{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T22:31:49Z","timestamp":1770417109729,"version":"3.49.0"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,3,6]],"date-time":"2019-03-06T00:00:00Z","timestamp":1551830400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,3,6]],"date-time":"2019-03-06T00:00:00Z","timestamp":1551830400000},"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>Knowledge on age-related miRNA changes in healthy individuals and their interaction with mRNAs is lacking. We studied age-related mRNA and miRNA expression changes and their interactions in normal airways. RNA and small RNA sequencing was performed on bronchial biopsies of 86 healthy individuals (age: 18\u201373) to determine age-related expression changes. Per age-related miRNA we determined the enrichment of age-related predicted targets and their correlation. We identified 285 age-related genes and 27 age-related miRNAs. Pathway enrichment showed that genes higher expressed with age were involved in synapse-related processes. Genes lower expressed with age were involved in cell cycle regulation, the immune system and DNA damage\/repair. MiR-146a-5p, miR-146b-5p and miR-142-5p were lower expressed with increasing age and we found a significant enrichment for predicted targets of these miRNAs among genes that were higher expressed with age. The expression levels of the enriched predicted targets <jats:italic>RIMS2<\/jats:italic> and <jats:italic>IGSF1<\/jats:italic> were negatively correlated with both miR-146a-5p and miR-146b-5p. <jats:italic>RIMS2<\/jats:italic> was present in the enriched process, i.e. positive regulation of synaptic transmission. In conclusion, genes decreased with ageing are involved in several of the ageing hallmarks. Genes higher expressed with ageing were involved in synapse-related processes, of which <jats:italic>RIMS2<\/jats:italic> is potentially regulated by two age-related miRNAs.<\/jats:p>","DOI":"10.1038\/s41598-019-39873-0","type":"journal-article","created":{"date-parts":[[2019,3,6]],"date-time":"2019-03-06T11:07:05Z","timestamp":1551870425000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Age-related gene and miRNA expression changes in airways of healthy individuals"],"prefix":"10.1038","volume":"9","author":[{"given":"J.","family":"Ong","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R. R.","family":"Woldhuis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"I. M.","family":"Boudewijn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8894-2638","authenticated-orcid":false,"given":"A.","family":"van den Berg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J.","family":"Kluiver","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"K.","family":"Kok","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. M.","family":"Terpstra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V.","family":"Guryev","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7210-8174","authenticated-orcid":false,"given":"M.","family":"de Vries","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C. J.","family":"Vermeulen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4146-6363","authenticated-orcid":false,"given":"W.","family":"Timens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"van den Berge","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C. A.","family":"Brandsma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,3,6]]},"reference":[{"key":"39873_CR1","unstructured":"WHO. Ageing and health, http:\/\/www.who.int\/mediacentre\/factsheets\/fs404\/en\/ (2015)."