.2002","volume":"70","author":"A Felk","year":"2002","unstructured":"Felk, A. et al. Candida albicans hyphal formation and the expression of the Efg1-regulated proteinases Sap4 to Sap6 are required for the invasion of parenchymal organs. Infect. Immun. 70, 3689\u20133700 (2002).","journal-title":"Infect. Immun."},{"key":"13_CR8","doi-asserted-by":"publisher","first-page":"119","DOI":"10.4161\/viru.22913","volume":"4","author":"FL Mayer","year":"2013","unstructured":"Mayer, F. L., Wilson, D. & Hube, B. Candida albicans pathogenicity mechanisms. Virulence 4, 119\u2013128 (2013).","journal-title":"Virulence"},{"key":"13_CR9","doi-asserted-by":"publisher","first-page":"1546","DOI":"10.1111\/j.1462-5822.2005.00616.x","volume":"7","author":"CA Kumamoto","year":"2005","unstructured":"Kumamoto, C. A. & Vinces, M. D. Contributions of hyphae and hypha-co-regulated genes to Candida albicans virulence. Cell Microbiol. 7, 1546\u20131554 (2005).","journal-title":"Cell Microbiol."},{"key":"13_CR10","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1128\/EC.00279-10","volume":"10","author":"Y Liu","year":"2011","unstructured":"Liu, Y. & Filler, S. G. Candida albicans Als3, a multifunctional adhesin and invasin. Eukaryot. Cell 10, 168\u2013173 (2011).","journal-title":"Eukaryot. Cell"},{"key":"13_CR11","doi-asserted-by":"crossref","first-page":"1783","DOI":"10.1128\/IAI.66.4.1783-1786.1998","volume":"66","author":"Y Fu","year":"1998","unstructured":"Fu, Y. et al. Expression of the Candida albicans gene ALS1 in Saccharomyces cerevisiae induces adherence to endothelial and epithelial cells. Infect. Immun. 66, 1783\u20131786 (1998).","journal-title":"Infect. Immun."},{"key":"13_CR12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/13693780701435317","volume":"46","author":"LL Hoyer","year":"2008","unstructured":"Hoyer, L. L. et al. Discovering the secrets of the Candida albicans agglutinin-like sequence (ALS) gene family\u2014a sticky pursuit. Med. Mycol. 46, 1\u201315 (2008).","journal-title":"Med. Mycol."},{"key":"13_CR13","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1126\/science.283.5407.1535","volume":"283","author":"JF Staab","year":"1999","unstructured":"Staab, J. F. et al. Adhesive and mammalian transglutaminase substrate properties of Candida albicans Hwp1. Science 283, 1535\u20131538 (1999).","journal-title":"Science"},{"key":"13_CR14","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1046\/j.1365-2958.1999.01590.x","volume":"34","author":"M Schaller","year":"1999","unstructured":"Schaller, M. et al. Secreted aspartic proteinase (Sap) activity contributes to tissue damage in a model of human oral candidosis. Mol. Microbiol. 34, 169\u2013180 (1999).","journal-title":"Mol. Microbiol."},{"key":"13_CR15","doi-asserted-by":"publisher","first-page":"2758","DOI":"10.1128\/IAI.73.5.2758-2765.2005","volume":"73","author":"M Schaller","year":"2005","unstructured":"Schaller, M. et al. Candida albicans-secreted aspartic proteinases modify the epithelial cytokine response in an in vitro model of vaginal candidiasis. Infect. Immun. 73, 2758\u20132765 (2005).","journal-title":"Infect. Immun."},{"key":"13_CR16","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1046\/j.1365-2958.1998.00957.x","volume":"29","author":"M Schaller","year":"1998","unstructured":"Schaller, M. et al. Differential expression of secreted aspartyl proteinases in a model of human oral candidosis and in patient samples from the oral cavity. Mol. Microbiol 29, 605\u2013615 (1998).","journal-title":"Mol. Microbiol"},{"key":"13_CR17","first-page":"3664","volume":"117","author":"G Weindl","year":"2007","unstructured":"Weindl, G. et al. Human epithelial cells establish direct antifungal defense through TLR4-mediated signaling. J. Clin. Invest. 117, 3664\u20133672 (2007).","journal-title":"J. Clin. Invest."},{"key":"13_CR18","doi-asserted-by":"publisher","first-page":"225","DOI":"10.1016\/j.chom.2010.08.002","volume":"8","author":"DL Moyes","year":"2010","unstructured":"Moyes, D. L. et al. A biphasic innate immune MAPK response discriminates between the yeast and hyphal forms of Candida albicans in epithelial cells. Cell Host Microbe 8, 225\u2013235 (2010).","journal-title":"Cell Host Microbe"},{"key":"13_CR19","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1038\/nature17625","volume":"532","author":"DL Moyes","year":"2016","unstructured":"Moyes, D. L. et al. Candidalysin is a fungal peptide toxin critical for mucosal infection. Nature 532, 64\u201368 (2016).","journal-title":"Nature"},{"key":"13_CR20","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1042\/bst0211034","volume":"21","author":"SL Kelly","year":"1993","unstructured":"Kelly, S. L., Arnoldi, A. & Kelly, D. E. Molecular genetic analysis of azole antifungal mode of action. Biochem. Soc. Trans. 