{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T03:07:25Z","timestamp":1779073645982,"version":"3.51.4"},"reference-count":47,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2019,6,1]],"date-time":"2019-06-01T00:00:00Z","timestamp":1559347200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2019,6,11]],"date-time":"2019-06-11T00:00:00Z","timestamp":1560211200000},"content-version":"vor","delay-in-days":10,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS|National Institutes of Health NIH","doi-asserted-by":"publisher","award":["DP2AG044279"],"award-info":[{"award-number":["DP2AG044279"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Syst Biol"],"published-print":{"date-parts":[[2019,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Quantifying virulence remains a central problem in human health, pest control, disease ecology, and evolutionary biology. Bacterial virulence is typically quantified by the\n                    <jats:italic>LT50<\/jats:italic>\n                    (i.e., the time taken to kill 50% of infected hosts); however, such an indicator cannot account for the full complexity of the infection process, such as distinguishing between the pathogen's ability to colonize versus kill the hosts. Indeed, the pathogen needs to breach the primary defenses in order to colonize, find a suitable environment to replicate, and finally express the virulence factors that cause disease. Here, we show that two virulence attributes, namely pathogen lethality and invasiveness, can be disentangled from the survival curves of a laboratory population of\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    nematodes exposed to three bacterial pathogens:\n                    <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                    ,\n                    <jats:italic>Serratia marcescens,<\/jats:italic>\n                    and\n                    <jats:italic>Salmonella enterica<\/jats:italic>\n                    . We first show that the host population eventually experiences a constant mortality rate, which quantifies the lethality of the pathogen. We then show that the time necessary to reach this constant mortality rate regime depends on the pathogen growth rate and colonization rate, and thus determines the pathogen invasiveness. Our framework reveals that\n                    <jats:italic>Serratia marcescens<\/jats:italic>\n                    is particularly good at the initial colonization of the host, whereas\n                    <jats:italic>Salmonella enterica<\/jats:italic>\n                    is a poor colonizer yet just as lethal once established.\n                    <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                    , on the other hand, is both a good colonizer and highly lethal after becoming established. The ability to quantitatively characterize the ability of different pathogens to perform each of these steps has implications for treatment and prevention of disease and for the evolution and ecology of pathogens.\n                  <\/jats:p>","DOI":"10.15252\/msb.20188707","type":"journal-article","created":{"date-parts":[[2019,6,11]],"date-time":"2019-06-11T11:35:51Z","timestamp":1560252951000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Disentangling bacterial invasiveness from lethality in an experimental host\u2010pathogen system"],"prefix":"10.1038","volume":"15","author":[{"given":"Tommaso","family":"Biancalani","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4583-8555","authenticated-orcid":false,"given":"Jeff","family":"Gore","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,6,11]]},"reference":[{"key":"BFMSB188707_CR1","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1111\/j.1558-5646.1995.tb04433.x","volume":"49","author":"PA Abrams","year":"1995","unstructured":"Abrams PA, Ludwig D (1995) Optimality theory, gompertz\u2019 law, and the disposable soma theory of senescence. Evol. Int. J. Org. Evol. 49: 1055\u20131066","journal-title":"Evol. Int. J. Org. Evol."