{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T10:35:36Z","timestamp":1785148536822,"version":"3.55.0"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1012545","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,11,7]],"date-time":"2024-11-07T00:00:00Z","timestamp":1730937600000}}],"reference-count":112,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T00:00:00Z","timestamp":1730073600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100019690","name":"Medical Research Council Centre for Medical Mycology","doi-asserted-by":"publisher","award":["MR\/N006364\/2 and MR\/V033417\/1"],"award-info":[{"award-number":["MR\/N006364\/2 and MR\/V033417\/1"]}],"id":[{"id":"10.13039\/501100019690","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/V006169\/1"],"award-info":[{"award-number":["MR\/V006169\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIHR Exeter Biomedical Research Centre","award":["NIHR203320"],"award-info":[{"award-number":["NIHR203320"]}]},{"DOI":"10.13039\/501100019690","name":"Medical Research Council Centre for Medical Mycology","doi-asserted-by":"publisher","award":["MR\/N006364\/2"],"award-info":[{"award-number":["MR\/N006364\/2"]}],"id":[{"id":"10.13039\/501100019690","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["224323\/Z\/21\/Z"],"award-info":[{"award-number":["224323\/Z\/21\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"name":"MRC Programme Grant","award":["MR\/M026663\/2"],"award-info":[{"award-number":["MR\/M026663\/2"]}]},{"DOI":"10.13039\/501100018781","name":"Leverhulme Research Centre for Functional Materials Design","doi-asserted-by":"publisher","award":["RC-2015-036"],"award-info":[{"award-number":["RC-2015-036"]}],"id":[{"id":"10.13039\/501100018781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000308","name":"Carnegie Corporation of New York","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000308","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["209293"],"award-info":[{"award-number":["209293"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Establishing suitable <jats:italic>in vitro<\/jats:italic> culture conditions for microorganisms is crucial for dissecting their biology and empowering potential applications. However, a significant number of bacterial and fungal species, including <jats:italic>Pneumocystis jirovecii<\/jats:italic>, remain unculturable, hampering research efforts. <jats:italic>P<\/jats:italic>. <jats:italic>jirovecii<\/jats:italic> is a deadly pathogen of humans that causes life-threatening pneumonia in immunocompromised individuals and transplant patients. Despite the major impact of <jats:italic>Pneumocystis<\/jats:italic> on human health, limited progress has been made in dissecting the pathobiology of this fungus. This is largely due to the fact that its experimental dissection has been constrained by the inability to culture the organism <jats:italic>in vitro<\/jats:italic>. We present a comprehensive <jats:italic>in silico<\/jats:italic> genome-scale metabolic model of <jats:italic>Pneumocystis<\/jats:italic> growth and metabolism, to identify metabolic requirements and imbalances that hinder growth <jats:italic>in vitro<\/jats:italic>. We utilise recently published genome data and available information in the literature as well as bioinformatics and software tools to develop and validate the model. In addition, we employ relaxed Flux Balance Analysis and Reinforcement Learning approaches to make predictions regarding metabolic fluxes and to identify critical components of the <jats:italic>Pneumocystis<\/jats:italic> growth medium. Our findings offer insights into the biology of <jats:italic>Pneumocystis<\/jats:italic> and provide a novel strategy to overcome the longstanding challenge of culturing this pathogen <jats:italic>in vitro<\/jats:italic>.