{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T05:39:49Z","timestamp":1788845989698,"version":"build-2803163510"},"update-to":[{"DOI":"10.1371\/journal.pntd.0012473","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,9,12]],"date-time":"2024-09-12T00:00:00Z","timestamp":1726099200000}}],"reference-count":60,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T00:00:00Z","timestamp":1724976000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001458","name":"American Kennel Club Canine Health Foundation","doi-asserted-by":"publisher","award":["02986"],"award-info":[{"award-number":["02986"]}],"id":[{"id":"10.13039\/100001458","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosntds.org"],"crossmark-restriction":false},"short-container-title":["PLoS Negl Trop Dis"],"abstract":"<jats:sec id=\"sec001\">\n<jats:title>Background<\/jats:title>\n<jats:p>Filarial nematodes cause severe illnesses in humans and canines including limb deformities and disfigurement, heart failure, blindness, and death, among others. There are no vaccines, and current drugs against filarial nematodes infections have only modest effects and are prone to complications.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methodology\/principal findings<\/jats:title>\n<jats:p>We identified a gene (herein called DiMT) encoding an <jats:italic>S<\/jats:italic>-adenosyl-<jats:italic>L<\/jats:italic>-methionine (SAM)-dependent methyltransferase with orthologs in parasite filarial worms but not in mammals. By <jats:italic>in silico<\/jats:italic> analysis, DiMT possesses catalytic sites for binding SAM and catecholamines with high affinity. We expressed and purified recombinant DiMT protein and used it as an enzyme in a series of SAM-dependent methylation assays. DiMT acted specifically as a catechol-<jats:italic>O<\/jats:italic>-methyltransferase (COMT), catalyzing catabolic methylation of dopamine, and depicted Michaelis Menten kinetics on substrate and co-substrate. Among a set of SAM-dependent methyltransferase inhibitors, we identified compounds that bound with high affinity to DiMT\u2019s catalytic sites and inhibited its enzymatic activity. By testing the efficacy of DiMT inhibitors against microfilariae of <jats:italic>Dirofilaria immitis<\/jats:italic> in culture, we identified three inhibitors with concentration- and time-dependent effect of killing <jats:italic>D<\/jats:italic>. <jats:italic>immitis<\/jats:italic> microfilariae. Importantly, RNAi silencing of a DiMT ortholog in <jats:italic>Caenorhabditis elegans<\/jats:italic> has been shown to be lethal, likely as a result of excessive accumulation of active catecholamines that inhibit worm locomotion, pharyngeal pumping and fecundity.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Conclusions\/significance<\/jats:title>\n<jats:p>Together, we have unveiled DiMT as an essential COMT that is conserved in parasitic filarial nematodes, but is significantly different from mammalian COMTs and, therefore, is a viable target for development of novel drugs against filarial nematode infections.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pntd.0012473","type":"journal-article","created":{"date-parts":[[2024,8,30]],"date-time":"2024-08-30T19:30:46Z","timestamp":1725046246000},"page":"e0012473","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Characterization of a unique catechol-O-methyltransferase as a molecular drug target in parasitic filarial nematodes"],"prefix":"10.1371","volume":"18","author":[{"given":"Md Mukthar","family":"Mia","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Idrees Mehraj","family":"Allaie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahbaz M.","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saki","family":"Kadotani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2308-0539","authenticated-orcid":true,"given":"William H.","family":"Witola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,8,30]]},"reference":[{"key":"pntd.0012473.ref001","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1006\/jmbi.1994.0117","article-title":"Universal catalytic domain structure of AdoMet-dependent methyltransferases","volume":"247","author":"G Schluckebier","year":"1995","journal-title":"Mol Biol"},{"key":"pntd.0012473.ref002","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/S0968-0004(03)00090-2","article-title":"Many paths to methyltransfer: a chronicle of convergence","volume":"28","author":"L Schubert H","year":"2003","journal-title":"Trends Biochem Sci"},{"key":"pntd.0012473.ref003","first-page":"191","volume-title":"Conjugation Reactions in Drug Metabolism","author":"DR Thakker","year":"1990"},{"key":"pntd.0012473.ref004","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/S0009-9120(88)80002-X","article-title":"Pharmacogenetics of methylation: relationship to drug metabolism","volume":"21","author":"R. Weinshilboum","year":"1988","journal-title":"Clin Biochem"},{"key":"pntd.0012473.ref005","volume-title":"Grand Rapids (Michigan)","author":"CT Walsh","year":"2006"},{"key":"pntd.0012473.ref006","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1016\/0006-2952(83)90582-8","article-title":"Human kidney thiopurine methyltransferase purification and biochemical properties","volume":"32","author":"LC Woodson","year":"1983","journal-title":"Biochem Pharmacol"},{"key":"pntd.0012473.ref007","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1021\/jm00153a009","article-title":"Thiopurine methyltransferase: structure-activity relationships for benzoic acid inhibitors and thiophenol substrates","volume":"29","author":"MM Ames","year":"1986","journal-title":"J Med Chem"},{"key":"pntd.0012473.ref008","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1038\/375073a0","article-title":"A calcium-channel homologue required for adaptation to dopamine and serotonin in Caenorhabditis elegans","volume":"375","author":"WR Schafer","year":"1995","journal-title":"Nature"},{"key":"pntd.0012473.ref009","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1111\/j.1471-4159.2004.02787.x","article-title":"Tyramine receptor (SER-2) isoforms are involved in the regulation of pharyngeal pumping and foraging behavior in Caenorhabditis elegans","volume":"91","author":"E Rex","year":"2004","journal-title":"J Neurochem"},{"key":"pntd.0012473.ref010","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1002\/neu.1078","article-title":"Regulation of the pharynx of Caenorhabditis elegans by 5-HT, octopamine, and FMRFamide-like neuropeptides","volume":"49","author":"CM Rogers","year":"2001","journal-title":"J Neurobiol"},{"key":"pntd.0012473.ref011","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1242\/jeb.00101","article-title":"Serotonin regulates repolarization of the C. elegans pharyngeal muscle","volume":"206","author":"T Niacaris","year":"2003","journal-title":"J Exp Biol"},{"key":"pntd.0012473.ref012","volume-title":"The C. elegans","author":"DL Chase","year":"2007"},{"key":"pntd.0012473.ref013","doi-asserted-by":"crossref","first-page":"3696","DOI":"10.1128\/jb.169.8.3696-3700.1987","article-title":"Kinetics and inhibition studies of catechol O-methyltransferase from the yeast Candida tropicalis","volume":"169","author":"J. Veser","year":"1987","journal-title":"J Bacteriol"},{"key":"pntd.0012473.ref014","volume-title":"Conjugation-Deconjugation Reactions in Drug Metabolism and Toxicity: Handbook of Experimental Pharmacology","author":"CR Creveling","year":"1994"},{"key":"pntd.0012473.ref015","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1038\/368354a0","volume":"368","author":"J Vidgren","year":"1994","journal-title":"Nature"},{"key":"pntd.0012473.ref016","doi-asserted-by":"crossref","first-page":"4650","DOI":"10.1096\/fj.12-205096","article-title":"The genome of the heartworm, Dirofilaria immitis, reveals drug and vaccine targets","volume":"26","author":"C Godel","year":"2012","journal-title":"FASEB J"},{"key":"pntd.0012473.ref017","doi-asserted-by":"crossref","first-page":"D225","DOI":"10.1093\/nar\/gkq1189","article-title":"CDD: A Conserved Domain Database for the functional annotation of proteins","volume":"39","author":"A Marchler-Bauer","year":"2011","journal-title":"Nucleic Acids Res"},{"key":"pntd.0012473.ref018","doi-asserted-by":"crossref","first-page":"D344","DOI":"10.1093\/nar\/gkaa977","article-title":"The InterPro protein families and domains database: 20 years on","volume":"49","author":"M Blum","year":"2021","journal-title":"Nucleic Acids Res"},{"key":"pntd.0012473.ref019","doi-asserted-by":"crossref","first-page":"D439","DOI":"10.1093\/nar\/gkab1061","article-title":"AlphaFold Protein Structure Database: Massively expanding the structural coverage of protein-sequence space with high-accuracy models","volume":"50","author":"M