{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,11]],"date-time":"2026-11-11T01:29:59Z","timestamp":1794360599353,"version":"4.9.0"},"reference-count":54,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2024,1,18]],"date-time":"2024-01-18T00:00:00Z","timestamp":1705536000000},"content-version":"vor","delay-in-days":2953,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2015,12,18]],"date-time":"2015-12-18T00:00:00Z","timestamp":1450396800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The effect of polymicrobial interactions on pathogen physiology and how it can act either to limit pathogen colonization or to potentiate pathogen expansion and virulence are not well understood. Pseudomonas aeruginosa and Staphylococcus aureus are opportunistic pathogens commonly found together in polymicrobial human infections. However, we have previously shown that the interactions between these two bacterial species are strain dependent. Whereas P. aeruginosa PAO1, a commonly used laboratory strain, effectively suppressed S. aureus growth, we observed a commensal-like interaction between the human host-adapted strain, DK2-P2M24-2003, and S. aureus. In this study, characterization by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) imaging mass spectrometry (IMS) and mass spectral (MS) molecular networking revealed a significant metabolic divergence between P. aeruginosa PAO1 and DK2-P2M24-2003, which comprised several virulence factors and signaling 4-hydroxy-2-alkylquinoline (HAQ) molecules. Strikingly, a further modulation of the HAQ profile was observed in DK2-P2M24-2003 during interaction with S. aureus, resulting in an area with thickened colony morphology at the P. aeruginosa\u2013S. aureus interface. In addition, we found an HAQ-mediated protection of S. aureus by DK2-P2M24-2003 from the killing effect of tobramycin. Our findings suggest a model where the metabolic divergence manifested in human host-adapted P. aeruginosa is further modulated during interaction with S. aureus and facilitate a proto-cooperative P. aeruginosa\u2013S. aureus relationship.<\/jats:p>","DOI":"10.1038\/ismej.2015.220","type":"journal-article","created":{"date-parts":[[2015,12,18]],"date-time":"2015-12-18T15:16:32Z","timestamp":1450451792000},"page":"1323-1336","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":95,"title":["Evolution of metabolic divergence in <i>Pseudomonas aeruginosa<\/i> during long-term infection facilitates a proto-cooperative interspecies interaction"],"prefix":"10.1093","volume":"10","author":[{"given":"Charlotte","family":"Frydenlund Michelsen","sequence":"first","affiliation":[{"name":"Department of Systems Biology, Technical University of Denmark , Lyngby, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seyed Mohammad","family":"Hossein Khademi","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, Technical University of Denmark , Lyngby, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helle","family":"Krogh Johansen","sequence":"additional","affiliation":[{"name":"Department of Clinical Microbiology, Rigshospitalet , Copenhagen, Denmark"},{"name":"The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark , H\u00f8rsholm, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanne","family":"Ingmer","sequence":"additional","affiliation":[{"name":"Department of Veterinary Disease Biology, Food Safety and Zoonoses, University of Copenhagen , Frederiksberg C, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter C","family":"Dorrestein","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of California at San Diego , La Jolla, CA, USA"},{"name":"Department of Chemistry and Biochemistry, University of California at San Diego , La Jolla, CA, USA"},{"name":"Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego , La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Jelsbak","sequence":"additional","affiliation":[{"name":"Department of Systems Biology, Technical University of Denmark , Lyngby, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2015,12,18]]},"reference":[{"key":"2024011819081837000_CR1","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1016\/S0022-2836(05)80360-2","article-title":"Basic local alignment search tool","volume":"215","author":"Altschul","year":"1990","journal-title":"J Mol Biol"},{"key":"2024011819081837000_CR2","first-page":"175","article-title":"Pseudomonas