21, 1034\u20131038 (1993).","journal-title":"Biochem. Soc. Trans."},{"key":"13_CR21","doi-asserted-by":"publisher","first-page":"2234","DOI":"10.1073\/pnas.1117280109","volume":"109","author":"KC Gray","year":"2012","unstructured":"Gray, K. C. et al. Amphotericin primarily kills yeast by simply binding ergosterol. Proc. Natl Acad. Sci. USA 109, 2234\u20132239 (2012).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"13_CR22","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1016\/S0966-842X(03)00117-3","volume":"11","author":"FC Odds","year":"2003","unstructured":"Odds, F. C., Brown, A. J. & Gow, N. A. Antifungal agents: mechanisms of action. Trends Microbiol 11, 272\u2013279 (2003).","journal-title":"Trends Microbiol"},{"key":"13_CR23","doi-asserted-by":"publisher","first-page":"e1000040","DOI":"10.1371\/journal.ppat.1000040","volume":"4","author":"LA Walker","year":"2008","unstructured":"Walker, L. A. et al. Stimulation of chitin synthesis rescues Candida albicans from echinocandins. PLoS Pathog. 4, e1000040 (2008).","journal-title":"PLoS Pathog."},{"key":"13_CR24","doi-asserted-by":"publisher","first-page":"1084","DOI":"10.1039\/b914961a","volume":"27","author":"R Di Santo","year":"2010","unstructured":"Di Santo, R. Natural products as antifungal agents against clinically relevant pathogens. Nat. Prod. Rep. 27, 1084\u20131098 (2010).","journal-title":"Nat. Prod. Rep."},{"key":"13_CR25","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1128\/CMR.12.4.501","volume":"12","author":"MA Ghannoum","year":"1999","unstructured":"Ghannoum, M. A. & Rice, L. B. Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance. Clin. Microbiol. Rev. 12, 501\u2013517 (1999).","journal-title":"Clin. Microbiol. Rev."},{"key":"13_CR26","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1086\/344058","volume":"35","author":"GM Eliopoulos","year":"2002","unstructured":"Eliopoulos, G. M., Perea, S. & Patterson, T. F. Antifungal resistance in pathogenic fungi. Clin. Infect. Dis. 35, 1073\u20131080 (2002).","journal-title":"Clin. Infect. Dis."},{"key":"13_CR27","doi-asserted-by":"crossref","first-page":"2835","DOI":"10.1128\/AAC.40.12.2835","volume":"40","author":"GD Albertson","year":"1996","unstructured":"Albertson, G. D. et al. Multiple efflux mechanisms are involved in Candida albicans fluconazole resistance. Antimicrob. Agents Chemother. 40, 2835\u20132841 (1996).","journal-title":"Antimicrob. Agents Chemother."},{"key":"13_CR28","doi-asserted-by":"publisher","first-page":"2708","DOI":"10.1128\/AAC.39.12.2708","volume":"39","author":"A Geber","year":"1995","unstructured":"Geber, A. et al. Deletion of the Candida glabrata ERG3 and ERG11 genes: effect on cell viability, cell growth, sterol composition, and antifungal susceptibility. Antimicrob. Agents Chemother. 39, 2708\u20132717 (1995).","journal-title":"Antimicrob. Agents Chemother."},{"key":"13_CR29","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1111\/j.1439-0507.2008.01550.x","volume":"52","author":"S Boreck\u00e1-Melkusov\u00e1","year":"2009","unstructured":"Boreck\u00e1-Melkusov\u00e1, S. et al. The expression of genes involved in the ergosterol biosynthesis pathway in Candida albicans and Candida dubliniensis biofilms exposed to fluconazole. Mycoses 52, 118\u2013128 (2009).","journal-title":"Mycoses"},{"key":"13_CR30","doi-asserted-by":"publisher","first-page":"2404","DOI":"10.1128\/AAC.47.8.2404-2412.2003","volume":"47","author":"D Sanglard","year":"2003","unstructured":"Sanglard, D. et al. Candida albicans mutations in the ergosterol biosynthetic pathway and resistance to several antifungal agents. Antimicrob. Agents Chemother. 47, 2404\u20132412 (2003).","journal-title":"Antimicrob. Agents Chemother."},{"key":"13_CR31","doi-asserted-by":"publisher","first-page":"1471","DOI":"10.1002\/(SICI)1097-0061(199812)14:16<1471::AID-YEA353>3.0.CO;2-Y","volume":"14","author":"G Daum","year":"1998","unstructured":"Daum, G. et al. Biochemistry, cell biology and molecular biology of lipids of Saccharomyces cerevisiae. Yeast 14, 1471\u20131510 (1998).","journal-title":"Yeast"},{"key":"13_CR32","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/S1471-4914(02)02280-3","volume":"8","author":"A Lupetti","year":"2002","unstructured":"Lupetti, A. et al. Molecular basis of resistance to azole antifungals. Trends Mol. Med. 8, 76\u201381 (2002).","journal-title":"Trends Mol. Med."},{"key":"13_CR33","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1128\/AAC.50.2.580-586.2006","volume":"50","author":"T Miyazaki","year":"2006","unstructured":"Miyazaki, T. et al. Fluconazole treatment is effective against a Candida albicans erg3\/erg3 mutant in vivo despite in vitro resistance. Antimicrob. Agents Chemother. 