{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T17:06:59Z","timestamp":1775668019204,"version":"3.50.1"},"reference-count":46,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,9,27]],"date-time":"2017-09-27T00:00:00Z","timestamp":1506470400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,9,27]],"date-time":"2017-09-27T00:00:00Z","timestamp":1506470400000},"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>The salmon louse is an ectoparasitic copepod of salmonids in the marine environment, and represents a global challenge to salmon aquaculture. A major issue is the reliance of the industry on a limited number of chemicals to delouse salmonids on farms, and the high levels of resistance that lice have developed to all of these agents. However, for most of these chemicals, resistance and dispersal mechanisms are unknown. We recently demonstrated that the Phe362Tyr mutation is the primary cause of organophosphate resistance in lice collected on Norwegian farms. In the present study, we genotyped &gt;2000 lice collected throughout the entire North Atlantic in the period 1998\u20132016, using Phe362Tyr and nine tightly linked SNPs. Our results showed that the Phe362Tyr mutation is strongly linked to lice survival following chemical treatment on farms located throughout the North Atlantic, demonstrating for the first time, that this mutation represents the primary mechanism for organophosphate resistance in salmon lice across the North Atlantic. Additionally, we observed multiple and diverse high frequency haplotypes linked with the allele conveying resistance to\u00a0organophosphate. We, therefore, conclude that Phe362Tyr is not a <jats:italic>de novo<\/jats:italic> mutation, but probably existed in salmon lice before the introduction of\u00a0organophosphates in commercial aquaculture.<\/jats:p>","DOI":"10.1038\/s41598-017-12384-6","type":"journal-article","created":{"date-parts":[[2017,9,21]],"date-time":"2017-09-21T09:55:07Z","timestamp":1505987707000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["The mechanism (Phe362Tyr mutation) behind resistance in Lepeophtheirus salmonis pre-dates organophosphate\u00a0use in salmon farming"],"prefix":"10.1038","volume":"7","author":[{"given":"Kiranpreet","family":"Kaur","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francois","family":"Besnier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kevin A.","family":"Glover","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank","family":"Nilsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vidar Teis","family":"Aspehaug","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8195-0582","authenticated-orcid":false,"given":"Helene B\u00f8rretzen","family":"Fj\u00f8rtoft","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tor Einar","family":"Horsberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,9,27]]},"reference":[{"key":"12384_CR1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2156-15-32","volume":"15","author":"R Skern-Mauritzen","year":"2014","unstructured":"Skern-Mauritzen, R., Torrissen, O. & Glover, K. A. Pacific and Atlantic Lepeophtheirus salmonis (Kr\u00f8yer, 1838) are allopatric subspecies: Lepeophtheirus salmonis salmonis and L. salmonis oncorhynchi subspecies novo. BMC Genet. \n                           15, 32 (2014).","journal-title":"BMC Genet."},{"key":"12384_CR2","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1006\/fsim.1999.0229","volume":"10","author":"A Mustafa","year":"2000","unstructured":"Mustafa, A. et al. Effects of sea lice (Lepeophtheirus salmonis Kr\u00f6yer, 1837) infestation on macrophage functions in Atlantic salmon (Salmo salar L.). Fish Shellfish Immunol. \n                           10, 47\u201359 (2000).","journal-title":"Fish Shellfish Immunol."},{"key":"12384_CR3","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1111\/j.1365-2761.1992.tb00684.x","volume":"15","author":"H Jonsdottir","year":"1992","unstructured":"Jonsdottir, H., Bron, J. E., Wootten, R. & Turnbull, J. F. The histopathology associated with the preadult and adult stages of Lepeophtheirus salmonis on the Atlantic salmon, Salmo salar L. J. Fish Dis. \n                           15, 521\u2013527 (1992).","journal-title":"J. Fish Dis."