{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:47:45Z","timestamp":1788223665821,"version":"build-2803163510"},"reference-count":49,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,6,7]],"date-time":"2016-06-07T00:00:00Z","timestamp":1465257600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,6,7]],"date-time":"2016-06-07T00:00:00Z","timestamp":1465257600000},"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>NIH projects such as ENCODE and Roadmap Epigenomics have revealed surprising complexity in the transcriptomes of mammalian cells. In this study, we explored transcriptional complexity in human neutrophils, cells generally regarded as nonspecific in their functions and responses. We studied distinct human disease phenotypes and found that, at the gene, gene isoform, and miRNA level, neutrophils exhibit considerable specificity in their transcriptomes. Thus, even cells whose responses are considered non-specific show tailoring of their transcriptional repertoire toward specific physiologic or pathologic contexts. We also found that miRNAs had a global impact on neutrophil transcriptome and are associated with innate immunity in juvenile idiopathic arthritis (JIA). These findings have important implications for our understanding of the link between genes, non-coding transcripts and disease phenotypes.<\/jats:p>","DOI":"10.1038\/srep27453","type":"journal-article","created":{"date-parts":[[2016,6,7]],"date-time":"2016-06-07T09:40:13Z","timestamp":1465292413000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Complexity and Specificity of the Neutrophil Transcriptomes in Juvenile Idiopathic Arthritis"],"prefix":"10.1038","volume":"6","author":[{"given":"Zihua","family":"Hu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaiyu","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark Barton","family":"Frank","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanmin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James N.","family":"Jarvis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,6,7]]},"reference":[{"key":"BFsrep27453_CR1","doi-asserted-by":"publisher","first-page":"1190","DOI":"10.1126\/science.1222794","volume":"337","author":"MT Maurano","year":"2012","unstructured":"Maurano, M. T. et al. Systematic localization of common disease-associated variation in regulatory DNA. Science 337, 1190\u20135 (2012).","journal-title":"Science"},{"key":"BFsrep27453_CR2","doi-asserted-by":"publisher","first-page":"664","DOI":"10.1038\/ng.2614","volume":"45","author":"A Hinks","year":"2013","unstructured":"Hinks, A. et al. Dense genotyping of immune-related disease regions identifies 14 new susceptibility loci for juvenile idiopathic arthritis. Nat Genet 45, 664\u20139 (2013).","journal-title":"Nat Genet"},{"key":"BFsrep27453_CR3","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1101\/gr.6525007","volume":"17","author":"TR Gingeras","year":"2007","unstructured":"Gingeras, T. R. Origin of phenotypes: genes and transcripts. Genome Res 17, 682\u201390 (2007).","journal-title":"Genome Res"},{"key":"BFsrep27453_CR4","doi-asserted-by":"publisher","first-page":"1602","DOI":"10.1101\/gr.146506.112","volume":"22","author":"JA Stamatoyannopoulos","year":"2012","unstructured":"Stamatoyannopoulos, J. A. What does our genome encode? Genome Res 22, 1602\u201311 (2012).","journal-title":"Genome Res"},{"key":"BFsrep27453_CR5","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1016\/j.cell.2013.06.020","volume":"154","author":"I Ulitsky","year":"2013","unstructured":"Ulitsky, I. & Bartel, D. P. lincRNAs: genomics, evolution, and mechanisms. Cell 154, 26\u201346 (2013).","journal-title":"Cell"},{"key":"BFsrep27453_CR6","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1002\/path.2638","volume":"220","author":"RJ Taft","year":"2010","unstructured":"Taft, R. J., Pang, K. C., Mercer, T. R., Dinger, M. & Mattick, J. S. Non-coding RNAs: regulators of disease. J Pathol 220, 126\u201339 (2010).","journal-title":"J