Varadi","year":"2022","journal-title":"Nucleic Acids Res"},{"key":"pntd.0012473.ref020","doi-asserted-by":"crossref","first-page":"10696","DOI":"10.1038\/s41598-022-14382-9","article-title":"AlphaFold2 models indicate that protein sequence determines both structure and dynamics","volume":"12","author":"HB Guo","year":"2022","journal-title":"Sci Rep"},{"key":"pntd.0012473.ref021","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1002\/pro.3289","article-title":"PDBsum: Structural summaries of PDB entries","volume":"27","author":"RA Laskowski","year":"2018","journal-title":"Protein Science"},{"key":"pntd.0012473.ref022","doi-asserted-by":"crossref","first-page":"e0221331","DOI":"10.1371\/journal.pone.0221331","article-title":"Identification of lead molecules against potential drug target protein MAPK4 from L. Donovani: An in silico approach using docking, molecular dynamics and binding free energy calculation","volume":"14","author":"S Raj","year":"2019","journal-title":"PLoS One"},{"key":"pntd.0012473.ref023","doi-asserted-by":"crossref","first-page":"5259","DOI":"10.1039\/D2RA06467G","article-title":"Design of highly active substrates using molecular docking for microbial transglutaminase detection","volume":"13","author":"L Zou","year":"2023","journal-title":"RSC Adv"},{"key":"pntd.0012473.ref024","doi-asserted-by":"crossref","first-page":"1044226","DOI":"10.3389\/fmicb.2022.1044226","article-title":"Directed evolution engineering to improve activity of glucose dehydrogenase by increasing pocket hydrophobicity","volume":"13","author":"L Hua","year":"2022","journal-title":"Front Microbiol"},{"key":"pntd.0012473.ref025","doi-asserted-by":"crossref","first-page":"408","DOI":"10.1007\/s12640-023-00648-1","article-title":"In silico Interactions of Natural and Synthetic Compounds with Key Proteins Involved in Alzheimer\u2019s Disease: Prospects for Designing New Therapeutics Compound","volume":"41","author":"ME Shah-abadi","year":"2023","journal-title":"Neurotox Res"},{"key":"pntd.0012473.ref026","doi-asserted-by":"crossref","first-page":"D1202","DOI":"10.1093\/nar\/gkv951","article-title":"PubChem Substance and Compound databases","volume":"44","author":"S Kim","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"pntd.0012473.ref027","doi-asserted-by":"crossref","first-page":"D1075","DOI":"10.1093\/nar\/gkt978","article-title":"PubChem BioAssay: 2014 update","volume":"42","author":"YL Wang","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"pntd.0012473.ref028","doi-asserted-by":"crossref","first-page":"274","DOI":"10.6026\/97320630013274","article-title":"Molecular dynamics simulation analysis of Focal Adhesive Kinase (FK) docked with solanesol as an anti-cancer agent","volume":"13","author":"B Daneial","year":"2017","journal-title":"Bioinformation"},{"key":"pntd.0012473.ref029","doi-asserted-by":"crossref","first-page":"10101","DOI":"10.1038\/s41598-021-89557-x","article-title":"Molecular docking analysis and evaluation of the antibacterial and antioxidant activities of the constituents of Ocimum cufodontii","volume":"11","author":"M Aliye","year":"2021","journal-title":"Sci Rep"},{"key":"pntd.0012473.ref030","doi-asserted-by":"crossref","first-page":"e0000823","DOI":"10.1128\/aac.00008-23","article-title":"Broad-Spectrum Inhibitors for Conserved Unique Phosphoethanolamine Methyltransferases in Parasitic Nematodes Possess Anthelmintic Efficacy","volume":"67","author":"X Zhang","year":"2023","journal-title":"Antimicrob Agents Chemother"},{"key":"pntd.0012473.ref031","doi-asserted-by":"crossref","first-page":"700502","DOI":"10.3389\/fcimb.2021.700502","article-title":"Combination treatment with remdesivir and ivermectin exerts highly synergistic and potent antiviral activity against murine Coronavirus infection","volume":"11","author":"YL Tan","year":"2021","journal-title":"Front Cell Infect Microbiol"},{"key":"pntd.0012473.ref032","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1017\/S003118201500061X","article-title":"The emergence of macrocyclic lactone resistance in the canine heartworm, Dirofilaria immitis","volume":"142","author":"AJ Wolstenholme","year":"2015","journal-title":"Parasitology"},{"key":"pntd.0012473.ref033","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.vetpar.2015.04.002","article-title":"Macrocyclic lactone resistance in Dirofilaria immitis: Failure of heartworm preventives and investigation of genetic markers