{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T05:20:36Z","timestamp":1793424036861,"version":"4.5.0"},"reference-count":46,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,8,29]],"date-time":"2017-08-29T00:00:00Z","timestamp":1503964800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,8,29]],"date-time":"2017-08-29T00:00:00Z","timestamp":1503964800000},"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>There is a well-defined regulatory framework governing the approval of chemicals for use as pharmaceuticals or release into the environment. Toxicity assessment is thus a major hurdle in the compound discovery pipeline, currently involving large scale animal testing. The search for alternative testing platforms is therefore an important priority. We have developed a convenient, low cost assay utilising the nematode <jats:italic>Caenorhabditis elegans<\/jats:italic>, to rapidly assess both acute toxicity and developmental and reproductive toxicity (DART). However the worm is protected by a robust cuticle that forms a barrier to chemical uptake. We assessed mutants with altered cuticle properties to identify sensitized strains optimized for toxicity assays. Evaluating the trade-off between increased permeability and reduced fitness identifies <jats:italic>bus-5(br19)<\/jats:italic> as the most suitable strain for chemical exposure. We demonstrate the applicability of this assay for a range of chemicals with differing properties, including a modified exposure protocol for volatile or less soluble compounds. This work enhances the effectiveness of <jats:italic>C. elegans<\/jats:italic> for convenient toxicity assessment, which could contribute to a reduction in the use of vertebrates particularly at the crucial early stages of product development. Strains identified in this work will also enhance the sensitivity of <jats:italic>C. elegans<\/jats:italic> based drug discovery platforms.<\/jats:p>","DOI":"10.1038\/s41598-017-10454-3","type":"journal-article","created":{"date-parts":[[2017,8,23]],"date-time":"2017-08-23T11:50:42Z","timestamp":1503489042000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":161,"title":["An enhanced C. elegans based platform for toxicity assessment"],"prefix":"10.1038","volume":"7","author":[{"given":"Huajiang","family":"Xiong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Pears","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Woollard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,8,29]]},"reference":[{"key":"10454_CR1","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.1038\/4601080a","volume":"460","author":"T Hartung","year":"2009","unstructured":"Hartung, T. & Rovida, C. Chemical regulators have overreached. Nature \n                           460, 1080\u20131081 (2009).","journal-title":"Nature"},{"key":"10454_CR2","doi-asserted-by":"crossref","unstructured":"Burden, N., Sewell, F. & Chapman, K. Testing Chemical Safety: What Is Needed to Ensure the Widespread Application of Non-animal Approaches? PLoS Biol. 13 (2015).","DOI":"10.1371\/journal.pbio.1002156"},{"key":"10454_CR3","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1101\/gr.10.5.703","volume":"10","author":"CH Lai","year":"2000","unstructured":"Lai, C. H., Chou, C. Y., Ch\u2019ang, L. Y., Liu, C. S. & Lin, W. Identification of novel human genes evolutionarily conserved in Caenorhabditis elegans by comparative proteomics. Genome Res. \n                           10, 703\u201313 (2000).","journal-title":"Genome Res."},{"key":"10454_CR4","doi-asserted-by":"publisher","first-page":"896","DOI":"10.1038\/ng1844","volume":"38","author":"B Lehner","year":"2006","unstructured":"Lehner, B., Crombie, C., Tischler, J., Fortunato, A. & Fraser, A. G. Systematic mapping of genetic interactions in Caenorhabditis elegans identifies common modifiers of diverse signaling pathways. Nat. Genet. \n                           38, 896\u2013903 (2006).","journal-title":"Nat. Genet."