{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T06:47:55Z","timestamp":1784616475951,"version":"3.55.0"},"reference-count":59,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,7,8]],"date-time":"2020-07-08T00:00:00Z","timestamp":1594166400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,7,8]],"date-time":"2020-07-08T00:00:00Z","timestamp":1594166400000},"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>Prevention therapy against <jats:italic>Dirofilaria immitis<\/jats:italic> in companion animals is currently threatened by the emergence of isolates resistant to macrocyclic lactone anthelmintics. Understanding the control over developmental processes in <jats:italic>D. immitis<\/jats:italic> is important for elucidating new approaches to heartworm control. The nuclear receptor DAF-12 plays a role in the entry and exit of dauer stage in <jats:italic>Caenorhabditis elegans<\/jats:italic> and in the development of free-living infective third-stage larvae (iL3) of some Clade IV and V parasitic nematodes. We identified a DAF-12 ortholog in the clade III nematode <jats:italic>D. immitis<\/jats:italic> and found that it exhibited a much higher affinity for dafachronic acids than described with other nematode DAF-12 investigated so far. We also modelled the DimDAF-12 structure and characterized the residues involved with DA binding. Moreover, we showed that cholesterol derivatives impacted the molting process from the iL3 to the fourth-stage larvae<jats:italic>.<\/jats:italic> Since <jats:italic>D. immitis<\/jats:italic> is unable to synthesize cholesterol and only completes its development upon host infection, we hypothesize that host environment contributes to its further molting inside the host vertebrate. Our discovery contributes to a better understanding of the developmental checkpoints of <jats:italic>D. immitis<\/jats:italic> and offers new perspectives for the development of novel therapies against filarial infections.<\/jats:p>","DOI":"10.1038\/s41598-020-67466-9","type":"journal-article","created":{"date-parts":[[2020,7,8]],"date-time":"2020-07-08T10:03:03Z","timestamp":1594202583000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["The development of the dog heartworm is highly sensitive to sterols which activate the orthologue of the nuclear receptor DAF-12"],"prefix":"10.1038","volume":"10","author":[{"given":"Thavy","family":"Long","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e9lanie","family":"Alberich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois","family":"Andr\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9cile","family":"Menez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger K.","family":"Prichard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Lespine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,7,8]]},"reference":[{"key":"67466_CR1","doi-asserted-by":"crossref","first-page":"335","DOI":"10.2174\/1568010042634541","volume":"3","author":"N Novac","year":"2004","unstructured":"Novac, N. & Heinzel, T. Nuclear receptors: overview and classification. Curr. Drug Targets Inflamm. Allergy 3, 335\u2013346 (2004).","journal-title":"Curr. Drug Targets Inflamm. Allergy"},{"key":"67466_CR2","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.cell.2014.03.012","volume":"157","author":"RM Evans","year":"2014","unstructured":"Evans, R. M. & Mangelsdorf, D. J. Nuclear receptors, RXR, and the big bang. Cell 157, 255\u2013266 (2014).","journal-title":"Cell"},{"key":"67466_CR3","doi-asserted-by":"crossref","first-page":"380","DOI":"10.3109\/10409238.2015.1067186","volume":"50","author":"JM Hoffmann","year":"2015","unstructured":"Hoffmann, J. M. & Partridge, L. Nuclear hormone receptors: roles of xenobiotic detoxification and sterol homeostasis in healthy aging. Crit. Rev. Biochem. Mol. Biol. 50, 380\u2013392 (2015).","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"67466_CR4","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1172\/JCI88890","volume":"127","author":"Z Wang","year":"2017","unstructured":"Wang, Z., Schaffer, N. E., Kliewer, S. A. & Mangelsdorf, D. J. Nuclear receptors: emerging drug targets for parasitic diseases. J. Clin. Investig. 