{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T01:57:49Z","timestamp":1775008669742,"version":"3.50.1"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T00:00:00Z","timestamp":1615248000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cell. Infect. Microbiol."],"abstract":"<jats:p>Coenzyme A (CoA) is a well-known cofactor that plays an essential role in many metabolic reactions in all organisms. In <jats:italic>Plasmodium falciparum<\/jats:italic>, the most deadly among <jats:italic>Plasmodium<\/jats:italic> species that cause malaria, CoA and its biosynthetic pathway have been proven to be indispensable. The first and rate-limiting reaction in the CoA biosynthetic pathway is catalyzed by two putative pantothenate kinases (<jats:italic>Pf<\/jats:italic>PanK1 and 2) in this parasite. Here we produced, purified, and biochemically characterized recombinant <jats:italic>Pf<\/jats:italic>PanK1 for the first time. <jats:italic>Pf<\/jats:italic>PanK1 showed activity using pantetheine besides pantothenate, as the primary substrate, indicating that CoA biosynthesis in the blood stage of <jats:italic>P. falciparum<\/jats:italic> can bypass pantothenate. We further developed a robust and reliable screening system to identify inhibitors using recombinant <jats:italic>Pf<\/jats:italic>PanK1 and identified four <jats:italic>Pf<\/jats:italic>PanK inhibitors from natural compounds.<\/jats:p>","DOI":"10.3389\/fcimb.2021.639065","type":"journal-article","created":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T06:19:47Z","timestamp":1615270787000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Characterization of Plasmodium falciparum Pantothenate Kinase and Identification of Its Inhibitors From Natural Products"],"prefix":"10.3389","volume":"11","author":[{"given":"Arif","family":"Nurkanto","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ghulam","family":"Jeelani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Herbert J.","family":"Santos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yulia","family":"Rahmawati","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mihoko","family":"Mori","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yumi","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kana","family":"Goto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoko","family":"Saikawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Annoura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuzuru","family":"Tozawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takaya","family":"Sakura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel Ken","family":"Inaoka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuro","family":"Shiomi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoyoshi","family":"Nozaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,3,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1007\/s10086-018-1772-2","article-title":"Reaction wood anatomy and lignin distribution in Gnetum gnemon branches","volume":"64","author":"Aiso-Sanada","year":"2018","journal-title":"J. Wood Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"20558","DOI":"10.1074\/jbc.M113.482992","article-title":"Identification and functional analysis of the primary pantothenate transporter, PfPAT, of the human malaria parasite Plasmodium falciparum","volume":"288","author":"Augagneur","year":"2013","journal-title":"J. Biol. Chem."},{"key":"B3","doi-asserted-by":"publisher","first-page":"3157","DOI":"10.1016\/j.tetlet.2008.03.019","article-title":"Kinamycin-mediated DNA cleavage under biomimetic conditions","volume":"49","author":"Ballard","year":"2008","journal-title":"Tetrahedron Lett."},{"key":"B4","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/s0083-6729(01)61005-7","article-title":"The biosynthesis of coenzyme A in bacteria","volume":"61","author":"Begley","year":"2001","journal-title":"Vitam. Horm."},{"key":"B5","doi-asserted-by":"publisher","first-page":"18262","DOI":"10.1073\/pnas.1313965110","article-title":"Plasmodium falciparum phosphoethanolamine methyltransferase is essential for malaria transmission","volume":"110","author":"Bobenchik","year":"2013","journal-title":"Proc. Natl. Acad. Sci. U.\u00a0S. A."},{"key":"B6","doi-asserted-by":"publisher","first-page":"20185","DOI":"10.1074\/jbc.C500044200","article-title":"Characterization of a new pantothenate kinase isoform from Helicobacter pylori","volume":"280","author":"Brand","year":"2005","journal-title":"J. Biol. Chem."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s12936-016-1675-x","article-title":"New developments in anti-malarial target candidate and product profiles","volume":"16","author":"Burrows","year":"2017","journal-title":"Malar. J"},{"key":"B8","doi-asserted-by":"publisher","first-page":"2014","DOI":"10.1074\/jbc.274.4.2014","article-title":"Cloning and characterization of a eukaryotic pantothenate kinase gene (PanK) from Aspergillus nidulans","volume":"274","author":"Calder","year":"1999","journal-title":"J. Biol. Chem."