aeruginosa induces pigment production and enhances virulence in a white phenotypic variant of Staphylococcus aureus","volume":"6","author":"Antonic","year":"2013","journal-title":"Infect Drug Resist"},{"key":"2024011819081837000_CR3","doi-asserted-by":"publisher","first-page":"948","DOI":"10.2144\/00295bm04","article-title":"Integration-proficient Pseudomonas aeruginosa vectors for isolation of single-copy chromosomal lacZ and lux gene fusions","volume":"29","author":"Becher","year":"2000","journal-title":"Biotechniques"},{"key":"2024011819081837000_CR4","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1101\/gr.3.2.85","article-title":"Amplifying DNA with arbitrary oligonucleotide primers","volume":"3","author":"Caetano-Anolles","year":"1993","journal-title":"PCR Methods Appl"},{"key":"2024011819081837000_CR5","doi-asserted-by":"publisher","first-page":"512","DOI":"10.1111\/j.1365-2958.2007.05678.x","article-title":"Growth phenotypes of Pseudomonas aeruginosa lasR mutants adapted to the airways of cystic fibrosis patients","volume":"64","author":"D\u2019Argenio","year":"2007","journal-title":"Mol Microbiol"},{"key":"2024011819081837000_CR6","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.jcf.2012.06.005","article-title":"A cohort study of the Copenhagen CF Centre eradication strategy against Staphylococcus aureus in patients with CF","volume":"12","author":"Dalboge","year":"2013","journal-title":"J Cyst Fibros"},{"key":"2024011819081837000_CR7","doi-asserted-by":"publisher","first-page":"7766","DOI":"10.1073\/pnas.1221466110","article-title":"Evolutionary remodeling of global regulatory networks during long-term bacterial adaptation to human hosts","volume":"110","author":"Damkiaer","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024011819081837000_CR8","doi-asserted-by":"publisher","first-page":"4718","DOI":"10.1128\/IAI.02198-14","article-title":"Synergistic interactions of Pseudomonas aeruginosa and Staphylococcus aureus in an in vitro wound model","volume":"82","author":"DeLeon","year":"2014","journal-title":"Infect Immun"},{"key":"2024011819081837000_CR9","doi-asserted-by":"publisher","first-page":"1339","DOI":"10.1073\/pnas.0307694100","article-title":"Analysis of Pseudomonas aeruginosa 4-hydroxy-2-alkylquinolines (HAQs) reveals a role for 4-hydroxy-2-heptylquinoline in cell-to-cell communication","volume":"101","author":"Deziel","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024011819081837000_CR10","doi-asserted-by":"publisher","first-page":"1477","DOI":"10.1046\/j.1365-2958.2003.03803.x","article-title":"Modulation of Pseudomonas aeruginosa gene expression by host microflora through interspecies communication","volume":"50","author":"Duan","year":"2003","journal-title":"Mol Microbiol"},{"key":"2024011819081837000_CR11","doi-asserted-by":"publisher","first-page":"3425","DOI":"10.1128\/JB.00209-07","article-title":"Two distinct pathways supply anthranilate as a precursor of the Pseudomonas quinolone signal","volume":"189","author":"Farrow","year":"2007","journal-title":"J Bacteriol"},{"key":"2024011819081837000_CR12","doi-asserted-by":"publisher","first-page":"e00537","DOI":"10.1128\/mBio.00537-12","article-title":"A Genetic resource for rapid and comprehensive phenotype screening of nonessential Staphylococcus aureus genes","volume":"4","author":"Fey","year":"2013","journal-title":"Mbio"},{"key":"2024011819081837000_CR13","doi-asserted-by":"publisher","first-page":"2683","DOI":"10.1111\/j.1462-2920.2007.01380.x","article-title":"A dual biosensor for 2-alkyl-4-quinolone quorum-sensing signal molecules","volume":"9","author":"Fletcher","year":"2007","journal-title":"Environ Microbiol"},{"key":"2024011819081837000_CR14","doi-asserted-by":"publisher","first-page":"e86705","DOI":"10.1371\/journal.pone.0086705","article-title":"Interspecific small molecule interactions between clinical Isolates of Pseudomonas aeruginosa and Staphylococcus aureus from adult cystic fibrosis patients","volume":"9","author":"Fugere","year":"2014","journal-title":"PloS ONE"},{"key":"2024011819081837000_CR15","doi-asserted-by":"publisher","first-page":"6472","DOI":"10.1128\/JB.184.23.6472-6480.2002","article-title":"Functions required for extracellular quinolone signaling by Pseudomonas aeruginosa","volume":"184","author":"Gallagher","year":"2002","journal-title":"J