127, 1165\u20131171 (2017).","journal-title":"J. Clin. Investig."},{"key":"67466_CR5","doi-asserted-by":"crossref","first-page":"36863","DOI":"10.1074\/jbc.R100047200","volume":"276","author":"JM Olefsky","year":"2001","unstructured":"Olefsky, J. M. Nuclear receptor minireview series. J. Biol. Chem. 276, 36863\u201336864 (2001).","journal-title":"J. Biol. Chem."},{"key":"67466_CR6","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.mce.2010.06.011","volume":"334","author":"W Wu","year":"2011","unstructured":"Wu, W. & LoVerde, P. T. Nuclear hormone receptors in parasitic helminths. Mol. Cell. Endocrinol. 334, 56\u201366 (2011).","journal-title":"Mol. Cell. Endocrinol."},{"key":"67466_CR7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1895\/wormbook.1.64.2","volume":"9","author":"A Antebi","year":"2015","unstructured":"Antebi, A. Nuclear receptor signal transduction in C. elegans. WormBook 9, 1\u201349 (2015).","journal-title":"WormBook"},{"key":"67466_CR8","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1242\/dev.125.7.1191","volume":"125","author":"A Antebi","year":"1998","unstructured":"Antebi, A., Culotti, J. G. & Hedgecock, E. M. DAF-12 regulates developmental age and the dauer alternative in Caenorhabditis elegans. Development 125, 1191\u20131205 (1998).","journal-title":"Development"},{"key":"67466_CR9","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1101\/gad.14.12.1512","volume":"14","author":"A Antebi","year":"2000","unstructured":"Antebi, A., Yeh, W. H., Tait, D., Hedgecock, E. M. & Riddle, D. L. DAF-12 encodes a nuclear receptor that regulates the dauer diapause and developmental age in C. elegans. Genes Dev. 14, 1512\u20131527 (2000).","journal-title":"Genes Dev."},{"key":"67466_CR10","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1016\/j.cell.2006.01.037","volume":"124","author":"DL Motola","year":"2006","unstructured":"Motola, D. L. et al. Identification of ligands for DAF-12 that govern dauer formation and reproduction in C. elegans. Cell 124, 1209\u20131223 (2006).","journal-title":"Cell"},{"key":"67466_CR11","doi-asserted-by":"crossref","first-page":"5014","DOI":"10.1073\/pnas.0700847104","volume":"104","author":"B Gerisch","year":"2007","unstructured":"Gerisch, B. et al. A bile acid-like steroid modulates Caenorhabditis elegans lifespan through nuclear receptor signaling. Proc. Natl. Acad. Sci. USA 104, 5014\u20135019 (2007).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"67466_CR12","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.cmet.2013.11.024","volume":"19","author":"P Mahanti","year":"2014","unstructured":"Mahanti, P. et al. Comparative metabolomics reveals endogenous ligands of DAF-12, a nuclear hormone receptor, regulating C. elegans development and lifespan. Cell Metab. 19, 73\u201383 (2014).","journal-title":"Cell Metab."},{"key":"67466_CR13","doi-asserted-by":"crossref","first-page":"1621","DOI":"10.1242\/dev.00363","volume":"130","author":"J Wang","year":"2003","unstructured":"Wang, J. & Kim, S. K. Global analysis of dauer gene expression in Caenorhabditis elegans. Development 130, 1621\u20131634 (2003).","journal-title":"Development"},{"key":"67466_CR14","doi-asserted-by":"crossref","first-page":"18668","DOI":"10.1073\/pnas.0908131106","volume":"106","author":"CM Hammell","year":"2009","unstructured":"Hammell, C. M., Karp, X. & Ambros, V. A feedback circuit involving let-7-family miRNAs and DAF-12 integrates environmental signals and developmental timing in Caenorhabditis elegans. Proc. Natl. Acad. Sci. USA 106, 18668\u201318673 (2009).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"67466_CR15","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1126\/science.1164899","volume":"324","author":"A Bethke","year":"2009","unstructured":"Bethke, A., Fielenbach, N., Wang, Z., Mangelsdorf, D. J. & Antebi, A. Nuclear hormone receptor regulation of microRNAs controls developmental progression. Science 324, 95\u201398 (2009).","journal-title":"Science"},{"key":"67466_CR16","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1016\/0012-1606(75)90109-8","volume":"46","author":"RC Cassada","year":"1975","unstructured":"Cassada, R. C. & Russell, R. L. The dauer larva, a post-embryonic developmental variant of the nematode Caenorhabditis elegans. Dev. Biol. 46, 326\u2013342 (1975).","journal-title":"Dev. Biol."