},{"key":"10454_CR5","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1002\/biot.201000183","volume":"5","author":"M Markaki","year":"2010","unstructured":"Markaki, M. & Tavernarakis, N. Modeling human diseases in Caenorhabditis elegans. Biotechnol. J \n                           5, 1261\u20131276 (2010).","journal-title":"Biotechnol. J"},{"key":"10454_CR6","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1016\/j.addr.2013.12.001","volume":"69\u201370","author":"LP O\u2019Reilly","year":"2014","unstructured":"O\u2019Reilly, L. P., Luke, C. J., Perlmutter, D. H., Silverman, G. A. & Pak, S. C. C. elegans in high-throughput drug discovery. Advanced Drug Delivery Reviews \n                           69\u201370, 247\u2013253 (2014).","journal-title":"Advanced Drug Delivery Reviews"},{"key":"10454_CR7","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1016\/j.vascn.2004.04.002","volume":"50","author":"M Dengg","year":"2004","unstructured":"Dengg, M. & van Meel, J. C. A. Caenorhabditis elegans as model system for rapid toxicity assessment of pharmaceutical compounds. J. Pharmacol. Toxicol. Methods \n                           50, 209\u2013214 (2004).","journal-title":"J. Pharmacol. Toxicol. Methods"},{"key":"10454_CR8","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/nrd2031","volume":"5","author":"T Kaletta","year":"2006","unstructured":"Kaletta, T. & Hengartner, M. O. Finding function in novel targets: C. elegans as a model organism. Nat. Rev. Drug Discov. \n                           5, 387\u201398 (2006).","journal-title":"Nat. Rev. Drug Discov."},{"key":"10454_CR9","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1093\/toxsci\/kfn121","volume":"106","author":"MCK Leung","year":"2008","unstructured":"Leung, M. C. K. et al. Caenorhabditis elegans: An emerging model in biomedical and environmental toxicology. Toxicological Sciences \n                           106, 5\u201328 (2008).","journal-title":"Toxicological Sciences"},{"key":"10454_CR10","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1039\/c0mt00064g","volume":"3","author":"EJ Martinez-Finley","year":"2011","unstructured":"Martinez-Finley, E. J., Avila, D. S., Chakraborty, S. & Aschner, M. Insights from Caenorhabditis elegans on the role of metals in neurodegenerative diseases. Metallomics \n                           3, 271\u20139 (2011).","journal-title":"Metallomics"},{"key":"10454_CR11","doi-asserted-by":"publisher","first-page":"236","DOI":"10.1177\/0960327110392084","volume":"31","author":"D Avila","year":"2012","unstructured":"Avila, D., Helmcke, K. & Aschner, M. The Caenorhabiditis elegans model as a reliable tool in neurotoxicology. Hum. Exp. Toxicol. \n                           31, 236\u201343 (2012).","journal-title":"Hum. Exp. Toxicol."},{"key":"10454_CR12","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1289\/ehp.1206301","volume":"121","author":"P Allard","year":"2013","unstructured":"Allard, P., Kleinstreuer, N. C., Knudsen, T. B. & Colai\u00e1covo, M. P. Disruption of Germline Function. Env. Heal. Perspect \n                           121, 717\u2013724 (2013).","journal-title":"Env. Heal. Perspect"},{"key":"10454_CR13","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.ntt.2008.12.004","volume":"32","author":"WA Boyd","year":"2010","unstructured":"Boyd, W. A., Smith, M. V., Kissling, G. E. & Freedman, J. H. Medium- and high-throughput screening of neurotoxicants using C. elegans. Neurotoxicol Teratol. \n                           32, 68\u201373 (2010).","journal-title":"Neurotoxicol Teratol."},{"key":"10454_CR14","doi-asserted-by":"publisher","DOI":"10.1038\/srep22965","volume":"6","author":"PH Harlow","year":"2016","unstructured":"Harlow, P. H. et al. The nematode Caenorhabditis elegans as a tool to predict chemical activity on mammalian development and identify mechanisms influencing toxicological outcome. Sci. Rep. \n                           6, 22965 (2016).","journal-title":"Sci. Rep."},{"key":"10454_CR15","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1289\/ehp.1409645","volume":"124","author":"WA Boyd","year":"2016","unstructured":"Boyd, W. A. et al. Developmental Effects of the ToxCastTM Phase I and Phase II Chemicals in Caenorhabditis elegans and Corresponding Responses in Zebrafish, Rats, and Rabbits. Env. Heal. Perspect. \n                           124, 586\u2013593 (2016).","journal-title":"Env. Heal. Perspect."},{"key":"10454_CR16","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1007\/978-1-61779-867-2_3","volume":"889","author":"WA Boyd","year":"2012","unstructured":"Boyd, W. A., Smith, M. V. & Freedman, J. H. Caenorhabditis elegans as a model in developmental toxicology. Methods Mol Biol. \n                           889, 15\u201324 (2012).","journal-title":"Methods Mol Biol."