Bacteriol"},{"key":"2024011819081837000_CR16","doi-asserted-by":"publisher","first-page":"918","DOI":"10.1164\/rccm.200304-505SO","article-title":"Pathophysiology and management of pulmonary infections in cystic fibrosis","volume":"168","author":"Gibson","year":"2003","journal-title":"Am J Respir Crit Care Med"},{"key":"2024011819081837000_CR17","doi-asserted-by":"publisher","first-page":"2485","DOI":"10.1099\/mic.0.048736-0","article-title":"Microbial competition between Bacillus subtilis and Staphylococcus aureus monitored by imaging mass spectrometry","volume":"157","author":"Gonzalez","year":"2011","journal-title":"Microbiology"},{"key":"2024011819081837000_CR18","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1186\/1471-2180-12-30","article-title":"Quorum sensing modulates colony morphology through alkyl quinolones in Pseudomonas aeruginosa","volume":"12","author":"Gupta","year":"2012","journal-title":"BMC Microbiol"},{"key":"2024011819081837000_CR19","doi-asserted-by":"publisher","first-page":"917","DOI":"10.1099\/mic.0.2006\/004077-0","article-title":"Microbial ecology of the cystic fibrosis lung","volume":"153","author":"Harrison","year":"2007","journal-title":"Microbiology"},{"key":"2024011819081837000_CR20","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1111\/j.1574-6976.2010.00247.x","article-title":"Quinolones: from antibiotics to autoinducers","volume":"35","author":"Heeb","year":"2011","journal-title":"FEMS Microbiol Rev"},{"key":"2024011819081837000_CR21","doi-asserted-by":"publisher","first-page":"19890","DOI":"10.1073\/pnas.0606756104","article-title":"Selection for Staphylococcus aureus small-colony variants due to growth in the presence of Pseudomonas aeruginosa","volume":"103","author":"Hoffman","year":"2006","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024011819081837000_CR22","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/j.jcf.2012.12.003","article-title":"Association between Staphylococcus aureus alone or combined with Pseudomonas aeruginosa and the clinical condition of patients with cystic fibrosis","volume":"12","author":"Hubert","year":"2013","journal-title":"J Cyst Fibros"},{"key":"2024011819081837000_CR23","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1007\/BF00587591","article-title":"A general system to integrate lacZ fusions into the chromosome of gram-negative eubacteria - regulation of the Pm promoter of the TOL plasmid studied with all controling elements in monocopy","volume":"233","author":"Kessler","year":"1992","journal-title":"Mol Gen Genet"},{"key":"2024011819081837000_CR24"},{"key":"2024011819081837000_CR25","doi-asserted-by":"publisher","first-page":"1059","DOI":"10.1073\/pnas.1214550110","article-title":"Community surveillance enhances Pseudomonas aeruginosa virulence during polymicrobial infection","volume":"110","author":"Korgaonkar","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024011819081837000_CR26","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1128\/JB.01175-10","article-title":"Pseudomonas aeruginosa enhances production of an antimicrobial in response to N-acetylglucosamine and peptidoglycan","volume":"193","author":"Korgaonkar","year":"2011","journal-title":"J Bacteriol"},{"key":"2024011819081837000_CR27","doi-asserted-by":"publisher","first-page":"368","DOI":"10.1111\/j.1365-2958.2004.04402.x","article-title":"A novel two-component system controls the expression of Pseudomonas aeruginosa fimbrial cup genes","volume":"55","author":"Kulasekara","year":"2005","journal-title":"Mol Microbiol"},{"key":"2024011819081837000_CR28","doi-asserted-by":"publisher","first-page":"1275","DOI":"10.1038\/ng.997","article-title":"Parallel bacterial evolution within multiple patients identifies candidate pathogenicity genes","volume":"43","author":"Lieberman","year":"2011","journal-title":"Nat Genet"},{"key":"2024011819081837000_CR29","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.jcf.2005.11.005","article-title":"Pulmonary infection in mild variant cystic fibrosis: implications for care","volume":"5","author":"Lording","year":"2006","journal-title":"J Cyst Fibros"},{"key":"2024011819081837000_CR30","doi-asserted-by":"publisher","first-page":"e01592","DOI":"10.1128\/mBio.01592-14","article-title":"Environmental heterogeneity drives within-host diversification and evolution of Pseudomonas