},{"key":"BFMSB188707_CR2","volume-title":"Integrated pest management: current concepts and ecological perspective","year":"2013","unstructured":"Abrol DP (ed) (2013) Integrated pest management: current concepts and ecological perspective, 1st edn. Amsterdam, Boston: Academic Press","edition":"1st edn"},{"key":"BFMSB188707_CR3","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1046\/j.1462-5822.2003.00287.x","volume":"5","author":"RA Alegado","year":"2003","unstructured":"Alegado RA, Campbell MC, Chen WC, Slutz SS, Tan M\u2010W (2003) Characterization of mediators of microbial virulence and innate immunity using the Caenorhabditis elegans host\u2013pathogen model. Cell Microbiol 5: 435\u2013444","journal-title":"Cell Microbiol"},{"key":"BFMSB188707_CR4","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1111\/j.1420-9101.2008.01658.x","volume":"22","author":"S Alizon","year":"2009","unstructured":"Alizon S, Hurford A, Mideo N, Baalen MV (2009) Virulence evolution and the trade\u2010off hypothesis: history, current state of affairs and the future. J Evol Biol 22: 245\u2013259","journal-title":"J Evol Biol"},{"key":"BFMSB188707_CR5","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1017\/S0031182000055360","volume":"85","author":"RM Anderson","year":"1982","unstructured":"Anderson RM, May RM (1982) Coevolution of hosts and parasites. Parasitology 85: 411\u2013426","journal-title":"Parasitology"},{"key":"BFMSB188707_CR6","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1126\/science.aat3119","volume":"360","author":"E Barbi","year":"2018","unstructured":"Barbi E, Lagona F, Marsili M, Vaupel JW, Wachter KW (2018) The plateau of human mortality: demography of longevity pioneers. Science 360: 1459\u20131461","journal-title":"Science"},{"key":"BFMSB188707_CR7","doi-asserted-by":"crossref","first-page":"2186","DOI":"10.1021\/acs.est.6b04030","volume":"51","author":"AF Brouwer","year":"2017","unstructured":"Brouwer AF, Eisenberg MC, Remais JV, Collender PA, Meza R, Eisenberg JNS (2017) Modeling biphasic environmental decay of pathogens and implications for risk analysis. Environ Sci Technol 51: 2186\u20132196","journal-title":"Environ Sci Technol"},{"key":"BFMSB188707_CR8","doi-asserted-by":"crossref","first-page":"3703","DOI":"10.1128\/IAI.67.8.3703-3713.1999","volume":"67","author":"A Casadevall","year":"1999","unstructured":"Casadevall A, Pirofski L (1999) Host\u2010pathogen interactions: redefining the basic concepts of virulence and pathogenicity. Infect Immun 67: 3703\u20133713","journal-title":"Infect Immun"},{"key":"BFMSB188707_CR9","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1086\/322044","volume":"184","author":"A Casadevall","year":"2001","unstructured":"Casadevall A, Pirofski L (2001) Host\u2010pathogen interactions: the attributes of virulence. J Infect Dis 184: 337\u2013344","journal-title":"J Infect Dis"},{"key":"BFMSB188707_CR10","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/cmi.12234","volume":"16","author":"LC Clark","year":"2014","unstructured":"Clark LC, Hodgkin J (2014) Commensals, probiotics and pathogens in the Caenorhabditis elegans model. Cell Microbiol 16: 27\u201338","journal-title":"Cell Microbiol"},{"key":"BFMSB188707_CR11","unstructured":"Comprehensive Toxicology \u2010 3rd Edition https:\/\/www.elsevier.com\/books\/comprehensive-toxicology\/mcqueen\/978-0-08-100601-6 [Accessed May 11, 2018]"},{"key":"BFMSB188707_CR12","doi-asserted-by":"crossref","unstructured":"Cook A (2006) Electrophysiological recordings from the pharynx. WormBookhttp:\/\/www.wormbook.org\/chapters\/www_pharyngealrecording\/pharyngealrecording.html [Accessed May 17, 2018]","DOI":"10.1895\/wormbook.1.110.1"},{"key":"BFMSB188707_CR13","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.micinf.2006.11.009","volume":"9","author":"M Diard","year":"2007","unstructured":"Diard M, Baeriswyl S, Clermont O, Gouriou S, Picard B, Taddei F, Denamur E, Matic I (2007) Caenorhabditis elegans as a simple model to study phenotypic and genetic virulence determinants of extraintestinal pathogenic Escherichia coli. Microbes Infect 9: 214\u2013223","journal-title":"Microbes Infect"},{"key":"BFMSB188707_CR14","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/377517a0","volume":"377","author":"WL Fineblum","year":"1995","unstructured":"Fineblum WL, Rausher MD (1995) Tradeoff between resistance and tolerance to herbivore damage in a morning glory. Nature 377: 517\u2013520","journal-title":"Nature"},{"key":"BFMSB188707_CR15","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.epidem.2014.09.009","volume":"10","author":"JR Gog","year":"2015","unstructured":"Gog JR, Pellis L, Wood JLN, McLean AR, Arinaminpathy N, Lloyd\u2010Smith JO (2015) Seven challenges in modeling pathogen dynamics within\u2010host and across scales. Epidemics 10: 45\u201348","journal-title":"Epidemics"},{"key":"BFMSB188707_CR16","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.tree.2017.05.009","volume":"32","author":"MD Hall","year":"2017","unstructured":"Hall MD, Bento G, Ebert D (2017) The evolutionary consequences of stepwise infection processes. Trends Ecol Evol 32: 612\u2013623","journal-title":"Trends Ecol Evol"},{"key":"BFMSB188707_CR17","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1126\/science.1073759","volume":"297","author":"DH Kim","year":"2002","unstructured":"Kim DH, Feinbaum R, Alloing G, Emerson FE, Garsin DA, Inoue H, Tanaka\u2010Hino M, Hisamoto N, Matsumoto K, Tan M\u2010W et\u00a0al (2002) A conserved p38 MAP kinase pathway in Caenorhabditis elegans innate immunity. Science 297: 623\u2013626","journal-title":"Science"},{"key":"BFMSB188707_CR18","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1038\/ismej.2015.259","volume":"10","author":"KC King","year":"2016","unstructured":"King KC, Brockhurst MA, Vasieva O, Paterson S, Betts A, Ford SA, Frost CL, Horsburgh MJ, Haldenby S, Hurst GD (2016) Rapid evolution of microbe\u2010mediated protection against pathogens in a worm host. ISME J 10: 1915\u20131924","journal-title":"ISME J"},{"key":"BFMSB188707_CR19","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1007\/978-1-4939-0473-0_50","volume-title":"Pseudomonas methods and protocols","author":"NV Kirienko","year":"2014","unstructured":"Kirienko NV, Cezairliyan BO, Ausubel FM, Powell JR (2014) Pseudomonas aeruginosa PA14 Pathogenesis in Caenorhabditis elegans. In Pseudomonas methods and protocols, Filloux A, Ramos J\u2010L (eds), pp 653\u2013669. New York, NY: Springer New York"},{"key":"BFMSB188707_CR20","doi-asserted-by":"crossref","first-page":"35862","DOI":"10.1038\/srep35862","volume":"6","author":"KS Lee","year":"2016","unstructured":"Lee KS, Lee LE, Levine E (2016) HandKAchip \u2010 Hands\u2010free killing assay on a chip. Sci Rep 6: 35862","journal-title":"Sci Rep"},{"key":"BFMSB188707_CR21","volume-title":"Brock biology of microorganisms","author":"MT Madigan","year":"2017","unstructured":"Madigan MT, Bender KS, Buckley DH, Sattley WM, Stahl DA (2017) Brock biology of microorganisms, 15th edn. New York, NY: Pearson","edition":"15th edn"},{"key":"BFMSB188707_CR22","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S0092-8674(00)80958-7","volume":"96","author":"S Mahajan\u2010Miklos","year":"1999","unstructured":"Mahajan\u2010Miklos S, Tan M\u2010W, Rahme LG, Ausubel FM (1999) Molecular mechanisms of bacterial virulence elucidated using a Pseudomonas aeruginosa\u2013Caenorhabditis elegans pathogenesis model. Cell 96: 47\u201356","journal-title":"Cell"},{"key":"BFMSB188707_CR23","doi-asserted-by":"crossref","first-page":"20172459","DOI":"10.1098\/rspb.2017.2459","volume":"285","author":"M Manhart","year":"2018","unstructured":"Manhart M, Adkar BV, Shakhnovich EI (2018) Trade\u2010offs between microbial growth phases lead to frequency\u2010dependent and non\u2010transitive selection. Proc R Soc B Biol Sci 285: 20172459","journal-title":"Proc R Soc B Biol Sci"},{"key":"BFMSB188707_CR24","doi-asserted-by":"crossref","first-page":"4224","DOI":"10.1073\/pnas.1511509113","volume":"113","author":"R Mathis","year":"2016","unstructured":"Mathis R, Ackermann M (2016) Response of single bacterial cells to stress gives rise to complex history dependence at the population level. Proc Natl Acad Sci USA 113: 4224\u20134229","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFMSB188707_CR25","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1126\/science.1214935","volume":"335","author":"R Medzhitov","year":"2012","unstructured":"Medzhitov R, Schneider DS, Soares MP (2012) Disease tolerance as a defense strategy. Science 335: 936\u2013941","journal-title":"Science"},{"key":"BFMSB188707_CR26","doi-asserted-by":"crossref","first-page":"775","DOI":"10.4161\/21505594.2014.960726","volume":"5","author":"P\u2010O M\u00e9thot","year":"2014","unstructured":"M\u00e9thot P\u2010O, Alizon S (2014) What is a pathogen? Toward a process view of host\u2010parasite interactions. Virulence 5: 775\u2013785","journal-title":"Virulence"},{"key":"BFMSB188707_CR27","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1111\/j.1469-8137.2010.03255.x","volume":"187","author":"SE