},{"key":"10454_CR17","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.taap.2010.02.014","volume":"245","author":"WA Boyd","year":"2010","unstructured":"Boyd, W. A., Mcbride, S. J., Rice, J. R., Snyder, D. W. & Freedman, J. H. A high-throughput method for assessing chemical toxicity using a Caenorhabditis elegans reproduction assay. Toxicol Appl Pharmacol. \n                           245, 153\u2013159 (2010).","journal-title":"Toxicol Appl Pharmacol."},{"key":"10454_CR18","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/S0168-9525(99)01857-0","volume":"16","author":"IL Johnstone","year":"2000","unstructured":"Johnstone, I. L. Cuticle collagen genes. Trends Genet. \n                           16, 21\u201327 (2000).","journal-title":"Trends Genet."},{"key":"10454_CR19","doi-asserted-by":"crossref","unstructured":"Fritz, J. A. & Behm, C. A. CUTI-1: A novel tetraspan protein involved in C. elegans CUTicle formation and epithelial integrity. PLoS One \n                           4 (2009).","DOI":"10.1371\/journal.pone.0005117"},{"key":"10454_CR20","doi-asserted-by":"publisher","DOI":"10.1080\/21688370.2015.1078432","volume":"8370","author":"C Taffoni","year":"2015","unstructured":"Taffoni, C. & Pujol, N. Mechanisms of innate immunity in C. elegans epidermis. Tissue Barriers. \n                           8370, e1078432 (2015).","journal-title":"Tissue Barriers."},{"key":"10454_CR21","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1007\/s10974-006-9070-9","volume":"27","author":"M Carre-Pierrat","year":"2006","unstructured":"Carre-Pierrat, M. et al. Blocking of striated muscle degeneration by serotonin in C. elegans. J. Muscle Res. Cell Motil. \n                           27, 253\u2013258 (2006).","journal-title":"J. Muscle Res. Cell Motil."},{"key":"10454_CR22","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1111\/j.1476-5381.2010.00725.x","volume":"160","author":"J Giacomotto","year":"2010","unstructured":"Giacomotto, J. & Segalat, L. High-throughput screening and small animal models, where are we? Br. J. Pharmacol. \n                           160, 204\u2013216 (2010).","journal-title":"Br. J. Pharmacol."},{"key":"10454_CR23","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1038\/nchembio.380","volume":"6","author":"AR Burns","year":"2010","unstructured":"Burns, A. R. et al. A predictive model for drug bioaccumulation and bioactivity in Caenorhabditis elegans. Nat Chem Biol. \n                           6, 549\u2013557 (2010).","journal-title":"Nat Chem Biol."},{"key":"10454_CR24","doi-asserted-by":"publisher","first-page":"1033","DOI":"10.1534\/genetics.105.045716","volume":"171","author":"MJ Gravato-Nobre","year":"2005","unstructured":"Gravato-Nobre, M. J. et al. Multiple genes affect sensitivity of Caenorhabditis elegans to the bacterial pathogen Microbacterium nematophilum. Genetics \n                           171, 1033\u20131045 (2005).","journal-title":"Genetics"},{"key":"10454_CR25","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1534\/genetics.110.122002","volume":"187","author":"MJ Gravato-nobre","year":"2011","unstructured":"Gravato-nobre, M. J., Stroud, D., Rourke, D. O., Darby, C. & Hodgkin, J. Glycosylation genes expressed in seam cells determine complex surface properties and bacterial adhesion to the cuticle of Caenorhabditis elegans. Genetics \n                           187, 141\u2013155 (2011).","journal-title":"Genetics"},{"key":"10454_CR26","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1016\/j.ydbio.2008.02.060","volume":"317","author":"FA Partridge","year":"2008","unstructured":"Partridge, F. A., Tearle, A. W., Gravato-Nobre, M. J., Schafer, W. R. & Hodgkin, J. The C. elegans glycosyltransferase BUS-8 has two distinct and essential roles in epidermal morphogenesis. Dev. Biol. \n                           317, 549\u2013559 (2008).","journal-title":"Dev. Biol."},{"key":"10454_CR27","doi-asserted-by":"publisher","first-page":"1507","DOI":"10.1042\/BCJ20160142","volume":"473","author":"L Feng","year":"2016","unstructured":"Feng, L., Shou, Q. & Butcher, R. A. Identification of a dTDP-rhamnose biosynthetic pathway that oscillates with the molting cycle in Caenorhabditis elegans. Biochem J. \n                           473, 1507\u20131521 (2016).","journal-title":"Biochem J."