},{"key":"12384_CR4","doi-asserted-by":"publisher","first-page":"1179","DOI":"10.1111\/j.1095-8649.1996.tb01813.x","volume":"48","author":"A Grimnes","year":"1996","unstructured":"Grimnes, A. & Jakobsen, P. J. The physiological effects of salmon lice infection on post-smolt of Atlantic salmon. J. Fish Biol. \n                           48, 1179\u20131194 (1996).","journal-title":"J. Fish Biol."},{"key":"12384_CR5","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1111\/jfd.12061","volume":"36","author":"O Torrissen","year":"2013","unstructured":"Torrissen, O. et al. Salmon lice \u2013impact on wild salmonids and salmon aquaculture. J. Fish Dis. \n                           36, 171\u2013194 (2013).","journal-title":"J. Fish Dis."},{"key":"12384_CR6","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1111\/j.1420-9101.2012.02474.x","volume":"25","author":"A Mennerat","year":"2012","unstructured":"Mennerat, A. et al. Life history and virulence are linked in the ectoparasitic salmon louse Lepeophtheirus salmonis. J. Evol Biol. \n                           25, 856\u2013861 (2012).","journal-title":"J. Evol Biol."},{"key":"12384_CR7","doi-asserted-by":"publisher","first-page":"1925","DOI":"10.1139\/F10-105","volume":"67","author":"MH Price","year":"2010","unstructured":"Price, M. H., Morton, A. & Reynolds, J. D. Evidence of farm-induced parasite infestations on wild juvenile salmon in multiple regions of coastal British Columbia, Canada. Can. J. Fish. Aquat. Sci. \n                           67, 1925\u20131932 (2010).","journal-title":"Can. J. Fish. Aquat. Sci."},{"key":"12384_CR8","doi-asserted-by":"publisher","first-page":"997","DOI":"10.1093\/icesjms\/fsu132","volume":"72","author":"GL Taranger","year":"2015","unstructured":"Taranger, G. L. et al. Risk assessment of the environmental impact of Norwegian Atlantic salmon farming. Ices J.Mar. Sci. \n                           72, 997\u20131021 (2015).","journal-title":"Ices J.Mar. Sci."},{"key":"12384_CR9","unstructured":"Lovdata 2012. Regulations on Combating Salmon Lice in Aquaculture Facilities (In Norwegian: Forskrift om bekjempelse av lakselus i akvakulturanlegg). In: https:\/\/lovdata.no\/dokument\/SF\/forskrift\/2012-12-05-1140 (accessed 25.02.16 2016)."},{"key":"12384_CR10","unstructured":"Espeland, S. H. et al. Kunnskapsstatus leppefisk: Utfordringer i et \u00f8kende fiskeri (knowledge status wrasses: challenges in an increased fishery). Fisken og havet 35."},{"key":"12384_CR11","unstructured":"Gr\u00f8ntvedt, R. N. et al. Thermal de-licing of salmonid fish \u2013documentation of fish welfare and effect. Report 13, Norwegian Veterinary Institute\u2019s Report series (2015)."},{"key":"12384_CR12","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.aquaculture.2016.02.014","volume":"458","author":"LH Stien","year":"2016","unstructured":"Stien, L. H. et al. \u2018Snorkel\u2019 sea lice barrier technology reduces sea lice loads on harvest-sized Atlantic salmon with minimal welfare impacts. Aquaculture. \n                           458, 29\u201337 (2016).","journal-title":"Aquaculture."},{"key":"12384_CR13","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.aquaculture.2004.11.047","volume":"245","author":"KA Glover","year":"2005","unstructured":"Glover, K. A., Aasmundstad, T., Nilsen, F., Storset, A. & Skaala, O. Variation of Atlantic salmon families (Salmo salar L.) in susceptibility to the sea lice Lepeophtheirus salmonis and Caligus elongatus. Aquaculture. \n                           245, 19\u201330 (2005).","journal-title":"Aquaculture."},{"key":"12384_CR14","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1016\/j.aquaculture.2005.02.009","volume":"247","author":"K Kolstad","year":"2005","unstructured":"Kolstad, K., Heuch, P. A., Gjerde, B., Gjedrem, T. & Salte, R. Genetic variation in resistance of Atlantic salmon (Salmo salar) to the salmon louse Lepeophtheirus salmonis. Aquaculture. \n                           247, 145\u2013151 (2005).","journal-title":"Aquaculture."},{"key":"12384_CR15","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1002\/ps.474","volume":"5","author":"RS Raynard","year":"2002","unstructured":"Raynard, R. S. et al. Development of vaccines against sea lice. Pest Manag Sci. \n                           5, 569\u2013575 (2002).","journal-title":"Pest Manag Sci."},{"key":"12384_CR16","doi-asserted-by":"publisher","first-page":"2810","DOI":"10.1016\/j.vaccine.2011.01.109","volume":"29","author":"Y Carpio","year":"2011","unstructured":"Carpio, Y. et al. Novel gene isolated from Caligus rogercresseyi: a promising target for vaccine development against sea lice. Vaccine. \n                           29, 2810\u20132820 (2011).","journal-title":"Vaccine."