Meyer","year":"2010","unstructured":"Meyer SE, Stewart TE, Clement S (2010) The quick and the deadly: growth versus virulence in a seed bank pathogen. New Phytol 187: 209\u2013216","journal-title":"New Phytol"},{"key":"BFMSB188707_CR28","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1128\/IAI.00653-12","volume":"81","author":"S Montalvo\u2010Katz","year":"2013","unstructured":"Montalvo\u2010Katz S, Huang H, Appel MD, Berg M, Shapira M (2013) Association with soil bacteria enhances p38\u2010dependent infection resistance in Caenorhabditis elegans. Infect Immun 81: 514\u2013520","journal-title":"Infect Immun"},{"key":"BFMSB188707_CR29","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1080\/10408699891274246","volume":"38","author":"M Peleg","year":"1998","unstructured":"Peleg M, Cole MB (1998) Reinterpretation of microbial survival curves. Crit Rev Food Sci Nutr 38: 353\u2013380","journal-title":"Crit Rev Food Sci Nutr"},{"key":"BFMSB188707_CR30","doi-asserted-by":"crossref","first-page":"e1004198","DOI":"10.1371\/journal.pcbi.1004198","volume":"11","author":"A Phaiboun","year":"2015","unstructured":"Phaiboun A, Zhang Y, Park B, Kim M (2015) Survival kinetics of starving bacteria is biphasic and density\u2010dependent. PLoS Comput Biol 11: e1004198","journal-title":"PLoS Comput Biol"},{"key":"BFMSB188707_CR31","doi-asserted-by":"crossref","first-page":"1288","DOI":"10.1128\/IAI.05522-11","volume":"80","author":"C Portal\u2010Celhay","year":"2012","unstructured":"Portal\u2010Celhay C, Blaser MJ (2012) Competition and resilience between founder and introduced bacteria in the Caenorhabditis elegans gut. Infect Immun 80: 1288\u20131299","journal-title":"Infect Immun"},{"key":"BFMSB188707_CR32","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/1471-2180-12-49","volume":"12","author":"C Portal\u2010Celhay","year":"2012","unstructured":"Portal\u2010Celhay C, Bradley ER, Blaser MJ (2012) Control of intestinal bacterial proliferation in regulation of lifespan in Caenorhabditis elegans. BMC Microbiol 12: 49","journal-title":"BMC Microbiol"},{"key":"BFMSB188707_CR33","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1126\/science.1148526","volume":"318","author":"L R\u00e5berg","year":"2007","unstructured":"R\u00e5berg L, Sim D, Read AF (2007) Disentangling genetic variation for resistance and tolerance to infectious diseases in animals. Science 318: 812\u2013814","journal-title":"Science"},{"key":"BFMSB188707_CR34","doi-asserted-by":"crossref","first-page":"e1001951","DOI":"10.1371\/journal.pbio.1001951","volume":"12","author":"RR Regoes","year":"2014","unstructured":"Regoes RR, McLaren PJ, Battegay M, Bernasconi E, Calmy A, G\u00fcnthard HF, Hoffmann M, Rauch A, Telenti A, Fellay J et\u00a0al (2014) Disentangling human tolerance and resistance against HIV. PLoS Biol 12: e1001951","journal-title":"PLoS Biol"},{"key":"BFMSB188707_CR35","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1111\/j.0014-3820.2000.tb00007.x","volume":"54","author":"BA Roy","year":"2000","unstructured":"Roy BA, Kirchner JW (2000) Evolutionary dynamics of pathogen resistance and tolerance. Evolution 54: 51\u201363","journal-title":"Evolution"},{"key":"BFMSB188707_CR36","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/mi.2010.77","volume":"4","author":"PJ Sansonetti","year":"2011","unstructured":"Sansonetti PJ (2011) To be or not to be a pathogen: that is the mucosally relevant question. Mucosal Immunol 4: 8\u201314","journal-title":"Mucosal Immunol"},{"key":"BFMSB188707_CR37","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1126\/science.1192588","volume":"330","author":"M Scott","year":"2010","unstructured":"Scott M, Gunderson CW, Mateescu EM, Zhang Z, Hwa T (2010) Interdependence of cell growth and gene expression: origins and consequences. Science 330: 1099\u20131102","journal-title":"Science"},{"key":"BFMSB188707_CR38","doi-asserted-by":"crossref","unstructured":"Stiernagle T (2006) Maintenance of C.