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1012545","type":"journal-article","created":{"date-parts":[[2024,10,28]],"date-time":"2024-10-28T17:42:49Z","timestamp":1730137369000},"page":"e1012545","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Metabolic modelling as a powerful tool to identify critical components of Pneumocystis growth medium"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0055-2211","authenticated-orcid":true,"given":"Olga A.","family":"Nev","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Zamaraeva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romain","family":"De Oliveira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilia","family":"Ryzhkov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8173-4644","authenticated-orcid":true,"given":"Lucian","family":"Duvenage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wassim","family":"Abou-Jaoud\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Djomangan Adama","family":"Ouattara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer Claire","family":"Hoving","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Gudelj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1406-4251","authenticated-orcid":true,"given":"Alistair J. P.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,10,28]]},"reference":[{"issue":"3","key":"pcbi.1012545.ref001","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1016\/j.cell.2009.09.033","article-title":"Induction of intestinal Th17 cells by segmented filamentous bacteria","volume":"139","author":"II Ivanov","year":"2009","journal-title":"Cell"},{"issue":"7","key":"pcbi.1012545.ref002","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.tim.2016.02.015","article-title":"Oscillospira: a central, enigmatic component of the human gut microbiota","volume":"24","author":"T Konikoff","year":"2016","journal-title":"Trends Microbiol"},{"issue":"11","key":"pcbi.1012545.ref003","doi-asserted-by":"crossref","first-page":"6808","DOI":"10.1128\/AEM.69.11.6808-6815.2003","article-title":"Ecology of uncultivated Oscillospira species in the rumen of cattle, sheep, and reindeer as assessed by microscopy and molecular approaches","volume":"69","author":"RI Mackie","year":"2003","journal-title":"Appl Environ Microbiol"},{"issue":"7","key":"pcbi.1012545.ref004","doi-asserted-by":"crossref","first-page":"e41294","DOI":"10.1371\/journal.pone.0041294","article-title":"The \u201cmost wanted\u201d taxa from the human microbiome for whole genome sequencing","volume":"7","author":"AA Fodor","year":"2012","journal-title":"PLoS One"},{"key":"pcbi.1012545.ref005","first-page":"258","article-title":"The importance of the viable but non-culturable state in human bacterial pathogens","volume":"5","author":"L Li","year":"2014","journal-title":"Front Microbiol"},{"issue":"1","key":"pcbi.1012545.ref006","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1009194","article-title":"Bacterial dormancy: a subpopulation of viable but non-culturable cells demonstrates better fitness for revival","volume":"17","author":"S Wagley","year":"2021","journal-title":"PLoS Pathog"},{"issue":"3","key":"pcbi.1012545.ref007","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1128\/CMR.15.3.401-413.2002","article-title":"In vitro cultivation of Microsporidia of clinical importance","volume":"15","author":"GS Visvesvara","year":"2002","journal-title":"Clin Microbiol Rev"},{"issue":"47","key":"pcbi.1012545.ref008","doi-asserted-by":"crossref","first-page":"18730","DOI":"10.1073\/pnas.0706756104","article-title":"Dandruff-associated Malassezia genomes reveal convergent and divergent virulence traits shared with plant and human fungal pathogens","volume":"104","author":"J Xu","year":"2007","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"10","key":"pcbi.1012545.ref009","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1086\/497381","article-title":"Genetic differences in Pneumocystis isolates recovered from immunocompetent infants and from adults with AIDS: epidemiological implications","volume":"192","author":"CB Beard","year":"2005","journal-title":"J Infect Dis"},{"issue":"6","key":"pcbi.1012545.ref010","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1086\/319340","article-title":"Search for primary infection by Pneumocystis carinii in a cohort of normal, healthy infants","volume":"32","author":"SL Vargas","year":"2001","journal-title":"Clin Infect Dis"},{"issue":"7","key":"pcbi.1012545.ref011","first-page":"673","article-title":"Outbreaks and clustering of Pneumocystis pneumonia in kidney transplant recipients: a systematic review","volume":"49","author":"MG de Boer","year":"2011","journal-title":"Med