},{"key":"10454_CR28","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1534\/genetics.106.060087","volume":"175","author":"K Yook","year":"2007","unstructured":"Yook, K. & Hodgkin, J. Mos1 Mutagenesis Reveals a Diversity of Mechanisms Affecting Response of Caenorhabditis elegans to the Bacterial Pathogen Microbacterium nematophilum. Genetics \n                           175, 681\u2013697 (2007).","journal-title":"Genetics"},{"key":"10454_CR29","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1534\/genetics.114.174110","volume":"200","author":"CM Loer","year":"2015","unstructured":"Loer, C. M. et al. Cuticle integrity and biogenic amine synthesis in Caenorhabditis elegans require the cofactor tetrahydrobiopterin (BH4). Genetics \n                           200, 237\u2013253 (2015).","journal-title":"Genetics"},{"key":"10454_CR30","doi-asserted-by":"publisher","first-page":"1906","DOI":"10.1038\/nprot.2006.283","volume":"1","author":"AR Burns","year":"2006","unstructured":"Burns, A. R. et al. High-throughput screening of small molecules for bioactivity and target identification in Caenorhabditis elegans. Nat Protoc. \n                           1, 1906\u20131914 (2006).","journal-title":"Nat Protoc."},{"key":"10454_CR31","doi-asserted-by":"publisher","first-page":"5209","DOI":"10.1242\/jcs.01403","volume":"117","author":"H Moribe","year":"2004","unstructured":"Moribe, H. et al. Tetraspanin protein (TSP-15) is required for epidermal integrity in Caenorhabditis elegans. J. Cell Sci. \n                           117, 5209\u20135220 (2004).","journal-title":"J. Cell Sci."},{"key":"10454_CR32","doi-asserted-by":"publisher","first-page":"537","DOI":"10.1242\/bio.017400","volume":"5","author":"N Hirani","year":"2016","unstructured":"Hirani, N., Westenberg, M., Seed, P. T. & Dolphin, C. T. C. elegans flavin-containing monooxygenase-4 is essential for osmoregulation in hypotonic stress. Biol. Open \n                           5, 537\u201349 (2016).","journal-title":"Biol. Open"},{"key":"10454_CR33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0092552","volume":"9","author":"JD Ward","year":"2014","unstructured":"Ward, J. D. et al. Defects in the C. elegans acyl-CoA synthase, acs-3, and nuclear hormone receptor, nhr-25, cause sensitivity to distinct, but overlapping stresses. PLoS One \n                           9, e92552 (2014).","journal-title":"PLoS One"},{"key":"10454_CR34","doi-asserted-by":"publisher","first-page":"285","DOI":"10.5483\/BMBRep.2011.44.4.285","volume":"44","author":"Y Li","year":"2011","unstructured":"Li, Y. & Paik, Y.-K. A potential role for fatty acid biosynthesis genes during molting and cuticle formation in Caenorhabditis elegans. BMB Rep. \n                           44, 285\u2013290 (2011).","journal-title":"BMB Rep."},{"key":"10454_CR35","doi-asserted-by":"publisher","first-page":"1648","DOI":"10.1091\/mbc.E08-07-0708","volume":"21","author":"VS Meli","year":"2010","unstructured":"Meli, V. S., Osuna, B., Ruvkun, G. & Frand, A. R. MLT-10 defines a family of DUF644 and proline-rich repeat proteins involved in the molting cycle of Caenorhabditis elegans. Mol. Biol. Cell \n                           21, 1648\u20131661 (2010).","journal-title":"Mol. Biol. Cell"},{"key":"10454_CR36","doi-asserted-by":"publisher","first-page":"17549","DOI":"10.1074\/jbc.M900831200","volume":"284","author":"MC Thein","year":"2009","unstructured":"Thein, M. C. et al. Combined extracellular matrix cross-linking activity of the peroxidase MLT-7 and the dual oxidase BLI-3 is critical for post-embryonic viability in Caenorhabditis elegans. J. Biol. Chem. \n                           284, 17549\u201317563 (2009).","journal-title":"J. Biol. Chem."},{"key":"10454_CR37","doi-asserted-by":"publisher","first-page":"2010","DOI":"10.1002\/cbic.200600262","volume":"7","author":"D Kokel","year":"2006","unstructured":"Kokel, D. & Xue, D. A class of benzenoid chemicals suppresses apoptosis in C. elegans. ChemBioChem \n                           7, 2010\u20132015 (2006).","journal-title":"ChemBioChem"},{"key":"10454_CR38","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004794","volume":"11","author":"W Law","year":"2015","unstructured":"Law, W. et al. Heterologous Expression in Remodeled C. elegans: A Platform for Monoaminergic Agonist Identification and Anthelmintic Screening. PLoS Pathog. \n                           11, e1004794 (2015).","journal-title":"PLoS Pathog."