},{"key":"39873_CR2","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1378\/chest.08-1419","volume":"135","author":"K Ito","year":"2009","unstructured":"Ito, K. & Barnes, P. J. COPD as a disease of accelerated lung aging. Chest 135, 173\u2013180, https:\/\/doi.org\/10.1378\/chest.08-1419 (2009).","journal-title":"Chest"},{"key":"39873_CR3","doi-asserted-by":"publisher","first-page":"1194","DOI":"10.1016\/j.cell.2013.05.039","volume":"153","author":"C Lopez-Otin","year":"2013","unstructured":"Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194\u20131217, https:\/\/doi.org\/10.1016\/j.cell.2013.05.039 (2013).","journal-title":"Cell"},{"key":"39873_CR4","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1183\/09031936.00186914","volume":"45","author":"S Meiners","year":"2015","unstructured":"Meiners, S., Eickelberg, O. & Konigshoff, M. Hallmarks of the ageing lung. The European respiratory journal 45, 807\u2013827, https:\/\/doi.org\/10.1183\/09031936.00186914 (2015).","journal-title":"The European respiratory journal"},{"key":"39873_CR5","doi-asserted-by":"publisher","first-page":"1489","DOI":"10.2147\/CIA.S51152","volume":"8","author":"EM Lowery","year":"2013","unstructured":"Lowery, E. M., Brubaker, A. L., Kuhlmann, E. & Kovacs, E. J. The aging lung. Clinical interventions in aging 8, 1489\u20131496, https:\/\/doi.org\/10.2147\/CIA.S51152 (2013).","journal-title":"Clinical interventions in aging"},{"key":"39873_CR6","doi-asserted-by":"publisher","DOI":"10.1186\/s12890-017-0363-0","volume":"17","author":"ED Telenga","year":"2017","unstructured":"Telenga, E. D. et al. Airway wall thickness on HRCT scans decreases with age and increases with smoking. BMC pulmonary medicine 17, 27, https:\/\/doi.org\/10.1186\/s12890-017-0363-0 (2017).","journal-title":"BMC pulmonary medicine"},{"key":"39873_CR7","doi-asserted-by":"publisher","DOI":"10.1186\/1465-9921-12-78","volume":"12","author":"F Zhou","year":"2011","unstructured":"Zhou, F., Onizawa, S., Nagai, A. & Aoshiba, K. Epithelial cell senescence impairs repair process and exacerbates inflammation after airway injury. Respiratory research 12, 78, https:\/\/doi.org\/10.1186\/1465-9921-12-78 (2011).","journal-title":"Respiratory research"},{"key":"39873_CR8","doi-asserted-by":"publisher","unstructured":"de Vries, M. et al. Lung tissue gene-expression signature for the ageing lung in COPD. Thorax, https:\/\/doi.org\/10.1136\/thoraxjnl-2017-210074 (2017).","DOI":"10.1136\/thoraxjnl-2017-210074"},{"key":"39873_CR9","doi-asserted-by":"publisher","first-page":"e0167460","DOI":"10.1371\/journal.pone.0167460","volume":"11","author":"M Dugo","year":"2016","unstructured":"Dugo, M. et al. Human Lung Tissue Transcriptome: Influence of Sex and Age. PloS one 11, e0167460, https:\/\/doi.org\/10.1371\/journal.pone.0167460 (2016).","journal-title":"PloS one"},{"key":"39873_CR10","doi-asserted-by":"publisher","first-page":"e10724","DOI":"10.1371\/journal.pone.0010724","volume":"5","author":"N Noren Hooten","year":"2010","unstructured":"Noren Hooten, N. et al. microRNA expression patterns reveal differential expression of target genes with age. PloS one 5, e10724, https:\/\/doi.org\/10.1371\/journal.pone.0010724 (2010).","journal-title":"PloS one"},{"issue":"Suppl 1","key":"39873_CR11","doi-asserted-by":"publisher","first-page":"S59","DOI":"10.1016\/j.arr.2010.08.002","volume":"9","author":"LH Chen","year":"2010","unstructured":"Chen, L. H., Chiou, G. Y., Chen, Y. W., Li, H. Y. & Chiou, S. H. MicroRNA and aging: a novel modulator in regulating the aging network. Ageing research reviews 9(Suppl 1), S59\u201366, https:\/\/doi.org\/10.1016\/j.arr.2010.08.002 (2010).","journal-title":"Ageing research reviews"},{"key":"39873_CR12","doi-asserted-by":"publisher","first-page":"656","DOI":"10.3390\/genes5030656","volume":"5","author":"LW Harries","year":"2014","unstructured":"Harries, L. W. MicroRNAs as Mediators of the Ageing Process. Genes 5, 656\u2013670, https:\/\/doi.org\/10.3390\/genes5030656 (2014).","journal-title":"Genes"},{"key":"39873_CR13","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1242\/jcs.099200","volume":"125","author":"T Smith-Vikos","year":"2012","unstructured":"Smith-Vikos, T. & Slack, F. J. MicroRNAs and their roles in aging. Journal of cell science 125, 7\u201317, https:\/\/doi.org\/10.1242\/jcs.099200 (2012).","journal-title":"Journal