Mycol"},{"issue":"1","key":"pcbi.1012545.ref012","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.jhin.2016.01.018","article-title":"Systematic review of outbreaks of Pneumocystis jirovecii pneumonia: evidence that P. jirovecii is a transmissible organism and the implications for healthcare infection control","volume":"93","author":"E Yiannakis","year":"2016","journal-title":"J Hosp Infect"},{"issue":"6","key":"pcbi.1012545.ref013","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1093\/infdis\/jiw085","article-title":"Incidence of AIDS-defining opportunistic infections in a multicohort analysis of HIV-infected persons in the United States and Canada, 2000\u20132010","volume":"214","author":"K Buchacz","year":"2016","journal-title":"J Infect Dis"},{"issue":"3","key":"pcbi.1012545.ref014","doi-asserted-by":"crossref","first-page":"386","DOI":"10.3201\/eid1903.121151","article-title":"Increasing Pneumocystis pneumonia, England, UK, 2000\u20132010","volume":"19","author":"R Maini","year":"2013","journal-title":"Emerg Infect Dis"},{"issue":"3","key":"pcbi.1012545.ref015","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1097\/INF.0000000000002119","article-title":"Pneumocystis infection in children: national trends and characteristics in the United States, 1997\u20132012","volume":"38","author":"K Inagaki","year":"2019","journal-title":"Pediatr Infect Dis J"},{"issue":"5","key":"pcbi.1012545.ref016","doi-asserted-by":"crossref","first-page":"2402","DOI":"10.1073\/pnas.96.5.2402","article-title":"Continuous axenic cultivation of Pneumocystis carinii","volume":"96","author":"S Merali","year":"1999","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"9","key":"pcbi.1012545.ref017","doi-asserted-by":"crossref","first-page":"903","DOI":"10.3390\/jof9090903","article-title":"Axenic long-term cultivation of Pneumocystis jirovecii","volume":"9","author":"D Riebold","year":"2023","journal-title":"J Fungi (Basel)"},{"issue":"3","key":"pcbi.1012545.ref018","first-page":"e00939","article-title":"Inability to culture Pneumocystis jirovecii","volume":"9","author":"Y Liu","year":"2018","journal-title":"mBio"},{"key":"pcbi.1012545.ref019","doi-asserted-by":"crossref","DOI":"10.3389\/fmicb.2021.681474","article-title":"The persistent challenge of Pneumocystis growth outside the mammalian lung: past and future approaches","volume":"12","author":"MT Cushion","year":"2021","journal-title":"Front Microbiol"},{"key":"pcbi.1012545.ref020","doi-asserted-by":"crossref","first-page":"10740","DOI":"10.1038\/ncomms10740","article-title":"Genome analysis of three Pneumocystis species reveals adaptation mechanisms to life exclusively in mammalian hosts","volume":"7","author":"L Ma","year":"2016","journal-title":"Nat Commun"},{"issue":"2","key":"pcbi.1012545.ref021","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1039\/B712395G","article-title":"Metabolic flux analysis and metabolic engineering of microorganisms","volume":"4","author":"HU Kim","year":"2008","journal-title":"Mol Biosyst"},{"key":"pcbi.1012545.ref022","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/nprot.2009.203","article-title":"A protocol for generating a high-quality genome-scale metabolic reconstruction","volume":"5","author":"I Thiele","year":"2010","journal-title":"Nat Protoc"},{"issue":"3","key":"pcbi.1012545.ref023","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/nbt.1614","article-title":"What is flux balance analysis?","volume":"28","author":"JD Orth","year":"2010","journal-title":"Nat Biotechnol"},{"issue":"6","key":"pcbi.1012545.ref024","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1038\/nbt1401","article-title":"The growing scope of applications of genome-scale metabolic reconstructions using Escherichia coli","volume":"26","author":"AM Feist","year":"2008","journal-title":"Nat Biotechnol"},{"key":"pcbi.1012545.ref025","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1038\/msb.2009.77","article-title":"Applications of genome-scale metabolic reconstructions","volume":"5","author":"MA Oberhardt","year":"2009","journal-title":"Mol Syst Biol"},{"key":"pcbi.1012545.ref026","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1186\/s13059-019-1730-3","article-title":"Current status and applications of genome-scale metabolic models","volume":"20","author":"C