Pathol"},{"key":"BFsrep27453_CR7","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/S0092-8674(04)00045-5","volume":"116","author":"DP Bartel","year":"2004","unstructured":"Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281\u201397 (2004).","journal-title":"Cell"},{"key":"BFsrep27453_CR8","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1038\/nrg2083","volume":"8","author":"P Kapranov","year":"2007","unstructured":"Kapranov, P., Willingham, A. T. & Gingeras, T. R. Genome-wide transcription and the implications for genomic organization. Nat Rev Genet 8, 413\u201323 (2007).","journal-title":"Nat Rev Genet"},{"key":"BFsrep27453_CR9","doi-asserted-by":"publisher","first-page":"746","DOI":"10.1101\/gr.5660607","volume":"17","author":"F Denoeud","year":"2007","unstructured":"Denoeud, F. et al. Prominent use of distal 5\u2032 transcription start sites and discovery of a large number of additional exons in ENCODE regions. Genome Res 17, 746\u201359 (2007).","journal-title":"Genome Res"},{"key":"BFsrep27453_CR10","doi-asserted-by":"publisher","first-page":"1488","DOI":"10.1002\/art.24450","volume":"60","author":"JN Jarvis","year":"2009","unstructured":"Jarvis, J. N. et al. Gene expression profiling in neutrophils from children with polyarticular juvenile idiopathic arthritis. Arthritis Rheum 60, 1488\u201395 (2009).","journal-title":"Arthritis Rheum"},{"key":"BFsrep27453_CR11","doi-asserted-by":"publisher","first-page":"482","DOI":"10.1016\/j.autrev.2011.02.001","volume":"10","author":"YT Lin","year":"2011","unstructured":"Lin, Y. T., Wang, C. T., Gershwin, M. E. & Chiang, B. L. The pathogenesis of oligoarticular\/polyarticular vs systemic juvenile idiopathic arthritis. Autoimmun Rev 10, 482\u20139 (2011).","journal-title":"Autoimmun Rev"},{"key":"BFsrep27453_CR12","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1186\/1755-8794-2-9","volume":"2","author":"MB Frank","year":"2009","unstructured":"Frank, M. B. et al. Disease-associated pathophysiologic structures in pediatric rheumatic diseases show characteristics of scale-free networks seen in physiologic systems: implications for pathogenesis and treatment. BMC Med Genomics 2, 9 (2009).","journal-title":"BMC Med Genomics"},{"key":"BFsrep27453_CR13","doi-asserted-by":"publisher","first-page":"R100","DOI":"10.1186\/ar4280","volume":"15","author":"K Jiang","year":"2013","unstructured":"Jiang, K., Frank, M. B., Chen, Y., Osban, J. & Jarvis, J. N. Genomic characterization of remission in juvenile idiopathic arthritis. Arthritis Res Ther 15, R100 (2013).","journal-title":"Arthritis Res Ther"},{"key":"BFsrep27453_CR14","doi-asserted-by":"publisher","first-page":"170","DOI":"10.1038\/ni.2194","volume":"13","author":"I Puga","year":"2012","unstructured":"Puga, I. et al. B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nat Immunol 13, 170\u201380 (2012).","journal-title":"Nat Immunol"},{"key":"BFsrep27453_CR15","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1038\/ni.1996","volume":"12","author":"J Sun","year":"2011","unstructured":"Sun, J., Dodd, H., Moser, E. K., Sharma, R. & Braciale, T. J. CD4+ T cell help and innate-derived IL-27 induce Blimp-1-dependent IL-10 production by antiviral CTLs. Nat Immunol 12, 327\u201334 (2011).","journal-title":"Nat Immunol"},{"key":"BFsrep27453_CR16","first-page":"390","volume":"31","author":"RE Petty","year":"2004","unstructured":"Petty, R. E. et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 31, 390\u20132 (2004).","journal-title":"J Rheumatol"},{"key":"BFsrep27453_CR17","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1038\/nprot.2008.211","volume":"4","author":"W Huang da","year":"2009","unstructured":"Huang da, W., Sherman, B. T. & Lempicki, R. A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4, 44\u201357 (2009).","journal-title":"Nat Protoc"},{"key":"BFsrep27453_CR18","doi-asserted-by":"publisher","first-page":"R15","DOI":"10.1186\/ar1018","volume":"6","author":"JN Jarvis","year":"2004","unstructured":"Jarvis, J. N. et al. Novel approaches to gene expression analysis of active polyarticular juvenile