of cell science"},{"key":"39873_CR14","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/j.tig.2011.03.005","volume":"27","author":"M Gorospe","year":"2011","unstructured":"Gorospe, M. & Abdelmohsen, K. MicroRegulators come of age in senescence. Trends in genetics: TIG 27, 233\u2013241, https:\/\/doi.org\/10.1016\/j.tig.2011.03.005 (2011).","journal-title":"Trends in genetics: TIG"},{"key":"39873_CR15","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1038\/cdd.2011.143","volume":"19","author":"R Faraonio","year":"2012","unstructured":"Faraonio, R. et al. A set of miRNAs participates in the cellular senescence program in human diploid fibroblasts. Cell death and differentiation 19, 713\u2013721, https:\/\/doi.org\/10.1038\/cdd.2011.143 (2012).","journal-title":"Cell death and differentiation"},{"key":"39873_CR16","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1093\/gerona\/glu145","volume":"70","author":"H Zhang","year":"2015","unstructured":"Zhang, H. et al. Investigation of microRNA expression in human serum during the aging process. The journals of gerontology. Series A, Biological sciences and medical sciences 70, 102\u2013109, https:\/\/doi.org\/10.1093\/gerona\/glu145 (2015).","journal-title":"Series A, Biological sciences and medical sciences"},{"key":"39873_CR17","doi-asserted-by":"publisher","first-page":"2673","DOI":"10.7150\/thno.18915","volume":"7","author":"Q Lei","year":"2017","unstructured":"Lei, Q. et al. Microvesicles as Potential Biomarkers for the Identification of Senescence in Human Mesenchymal Stem Cells. Theranostics 7, 2673\u20132689, https:\/\/doi.org\/10.7150\/thno.18915 (2017).","journal-title":"Theranostics"},{"key":"39873_CR18","doi-asserted-by":"publisher","first-page":"402","DOI":"10.18632\/aging.100042","volume":"1","author":"D Bhaumik","year":"2009","unstructured":"Bhaumik, D. et al. MicroRNAs miR-146a\/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8. Aging 1, 402\u2013411, https:\/\/doi.org\/10.18632\/aging.100042 (2009).","journal-title":"Aging"},{"key":"39873_CR19","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1152\/physiolgenomics.00133.2016","volume":"49","author":"MR Paterson","year":"2017","unstructured":"Paterson, M. R. & Kriegel, A. J. MiR-146a\/b: a family with shared seeds and different roots. Physiological genomics 49, 243\u2013252, https:\/\/doi.org\/10.1152\/physiolgenomics.00133.2016 (2017).","journal-title":"Physiological genomics"},{"key":"39873_CR20","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1007\/s00441-016-2511-x","volume":"367","author":"C Brandenberger","year":"2017","unstructured":"Brandenberger, C. & Muhlfeld, C. Mechanisms of lung aging. Cell and tissue research 367, 469\u2013480, https:\/\/doi.org\/10.1007\/s00441-016-2511-x (2017).","journal-title":"Cell and tissue research"},{"key":"39873_CR21","doi-asserted-by":"publisher","first-page":"619","DOI":"10.3892\/br.2013.101","volume":"1","author":"KT Kim","year":"2013","unstructured":"Kim, K. T. et al. Association between regulating synaptic membrane exocytosis 2 gene polymorphisms and degenerative lumbar scoliosis. Biomedical reports 1, 619\u2013623, https:\/\/doi.org\/10.3892\/br.2013.101 (2013).","journal-title":"Biomedical reports"},{"key":"39873_CR22","doi-asserted-by":"publisher","unstructured":"Sudhof, T. C. & Rizo, J. Synaptic vesicle exocytosis. Cold Spring Harbor perspectives in biology 3, https:\/\/doi.org\/10.1101\/cshperspect.a005637 (2011).","DOI":"10.1101\/cshperspect.a005637"},{"key":"39873_CR23","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3389\/fnmol.2012.00012","volume":"5","author":"GL Clarke","year":"2012","unstructured":"Clarke, G. L., Chen, J. & Nishimune, H. Presynaptic Active Zone Density during Development and Synaptic Plasticity. Frontiers in molecular neuroscience 5, 12, https:\/\/doi.org\/10.3389\/fnmol.2012.00012 (2012).","journal-title":"Frontiers in molecular