Gu","year":"2019","journal-title":"Genome Biol"},{"issue":"11","key":"pcbi.1012545.ref027","doi-asserted-by":"crossref","first-page":"7253","DOI":"10.1128\/AEM.71.11.7253-7262.2005","article-title":"In silico reconstruction of the metabolic pathways of Lactobacillus plantarum: comparing predictions of nutrient requirements with those from growth experiments","volume":"71","author":"B Teusink","year":"2005","journal-title":"Appl Environ Microbiol"},{"issue":"1","key":"pcbi.1012545.ref028","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/nbt.3703","article-title":"Generation of genome-scale metabolic reconstructions for 773 members of the human gut microbiota","volume":"35","author":"S Magn\u00fasd\u00f3ttir","year":"2017","journal-title":"Nat Biotechnol"},{"issue":"4","key":"pcbi.1012545.ref029","doi-asserted-by":"crossref","first-page":"1990","DOI":"10.1073\/pnas.0337704100","article-title":"Complete genome sequence of Lactobacillus plantarum WCFS1","volume":"100","author":"M Kleerebezem","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"18","key":"pcbi.1012545.ref030","doi-asserted-by":"crossref","first-page":"3289","DOI":"10.1128\/JB.01780-14","article-title":"Functional metabolic map of Faecalibacterium prausnitzii, a beneficial human gut microbe","volume":"196","author":"A Heinken","year":"2014","journal-title":"J Bacteriol"},{"key":"pcbi.1012545.ref031","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1471-2180-5-8","article-title":"Genome-scale reconstruction of the metabolic network in Staphylococcus aureus N315: an initial draft to the two-dimensional annotation","volume":"5","author":"SA Becker","year":"2005","journal-title":"BMC Microbiol"},{"issue":"7","key":"pcbi.1012545.ref032","doi-asserted-by":"crossref","first-page":"R136","DOI":"10.1186\/gb-2007-8-7-r136","article-title":"Modeling Neisseria meningitidis metabolism: from genome to metabolic fluxes","volume":"8","author":"GJ Baart","year":"2007","journal-title":"Genome Biol"},{"issue":"16","key":"pcbi.1012545.ref033","doi-asserted-by":"crossref","first-page":"4582","DOI":"10.1128\/JB.184.16.4582-4593.2002","article-title":"Genome-scale metabolic model of Helicobacter pylori 26695","volume":"184","author":"CH Schilling","year":"2002","journal-title":"J Bacteriol"},{"issue":"6","key":"pcbi.1012545.ref034","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1007\/s10529-015-1782-8","article-title":"Current state of genome-scale modeling in filamentous fungi","volume":"37","author":"J Brandl","year":"2015","journal-title":"Biotechnol Lett"},{"key":"pcbi.1012545.ref035","doi-asserted-by":"crossref","first-page":"103005","DOI":"10.1016\/j.copbio.2023.103005","article-title":"Advances in genome-scale metabolic models of industrially important fungi","volume":"84","author":"Y Han","year":"2023","journal-title":"Curr Opin Biotechnol"},{"issue":"1","key":"pcbi.1012545.ref036","doi-asserted-by":"crossref","first-page":"e00002","DOI":"10.1128\/mSystems.00002-21","article-title":"Experimentally validated reconstruction and analysis of a genome-scale metabolic model of an anaerobic Neocallimastigomycota fungus","volume":"6","author":"SE Wilken","year":"2021","journal-title":"mSystems"},{"issue":"1","key":"pcbi.1012545.ref037","doi-asserted-by":"crossref","first-page":"4369","DOI":"10.1038\/s41467-023-39982-5","article-title":"Genome-scale metabolic modeling of Aspergillus fumigatus strains reveals growth dependencies on the lung microbiome","volume":"14","author":"MH Mirhakkak","year":"2023","journal-title":"Nat Commun"},{"key":"pcbi.1012545.ref038","doi-asserted-by":"crossref","first-page":"1121409","DOI":"10.3389\/fbinf.2023.1121409","article-title":"Comprehensive genome-scale metabolic model of the human pathogen Cryptococcus neoformans: a platform for understanding pathogen metabolism and identifying new drug targets","volume":"3","author":"EF Tezcan","year":"2023","journal-title":"Front Bioinform"},{"issue":"1","key":"pcbi.1012545.ref039","doi-asserted-by":"crossref","first-page":"foac003","DOI":"10.1093\/femsyr\/foac003","article-title":"Genome-scale modeling of yeast metabolism: retrospectives and perspectives","volume":"22","author":"Y Chen","year":"2022","journal-title":"FEMS Yeast