},{"key":"12384_CR17","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1163\/18759866-0690102012","volume":"69","author":"M Roth","year":"2000","unstructured":"Roth, M. The availability and use of chemotherapeutic sea lice control products. Contrib. Zool. \n                           69, 109\u2013118 (2000).","journal-title":"Contrib. Zool."},{"key":"12384_CR18","doi-asserted-by":"publisher","first-page":"877","DOI":"10.1111\/jfd.12223","volume":"37","author":"KO Helgesen","year":"2014","unstructured":"Helgesen, K. O., Bravo, S., Sevatdal, S., Mendoza, J. & Horsberg, T. E. Deltamethrin resistance in the sea louse Caligus rogercresseyi (Boxhall and Bravo) in Chile: bioassay results and usage data for antiparasitic agents with references to Norwegian conditions. J. Fish Dis. \n                           37, 877\u2013890 (2014).","journal-title":"J. Fish Dis."},{"key":"12384_CR19","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.pt.2014.12.006","volume":"31","author":"SM Aaen","year":"2015","unstructured":"Aaen, S. M., Helgesen, K. O., Bakke, M. J., Kaur, K. & Horsberg, T. E. Drug resistance in sea lice: a threat to salmonid aquaculture. Trends Parasitol. \n                           31, 72\u201381 (2015).","journal-title":"Trends Parasitol."},{"key":"12384_CR20","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1111\/j.1365-2761.1992.tb00654.x","volume":"15","author":"MW Jones","year":"1992","unstructured":"Jones, M. W., Sommerville, C. & Wootten, R. Reduced sensitivity of the salmon louse, Lepeophtheirus salmonis, to the organophosphate dichlorvos. J. Fish Dis. \n                           15, 197\u2013202 (1992).","journal-title":"J. Fish Dis."},{"key":"12384_CR21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0001549","volume":"3","author":"F Lees","year":"2008","unstructured":"Lees, F., Baillie, M., Gettinby, G. & Revie, C. W. The Efficacy of Emamectin Benzoate against Infestations of Lepeophtheirus salmonis on Farmed Atlantic Salmon (Salmo salar L) in Scotland, 2002\u20132006. PLOS ONE. \n                           3, e1549, https:\/\/doi.org\/10.1371\/journal.pone.0001549 (2008).","journal-title":"PLOS ONE."},{"key":"12384_CR22","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.prevetmed.2015.09.017","volume":"122","author":"SL Marin","year":"2015","unstructured":"Marin, S. L., Ibarra, R., Medina, M. H. & Jansen, P. A. Sensitivity of Caligus rogercresseyi (Boxhall and Bravo 2000) to pyretroids and azamethiphos measured using bioassay tests\u2014A large scale spatial study. Prev Vet Med. \n                           122, 33\u201341 (2015).","journal-title":"Prev Vet Med."},{"key":"12384_CR23","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1002\/ps.482","volume":"58","author":"I Denholm","year":"2002","unstructured":"Denholm, I. et al. Analysis and management of resistance to chemotherapeutants in salmon lice, Lepeophtheirus salmonis (Copepoda: Caligidae). Pest Manag. Sci. \n                           58, 528\u2013536 (2002).","journal-title":"Pest Manag. Sci."},{"key":"12384_CR24","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/S0044-8486(99)00374-9","volume":"186","author":"J Stone","year":"2000","unstructured":"Stone, J., Sutherlandm, I. H., Sommerville, C., Richards, R. H. & Varma, K. J. Field trials to evaluate the efficacy of emamectin benzoate in the control of sea lice, Lepeophtheirus salmonis (Kroyer) and Caligus elongatus Nordmann, infestations in Atlantic salmon Salmo salar L. Aquaculture. \n                           186, 205\u2013219 (2000).","journal-title":"Aquaculture."},{"key":"12384_CR25","unstructured":"Gr\u00f8ntvedt, R. N., Jansen, P. A., Horsberg, T. A., Helgesen, K., Tarpai, A. The surveillance programme for resistance to chemotherapeutants in L. salmonis in Norway. Surveillance programmes for terrestrial and aquatic animals in Norway 2014. Annual report 2013. Oslo: Norwegian Veterinary Institute."},{"key":"12384_CR26","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0149006","volume":"18","author":"PA Jansen","year":"2016","unstructured":"Jansen, P. A., Gr\u00f8ntvedt, R. N., Tarpai, A., Helgesen, K. O. & Horsberg, T. E. Surveillance of the Sensitivity towards Antiparasitic Bath-Treatments in the Salmon Louse (Lepeophtheirus salmonis). PLOS ONE. \n                           18, e0149006 (2016).","journal-title":"PLOS ONE."