\u00a0elegans. WormBookhttp:\/\/www.wormbook.org\/chapters\/www_strainmaintain\/strainmaintain.html [Accessed May 31, 2018]","DOI":"10.1895\/wormbook.1.101.1"},{"key":"BFMSB188707_CR39","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/nature16550","volume":"530","author":"N Stroustrup","year":"2016","unstructured":"Stroustrup N, Anthony WE, Nash ZM, Gowda V, Gomez A, L\u00f3pez\u2010Moyado IF, Apfeld J, Fontana W (2016) The temporal scaling of Caenorhabditis elegans ageing. Nature 530: 103\u2013107","journal-title":"Nature"},{"key":"BFMSB188707_CR501","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1038\/nmeth.2475","volume":"10","author":"N Stroustrup","year":"2013","unstructured":"Stroustrup N, Ulmschneider BE, Nash ZM, L\u00f3pez\u2010Moyado IF, Apfeld J, and Fontana W (2013) The Caenorhabditis elegans Lifespan Machine. Nature Methods 10: 665\u2013670","journal-title":"Nature Methods"},{"key":"BFMSB188707_CR40","doi-asserted-by":"crossref","first-page":"2408","DOI":"10.1073\/pnas.96.5.2408","volume":"96","author":"M\u2010W Tan","year":"1999","unstructured":"Tan M\u2010W, Rahme LG, Sternberg JA, Tompkins RG, Ausubel FM (1999) Pseudomonas aeruginosa killing of Caenorhabditis elegans used to identify P.\u00a0aeruginosa virulence factors. Proc Natl Acad Sci USA 96: 2408\u20132413","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFMSB188707_CR41","doi-asserted-by":"crossref","first-page":"2289","DOI":"10.1073\/pnas.1608961114","volume":"114","author":"S Thutupalli","year":"2017","unstructured":"Thutupalli S, Uppaluri S, Constable GWA, Levin SA, Stone HA, Tarnita CE, Brangwynne CP (2017) Farming and public goods production in Caenorhabditis elegans populations. Proc Natl Acad Sci USA 114: 2289\u20132294","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFMSB188707_CR42","doi-asserted-by":"crossref","first-page":"e2000633","DOI":"10.1371\/journal.pbio.2000633","volume":"15","author":"NM Vega","year":"2017","unstructured":"Vega NM, Gore J (2017) Stochastic assembly produces heterogeneous communities in the Caenorhabditis elegans intestine. PLoS Biol 15: e2000633","journal-title":"PLoS Biol"},{"key":"BFMSB188707_CR43","doi-asserted-by":"crossref","first-page":"011918","DOI":"10.1103\/PhysRevE.82.011918","volume":"82","author":"Z Wang","year":"2010","unstructured":"Wang Z, Goldenfeld N (2010) Fixed points and limit cycles in the population dynamics of lysogenic viruses and their hosts. Phys Rev E 82: 011918","journal-title":"Phys Rev E"},{"key":"BFMSB188707_CR44","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1017\/S0022172400035361","volume":"42","author":"ER Withell","year":"1942","unstructured":"Withell ER (1942) The significance of the variation in shape of time\u2010survivor curves. J. Hyg. 42: 124\u2013183","journal-title":"J. Hyg."},{"key":"BFMSB188707_CR45","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nature04216","volume":"438","author":"Y Zhang","year":"2005","unstructured":"Zhang Y, Lu H, Bargmann CI (2005) Pathogenic bacteria induce aversive olfactory learning in Caenorhabditis elegans. Nature 438: 179\u2013184","journal-title":"Nature"},{"key":"BFMSB188707_CR46","first-page":"485","volume":"8","author":"F Zhang","year":"2017","unstructured":"Zhang F, Berg M, Dierking K, F\u00e9lix M\u2010A, Shapira M, Samuel BS, Schulenburg H (2017) Caenorhabditis elegans as a model for microbiome research. Front Microbiol 8: 485","journal-title":"Front Microbiol"}],"container-title":["Molecular Systems Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.15252\/msb.20188707.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.15252\/msb.20188707","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.15252\/msb.20188707\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.embopress.org\/doi\/pdf\/10.15252\/msb.20188707","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.15252\/msb.20188707.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T02:35:52Z","timestamp":1779071752000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.15252\/msb.20188707"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,1]]},"references-count":47,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2019,6,1]]}},"alternative-id":["BFMSB188707"],"URL":"https:\/\/doi.org\/10.15252\/msb.20188707","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/361584","asserted-by":"object"}]},"ISSN":["1744-4292"],"issn-type":[{"value":"1744-4292","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,1]]},"assertion":[{"value":"29 October 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 May 2019","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 May 2019","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 June 2019","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"MSB188707"}}