},{"key":"B9","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1007\/s11103-008-9386-5","article-title":"Towards engineering increased pantothenate (vitamin B5) levels in plants","volume":"68","author":"Chakauya","year":"2008","journal-title":"Plant Mol. Biol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1111\/j.1550-7408.1985.tb03013.x","article-title":"Nutritional Requirements of Plasmodium falciparum in Culture. I. Exogenously Supplied Dialyzable Components Necessary for Continuous Growth","volume":"32","author":"Divo","year":"1985","journal-title":"J. Protozool."},{"key":"B11","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1056\/NEJMoa0808859","article-title":"Artemisinin resistance in Plasmodium falciparum malaria","volume":"361","author":"Dondorp","year":"2009","journal-title":"N. Engl. J. Med"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1792","DOI":"10.1093\/nar\/gkh340","article-title":"MUSCLE: Multiple sequence alignment with high accuracy and high throughput","volume":"32","author":"Edgar","year":"2004","journal-title":"Nucleic Acids Res."},{"key":"B13","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/j.canlet.2017.04.027","article-title":"The simultaneous inhibition of the mTOR and MAPK pathways with Gnetin-C induces apoptosis in acute myeloid leukemia","volume":"400","author":"Espinoza","year":"2017","journal-title":"Cancer Lett."},{"key":"B14","doi-asserted-by":"publisher","first-page":"642","DOI":"10.1016\/j.chom.2020.02.005","article-title":"Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle","volume":"27","author":"Favuzza","year":"2020","journal-title":"Cell Host Microbe"},{"key":"B15","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1038\/465297a","article-title":"Drug discovery: Priming the antimalarial pipeline","volume":"465","author":"Fidock","year":"2010","journal-title":"Nature"},{"key":"B16","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1186\/1475-2875-13-343","article-title":"A novel approach for the discovery of chemically diverse anti-malarial compounds targeting the Plasmodium falciparum Coenzyme A synthesis pathway","volume":"13","author":"Fletcher","year":"2014","journal-title":"Malar. J."},{"key":"B17","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1186\/s13071-016-1860-3","article-title":"Biological characterization of chemically diverse compounds targeting the Plasmodium falciparum coenzyme A synthesis pathway","volume":"9","author":"Fletcher","year":"2016","journal-title":"Parasit. Vectors"},{"key":"B18","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1093\/molbev\/msp259","article-title":"SeaView Version 4: A Multiplatform Graphical User Interface for Sequence Alignment and Phylogenetic Tree Building","volume":"27","author":"Gouy","year":"2010","journal-title":"Mol. Biol. Evol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"681","DOI":"10.3390\/ph4050681","article-title":"Expanding the antimalarial drug arsenal-now, but how","volume":"4","author":"Grimberg","year":"2011","journal-title":"Pharmaceuticals"},{"key":"B20","doi-asserted-by":"publisher","first-page":"33518","DOI":"10.1038\/srep33518","article-title":"Genetic characterization of plasmodium putative pantothenate kinase genes reveals their essential role in malaria parasite transmission to the mosquito","volume":"6","author":"Hart","year":"2016","journal-title":"Sci. Rep."},{"key":"B21","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/j.bbabio.2017.12.004","article-title":"Biochemical studies of membrane bound Plasmodium falciparum mitochondrial L-malate:quinone oxidoreductase, a potential drug target","volume":"1859","author":"Hartuti","year":"2018","journal-title":"Biochim. Biophys. Acta - Bioenerg."},{"key":"B22","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1097\/01.cad.0000224442.78211.27","article-title":"Kinamycins A and C, bacterial metabolites that contain an unusual diazo group, as potential new anticancer agents: Antiproliferative and cell cycle effects","volume":"17","author":"Hasinoff","year":"2006","journal-title":"Anticancer Drugs"},{"key":"B23","doi-asserted-by":"publisher","first-page":"7146","DOI":"10.1128\/AAC.01436-16","article-title":"Triazole substitution of a labile amide bond stabilizes pantothenamides and improves their antiplasmodial potency","volume":"60","author":"Howieson","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/ja.2008.38","article-title":"Simaomicin \u03b1: Effects on the cell cycle of synchronized, cultured Plasmodium falciparum","author":"Ishiyama","year":"2008","journal-title":"J. Antibiot. (Tokyo)"},{"key":"B25","doi-asserted-by":"publisher","first-page":"254","DOI":"10.1111\/j.1349-7006.2008.01033.x","article-title":"Simaomicin \u03b1, a polycyclic xanthone, induces G1 arrest with suppression of retinoblastoma protein phosphorylation","volume":"61","author":"Koizumi","year":"2009","journal-title":"Cancer Sci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"418","DOI":"10.2307\/3280287","article-title":"Synchronization of Plasmodium falciparum Erythrocytic Stages in Culture","volume":"65","author":"Lambros","year":"1979","journal-title":"J. Parasitol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1771","DOI":"10.1039\/C39890001771","article-title":"Structure determination of simaomicins \u03b1 and \u03b2, extremely potent, novel anticoccidal agents produced by Actinomadura","volume":"22","author":"Lee","year":"1989","journal-title":"J. Chem. Soc Chem. Commun."