},{"key":"67466_CR17","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/32160","volume":"392","author":"ML Blaxter","year":"1998","unstructured":"Blaxter, M. L. et al. A molecular evolutionary framework for the phylum Nematoda. Nature 392, 71\u201375 (1998).","journal-title":"Nature"},{"key":"67466_CR18","doi-asserted-by":"crossref","first-page":"e1007960","DOI":"10.1371\/journal.ppat.1007960","volume":"15","author":"G Ma","year":"2019","unstructured":"Ma, G. et al. Dafachronic acid promotes larval development in Haemonchus contortus by modulating dauer signaling and lipid metabolism. PLoS Pathog. 15, e1007960 (2019).","journal-title":"PLoS Pathog."},{"key":"67466_CR19","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1186\/s13071-019-3419-6","volume":"12","author":"G Ma","year":"2019","unstructured":"Ma, G. et al. Dauer signalling pathway model for Haemonchus contortus. Parasites Vectors 12, 187 (2019).","journal-title":"Parasites Vectors"},{"key":"67466_CR20","doi-asserted-by":"crossref","first-page":"9138","DOI":"10.1073\/pnas.0904064106","volume":"106","author":"Z Wang","year":"2009","unstructured":"Wang, Z. et al. Identification of the nuclear receptor DAF-12 as a therapeutic target in parasitic nematodes. Proc. Natl. Acad. Sci. USA 106, 9138\u20139143 (2009).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"67466_CR21","doi-asserted-by":"crossref","first-page":"4894","DOI":"10.1074\/jbc.M111.315242","volume":"287","author":"X Zhi","year":"2012","unstructured":"Zhi, X. et al. Structural conservation of ligand binding reveals a bile acid-like signaling pathway in nematodes. J. Biol. Chem. 287, 4894\u20134903 (2012).","journal-title":"J. Biol. Chem."},{"key":"67466_CR22","doi-asserted-by":"crossref","first-page":"e1005358","DOI":"10.1371\/journal.ppat.1005358","volume":"12","author":"MM Albarqi","year":"2016","unstructured":"Albarqi, M. M. et al. Regulation of life cycle checkpoints and developmental activation of infective larvae in Strongyloides stercoralis by dafachronic acid. PLoS Pathog. 12, e1005358 (2016).","journal-title":"PLoS Pathog."},{"key":"67466_CR23","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1186\/s12864-016-2770-7","volume":"17","author":"A Gilabert","year":"2016","unstructured":"Gilabert, A., Curran, D. M., Harvey, S. C. & Wasmuth, J. D. Expanding the view on the evolution of the nematode dauer signalling pathways: refinement through gene gain and pathway co-option. BMC Genom. 17, 476 (2016).","journal-title":"BMC Genom."},{"key":"67466_CR24","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/s13071-018-3265-y","volume":"12","author":"G Ma","year":"2019","unstructured":"Ma, G. et al. Comparative bioinformatic analysis suggests that specific dauer-like signalling pathway components regulate Toxocara canis development and migration in the mammalian host. Parasites Vectors 12, 32 (2019).","journal-title":"Parasites Vectors."},{"key":"67466_CR25","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.cub.2008.11.063","volume":"19","author":"A Ogawa","year":"2009","unstructured":"Ogawa, A., Streit, A., Antebi, A. & Sommer, R. J. A conserved endocrine mechanism controls the formation of dauer and infective larvae in nematodes. Curr. Biol. 19, 67\u201371 (2009).","journal-title":"Curr. Biol."},{"key":"67466_CR26","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1210\/me.2008-0415","volume":"23","author":"KK Sharma","year":"2009","unstructured":"Sharma, K. K. et al. Synthesis and activity of dafachronic acid ligands for the C. elegans DAF-12 nuclear hormone receptor. Mol. Endocrinol. 23, 640\u2013648 (2009).","journal-title":"Mol. Endocrinol."},{"key":"67466_CR27","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1042\/BJ20140833","volume":"465","author":"MV Dansey","year":"2015","unstructured":"Dansey, M. V. et al. Synthetic DAF-12 modulators with potential use in controlling the nematode life cycle. Biochem. J. 465, 175\u2013184 (2015).","journal-title":"Biochem. J."