Res"},{"key":"pcbi.1012545.ref040","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/1752-0509-3-37","article-title":"Connecting extracellular metabolomic measurements to intracellular flux states in yeast","volume":"3","author":"ML Mo","year":"2009","journal-title":"BMC Syst Biol"},{"key":"pcbi.1012545.ref041","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1186\/1752-0509-6-49","article-title":"Genome-scale metabolic model of the fission yeast Schizosaccharomyces pombe and the reconciliation of in silico\/in vivo mutant growth","volume":"6","author":"SB Sohn","year":"2012","journal-title":"BMC Syst Biol"},{"issue":"5","key":"pcbi.1012545.ref042","doi-asserted-by":"crossref","first-page":"e00488","DOI":"10.1128\/mSphere.00488-19","article-title":"Transcriptomic and proteomic approaches to finding novel diagnostic and immunogenic candidates in Pneumocystis","volume":"4","author":"T Eddens","year":"2019","journal-title":"mSphere"},{"issue":"D1","key":"pcbi.1012545.ref043","doi-asserted-by":"crossref","first-page":"D1214","DOI":"10.1093\/nar\/gkv1031","article-title":"ChEBI in 2016: improved services and an expanding collection of metabolites","volume":"44","author":"J Hastings","year":"2016","journal-title":"Nucleic Acids Res"},{"issue":"D1","key":"pcbi.1012545.ref044","doi-asserted-by":"crossref","first-page":"D498","DOI":"10.1093\/nar\/gkaa1025","article-title":"BRENDA, the ELIXIR core data resource in 2021: new developments and updates","volume":"49","author":"A Chang","year":"2021","journal-title":"Nucleic Acids Res"},{"issue":"D1","key":"pcbi.1012545.ref045","doi-asserted-by":"crossref","first-page":"D693","DOI":"10.1093\/nar\/gkab1016","article-title":"Rhea, the reaction knowledgebase in 2022","volume":"50","author":"P Bansal","year":"2022","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"pcbi.1012545.ref046","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: kyoto encyclopedia of genes and genomes","volume":"28","author":"M Kanehisa","year":"2000","journal-title":"Nucleic Acids Res"},{"issue":"3","key":"pcbi.1012545.ref047","first-page":"e00009","article-title":"A molecular window into the biology and epidemiology of Pneumocystis spp","volume":"31","author":"L Ma","year":"2018","journal-title":"Clin Microbiol Rev"},{"issue":"3","key":"pcbi.1012545.ref048","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.mib.2010.03.003","article-title":"The biomass objective function","volume":"13","author":"AM Feist","year":"2010","journal-title":"Curr Opin Microbiol"},{"issue":"2","key":"pcbi.1012545.ref049","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1515\/jib-2016-285","article-title":"Estimation of biomass composition from genomic and transcriptomic information","volume":"13","author":"S Santos","year":"2016","journal-title":"J Integr Bioinform"},{"issue":"9","key":"pcbi.1012545.ref050","doi-asserted-by":"crossref","first-page":"e1011499","DOI":"10.1371\/journal.pcbi.1011499","article-title":"The first multi-tissue genome-scale metabolic model of a woody plant highlights suberin biosynthesis pathways in Quercus suber","volume":"19","author":"E Cunha","year":"2023","journal-title":"PLoS Comput Biol"},{"issue":"2","key":"pcbi.1012545.ref051","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1042\/BST20170268","article-title":"Constraint-based modeling in microbial food biotechnology","volume":"46","author":"MH Rau","year":"2018","journal-title":"Biochem Soc Trans"},{"issue":"1","key":"pcbi.1012545.ref052","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1128\/CMR.11.1.27","article-title":"The lipids of Pneumocystis carinii","volume":"11","author":"ES Kaneshiro","year":"1998","journal-title":"Clin Microbiol Rev"},{"issue":"4","key":"pcbi.1012545.ref053","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1128\/iai.63.4.1286-1290.1995","article-title":"Phospholipid composition of Pneumocystis carinii carinii and effects of methylprednisolone immunosuppression on rat lung lipids","volume":"63","author":"Z Guo","year":"1995","journal-title":"Infect Immun"},{"issue":"6","key":"pcbi.1012545.ref054","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1128\/CDLI.6.6.970-976.1999","article-title":"Sterols of Pneumocystis carinii hominis organisms isolated from human lungs","volume":"6","author":"ES Kaneshiro","year":"1999","journal-title":"Clin