},{"key":"B28","doi-asserted-by":"publisher","first-page":"991","DOI":"10.1056\/NEJMc1612765","article-title":"Emergence of indigenous artemisinin-resistant Plasmodium falciparum in Africa","volume":"376","author":"Lu","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"B29","doi-asserted-by":"publisher","first-page":"3666","DOI":"10.1128\/AAC.04970-14","article-title":"A pantetheinase-resistant pantothenamide with potent, on-target, and selective antiplasmodial activity","volume":"59","author":"Macuamule","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"B30","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1002\/ddr.20347","article-title":"Targeting the lipid metabolic pathways for the treatment of malaria","volume":"71","author":"Mamoun","year":"2010","journal-title":"Drug Dev. Res."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2015.00962","article-title":"Identification of natural inhibitors of Entamoeba histolytica cysteine synthase from microbial secondary metabolites","volume":"6","author":"Mori","year":"2015","journal-title":"Front. Microbiol."},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3390\/nu11061403","article-title":"Immunomodulatory and metabolic changes after Gnetin-C supplementation in humans","author":"Nakagami","year":"2019","journal-title":"Nutrients"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1403","DOI":"10.1002\/cam4.520","article-title":"Antitumor activity of melinjo (Gnetum gnemon L.) seed extract in human and murine tumor models in vitro and in acolon-26 tumor-bearing mouse model in vivo","volume":"11","author":"Narayanan","year":"2015","journal-title":"Cancer Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1093\/molbev\/msu300","article-title":"IQ-TREE: A fast and effective stochastic algorithm for estimating maximum-likelihood phylogenies","volume":"32","author":"Nguyen","year":"2015","journal-title":"Mol. Biol. Evol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1815","DOI":"10.1093\/pcp\/pcm150","article-title":"A cell-free translation and proteoliposome reconstitution system for functional analysis of plant solute transporters","volume":"48","author":"Nozawa","year":"2007","journal-title":"Plant Cell Physiol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.ijpddr.2018.02.004","article-title":"Characterization and validation of Entamoeba histolytica pantothenate kinase as a novel anti-amebic drug target","volume":"8","author":"Nurkanto","year":"2018","journal-title":"Int. J. Parasitol. Drugs Drug Resist."},{"key":"B37","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1006\/jsbi.2001.4428","article-title":"Crystal structure of dephospho-coenzyme A kinase from Haemophilus influenzae","volume":"136","author":"Obmolova","year":"2001","journal-title":"J. Struct. Biol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1738","DOI":"10.1016\/j.bbamcr.2015.04.007","article-title":"Presumed pseudokinase VRK3 functions as a BAF kinase","volume":"1853","author":"Park","year":"2015","journal-title":"Biochim. Biophys. Acta - Mol. Cell Res"},{"key":"B39","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1186\/s12936-015-0673-8","article-title":"Novel pantothenate derivatives for anti-malarial chemotherapy","volume":"14","author":"Pett","year":"2015","journal-title":"Malar. J."},{"key":"B40","doi-asserted-by":"publisher","first-page":"18115","DOI":"10.1074\/jbc.M010942200","article-title":"H+-coupled Pantothenate Transport in the Intracellular Malaria Parasite","volume":"276","author":"Saliba","year":"2001","journal-title":"J. Biol. Chem."},{"key":"B41","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.molbiopara.2005.02.003","article-title":"CJ-15,801, a fungal natural product, inhibits the intraerythrocytic stage of Plasmodium falciparum in vitro via an effect on pantothenic acid utilisation","volume":"141","author":"Saliba","year":"2005","journal-title":"Mol. Biochem. Parasitol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"10190","DOI":"10.1074\/jbc.273.17.10190","article-title":"Transport and metabolism of the essential vitamin pantothenic acid in human erythrocytes infected with the malaria parasite Plasmodium falciparum","volume":"273","author":"Saliba","year":"1998","journal-title":"J. Biol. Chem."},{"key":"B43","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1128\/AAC.49.2.632-637.2005","article-title":"Provitamin B5 (Pantothenol) inhibits growth of the intraerythrocytic malaria parasite","volume":"49","author":"Saliba","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"B44","doi-asserted-by":"publisher","first-page":"eaas9917","DOI":"10.1126\/scitranslmed.aas9917","article-title":"Antimalarial pantothenamide metabolites target acetyl-coenzyme A biosynthesis in Plasmodium falciparum","volume":"11","author":"Schalkwijk","year":"2019","journal-title":"Sci. Transl. Med"},{"key":"B45","doi-asserted-by":"publisher","first-page":"24904","DOI":"10.1074\/jbc.M109.025312","article-title":"The human malaria parasite Plasmodium falciparum is not dependent on host coenzyme A biosynthesis","volume":"284","author":"Spry","year":"2009","journal-title":"J. Biol. Chem."