{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T05:58:20Z","timestamp":1790402300110,"version":"4.1.0"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,6,9]],"date-time":"2017-06-09T00:00:00Z","timestamp":1496966400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,6,9]],"date-time":"2017-06-09T00:00:00Z","timestamp":1496966400000},"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>Nontypeable <jats:italic>Haemophilus influenzae<\/jats:italic> (NTHI) is the causative agent of multiple respiratory tract infections. Several human pathogens, including NTHI, possess a novel genetic system, termed the phasevarion, which mediates a rapid and reversible change in the expression of many genes throughout the chromosome. This occurs by phase variation of a single gene (<jats:italic>modA<\/jats:italic>) that encodes a DNA methyltransferase and results in two phenotypically distinct subpopulations, ON and OFF. NTHI encounters many pressures within the various microenvironments of its human host as the disease course evolves from one of asymptomatic nasopharyngeal carriage to overt disease. These include oxidative stresses, which are present throughout the respiratory tract. To persist in the human nasopharynx and as a pathogen throughout the airways, NTHI must be able to mitigate toxic levels of oxidative stress. Here we show that expression of ModA2, <jats:italic>modA2<\/jats:italic> ON status, resulted in increased sensitivity to oxidative stress. Furthermore, the <jats:italic>modA2<\/jats:italic> ON status resulted in decreased resistance to neutrophil-mediated killing, which resulted in selection for the <jats:italic>modA2<\/jats:italic> OFF subpopulation in an <jats:italic>ex vivo<\/jats:italic> survival assay. These findings highlight the importance of the ModA2 phasevarion in adaptation to innate host defences and reveal an additional microenvironmental pressure that selected for a specific ModA2 subpopulation.<\/jats:p>","DOI":"10.1038\/s41598-017-03552-9","type":"journal-article","created":{"date-parts":[[2017,6,5]],"date-time":"2017-06-05T10:19:39Z","timestamp":1496657979000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["The ModA2 Phasevarion of nontypeable Haemophilus influenzae Regulates Resistance to Oxidative Stress and Killing by Human Neutrophils"],"prefix":"10.1038","volume":"7","author":[{"given":"Kenneth L.","family":"Brockman","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. Taylor","family":"Branstool","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Atack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5583-9194","authenticated-orcid":false,"given":"Frank","family":"Robledo-Avila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2996-9440","authenticated-orcid":false,"given":"Santiago","family":"Partida-Sanchez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P.","family":"Jennings","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren O.","family":"Bakaletz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,6,9]]},"reference":[{"issue":"Suppl 7","key":"3552_CR1","doi-asserted-by":"publisher","first-page":"G20","DOI":"10.1016\/j.vaccine.2008.11.009","volume":"26","author":"M Haggard","year":"2008","unstructured":"Haggard, M. Otitis media: prospects for prevention. Vaccine \n                           26(Suppl 7), G20\u201324, doi:10.1016\/j.vaccine.2008.11.009 (2008).","journal-title":"Vaccine"},{"key":"3552_CR2","doi-asserted-by":"publisher","first-page":"E1","DOI":"10.1002\/lary.24862","volume":"125","author":"TJ Autio","year":"2015","unstructured":"Autio, T. J. et al. The role of microbes in the pathogenesis of acute rhinosinusitis in young adults. The Laryngoscope \n                           125, E1\u20137, doi:10.1002\/lary.24862 (2015).","journal-title":"The Laryngoscope"},{"key":"3552_CR3","doi-asserted-by":"publisher","first-page":"2114","DOI":"10.1164\/ajrccm.164.11.2104093","volume":"164","author":"V Bandi","year":"2001","unstructured":"Bandi, V. et al. Nontypeable Haemophilus influenzae in the lower respiratory tract of patients with chronic bronchitis. American journal of respiratory and critical care medicine \n                           164, 2114\u20132119, doi:10.1164\/ajrccm.164.11.2104093 (2001).","journal-title":"American journal of respiratory and critical care