rheumatoid arthritis. Arthritis Res Ther 6, R15\u2013r32 (2004).","journal-title":"Arthritis Res Ther"},{"key":"BFsrep27453_CR19","doi-asserted-by":"publisher","first-page":"R154","DOI":"10.1186\/ar2048","volume":"8","author":"JN Jarvis","year":"2006","unstructured":"Jarvis, J. N. et al. Evidence for chronic, peripheral activation of neutrophils in polyarticular juvenile rheumatoid arthritis. Arthritis Res Ther 8, R154 (2006).","journal-title":"Arthritis Res Ther"},{"key":"BFsrep27453_CR20","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1016\/j.cell.2011.09.041","volume":"147","author":"P Sumazin","year":"2011","unstructured":"Sumazin, P. et al. An extensive microRNA-mediated network of RNA-RNA interactions regulates established oncogenic pathways in glioblastoma. Cell 147, 370\u201381 (2011).","journal-title":"Cell"},{"key":"BFsrep27453_CR21","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1016\/j.cell.2011.09.032","volume":"147","author":"FA Karreth","year":"2011","unstructured":"Karreth, F. A. et al. In vivo identification of tumor- suppressive PTEN ceRNAs in an oncogenic BRAF-induced mouse model of melanoma. Cell 147, 382\u201395 (2011).","journal-title":"Cell"},{"key":"BFsrep27453_CR22","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.cell.2004.12.035","volume":"120","author":"BP Lewis","year":"2005","unstructured":"Lewis, B. P., Burge, C. B. & Bartel, D. P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15\u201320 (2005).","journal-title":"Cell"},{"key":"BFsrep27453_CR23","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1007\/978-1-60761-987-1_18","volume":"696","author":"M Kohl","year":"2011","unstructured":"Kohl, M., Wiese, S. & Warscheid, B. Cytoscape: software for visualization and analysis of biological networks. Methods Mol Biol 696, 291\u2013303 (2011).","journal-title":"Methods Mol Biol"},{"key":"BFsrep27453_CR24","doi-asserted-by":"publisher","first-page":"D767","DOI":"10.1093\/nar\/gkn892","volume":"37","author":"TS Keshava Prasad","year":"2009","unstructured":"Keshava Prasad, T. S. et al. Human Protein Reference Database\u20132009 update. Nucleic Acids Res 37, D767\u201372 (2009).","journal-title":"Nucleic Acids Res"},{"key":"BFsrep27453_CR25","doi-asserted-by":"publisher","first-page":"1263","DOI":"10.1002\/art.34348","volume":"64","author":"T Beukelman","year":"2012","unstructured":"Beukelman, T. et al. Rates of malignancy associated with juvenile idiopathic arthritis and its treatment. Arthritis Rheum 64, 1263\u201371 (2012).","journal-title":"Arthritis Rheum"},{"key":"BFsrep27453_CR26","doi-asserted-by":"publisher","first-page":"R45","DOI":"10.1186\/gb-2006-7-6-r45","volume":"7","author":"D Ekman","year":"2006","unstructured":"Ekman, D., Light, S., Bjorklund, A. K. & Elofsson, A. What properties characterize the hub proteins of the protein-protein interaction network of Saccharomyces cerevisiae? Genome Biol 7, R45 (2006).","journal-title":"Genome Biol"},{"key":"BFsrep27453_CR27","doi-asserted-by":"publisher","first-page":"e1000817","DOI":"10.1371\/journal.pcbi.1000817","volume":"6","author":"S Agarwal","year":"2010","unstructured":"Agarwal, S., Deane, C. M., Porter, M. A. & Jones, N. S. Revisiting date and party hubs: novel approaches to role assignment in protein interaction networks. PLoS Comput Biol 6, e1000817 (2010).","journal-title":"PLoS Comput Biol"},{"key":"BFsrep27453_CR28","doi-asserted-by":"publisher","first-page":"e5344","DOI":"10.1371\/journal.pone.0005344","volume":"4","author":"RR Vallabhajosyula","year":"2009","unstructured":"Vallabhajosyula, R. R., Chakravarti, D., Lutfeali, S., Ray, A. & Raval, A. Identifying hubs in protein interaction networks. PLoS One 4, e5344 (2009).","journal-title":"PLoS One"},{"key":"BFsrep27453_CR29","doi-asserted-by":"publisher","first-page":"R90","DOI":"10.1186\/gb-2009-10-9-r90","volume":"10","author":"C Cheng","year":"2009","unstructured":"Cheng, C., Fu, X., Alves, P. & Gerstein, M. mRNA expression profiles show differential regulatory effects of microRNAs between estrogen