},{"key":"B46","doi-asserted-by":"publisher","first-page":"4649","DOI":"10.1128\/AAC.49.11.4649-4657.2005","article-title":"A class of pantothenic acid analogs inhibits Plasmodium falciparum pantothenate kinase and represses the proliferation of malaria parasites","volume":"49","author":"Spry","year":"2005","journal-title":"Antimicrob. Agents Chemother."},{"key":"B47","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1111\/j.1574-6976.2007.00093.x","article-title":"Coenzyme A biosynthesis: An antimicrobial drug target","volume":"32","author":"Spry","year":"2008","journal-title":"FEMS Microbiol. Rev."},{"key":"B48","doi-asserted-by":"publisher","first-page":"200","DOI":"10.2174\/187152610791163390","article-title":"Pantothenate Utilization by Plasmodium as a Target for Antimalarial Chemotherapy","volume":"10","author":"Spry","year":"2010","journal-title":"Infect. Disord. - Drug Targets"},{"key":"B49","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.1016\/j.ejmech.2017.08.050","article-title":"Structure-activity analysis of CJ-15,801 analogues that interact with Plasmodium falciparum pantothenate kinase and inhibit parasite proliferation","volume":"143","author":"Spry","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"B50","doi-asserted-by":"publisher","first-page":"2688","DOI":"10.1093\/bioinformatics\/btl446","article-title":"RAxML-VI-HPC: Maximum likelihood-based phylogenetic analyses with thousands of taxa and mixed models","volume":"22","author":"Stamatakis","year":"2006","journal-title":"Bioinformatics"},{"key":"B51","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1128\/JB.01021-09","article-title":"Pantothenate kinase from the thermoacidophilic archaeon Picrophilus torridus","volume":"192","author":"Takagi","year":"2010","journal-title":"J. Bacteriol."},{"key":"B52","doi-asserted-by":"publisher","first-page":"e1006918","DOI":"10.1371\/journal.ppat.1006918","article-title":"Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues","volume":"14","author":"Tjhin","year":"2018","journal-title":"PLoS Pathog."},{"key":"B53","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1186\/s12936-019-2724-z","article-title":"The past, present and future of anti-malarial medicines","volume":"18","author":"Tse","year":"2019","journal-title":"Malar. J."},{"key":"B54","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1038\/ja.2007.27","article-title":"Selective and potent in vitro antimalarial activities found in four microbial metabolites","volume":"60","author":"Ui","year":"2007","journal-title":"J. Antibiot. (Tokyo)"},{"key":"B55","doi-asserted-by":"publisher","first-page":"2468","DOI":"10.1016\/S0021-9258(18)61527-3","article-title":"Regulation of pantothenate kinase by coenzyme A and its thioesters","volume":"262","author":"Vallari","year":"1987","journal-title":"J. Biol. Chem."},{"key":"B56","doi-asserted-by":"publisher","first-page":"2219","DOI":"10.1517\/14656566.2014.944499","article-title":"Malaria: An update on current chemotherapy","volume":"15","author":"Visser","year":"2014","journal-title":"Expert Opin. Pharmacother."},{"key":"B57","doi-asserted-by":"publisher","first-page":"10796","DOI":"10.1002\/anie.201304812","article-title":"Dehydrogenative coupling to enable the enantioselective total synthesis of (-)-simaomicin \u03b1","volume":"52","author":"Wang","year":"2013","journal-title":"Angew. Chem. - Int. Ed"},{"key":"B58","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1186\/s12936-017-1839-3","article-title":"Antiplasmodial dihetarylthioethers target the coenzyme A synthesis pathway in Plasmodium falciparum erythrocytic stages","volume":"16","author":"Weidner","year":"2017","journal-title":"Malar. J."},{"key":"B59","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1038\/nrd4573","article-title":"Malaria medicines: a glass half full","volume":"14","author":"Wells","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"B60","volume-title":"World Malaria Report 2017","year":"2017"},{"key":"B61","volume-title":"World Malaria Report 2019","year":"2019"},{"key":"B62","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1177\/108705719900400206","article-title":"A simple statistical parameter for use in evaluation and validation of high throughput screening assays","volume":"4","author":"Zhang","year":"1999","journal-title":"J. Biomol. Screen"}],"container-title":["Frontiers in Cellular and Infection Microbiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2021.639065\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T06:19:51Z","timestamp":1615270791000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcimb.2021.639065\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,9]]},"references-count":62,"alternative-id":["10.3389\/fcimb.2021.639065"],"URL":"https:\/\/doi.org\/10.3389\/fcimb.2021.639065","relation":{},"ISSN":["2235-2988"],"issn-type":[{"value":"2235-2988","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,9]]},"article-number":"639065"}}