50, 580\u2013586 (2006).","journal-title":"Antimicrob. Agents Chemother."},{"key":"13_CR34","doi-asserted-by":"publisher","first-page":"22044","DOI":"10.1073\/pnas.1009845107","volume":"107","author":"JM Becker","year":"2010","unstructured":"Becker, J. M. et al. Pathway analysis of Candida albicans survival and virulence determinants in a murine infection model. Proc. Natl Acad. Sci. USA 107, 22044\u201322049 (2010).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"13_CR35","doi-asserted-by":"publisher","first-page":"1626","DOI":"10.1128\/AAC.36.8.1626","volume":"36","author":"O Shimokawa","year":"1992","unstructured":"Shimokawa, O. & Nakayama, H. Increased sensitivity of Candida albicans cells accumulating 14 alpha-methylated sterols to active oxygen: possible relevance to in vivo efficacies of azole antifungal agents. Antimicrob. Agents Chemother. 36, 1626\u20131629 (1992).","journal-title":"Antimicrob. Agents Chemother."},{"key":"13_CR36","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1128\/AAC.40.7.1717","volume":"40","author":"VL Kan","year":"1996","unstructured":"Kan, V. L., Geber, A. & Bennett, J. E. Enhanced oxidative killing of azole-resistant Candida glabrata strains with ERG11 deletion. Antimicrob. Agents Chemother. 40, 1717\u20131719 (1996).","journal-title":"Antimicrob. Agents Chemother."},{"key":"13_CR37","doi-asserted-by":"publisher","first-page":"1476","DOI":"10.1128\/AAC.01645-09","volume":"54","author":"DM MacCallum","year":"2010","unstructured":"MacCallum, D. M. et al. Genetic dissection of azole resistance mechanisms in Candida albicans and their validation in a mouse model of disseminated infection. Antimicrob. Agents Chemother. 54, 1476\u20131483 (2010).","journal-title":"Antimicrob. Agents Chemother."},{"key":"13_CR38","doi-asserted-by":"publisher","first-page":"1753","DOI":"10.1128\/AAC.01728-09","volume":"54","author":"S Gamarra","year":"2010","unstructured":"Gamarra, S. et al. Mechanism of the synergistic effect of amiodarone and fluconazole in Candida albicans. Antimicrob. Agents Chemother. 54, 1753\u20131761 (2010).","journal-title":"Antimicrob. Agents Chemother."},{"key":"13_CR39","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1021\/pr100710g","volume":"10","author":"L Monteoliva","year":"2011","unstructured":"Monteoliva, L. et al. Quantitative proteome and acidic subproteome profiling of Candida albicans yeast-to-hypha transition. J. Proteome Res. 10, 502\u2013517 (2011).","journal-title":"J. Proteome Res."},{"key":"13_CR40","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1586\/eri.11.152","volume":"10","author":"ID Jacobsen","year":"2012","unstructured":"Jacobsen, I. D. et al. Candida albicans dimorphism as a therapeutic target. Expert Rev. Anti Infect. Ther. 10, 85\u201393 (2012).","journal-title":"Expert Rev. Anti Infect. Ther."},{"key":"13_CR41","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1006\/bbrc.1995.1272","volume":"207","author":"SL Kelly","year":"1995","unstructured":"Kelly, S. L. et al. Mode of action and resistance to azole antifungals associated with the formation of 14 alpha-methylergosta-8, 24(28)-dien-3beta, 6 alpha-diol. Biochem. Biophys. Res. Commun. 207, 910\u2013915 (1995).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"13_CR42","doi-asserted-by":"publisher","first-page":"637","DOI":"10.1038\/nprot.2012.011","volume":"7","author":"NV Solis","year":"2012","unstructured":"Solis, N. V. & Filler, S. G. Mouse model of oropharyngeal candidiasis. Nat. Protoc. 7, 637\u2013642 (2012).","journal-title":"Nat. Protoc."}],"container-title":["International Journal of Oral Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41368-018-0013-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41368-018-0013-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41368-018-0013-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T05:52:54Z","timestamp":1671515574000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41368-018-0013-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,16]]},"references-count":42,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2018,6]]}},"alternative-id":["13"],"URL":"https:\/\/doi.org\/10.1038\/s41368-018-0013-2","relation":{},"ISSN":["2049-3169"],"issn-type":[{"value":"2049-3169","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,3,16]]},"assertion":[{"value":"20 September 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 December 2017","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 January 2018","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 March 2018","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"9"}}