receptor-positive and estrogen receptor-negative breast cancer. Genome Biol 10, R90 (2009).","journal-title":"Genome Biol"},{"key":"BFsrep27453_CR30","doi-asserted-by":"publisher","first-page":"890","DOI":"10.4049\/jimmunol.182.2.890","volume":"182","author":"KL Good","year":"2009","unstructured":"Good, K. L., Avery, D. T. & Tangye, S. G. Resting human memory B cells are intrinsically programmed for enhanced survival and responsiveness to diverse stimuli compared to naive B cells. J Immunol 182, 890\u2013901 (2009).","journal-title":"J Immunol"},{"key":"BFsrep27453_CR31","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1084\/jem.20071641","volume":"205","author":"S Sarkar","year":"2008","unstructured":"Sarkar, S. et al. Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates. J Exp Med 205, 625\u201340 (2008).","journal-title":"J Exp Med"},{"key":"BFsrep27453_CR32","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1038\/ni.1688","volume":"10","author":"TD Querec","year":"2009","unstructured":"Querec, T. D. et al. Systems biology approach predicts immunogenicity of the yellow fever vaccine in humans. Nat Immunol 10, 116\u201325 (2009).","journal-title":"Nat Immunol"},{"key":"BFsrep27453_CR33","doi-asserted-by":"publisher","first-page":"786","DOI":"10.1038\/ni.2067","volume":"12","author":"HI Nakaya","year":"2011","unstructured":"Nakaya, H. I. et al. Systems biology of vaccination for seasonal influenza in humans. Nat Immunol 12, 786\u201395 (2011).","journal-title":"Nat Immunol"},{"key":"BFsrep27453_CR34","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1038\/ni1223","volume":"6","author":"G Napolitani","year":"2005","unstructured":"Napolitani, G., Rinaldi, A., Bertoni, F., Sallusto, F. & Lanzavecchia, A. Selected Toll-like receptor agonist combinations synergistically trigger a T helper type 1-polarizing program in dendritic cells. Nat Immunol 6, 769\u201376 (2005).","journal-title":"Nat Immunol"},{"key":"BFsrep27453_CR35","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1126\/science.1179050","volume":"326","author":"I Amit","year":"2009","unstructured":"Amit, I. et al. Unbiased reconstruction of a mammalian transcriptional network mediating pathogen responses. Science 326, 257\u201363 (2009).","journal-title":"Science"},{"key":"BFsrep27453_CR36","doi-asserted-by":"publisher","first-page":"2908","DOI":"10.4049\/jimmunol.0903453","volume":"184","author":"E Zaslavsky","year":"2010","unstructured":"Zaslavsky, E. et al. Antiviral response dictated by choreographed cascade of transcription factors. J Immunol 184, 2908\u201317 (2010).","journal-title":"J Immunol"},{"key":"BFsrep27453_CR37","doi-asserted-by":"publisher","first-page":"1109","DOI":"10.1093\/intimm\/dxh112","volume":"16","author":"MS Lee","year":"2004","unstructured":"Lee, M. S., Hanspers, K., Barker, C. S., Korn, A. P. & McCune, J. M. Gene expression profiles during human CD4+ T cell differentiation. Int Immunol 16, 1109\u201324 (2004).","journal-title":"Int Immunol"},{"key":"BFsrep27453_CR38","doi-asserted-by":"publisher","first-page":"3233","DOI":"10.4049\/jimmunol.170.6.3233","volume":"170","author":"C Ryckman","year":"2003","unstructured":"Ryckman, C., Vandal, K., Rouleau, P., Talbot, M. & Tessier, P. A. Proinflammatory activities of S100: proteins S100A8, S100A9, and S100A8\/A9 induce neutrophil chemotaxis and adhesion. J Immunol 170, 3233\u201342 (2003).","journal-title":"J Immunol"},{"key":"BFsrep27453_CR39","doi-asserted-by":"publisher","first-page":"W416","DOI":"10.1093\/nar\/gkr276","volume":"39","author":"GT Huang","year":"2011","unstructured":"Huang, G. T., Athanassiou, C. & Benos, P. V. mirConnX: condition-specific mRNA-microRNA network integrator. Nucleic Acids Res 39, W416\u201323 (2011).","journal-title":"Nucleic Acids Res"},{"key":"BFsrep27453_CR40","doi-asserted-by":"publisher","first-page":"R23","DOI":"10.1186\/gb-2010-11-2-r23","volume":"11","author":"JH Hung","year":"2010","unstructured":"Hung, J. H. et al. Identification of functional modules that correlate with phenotypic