medicine"},{"key":"3552_CR4","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1007\/s10096-016-2640-x","volume":"35","author":"I Brook","year":"2016","unstructured":"Brook, I. Microbiology of chronic rhinosinusitis. European journal of clinical microbiology & infectious diseases: official publication of the European Society of Clinical Microbiology \n                           35, 1059\u20131068, doi:10.1007\/s10096-016-2640-x (2016).","journal-title":"European journal of clinical microbiology & infectious diseases: official publication of the European Society of Clinical Microbiology"},{"key":"3552_CR5","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1128\/CMR.00068-09","volume":"23","author":"JJ Lipuma","year":"2010","unstructured":"Lipuma, J. J. The changing microbial epidemiology in cystic fibrosis. Clinical microbiology reviews \n                           23, 299\u2013323, doi:10.1128\/CMR.00068-09 (2010).","journal-title":"Clinical microbiology reviews"},{"key":"3552_CR6","doi-asserted-by":"publisher","first-page":"5547","DOI":"10.1073\/pnas.0501169102","volume":"102","author":"YN Srikhanta","year":"2005","unstructured":"Srikhanta, Y. N., Maguire, T. L., Stacey, K. J., Grimmond, S. M. & Jennings, M. P. The phasevarion: a genetic system controlling coordinated, random switching of expression of multiple genes. Proc Natl Acad Sci USA \n                           102, 5547\u20135551, doi:10.1073\/pnas.0501169102 (2005).","journal-title":"Proc Natl Acad Sci USA"},{"key":"3552_CR7","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1038\/nrmicro2283","volume":"8","author":"YN Srikhanta","year":"2010","unstructured":"Srikhanta, Y. N., Fox, K. L. & Jennings, M. P. The phasevarion: phase variation of type III DNA methyltransferases controls coordinated switching in multiple genes. Nature reviews. Microbiology \n                           8, 196\u2013206, doi:10.1038\/nrmicro2283 (2010).","journal-title":"Nature reviews. Microbiology"},{"key":"3552_CR8","doi-asserted-by":"publisher","first-page":"7828","DOI":"10.1038\/ncomms8828","volume":"6","author":"JM Atack","year":"2015","unstructured":"Atack, J. M. et al. A biphasic epigenetic switch controls immunoevasion, virulence and niche adaptation in non-typeable Haemophilus influenzae. Nature communications \n                           6, 7828, doi:10.1038\/ncomms8828 (2015).","journal-title":"Nature communications"},{"key":"3552_CR9","doi-asserted-by":"publisher","first-page":"e32337","DOI":"10.1371\/journal.pone.0032337","volume":"7","author":"JA Gawthorne","year":"2012","unstructured":"Gawthorne, J. A., Beatson, S. A., Srikhanta, Y. N., Fox, K. L. & Jennings, M. P. Origin of the diversity in DNA recognition domains in phasevarion associated modA genes of pathogenic Neisseria and Haemophilus influenzae. PloS one \n                           7, e32337, doi:10.1371\/journal.pone.0032337 (2012).","journal-title":"PloS one"},{"key":"3552_CR10","doi-asserted-by":"publisher","first-page":"5055","DOI":"10.1038\/ncomms6055","volume":"5","author":"AS Manso","year":"2014","unstructured":"Manso, A. S. et al. A random six-phase switch regulates pneumococcal virulence via global epigenetic changes. Nature communications \n                           5, 5055, doi:10.1038\/ncomms6055 (2014).","journal-title":"Nature communications"},{"key":"3552_CR11","doi-asserted-by":"publisher","first-page":"5197","DOI":"10.1096\/fj.14-256578","volume":"28","author":"LV Blakeway","year":"2014","unstructured":"Blakeway, L. V. et al. ModM DNA methyltransferase methylome analysis reveals a potential role for Moraxella catarrhalis phasevarions in otitis media. FASEB journal: official publication of the Federation of American Societies for Experimental Biology \n                           28, 5197\u20135207, doi:10.1096\/fj.14-256578 (2014).","journal-title":"FASEB journal: official publication of the Federation of American Societies for Experimental Biology"},{"key":"3552_CR12","doi-asserted-by":"publisher","first-page":"e27569","DOI":"10.1371\/journal.pone.0027569","volume":"6","author":"YN Srikhanta","year":"2011","unstructured":"Srikhanta, Y. N. et al. Phasevarion mediated epigenetic gene regulation in Helicobacter pylori. PloS one \n                           6, e27569, doi:10.1371\/journal.pone.0027569 (2011).","journal-title":"PloS