},{"key":"12384_CR27","unstructured":"Gr\u00f8ntvedt, R. N., Jansen, P. A., Horsberg, T. A., Helgesen, K. & Tarpai, A. The surveillance programme for resistance to chemotherapeutants in L. salmonis in Norway. Surveillance programmes for terrestrial and aquatic animals in Norway 2015. Annual report 2014. Oslo: Norwegian Veterinary Institute."},{"key":"12384_CR28","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1042\/bj0460451","volume":"46","author":"WN Aldridge","year":"1950","unstructured":"Aldridge, W. N. Some properties of specific cholinesterase with particular reference to the mechanism of inhibition by diethyl p-nitrophenyl thiophosphate (E 605) and analogues. Biochem J. \n                           46, 451\u2013460 (1950).","journal-title":"Biochem J."},{"key":"12384_CR29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0124220","volume":"10","author":"K Kaur","year":"2015","unstructured":"Kaur, K., Helgesen, K. O., Bakke, M. J. & Horsberg, T. E. Mechanism behind Resistance against the Organophosphate Azamethiphos in Salmon Lice (Lepeophtheirus salmonis). PLOS ONE. \n                           10, e0124220 (2015).","journal-title":"PLOS ONE."},{"key":"12384_CR30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0149264","volume":"11","author":"K Kaur","year":"2016","unstructured":"Kaur, K., Jansen, P. A., Aspehaug, V. T. & Horsberg, T. E. Phe362Tyr in AChE: A Major Factor Responsible for Azamethiphos Resistance in Lepeophtheirus salmonis in Norway. PLOS ONE. \n                           11, e0149264 (2016).","journal-title":"PLOS ONE."},{"key":"12384_CR31","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1016\/j.aquaculture.2016.08.008","volume":"464","author":"SK Whyte","year":"2016","unstructured":"Whyte, S. K., Westcott, J. D., Revie, C. W. & Hammell, K. L. Sensitivity of salmon lice (Lepeophtheirus salmonis) in New Brunswick, Canada, to the organophosphate Salmosan (w\/w 50% azamethiphos) using bioassays. Aquaculture. \n                           464, 593\u2013600 (2016).","journal-title":"Aquaculture."},{"key":"12384_CR32","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/0044-8486(95)01181-1","volume":"140","author":"M Roth","year":"1996","unstructured":"Roth, M., Richards, R. H., Dobson, D. P. & Rae, G. H. Field trials on the efficacy of the organophosphorus compound azamthiphos for the control of sea lice (Copepods: Caligidae) infestations of farmed Atlantic salmon (Salmo salar). Aquaculture. \n                           140, 217\u2013239 (1996).","journal-title":"Aquaculture."},{"key":"12384_CR33","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-15-937","volume":"15","author":"F Besnier","year":"2014","unstructured":"Besnier, F. et al. Human-induced evolution caught in action:SNP-array reveals rapid amphi-atlantic spread of pesticide resistance in the salmon ecotoparasite Lepeophtheirus salmonis. BMC Genomics. \n                           15, 937 (2014).","journal-title":"BMC Genomics."},{"key":"12384_CR34","doi-asserted-by":"publisher","first-page":"161","DOI":"10.3354\/meps09045","volume":"427","author":"KA Glover","year":"2011","unstructured":"Glover, K. A. et al. Population genetic structure of the parasitic copepod Lepeophtheirus salmonis throughout the Atlantic. Mar Ecol Prog Ser. \n                           427, 161\u2013172 (2011).","journal-title":"Mar Ecol Prog Ser."},{"key":"12384_CR35","doi-asserted-by":"publisher","first-page":"251","DOI":"10.3354\/dao068251","volume":"68","author":"K Tjensvoll","year":"2006","unstructured":"Tjensvoll, K., Glover, K. A. & Nylund, A. Sequence variation in four mitochondrial genes of the salmon louse Lepeophtheirus salmonis. Dis Aquat Organ. \n                           68, 251\u2013259 (2006).","journal-title":"Dis Aquat Organ."},{"key":"12384_CR36","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2148-14-108","volume":"14","author":"LER Ljungfeldt","year":"2014","unstructured":"Ljungfeldt, L. E. R., Espedal, P. G., Nilsen, F., Skern-Mauritzen, M. & Glover, K. A. A common-garden experiment to quantify evolutionary processes in copepods: the case of emamectin benzoate resistance in the parasitic sea louse Lepeophtheirus salmonis. BMC Evol Biol. \n                           14, 108 (2014).","journal-title":"BMC Evol Biol."