},{"key":"67466_CR28","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S0065-308X(08)00204-2","volume":"66","author":"JW McCall","year":"2008","unstructured":"McCall, J. W., Genchi, C., Kramer, L. H., Guerrero, J. & Venco, L. Heartworm disease in animals and humans. Adv. Parasitol. 66, 193\u2013285 (2008).","journal-title":"Adv. Parasitol."},{"key":"67466_CR29","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1128\/CMR.00012-12","volume":"25","author":"F Sim\u00f3n","year":"2012","unstructured":"Sim\u00f3n, F. et al. Human and animal dirofilariasis: the emergence of a zoonotic mosaic. Clin. Microbiol. Rev. 25, 507\u2013544 (2012).","journal-title":"Clin. Microbiol. Rev."},{"key":"67466_CR30","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.vetpar.2008.10.093","volume":"160","author":"D Bowman","year":"2009","unstructured":"Bowman, D. et al. Prevalence and geographic distribution of Dirofilaria immitis, Borrelia burgdorferi, Ehrlichia canis, and Anaplasma phagocytophilum in dogs in the United States: results of a national clinic-based serologic survey. Vet. Parasitol. 160, 138\u2013148 (2009).","journal-title":"Vet. Parasitol."},{"key":"67466_CR31","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.pt.2010.01.003","volume":"26","author":"AC Lee","year":"2010","unstructured":"Lee, A. C., Montgomery, S. P., Theis, J. H., Blagburn, B. L. & Eberhard, M. L. Public health issues concerning the widespread distribution of canine heartworm disease. Trends Parasitol. 26, 168\u2013173 (2010).","journal-title":"Trends Parasitol."},{"key":"67466_CR32","doi-asserted-by":"crossref","first-page":"e0004929","DOI":"10.1371\/journal.pntd.0004929","volume":"10","author":"C Ballesteros","year":"2016","unstructured":"Ballesteros, C. et al. The effects of ivermectin on Brugia malayi females in vitro: a transcriptomic approach. PLoS Negl. Trop. Dis. 10, e0004929 (2016).","journal-title":"PLoS Negl. Trop. Dis."},{"key":"67466_CR33","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.vetpar.2015.04.002","volume":"210","author":"C Bourguinat","year":"2015","unstructured":"Bourguinat, C. et al. Macrocyclic lactone resistance in Dirofilaria immitis: failure of heartworm preventives and investigation of genetic markers for resistance. Vet. Parasitol. 210, 167\u2013178 (2015).","journal-title":"Vet. Parasitol."},{"key":"67466_CR34","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1186\/s13071-014-0494-6","volume":"7","author":"CN Pulaski","year":"2014","unstructured":"Pulaski, C. N. et al. Establishment of macrocyclic lactone resistant Dirofilaria immitis isolates in experimentally infected laboratory dogs. Parasites Vectors 7, 494 (2014).","journal-title":"Parasites Vectors"},{"key":"67466_CR35","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1053\/j.tcam.2011.07.001","volume":"26","author":"DD Bowman","year":"2011","unstructured":"Bowman, D. D. & Mannella, C. Macrocyclic lactones and Dirofilaria immitis microfilariae. Top. Companion Anim. Med. 26, 160\u2013172 (2011).","journal-title":"Top. Companion Anim. Med."},{"key":"67466_CR36","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.vetpar.2005.04.004","volume":"133","author":"VA Hampshire","year":"2005","unstructured":"Hampshire, V. A. Evaluation of efficacy of heartworm preventive products at the FDA. Vet. Parasitol. 133, 191\u2013195 (2005).","journal-title":"Vet. Parasitol."},{"key":"67466_CR37","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/0304-4017(94)90094-9","volume":"54","author":"R Prichard","year":"1994","unstructured":"Prichard, R. Anthelmintic resistance. Vet. Parasitol. 54, 259\u2013268 (1994).","journal-title":"Vet. Parasitol."