one"},{"key":"3552_CR13","doi-asserted-by":"publisher","first-page":"e1000400","DOI":"10.1371\/journal.ppat.1000400","volume":"5","author":"YN Srikhanta","year":"2009","unstructured":"Srikhanta, Y. N. et al. Phasevarions mediate random switching of gene expression in pathogenic Neisseria. PLoS pathogens \n                           5, e1000400, doi:10.1371\/journal.ppat.1000400 (2009).","journal-title":"PLoS pathogens"},{"key":"3552_CR14","doi-asserted-by":"publisher","first-page":"3622","DOI":"10.1096\/fj.11-183590","volume":"25","author":"KL Seib","year":"2011","unstructured":"Seib, K. L. et al. A novel epigenetic regulator associated with the hypervirulent Neisseria meningitidis clonal complex 41\/44. FASEB J \n                           25, 3622\u20133633, doi:10.1096\/fj.11-183590 (2011).","journal-title":"FASEB J"},{"key":"3552_CR15","doi-asserted-by":"publisher","first-page":"817","DOI":"10.1093\/infdis\/jiw243","volume":"214","author":"KL Brockman","year":"2016","unstructured":"Brockman, K. L. et al. ModA2 Phasevarion Switching in Nontypeable Haemophilus influenzae Increases the Severity of Experimental Otitis Media. J Infect Dis \n                           214, 817\u2013824, doi:10.1093\/infdis\/jiw243 (2016).","journal-title":"J Infect Dis"},{"key":"3552_CR16","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.micpath.2014.07.002","volume":"74","author":"MM Eason","year":"2014","unstructured":"Eason, M. M. & Fan, X. The role and regulation of catalase in respiratory tract opportunistic bacterial pathogens. Microb Pathog \n                           74, 50\u201358, doi:10.1016\/j.micpath.2014.07.002 (2014).","journal-title":"Microb Pathog"},{"key":"3552_CR17","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1128\/JB.01973-14","volume":"197","author":"A Harrison","year":"2015","unstructured":"Harrison, A., Baker, B. D. & Munson, R. S. Jr. Overlapping and complementary oxidative stress defense mechanisms in nontypeable Haemophilus influenzae. Journal of bacteriology \n                           197, 277\u2013285, doi:10.1128\/JB.01973-14 (2015).","journal-title":"Journal of bacteriology"},{"key":"3552_CR18","doi-asserted-by":"publisher","first-page":"e50588","DOI":"10.1371\/journal.pone.0050588","volume":"7","author":"PW Whitby","year":"2012","unstructured":"Whitby, P. W. et al. Haemophilus influenzae OxyR: characterization of its regulation, regulon and role in fitness. PloS one \n                           7, e50588, doi:10.1371\/journal.pone.0050588 (2012).","journal-title":"PloS one"},{"key":"3552_CR19","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.1128\/JB.01040-06","volume":"189","author":"A Harrison","year":"2007","unstructured":"Harrison, A. et al. The OxyR regulon in nontypeable Haemophilus influenzae. Journal of bacteriology \n                           189, 1004\u20131012, doi:10.1128\/JB.01040-06 (2007).","journal-title":"Journal of bacteriology"},{"key":"3552_CR20","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1007\/5584_2015_117","volume":"857","author":"A Manda-Handzlik","year":"2015","unstructured":"Manda-Handzlik, A. & Demkow, U. Neutrophils: The Role of Oxidative and Nitrosative Stress in Health and Disease. Adv Exp Med Biol \n                           857, 51\u201360, doi:10.1007\/5584_2015_117 (2015).","journal-title":"Adv Exp Med Biol"},{"key":"3552_CR21","doi-asserted-by":"publisher","first-page":"1532","DOI":"10.1126\/science.1092385","volume":"303","author":"V Brinkmann","year":"2004","unstructured":"Brinkmann, V. et al. Neutrophil extracellular traps kill bacteria. Science \n                           303, 1532\u20131535, doi:10.1126\/science.1092385 (2004).","journal-title":"Science"},{"key":"3552_CR22","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1002\/jlb.67.3.396","volume":"67","author":"A Karlsson","year":"2000","unstructured":"Karlsson, A., Nixon, J. B. & McPhail, L. C. Phorbol myristate acetate induces neutrophil NADPH-oxidase activity by two separate signal transduction pathways: dependent or independent of phosphatidylinositol 3-kinase. Journal of leukocyte biology \n                           67, 396\u2013404 (2000).","journal-title":"Journal of leukocyte biology"},{"key":"3552_CR23","doi-asserted-by":"publisher","first-page":"e01478","DOI":"10.1128\/mBio.01478-14","volume":"5","author":"JD