},{"key":"10454_CR39","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1002\/ps.4564","volume":"73","author":"MM Kudelska","year":"2017","unstructured":"Kudelska, M. M., Holden-Dye, L., O\u2019Connor, V. & Doyle, D. A. Concentration-dependent effects of acute and chronic neonicotinoid exposure on the behaviour and development of the nematode Caenorhabditis elegans. Pest Manag Sci. \n                           73, 1345\u20131351 (2017).","journal-title":"Pest Manag Sci."},{"key":"10454_CR40","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.chemosphere.2005.01.077","volume":"61","author":"K Reichert","year":"2005","unstructured":"Reichert, K. & Menzel, R. Expression profiling of five different xenobiotics using a Caenorhabditis elegans whole genome microarray. Chemosphere \n                           61, 229\u2013237 (2005).","journal-title":"Chemosphere"},{"key":"10454_CR41","doi-asserted-by":"crossref","unstructured":"Gosai, S. J. et al. Automated high-content live animal drug screening using C. elegans expressing the aggregation prone serpin \u03b11-antitrypsin Z. PLoS One \n                           5 (2010).","DOI":"10.1371\/journal.pone.0015460"},{"key":"10454_CR42","doi-asserted-by":"publisher","first-page":"5123","DOI":"10.1093\/hmg\/ddu236","volume":"23","author":"LP O\u2019Reilly","year":"2014","unstructured":"O\u2019Reilly, L. P. et al. A genome-wide RNAi screen identifies potential drug targets in a C. elegans model of \u03b11-antitrypsin deficiency. Hum. Mol. Genet. \n                           23, 5123\u20135132 (2014).","journal-title":"Hum. Mol. Genet."},{"key":"10454_CR43","doi-asserted-by":"publisher","first-page":"718","DOI":"10.1242\/bio.20134549","volume":"2","author":"S Hughes","year":"2013","unstructured":"Hughes, S., Brabin, C., Appleford, P. J. & Woollard, A. CEH-20\/Pbx and UNC-62\/Meis function upstream of rnt-1\/Runx to regulate asymmetric divisions of the C. elegans stem-like seam cells. Biol. Open \n                           2, 718\u201327 (2013).","journal-title":"Biol. Open"},{"key":"10454_CR44","doi-asserted-by":"publisher","first-page":"1405","DOI":"10.1002\/biot.200600176","volume":"1","author":"M Artal-Sanz","year":"2006","unstructured":"Artal-Sanz, M., de Jong, L. & Tavernarakis, N. Caenorhabditis elegans: A versatile platform for drug discovery. Biotechnology Journal \n                           1, 1405\u20131418 (2006).","journal-title":"Biotechnology Journal"},{"key":"10454_CR45","doi-asserted-by":"publisher","first-page":"625","DOI":"10.1080\/17460441.2017.1319358","volume":"12","author":"W Kim","year":"2017","unstructured":"Kim, W., Hendricks, G. L., Lee, K. & Mylonakis, E. An update on the use of C. elegans for preclinical drug discovery: screening and identifying anti-infective drugs. Expert Opin. Drug Discov. \n                           12, 625\u2013633 (2017).","journal-title":"Expert Opin. Drug Discov."},{"key":"10454_CR46","first-page":"71","volume":"77","author":"S Brenner","year":"1974","unstructured":"Brenner, S. The genetics of C.elegans. Methods \n                           77, 71\u201394 (1974).","journal-title":"Methods"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-10454-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-10454-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-10454-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T09:50:12Z","timestamp":1671789012000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-10454-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8,29]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["10454"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-10454-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,8,29]]},"assertion":[{"value":"18 May 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 August 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 August 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":"9839"}}