},{"key":"67466_CR38","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1186\/s13071-017-2428-6","volume":"10","author":"C Bourguinat","year":"2017","unstructured":"Bourguinat, C. et al. Genetic profiles of ten Dirofilaria immitis isolates susceptible or resistant to macrocyclic lactone heartworm preventives. Parasites Vectors 10, 504 (2017).","journal-title":"Parasites Vectors"},{"key":"67466_CR39","doi-asserted-by":"crossref","first-page":"4650","DOI":"10.1096\/fj.12-205096","volume":"26","author":"C Godel","year":"2012","unstructured":"Godel, C. et al. The genome of the heartworm, Dirofilaria immitis, reveals drug and vaccine targets. FASEB J. 26, 4650\u20134661 (2012).","journal-title":"FASEB J."},{"key":"67466_CR40","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/0092-8674(95)90199-X","volume":"83","author":"DJ Mangelsdorf","year":"1995","unstructured":"Mangelsdorf, D. J. et al. The nuclear receptor superfamily: the second decade. Cell 83, 835\u2013839 (1995).","journal-title":"Cell"},{"key":"67466_CR41","doi-asserted-by":"crossref","first-page":"2529","DOI":"10.1101\/gad.1218504","volume":"18","author":"Y Shostak","year":"2004","unstructured":"Shostak, Y., Van Gilst, M. R., Antebi, A. & Yamamoto, K. R. Identification of C. elegans DAF-12-binding sites, response elements, and target genes. Genes Dev. 18, 2529\u20132544 (2004).","journal-title":"Genes Dev."},{"key":"67466_CR42","doi-asserted-by":"crossref","first-page":"1798","DOI":"10.1002\/prot.24076","volume":"80","author":"LD Alvarez","year":"2012","unstructured":"Alvarez, L. D., Manez, P. A., Estrin, D. A. & Burton, G. The Caenorhabditis elegans DAF-12 nuclear receptor: structure, dynamics, and interaction with ligands. Proteins 80, 1798\u20131809 (2012).","journal-title":"Proteins"},{"key":"67466_CR43","doi-asserted-by":"crossref","first-page":"1765","DOI":"10.1242\/dev.01068","volume":"131","author":"B Gerisch","year":"2004","unstructured":"Gerisch, B. & Antebi, A. Hormonal signals produced by DAF-9\/cytochrome P450 regulate C. elegans dauer diapause in response to environmental cues. Development 131, 1765\u20131776 (2004).","journal-title":"Development"},{"key":"67466_CR44","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1038\/ncb0803-684","volume":"5","author":"TV Kurzchalia","year":"2003","unstructured":"Kurzchalia, T. V. & Ward, S. Why do worms need cholesterol?. Nat. Cell Biol. 5, 684\u2013688 (2003).","journal-title":"Nat. Cell Biol."},{"key":"67466_CR45","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1111\/j.1474-9726.2006.00218.x","volume":"5","author":"JM Held","year":"2006","unstructured":"Held, J. M. et al. DAF-12-dependent rescue of dauer formation in Caenorhabditis elegans by (25S)-cholestenoic acid. Aging Cell 5, 283\u2013291 (2006).","journal-title":"Aging Cell"},{"key":"67466_CR46","doi-asserted-by":"crossref","first-page":"e1002179","DOI":"10.1371\/journal.pgen.1002179","volume":"7","author":"D Hochbaum","year":"2011","unstructured":"Hochbaum, D. et al. DAF-12 regulates a connected network of genes to ensure robust developmental decisions. PLoS Genet. 7, e1002179 (2011).","journal-title":"PLoS Genet."},{"key":"67466_CR47","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1186\/s12864-015-1536-y","volume":"16","author":"AD Winter","year":"2015","unstructured":"Winter, A. D. et al. A novel member of the let-7 microRNA family is associated with developmental transitions in filarial nematode parasites. BMC Genom. 16, 331 (2015).","journal-title":"BMC Genom."},{"key":"67466_CR48","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1016\/0014-4894(90)90113-Q","volume":"70","author":"D Abraham","year":"1990","unstructured":"Abraham, D., Grieve, R. B. & Oaks, J. A. Dirofilaria immitis: molting process of third-stage larvae. Exp. Parasitol. 70, 314\u2013322 (1990).","journal-title":"Exp. Parasitol."},{"key":"67466_CR49","first-page":"145","volume":"41","author":"JB Lok","year":"1984","unstructured":"Lok, J. B., Mika-Grieve, M., Grieve, R. B. & Chin, T. K. In vitro development of third- and fourth-stage larvae of Dirofilaria immitis: comparison of basal culture media, serum levels and possible serum substitutes. Acta Trop. 41, 145\u2013154 (1984).","journal-title":"Acta Trop."},{"key":"67466_CR50","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1006\/jmbi.1993.1626","volume":"234","author":"A Sali","year":"1993","unstructured":"Sali, A. & Blundell, T. L. Comparative protein modelling by satisfaction of spatial restraints. J. Mol. Biol. 234, 779\u2013815 (1993).","journal-title":"J. Mol. Biol."