Langereis","year":"2014","unstructured":"Langereis, J. D. & Weiser, J. N. Shielding of a lipooligosaccharide IgM epitope allows evasion of neutrophil-mediated killing of an invasive strain of nontypeable Haemophilus influenzae. mBio \n                           5, e01478\u201301414, doi:10.1128\/mBio.01478-14 (2014).","journal-title":"mBio"},{"key":"3552_CR24","doi-asserted-by":"publisher","first-page":"440","DOI":"10.4161\/viru.1.5.12983","volume":"1","author":"J Wiesner","year":"2010","unstructured":"Wiesner, J. & Vilcinskas, A. Antimicrobial peptides: the ancient arm of the human immune system. Virulence \n                           1, 440\u2013464, doi:10.4161\/viru.1.5.12983 (2010).","journal-title":"Virulence"},{"key":"3552_CR25","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1042\/bj2370111","volume":"237","author":"AR Cross","year":"1986","unstructured":"Cross, A. R. & Jones, O. T. The effect of the inhibitor diphenylene iodonium on the superoxide-generating system of neutrophils. Specific labelling of a component polypeptide of the oxidase. The Biochemical journal \n                           237, 111\u2013116 (1986).","journal-title":"The Biochemical journal"},{"key":"3552_CR26","doi-asserted-by":"crossref","first-page":"21037","DOI":"10.1016\/S0021-9258(17)31926-9","volume":"269","author":"A Majander","year":"1994","unstructured":"Majander, A., Finel, M. & Wikstrom, M. Diphenyleneiodonium inhibits reduction of iron-sulfur clusters in the mitochondrial NADH-ubiquinone oxidoreductase (Complex I). The Journal of biological chemistry \n                           269, 21037\u201321042 (1994).","journal-title":"The Journal of biological chemistry"},{"key":"3552_CR27","doi-asserted-by":"publisher","first-page":"40","DOI":"10.3389\/fcimb.2012.00040","volume":"2","author":"A Harrison","year":"2012","unstructured":"Harrison, A., Bakaletz, L. O. & Munson, R. S. Jr. Haemophilus influenzae and oxidative stress. Frontiers in cellular and infection microbiology \n                           2, 40, doi:10.3389\/fcimb.2012.00040 (2012).","journal-title":"Frontiers in cellular and infection microbiology"},{"key":"3552_CR28","doi-asserted-by":"publisher","first-page":"3990","DOI":"10.1128\/IAI.68.7.3990-3997.2000","volume":"68","author":"CD Pericone","year":"2000","unstructured":"Pericone, C. D., Overweg, K., Hermans, P. W. & Weiser, J. N. Inhibitory and bactericidal effects of hydrogen peroxide production by Streptococcus pneumoniae on other inhabitants of the upper respiratory tract. Infection and immunity \n                           68, 3990\u20133997 (2000).","journal-title":"Infection and immunity"},{"key":"3552_CR29","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1146\/annurev.biochem.77.061606.161055","volume":"77","author":"JA Imlay","year":"2008","unstructured":"Imlay, J. A. Cellular defenses against superoxide and hydrogen peroxide. Annual review of biochemistry \n                           77, 755\u2013776, doi:10.1146\/annurev.biochem.77.061606.161055 (2008).","journal-title":"Annual review of biochemistry"},{"key":"3552_CR30","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1146\/annurev.micro.57.030502.090938","volume":"57","author":"JA Imlay","year":"2003","unstructured":"Imlay, J. A. Pathways of oxidative damage. Annual review of microbiology \n                           57, 395\u2013418, doi:10.1146\/annurev.micro.57.030502.090938 (2003).","journal-title":"Annual review of microbiology"},{"key":"3552_CR31","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1016\/j.exger.2013.02.021","volume":"48","author":"I Sanchez-Roman","year":"2013","unstructured":"Sanchez-Roman, I. & Barja, G. Regulation of longevity and oxidative stress by nutritional interventions: role of methionine restriction. Experimental gerontology \n                           48, 1030\u20131042, doi:10.1016\/j.exger.2013.02.021 (2013).","journal-title":"Experimental gerontology"},{"key":"3552_CR32","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1002\/mas.21386","volume":"33","author":"B Ghesquiere","year":"2014","unstructured":"Ghesquiere, B. & Gevaert, K. Proteomics methods to study methionine oxidation. Mass spectrometry reviews \n                           33, 147\u2013156, doi:10.1002\/mas.21386 (2014).","journal-title":"Mass spectrometry