difference: the influence of network topology. Genome Biol 11, R23 (2010).","journal-title":"Genome Biol"},{"key":"BFsrep27453_CR41","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/nrg2918","volume":"12","author":"AL Barabasi","year":"2011","unstructured":"Barabasi, A. L., Gulbahce, N. & Loscalzo, J. Network medicine: a network-based approach to human disease. Nat Rev Genet 12, 56\u201368 (2011).","journal-title":"Nat Rev Genet"},{"key":"BFsrep27453_CR42","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1038\/msb.2010.117","volume":"7","author":"A Califano","year":"2011","unstructured":"Califano, A. Rewiring makes the difference. Mol Syst Biol 7, 463 (2011).","journal-title":"Mol Syst Biol"},{"key":"BFsrep27453_CR43","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1186\/s13073-015-0227-2","volume":"7","author":"N Du","year":"2015","unstructured":"Du, N. et al. Dynamic tracking of functional gene modules in treated juvenile idiopathic arthritis. Genome Med 7, 109 (2015).","journal-title":"Genome Med"},{"key":"BFsrep27453_CR44","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1038\/nrg2223","volume":"9","author":"S Komili","year":"2008","unstructured":"Komili, S. & Silver, P. A. Coupling and coordination in gene expression processes: a systems biology view. Nat Rev Genet 9, 38\u201348 (2008).","journal-title":"Nat Rev Genet"},{"key":"BFsrep27453_CR45","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1038\/nri1497","volume":"4","author":"KW Lynch","year":"2004","unstructured":"Lynch, K. W. Consequences of regulated pre-mRNA splicing in the immune system. Nat Rev Immunol 4, 931\u201340 (2004).","journal-title":"Nat Rev Immunol"},{"key":"BFsrep27453_CR46","doi-asserted-by":"publisher","first-page":"854","DOI":"10.1038\/ng.905","volume":"43","author":"S Mukherji","year":"2011","unstructured":"Mukherji, S. et al. MicroRNAs can generate thresholds in target gene expression. Nat Genet 43, 854\u20139 (2011).","journal-title":"Nat Genet"},{"key":"BFsrep27453_CR47","doi-asserted-by":"publisher","first-page":"R109","DOI":"10.1186\/ar4559","volume":"16","author":"A Stevens","year":"2014","unstructured":"Stevens, A., Meyer, S., Hanson, D., Clayton, P. & Donn, R. P. Network analysis identifies protein clusters of functional importance in juvenile idiopathic arthritis. Arthritis Res Ther 16, R109 (2014).","journal-title":"Arthritis Res Ther"},{"key":"BFsrep27453_CR48","doi-asserted-by":"publisher","first-page":"1966","DOI":"10.1002\/art.39135","volume":"67","author":"K Jiang","year":"2015","unstructured":"Jiang, K. et al. Disease-Associated Single-Nucleotide Polymorphisms From Noncoding Regions in Juvenile Idiopathic Arthritis Are Located Within or Adjacent to Functional Genomic Elements of Human Neutrophils and CD4+ T Cells. Arthritis Rheumatol 67, 1966\u201377 (2015).","journal-title":"Arthritis Rheumatol"},{"key":"BFsrep27453_CR49","doi-asserted-by":"publisher","first-page":"634","DOI":"10.1093\/bib\/bbq086","volume":"12","author":"HE Lockstone","year":"2011","unstructured":"Lockstone, H. E. Exon array data analysis using Affymetrix power tools and R statistical software. Brief Bioinform 12, 634\u201344 (2011).","journal-title":"Brief Bioinform"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep27453.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep27453","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep27453.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T05:29:17Z","timestamp":1672896557000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep27453"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,6,7]]},"references-count":49,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,6,20]]}},"alternative-id":["BFsrep27453"],"URL":"https:\/\/doi.org\/10.1038\/srep27453","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,6,7]]},"assertion":[{"value":"26 June 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 May 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 June 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":"27453"}}