},{"key":"67466_CR51","doi-asserted-by":"crossref","first-page":"5.6.1","DOI":"10.1002\/0471250953.bi0506s47","volume":"47","author":"B Webb","year":"2014","unstructured":"Webb, B. & Sali, A. Comparative protein structure modeling using MODELLER. Curr. Protoc. Bioinform. 47, 5.6.1-5.6.32 (2014).","journal-title":"Curr. Protoc. Bioinform."},{"key":"67466_CR52","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.ijpddr.2018.02.001","volume":"8","author":"M David","year":"2018","unstructured":"David, M. et al. Structural model, functional modulation by ivermectin and tissue localization of Haemonchus contortus p-glycoprotein-13. Int. J. Parasitol. Drugs Drug Resist. 8, 145\u2013157 (2018).","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"67466_CR53","doi-asserted-by":"crossref","first-page":"2507","DOI":"10.1110\/ps.062416606","volume":"15","author":"MY Shen","year":"2006","unstructured":"Shen, M. Y. & Sali, A. Statistical potential for assessment and prediction of protein structures. Protein Sci. 15, 2507\u20132524 (2006).","journal-title":"Protein Sci."},{"issue":"Web Server issu","key":"67466_CR54","first-page":"W510-4","volume":"37","author":"P Benkert","year":"2009","unstructured":"Benkert, P., Kunzli, M. & Schwede, T. QMEAN server for protein model quality estimation. Nucleic Acids Res. 37(Web Server issue), W510-4 (2009).","journal-title":"Nucleic Acids Res."},{"key":"67466_CR55","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1002\/prot.340170404","volume":"17","author":"MJ Sippl","year":"1993","unstructured":"Sippl, M. J. Recognition of errors in three-dimensional structures of proteins. Proteins 17, 355\u2013362 (1993).","journal-title":"Proteins"},{"issue":"Web Server issu","key":"67466_CR56","first-page":"W407-10","volume":"35","author":"M Wiederstein","year":"2007","unstructured":"Wiederstein, M. & Sippl, M. J. ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucleic Acids Res. 35(Web Server issue), W407-10 (2007).","journal-title":"Nucleic Acids Res."},{"key":"67466_CR57","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1107\/S0021889892009944","volume":"26","author":"RA Laskowski","year":"1993","unstructured":"Laskowski, R. A., MacArthur, M. W., Moss, D. S. & Thornton, J. M. PROCHECK: a program to check the stereochemical quality of protein structures. J. Appl. Crystallogr. 26, 283\u2013291 (1993).","journal-title":"J. Appl. Crystallogr."},{"key":"67466_CR58","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.ijpddr.2016.09.001","volume":"6","author":"MA David","year":"2016","unstructured":"David, M. A. et al. In silico analysis of the binding of anthelmintics to Caenorhabditis elegans p-glycoprotein 1. Int. J. Parasitol. Drugs Drug Resist. 6, 299\u2013313 (2016).","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"67466_CR59","doi-asserted-by":"crossref","first-page":"e1261","DOI":"10.1371\/journal.pntd.0001261","volume":"5","author":"ML Michalski","year":"2011","unstructured":"Michalski, M. L., Griffiths, K. G., Williams, S. A., Kaplan, R. M. & Moorhead, A. R. The NIH-NIAID filariasis research reagent resource center. PLoS Negl. Trop. Dis. 5, e1261 (2011).","journal-title":"PLoS Negl. Trop. Dis."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-67466-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-67466-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-67466-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T13:10:12Z","timestamp":1670332212000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-67466-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,8]]},"references-count":59,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["67466"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-67466-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,8]]},"assertion":[{"value":"16 January 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 May 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 July 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"11207"}}