aeruginosa","volume":"5","author":"Markussen","year":"2014","journal-title":"Mbio"},{"key":"2024011819081837000_CR31","doi-asserted-by":"publisher","first-page":"e00966","DOI":"10.1128\/mBio.00966-14","article-title":"Within-host evolution of Pseudomonas aeruginosa reveals adaptation toward iron acquisition from hemoglobin","volume":"5","author":"Marvig","year":"2014","journal-title":"Mbio"},{"key":"2024011819081837000_CR32","doi-asserted-by":"publisher","first-page":"e1003741","DOI":"10.1371\/journal.pgen.1003741","article-title":"Genome analysis of a transmissible lineage of Pseudomonas aeruginosa reveals pathoadaptive mutations and distinct evolutionary paths of hypermutators","volume":"9","author":"Marvig","year":"2013","journal-title":"PLoS Genet"},{"key":"2024011819081837000_CR33","doi-asserted-by":"publisher","first-page":"554","DOI":"10.1128\/JB.187.2.554-566.2005","article-title":"Staphylococcus aureus serves as an iron source for Pseudomonas aeruginosa during in vivo coculture","volume":"187","author":"Mashburn","year":"2005","journal-title":"J Bacteriol"},{"key":"2024011819081837000_CR34","doi-asserted-by":"publisher","first-page":"3903","DOI":"10.1128\/JB.02006-14","article-title":"Staphylococcus aureus alters growth activity, autolysis, and antibiotic tolerance in a human host-adapted Pseudomonas aeruginosa lineage","volume":"196","author":"Michelsen","year":"2014","journal-title":"J Bacteriol"},{"key":"2024011819081837000_CR35","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/1471-2180-10-33","article-title":"Staphylococcus aureus sigma B-dependent emergence of small-colony variants and biofilm production following exposure to Pseudomonas aeruginosa 4-hydroxy-2-heptylquinoline-N-oxide","volume":"10","author":"Mitchell","year":"2010","journal-title":"BMC Microbiol"},{"key":"2024011819081837000_CR36","doi-asserted-by":"publisher","first-page":"13811","DOI":"10.1073\/pnas.1206855109","article-title":"Interkingdom metabolic transformations captured by microbial imaging mass spectrometry","volume":"109","author":"Moree","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024011819081837000_CR37","doi-asserted-by":"publisher","first-page":"5267","DOI":"10.1128\/JB.187.15.5267-5277.2005","article-title":"Cystic fibrosis sputum supports growth and cues key aspects of Pseudomonas aeruginosa physiology","volume":"187","author":"Palmer","year":"2005","journal-title":"J Bacteriol"},{"key":"2024011819081837000_CR38","doi-asserted-by":"publisher","first-page":"e56846","DOI":"10.1371\/journal.pone.0056846","article-title":"Interactions of methicillin resistant Staphylococcus aureus USA300 and Pseudomonas aeruginosa in polymicrobial wound infection","volume":"8","author":"Pastar","year":"2013","journal-title":"PloS ONE"},{"key":"2024011819081837000_CR39","doi-asserted-by":"publisher","first-page":"5756","DOI":"10.1128\/jb.179.18.5756-5767.1997","article-title":"Roles of Pseudomonas aeruginosa las and rhl quorum-sensing systems in control of elastase and rhamnolipid biosynthesis genes","volume":"179","author":"Pearson","year":"1997","journal-title":"J Bacteriol"},{"key":"2024011819081837000_CR40","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1128\/CMR.00013-11","article-title":"Polymicrobial interactions: Impact on pathogenesis and human disease","volume":"25","author":"Peters","year":"2012","journal-title":"Clin Microbiol Rev"},{"key":"2024011819081837000_CR41","doi-asserted-by":"publisher","first-page":"1683","DOI":"10.1128\/JB.01258-13","article-title":"Impact of a transposon insertion in phzF2 on the specialized metabolite production and interkingdom interactions of Pseudomonas aeruginosa","volume":"196","author":"Phelan","year":"2014","journal-title":"J Bacteriol"},{"key":"2024011819081837000_CR42","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1016\/j.tim.2014.05.007","article-title":"Polybacterial human disease: the ills of social networking","volume":"22","author":"Short","year":"2014","journal-title":"Trends Microbiol"},{"key":"2024011819081837000_CR43","doi-asserted-by":"publisher","first-page":"8487","DOI":"10.1073\/pnas.0602138103","article-title":"Genetic adaptation by Pseudomonas aeruginosa to the airways of cystic fibrosis patients","volume":"103","author":"Smith","year":"2006","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024011819081837000_CR44","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1093\/bioinformatics\/btq675","article-title":"Cytoscape 2.8: new features for data