for resistance","volume":"210","author":"C Bourguinat","year":"2015","journal-title":"Vet Parasitol"},{"key":"pntd.0012473.ref034","doi-asserted-by":"crossref","first-page":"S7","DOI":"10.1017\/S0031182000073261","article-title":"Evolutionary aspects of transmitter molecules, their receptors and channels","volume":"102","author":"RJ Walker","year":"1991","journal-title":"Parasitology"},{"key":"pntd.0012473.ref035","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1111\/bcp.12169","article-title":"Structure-based drug design of catechol-O-methyltransferase inhibitors for CNS disorders","volume":"77","author":"Z Ma","year":"2014","journal-title":"Br J Clin Pharmacol"},{"key":"pntd.0012473.ref036","doi-asserted-by":"crossref","first-page":"1120370","DOI":"10.3389\/fbinf.2023.1120370","article-title":"Before and after AlphaFold2: An overview of protein structure prediction","volume":"3","author":"MF Bertoline","year":"2023","journal-title":"Front Bioinform"},{"key":"pntd.0012473.ref037","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1093\/bib\/bbaa362","article-title":"The impact of structural bioinformatics tools and resources on SARS-CoV-2 research and therapeutic strategies","volume":"22","author":"VP Waman","year":"2021","journal-title":"Brief Bioinform"},{"key":"pntd.0012473.ref038","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/s41586-021-03828-1","article-title":"Highly accurate protein structure prediction for the human proteome","volume":"596","author":"K Tunyasuvunakool","year":"2021","journal-title":"Nature"},{"key":"pntd.0012473.ref039","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"96","author":"J Jumper","year":"2021","journal-title":"Nature"},{"key":"pntd.0012473.ref040","doi-asserted-by":"crossref","first-page":"e99","DOI":"10.1016\/j.jinf.2022.07.001","article-title":"Targeting F13 from monkeypox virus and variola virus by tecovirimat: Molecular simulation analysis","volume":"85","author":"D Li","year":"2022","journal-title":"J Infect"},{"key":"pntd.0012473.ref041","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.jmb.2008.04.040","article-title":"Crystal Structures of Human 108V and 108M Catechol O-Methyltransferase","volume":"380","author":"K Rutherford","year":"2008","journal-title":"J Mol Biol"},{"key":"pntd.0012473.ref042","doi-asserted-by":"crossref","first-page":"e202200642","DOI":"10.1002\/cbic.202200642","article-title":"Substrate Specificity of the Highly Thermostable Esterase EstDZ3","volume":"24","author":"A Papanikolaou","year":"2023","journal-title":"ChemBioChem"},{"key":"pntd.0012473.ref043","doi-asserted-by":"crossref","first-page":"3121","DOI":"10.1110\/ps.051821805","article-title":"The crystal structure of a novel SAM-dependent methyltransferase PH1915 from Pyrococcus horikoshii","volume":"14","author":"W Sun","year":"2005","journal-title":"Prot Sci"},{"key":"pntd.0012473.ref044","first-page":"526","article-title":"Protein post-translational modifications in the regulation of cancer hallmarks","volume":"30","author":"H Wang","year":"2022","journal-title":"Cancer Gene Ther"},{"key":"pntd.0012473.ref045","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1124\/molpharm.122.000604","article-title":"Protein Kinases and Cross-talk between Post-translational Modifications in the Regulation of Drug Transporters","volume":"103","author":"X Wang","year":"2023","journal-title":"Mol Pharmacol"},{"key":"pntd.0012473.ref046","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1016\/j.molcatb.2009.04.014","article-title":"Inhibition of catechol-O-methyltransferase (COMT) by some plant-derived alkaloids and phenolics","volume":"64","author":"D Yalcin","year":"2010","journal-title":"J Mol Catal B Enzym"},{"key":"pntd.0012473.ref047","doi-asserted-by":"crossref","first-page":"173909","DOI":"10.1016\/j.ejphar.2021.173909","article-title":"Membrane-bound catechol-O-methyltransferase is the dominant isoform for dopamine metabolism in PC12 cells and rat brain","volume":"896","author":"Y Su","year":"2021","journal-title":"Eur J Pharmacol"},{"key":"pntd.0012473.ref048","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1007\/BF01980873","article-title":"Mouse kidney histamine N-methyltransferase: Assay conditions, biochemical properties and strain variation","volume":"32","author":"MC Scott","year":"1991","journal-title":"Agents