neuroscience"},{"key":"39873_CR24","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1210\/js.2017-00478","volume":"2","author":"DJ Bernard","year":"2018","unstructured":"Bernard, D. J., Brule, E., Smith, C. L., Joustra, S. D. & Wit, J. M. From Consternation to Revelation: Discovery of a Role for IGSF1 in Pituitary Control of Thyroid Function. Journal of the Endocrine Society 2, 220\u2013231, https:\/\/doi.org\/10.1210\/js.2017-00478 (2018).","journal-title":"Journal of the Endocrine Society"},{"key":"39873_CR25","doi-asserted-by":"publisher","DOI":"10.1038\/srep42937","volume":"7","author":"M Garcia","year":"2017","unstructured":"Garcia, M. et al. The syndrome of central hypothyroidism and macroorchidism: IGSF1 controls TRHR and FSHB expression by differential modulation of pituitary TGFbeta and Activin pathways. Scientific reports 7, 42937, https:\/\/doi.org\/10.1038\/srep42937 (2017).","journal-title":"Scientific reports"},{"key":"39873_CR26","doi-asserted-by":"publisher","first-page":"D239","DOI":"10.1093\/nar\/gkx1141","volume":"46","author":"D Karagkouni","year":"2018","unstructured":"Karagkouni, D. et al. DIANA-TarBasev8: a decade-long collection of experimentally supported miRNA-gene interactions. Nucleic acids research 46, D239\u2013D245, https:\/\/doi.org\/10.1093\/nar\/gkx1141 (2018).","journal-title":"Nucleic acids research"},{"key":"39873_CR27","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1016\/j.celrep.2015.09.017","volume":"13","author":"LM Young","year":"2015","unstructured":"Young, L. M. et al. TIMELESS Forms a Complex with PARP1 Distinct from Its Complex with TIPIN and Plays a Role in the DNA Damage Response. Cell reports 13, 451\u2013459, https:\/\/doi.org\/10.1016\/j.celrep.2015.09.017 (2015).","journal-title":"Cell reports"},{"key":"39873_CR28","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1038\/nrm.2017.53","volume":"18","author":"A Ray Chaudhuri","year":"2017","unstructured":"Ray Chaudhuri, A. & Nussenzweig, A. The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nature reviews. Molecular cell biology 18, 610\u2013621, https:\/\/doi.org\/10.1038\/nrm.2017.53 (2017).","journal-title":"Nature reviews. Molecular cell biology"},{"key":"39873_CR29","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/S0092-8674(01)00304-X","volume":"105","author":"SB Cantor","year":"2001","unstructured":"Cantor, S. B. et al. BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell 105, 149\u2013160 (2001).","journal-title":"Cell"},{"key":"39873_CR30","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1126\/science.1088753","volume":"302","author":"X Yu","year":"2003","unstructured":"Yu, X., Chini, C. C., He, M., Mer, G. & Chen, J. The BRCT domain is a phospho-protein binding domain. Science 302, 639\u2013642, https:\/\/doi.org\/10.1126\/science.1088753 (2003).","journal-title":"Science"},{"key":"39873_CR31","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2334-9-125","volume":"9","author":"S Sarfraz","year":"2009","unstructured":"Sarfraz, S., Hamid, S., Ali, S., Jafri, W. & Siddiqui, A. A. Modulations of cell cycle checkpoints during HCV associated disease. BMC infectious diseases 9, 125, https:\/\/doi.org\/10.1186\/1471-2334-9-125 (2009).","journal-title":"BMC infectious diseases"},{"key":"39873_CR32","doi-asserted-by":"publisher","first-page":"e91788","DOI":"10.1371\/journal.pone.0091788","volume":"9","author":"SJ Hoonhorst","year":"2014","unstructured":"Hoonhorst, S. J. et al. Lower corticosteroid skin blanching response is associated with severe COPD. PloS one 9, e91788, https:\/\/doi.org\/10.1371\/journal.pone.0091788 (2014).","journal-title":"PloS one"},{"key":"39873_CR33","doi-asserted-by":"publisher","first-page":"357","DOI":"10.1038\/nmeth.3317","volume":"12","author":"D Kim","year":"2015","unstructured":"Kim, D., Langmead, B. & Salzberg, S. L. HISAT: a fast spliced aligner with low memory requirements. Nature methods 12, 357\u2013360, https:\/\/doi.org\/10.1038\/nmeth.3317 (2015).","journal-title":"Nature