},{"key":"12384_CR37","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6281","volume":"5","author":"JD Jensen","year":"2014","unstructured":"Jensen, J. D. On the unfounded enthusiasm for soft selective sweeps. Nat Commun. \n                           5, 5281 (2014).","journal-title":"Nat Commun."},{"key":"12384_CR38","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1584\/jpestics.R10-10","volume":"35","author":"T Hotelier","year":"2010","unstructured":"Hotelier, T., N\u00e8gre, V., Marchot, P. & Chatonnet, A. Insecticide resistance through mutations in cholinesterases or carboxylesterases: data mining in the ESTHER database. J Pestic Sci. \n                           35, 315\u2013320 (2010).","journal-title":"J Pestic Sci."},{"key":"12384_CR39","doi-asserted-by":"publisher","first-page":"8757","DOI":"10.1073\/pnas.0509590103","volume":"103","author":"CJ Hartley","year":"2006","unstructured":"Hartley, C. J. et al. Amplification of DNA from preserved specimens shows blowflies were preadapted for the rapid evolution of insecticide resistance. Proc Natl Acad Sci USA \n                           103, 8757\u20138762 (2006).","journal-title":"Proc Natl Acad Sci USA"},{"key":"12384_CR40","doi-asserted-by":"publisher","first-page":"764","DOI":"10.1126\/science.1112699","volume":"309","author":"YT Aminetzach","year":"2005","unstructured":"Aminetzach, Y. T., Macpherson, J. M. & Petrov, D. A. Pesticide resistance via transposition-mediated adaptive gene truncation in Drosophila. Science. \n                           309, 764\u2013767 (2005).","journal-title":"Science."},{"key":"12384_CR41","doi-asserted-by":"publisher","first-page":"1162","DOI":"10.1086\/379378","volume":"73","author":"M Stephens","year":"2003","unstructured":"Stephens, M. & Donnelly, P. A comparison of Bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet. \n                           73, 1162\u20131169 (2003).","journal-title":"Am J Hum Genet."},{"key":"12384_CR42","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1093\/bioinformatics\/btg412","volume":"20","author":"E Paradis","year":"2004","unstructured":"Paradis, E., Claude, J. & Strimmer, K. APE: analyses of phylogenetics and evolution in R language. Bioinformatics. \n                           20, 289\u2013290 (2004).","journal-title":"Bioinformatics."},{"key":"12384_CR43","doi-asserted-by":"publisher","first-page":"1536","DOI":"10.1093\/bioinformatics\/bts184","volume":"28","author":"A-A Popescu","year":"2012","unstructured":"Popescu, A.-A., Huber, K. T. & Paradis, E. ape 3.0: new tools for distance based phylogenetics and evolutionary analysis in R. Bioinformatics. \n                           28, 1536\u20131537 (2012).","journal-title":"Bioinformatics."},{"key":"12384_CR44","doi-asserted-by":"publisher","first-page":"1064","DOI":"10.1111\/j.0006-341X.1999.01064.x","volume":"55","author":"G McGuire","year":"1999","unstructured":"McGuire, G., Prentice, M. J. & Wright, F. Improved error bounds for genetic distances from DNA sequences. Biometrics. \n                           55, 1064\u20131070 (1999).","journal-title":"Biometrics."},{"key":"12384_CR45","doi-asserted-by":"publisher","first-page":"685","DOI":"10.1093\/oxfordjournals.molbev.a025808","volume":"14","author":"O Gascuel","year":"1997","unstructured":"Gascuel, O. BIONJ: an improved version of the NJ algorithm based on a simple model of sequence data. Molecular Biology and Evolution. \n                           14, 685\u2013695 (1997).","journal-title":"Molecular Biology and Evolution."},{"key":"12384_CR46","unstructured":"R Core Team R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. http:\/\/www.R-project.org\/ (2015)."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-12384-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-12384-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-12384-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T11:26:31Z","timestamp":1671794791000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-12384-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9,27]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["12384"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-12384-6","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,9,27]]},"assertion":[{"value":"13 March 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 September 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 September 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":"12349"}}