reviews"},{"key":"3552_CR33","doi-asserted-by":"publisher","first-page":"334","DOI":"10.3390\/ijms12010334","volume":"12","author":"R Spooner","year":"2011","unstructured":"Spooner, R. & Yilmaz, O. The role of reactive-oxygen-species in microbial persistence and inflammation. International journal of molecular sciences \n                           12, 334\u2013352, doi:10.3390\/ijms12010334 (2011).","journal-title":"International journal of molecular sciences"},{"key":"3552_CR34","first-page":"79","volume":"22","author":"J Nuutinen","year":"1993","unstructured":"Nuutinen, J., Torkkeli, T. & Penttila, I. The pH of secretions in sinusitis and otitis media. The Journal of otolaryngology \n                           22, 79\u201382 (1993).","journal-title":"The Journal of otolaryngology"},{"key":"3552_CR35","first-page":"131","volume":"54","author":"MT Wezyk","year":"2000","unstructured":"Wezyk, M. T. & Makowski, A. pH of fluid collected from middle ear in the course of otitis media in children. Otolaryngologia polska. The Polish otolaryngology \n                           54, 131\u2013133 (2000).","journal-title":"Otolaryngologia polska. The Polish otolaryngology"},{"key":"3552_CR36","doi-asserted-by":"publisher","first-page":"1623","DOI":"10.1128\/JCM.41.4.1623-1636.2003","volume":"41","author":"E Meats","year":"2003","unstructured":"Meats, E. et al. Characterization of encapsulated and noncapsulated Haemophilus influenzae and determination of phylogenetic relationships by multilocus sequence typing. Journal of clinical microbiology \n                           41, 1623\u20131636 (2003).","journal-title":"Journal of clinical microbiology"},{"key":"3552_CR37","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1128\/jb.101.2.517-524.1970","volume":"101","author":"RM Herriott","year":"1970","unstructured":"Herriott, R. M., Meyer, E. M. & Vogt, M. Defined nongrowth media for stage II development of competence in Haemophilus influenzae. Journal of bacteriology \n                           101, 517\u2013524 (1970).","journal-title":"Journal of bacteriology"},{"key":"3552_CR38","doi-asserted-by":"publisher","first-page":"1635","DOI":"10.1128\/IAI.73.3.1635-1643.2005","volume":"73","author":"LO Bakaletz","year":"2005","unstructured":"Bakaletz, L. O. et al. Demonstration of Type IV pilus expression and a twitching phenotype by Haemophilus influenzae. Infection and immunity \n                           73, 1635\u20131643, doi:10.1128\/IAI.73.3.1635-1643.2005 (2005).","journal-title":"Infection and immunity"},{"key":"3552_CR39","doi-asserted-by":"publisher","first-page":"2619","DOI":"10.1128\/JB.01022-15","volume":"198","author":"EM Mokrzan","year":"2016","unstructured":"Mokrzan, E. M., Ward, M. O. & Bakaletz, L. O. Type IV Pilus Expression Is Upregulated in Nontypeable Haemophilus influenzae Biofilms Formed at the Temperature of the Human Nasopharynx. Journal of bacteriology \n                           198, 2619\u20132630, doi:10.1128\/JB.01022-15 (2016).","journal-title":"Journal of bacteriology"},{"key":"3552_CR40","doi-asserted-by":"publisher","first-page":"e1003709","DOI":"10.1371\/journal.ppat.1003709","volume":"9","author":"BR Szelestey","year":"2013","unstructured":"Szelestey, B. R., Heimlich, D. R., Raffel, F. K., Justice, S. S. & Mason, K. M. Haemophilus responses to nutritional immunity: epigenetic and morphological contribution to biofilm architecture, invasion, persistence and disease severity. PLoS pathogens \n                           9, e1003709, doi:10.1371\/journal.ppat.1003709 (2013).","journal-title":"PLoS pathogens"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-03552-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-03552-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-03552-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T05:14:19Z","timestamp":1671772459000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-03552-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,6,9]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["3552"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-03552-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,6,9]]},"assertion":[{"value":"7 December 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 May 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 June 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"3161"}}