methods"},{"key":"39873_CR34","doi-asserted-by":"publisher","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","volume":"25","author":"H Li","year":"2009","unstructured":"Li, H. et al. The Sequence Alignment\/Map format and SAMtools. Bioinformatics 25, 2078\u20132079, https:\/\/doi.org\/10.1093\/bioinformatics\/btp352 (2009).","journal-title":"Bioinformatics"},{"key":"39873_CR35","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1093\/bioinformatics\/btu638","volume":"31","author":"S Anders","year":"2015","unstructured":"Anders, S., Pyl, P. T. & Huber, W. HTSeq\u2013a Python framework to work with high-throughput sequencing data. Bioinformatics 31, 166\u2013169, https:\/\/doi.org\/10.1093\/bioinformatics\/btu638 (2015).","journal-title":"Bioinformatics"},{"key":"39873_CR36","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1093\/nar\/gkr688","volume":"40","author":"MR Friedlander","year":"2012","unstructured":"Friedlander, M. R., Mackowiak, S. D., Li, N., Chen, W. & Rajewsky, N. miRDeep2 accurately identifies known and hundreds of novel microRNA genes in seven animal clades. Nucleic acids research 40, 37\u201352, https:\/\/doi.org\/10.1093\/nar\/gkr688 (2012).","journal-title":"Nucleic acids research"},{"key":"39873_CR37","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1093\/bioinformatics\/18.1.207","volume":"18","author":"A Sturn","year":"2002","unstructured":"Sturn, A., Quackenbush, J. & Trajanoski, Z. Genesis: cluster analysis of microarray data. Bioinformatics 18, 207\u2013208 (2002).","journal-title":"Bioinformatics"},{"key":"39873_CR38","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-128","volume":"14","author":"EY Chen","year":"2013","unstructured":"Chen, E. Y. et al. Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC bioinformatics 14, 128, https:\/\/doi.org\/10.1186\/1471-2105-14-128 (2013).","journal-title":"BMC bioinformatics"},{"key":"39873_CR39","doi-asserted-by":"publisher","first-page":"W90","DOI":"10.1093\/nar\/gkw377","volume":"44","author":"MV Kuleshov","year":"2016","unstructured":"Kuleshov, M. V. et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic acids research 44, W90\u201397, https:\/\/doi.org\/10.1093\/nar\/gkw377 (2016).","journal-title":"Nucleic acids research"},{"key":"39873_CR40","doi-asserted-by":"publisher","first-page":"W83","DOI":"10.1093\/nar\/gkw199","volume":"44","author":"J Reimand","year":"2016","unstructured":"Reimand, J. et al. g:Profiler-a web server for functional interpretation of gene lists (2016 update). Nucleic acids research 44, W83\u201389, https:\/\/doi.org\/10.1093\/nar\/gkw199 (2016).","journal-title":"Nucleic acids research"},{"key":"39873_CR41","doi-asserted-by":"publisher","unstructured":"Agarwal, V., Bell, G. W., Nam, J. W. & Bartel, D. P. Predicting effective microRNA target sites in mammalian mRNAs. eLife 4, https:\/\/doi.org\/10.7554\/eLife.05005 (2015).","DOI":"10.7554\/eLife.05005"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-39873-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-39873-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-39873-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T07:16:12Z","timestamp":1671261372000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-39873-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,6]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["39873"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-39873-0","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,6]]},"assertion":[{"value":"28 August 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 February 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 March 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"I.M.B. reports consultancy fees paid to the university by G.S.K. C.J.V. was supported by a grant from G.S.K. J.O., R.R.W., A.v.d.B., J.K., K.K., M.M.T., V.G., M.d.V., W.T., M.v.d.B. and C.A.B. have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"3765"}}