integration and network visualization","volume":"27","author":"Smoot","year":"2011","journal-title":"Bioinformatics"},{"key":"2024011819081837000_CR45","doi-asserted-by":"publisher","first-page":"959","DOI":"10.1038\/35023079","article-title":"Complete genome sequence of Pseudomonas aeruginosa PAO1, an opportunistic pathogen","volume":"406","author":"Stover","year":"2000","journal-title":"Nature"},{"key":"2024011819081837000_CR46","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1007\/s13213-011-0273-y","article-title":"Contribution of an arsenal of virulence factors to pathogenesis of Pseudomonas aeruginosa infections","volume":"61","author":"Strateva","year":"2011","journal-title":"Ann Microbiol"},{"key":"2024011819081837000_CR47","volume-title":"R: A Language and Environment for Statistical Computing","author":"R Development Core Team","year":"2009"},{"key":"2024011819081837000_CR48","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1111\/j.1574-6968.1993.tb06137.x","article-title":"Enhanced conjugative transfer of plasmid DNA from Escherichia coli to Staphylococcus aureus and Listeria monocytogenes","volume":"109","author":"Trieucuot","year":"1993","journal-title":"FEMS Microbiol Lett"},{"key":"2024011819081837000_CR49","doi-asserted-by":"publisher","first-page":"14420","DOI":"10.1073\/pnas.1308085110","article-title":"Salmonella typhimurium intercepts Escherichia coli signaling to enhance antibiotic tolerance","volume":"110","author":"Vega","year":"2013","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024011819081837000_CR50","doi-asserted-by":"publisher","first-page":"E1743","DOI":"10.1073\/pnas.1203689109","article-title":"Mass spectral molecular networking of living microbial colonies","volume":"109","author":"Watrous","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024011819081837000_CR51","doi-asserted-by":"publisher","first-page":"1686","DOI":"10.1021\/np400413s","article-title":"Molecular networking as a dereplication strategy","volume":"76","author":"Yang","year":"2013","journal-title":"J Nat Prod"},{"key":"2024011819081837000_CR52","doi-asserted-by":"publisher","first-page":"7481","DOI":"10.1073\/pnas.1018249108","article-title":"Evolutionary dynamics of bacteria in a human host environment","volume":"108","author":"Yang","year":"2011","journal-title":"Proc Natl Acad Sci USA"},{"key":"2024011819081837000_CR53","doi-asserted-by":"publisher","first-page":"885","DOI":"10.1038\/nchembio.252","article-title":"Translating metabolic exchange with imaging mass spectrometry","volume":"5","author":"Yang","year":"2009","journal-title":"Nat Chem Biol"},{"key":"2024011819081837000_CR54","doi-asserted-by":"publisher","first-page":"5809","DOI":"10.1073\/pnas.1120577109","article-title":"Decade-long bacterial community dynamics in cystic fibrosis airways","volume":"109","author":"Zhao","year":"2012","journal-title":"Proc Natl Acad Sci USA"}],"container-title":["The ISME Journal"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.nature.com\/articles\/ismej2015220.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/ismej2015220","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/ismej\/article-pdf\/10\/6\/1323\/56171568\/41396_2016_article_bfismej2015220.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/www.nature.com\/articles\/ismej2015220.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/academic.oup.com\/ismej\/article-pdf\/10\/6\/1323\/56171568\/41396_2016_article_bfismej2015220.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,14]],"date-time":"2024-02-14T17:58:44Z","timestamp":1707933524000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ismej\/article\/10\/6\/1323-1336\/7538278"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,12,18]]},"references-count":54,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2016,6,1]]}},"URL":"https:\/\/doi.org\/10.1038\/ismej.2015.220","relation":{},"ISSN":["1751-7362","1751-7370"],"issn-type":[{"value":"1751-7362","type":"print"},{"value":"1751-7370","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2016,6]]},"published":{"date-parts":[[2015,12,18]]},"assertion":[{"value":"15 May 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 October 2015","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 October 2015","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 December 2015","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}