Actions"},{"key":"pntd.0012473.ref049","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1586\/eri.13.49","article-title":"Addressing the current challenges to finding new anthelminthic drugs","volume":"11","author":"CD Mackenzie","year":"2013","journal-title":"Expert Rev Anti Infect Ther"},{"key":"pntd.0012473.ref050","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.3762\/bjoc.16.105","article-title":"Anthelmintic drug discovery: target identification, screening methods and the role of open science","volume":"16","author":"FA Partridge","year":"2020","journal-title":"Beilstein J Org Chem"},{"key":"pntd.0012473.ref051","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/S1090-0233(05)80005-X","article-title":"Modes of action of anthelmintic drugs","volume":"154","author":"R. Martin","year":"1997","journal-title":"Vet J"},{"key":"pntd.0012473.ref052","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/S0304-4017(98)00211-8","article-title":"Comparison of six in vitro tests in determining benzimidazole and levamisole resistance in Haemonchus contortus and Ostertagia circumcincta of sheep","volume":"80","author":"M V\u00e1rady","year":"1999","journal-title":"Vet Parasitol"},{"key":"pntd.0012473.ref053","first-page":"22","article-title":"Motility in the L3 stage is a poor phenotype for detecting and measuring resistance to avermectin\/milbemycin drugs in gastrointestinal nematodes of livestock","volume":"8","author":"MM George","year":"2018","journal-title":"Int J Parasitol: Drugs Drug Resist"},{"key":"pntd.0012473.ref054","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1042\/BJ20060513","article-title":"Structural basis for non-competitive product inhibition in human thymidine phosphorylase: Implications for drug design","volume":"399","author":"K El Omari","year":"2006","journal-title":"Biochem J"},{"key":"pntd.0012473.ref055","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1111\/j.1747-0285.2010.00972.x","article-title":"Non-competitive inhibition by active site binders","volume":"75","author":"Y. Blat","year":"2010","journal-title":"Chem Biol Drug Des"},{"key":"pntd.0012473.ref056","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1016\/S1074-5521(00)00045-4","article-title":"Efficient identification of inhibitors targeting the closed active site conformation of the HPRT from Trypanosoma cruzi","volume":"7","author":"DM Freymann","year":"2000","journal-title":"Chem Biol"},{"key":"pntd.0012473.ref057","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/j.chembiol.2005.04.011","article-title":"Features of selective kinase inhibitors","volume":"12","author":"ZA Knight","year":"2005","journal-title":"Chem Biol"},{"key":"pntd.0012473.ref058","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1126\/science.6805073","article-title":"Serotonin and octopamine in the nematode Caenorhabditis elegans","volume":"216","author":"HR Horvitz","year":"1979","journal-title":"Science"},{"key":"pntd.0012473.ref059","doi-asserted-by":"crossref","first-page":"11","DOI":"10.7164\/antibiotics.25.11","article-title":"Tolypomycin, a new antibiotic. III: Isolation and characterization of tolypomycin Y","volume":"25","author":"T Kishi","year":"1972","journal-title":"J. Antibiot"},{"key":"pntd.0012473.ref060","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1021\/cr030112j","article-title":"Rifamycin\u2014Mode of action, resistance, and biosynthesis","volume":"105","author":"HG Floss","year":"2005","journal-title":"Chem Rev"}],"updated-by":[{"DOI":"10.1371\/journal.pntd.0012473","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,9,12]],"date-time":"2024-09-12T00:00:00Z","timestamp":1726099200000}}],"container-title":["PLOS Neglected Tropical Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0012473","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,12]],"date-time":"2024-09-12T17:44:21Z","timestamp":1726163061000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pntd.0012473"}},"subtitle":[],"editor":[{"given":"Uriel","family":"Koziol","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,8,30]]},"references-count":60,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2024,8,30]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pntd.0012473","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pntd.0012473","asserted-by":"object"}]},"ISSN":["1935-2735"],"issn-type":[{"value":"1935-2735","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,30]]}}}