Diagn Lab Immunol"},{"issue":"5","key":"pcbi.1012545.ref055","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1093\/infdis\/163.5.1121","article-title":"Polyamine metabolism in Pneumocystis carinii","volume":"163","author":"GY Lipschik","year":"1991","journal-title":"J Infect Dis"},{"issue":"7","key":"pcbi.1012545.ref056","doi-asserted-by":"crossref","first-page":"3755","DOI":"10.4049\/jimmunol.164.7.3755","article-title":"Isolated Pneumocystis carinii cell wall glucan provokes lower respiratory tract inflammatory responses","volume":"164","author":"R Vassallo","year":"2000","journal-title":"J Immunol"},{"issue":"7","key":"pcbi.1012545.ref057","doi-asserted-by":"crossref","first-page":"2816","DOI":"10.1128\/IAI.00196-15","article-title":"Evidence for proinflammatory \u03b2-1, 6 glucans in the Pneumocystis carinii cell wall","volume":"83","author":"TJ Kottom","year":"2015","journal-title":"Infect Immun"},{"issue":"8","key":"pcbi.1012545.ref058","doi-asserted-by":"crossref","first-page":"2790","DOI":"10.1128\/JB.01583-07","article-title":"Genome-scale metabolic network analysis of the opportunistic pathogen Pseudomonas aeruginosa PAO1","volume":"190","author":"MA Oberhardt","year":"2008","journal-title":"J Bacteriol"},{"issue":"5","key":"pcbi.1012545.ref059","doi-asserted-by":"crossref","first-page":"e46","DOI":"10.1371\/journal.pcbi.0010046","article-title":"Flux balance analysis of mycolic acid pathway: targets for anti-tubercular drugs","volume":"1","author":"K Raman","year":"2005","journal-title":"PLoS Comput Biol"},{"issue":"1","key":"pcbi.1012545.ref060","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s12918-018-0557-y","article-title":"Updated and standardized genome-scale reconstruction of Mycobacterium tuberculosis H37Rv, iEK1011, simulates flux states indicative of physiological conditions","volume":"12","author":"ES Kavvas","year":"2018","journal-title":"BMC Syst Biol"},{"key":"pcbi.1012545.ref061","doi-asserted-by":"crossref","first-page":"144","DOI":"10.3389\/fcimb.2019.00144","article-title":"Modeling host-pathogen interaction to elucidate the metabolic drug response of intracellular Mycobacterium tuberculosis","volume":"9","author":"RA Rienksma","year":"2019","journal-title":"Front Cell Infect Microbiol"},{"issue":"2","key":"pcbi.1012545.ref062","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1038\/84379","article-title":"In silico predictions of Escherichia coli metabolic capabilities are consistent with experimental data","volume":"19","author":"JS Edwards","year":"2001","journal-title":"Nat Biotechnol"},{"issue":"4","key":"pcbi.1012545.ref063","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1006\/jtbi.1993.1202","article-title":"Metabolic capabilities of Escherichia coli: I. Synthesis of biosynthetic precursors and cofactors","volume":"165","author":"A Varma","year":"1993","journal-title":"J Theor Biol"},{"issue":"8","key":"pcbi.1012545.ref064","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0043006","article-title":"Predictive potential of flux balance analysis of Saccharomyces cerevisiae using as optimization function combinations of cell compartmental objectives","volume":"7","author":"CE Garc\u00eda S\u00e1nchez","year":"2012","journal-title":"PLoS One"},{"issue":"8","key":"pcbi.1012545.ref065","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1007\/s11745-004-1292-5","article-title":"Sterol metabolism in the opportunistic pathogen Pneumocystis: advances and new insights","volume":"39","author":"ES Kaneshiro","year":"2004","journal-title":"Lipids"},{"issue":"6","key":"pcbi.1012545.ref066","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1111\/j.1550-7408.1994.tb01525.x","article-title":"Incorporation of fatty acids and amino acids by cultured Pneumocystis carinii","volume":"41","author":"JR Paulsrud","year":"1994","journal-title":"J Eukaryot Microbiol"},{"key":"pcbi.1012545.ref067","volume-title":"Reinforcement learning: An Introduction","author":"RS Sutton","year":"2018"},{"key":"pcbi.1012545.ref068","article-title":"A review of reinforcement learning in chemistry","author":"S Gow","year":"2022","journal-title":"Digital Discovery"},{"key":"pcbi.1012545.ref069","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.1039\/D3DD00063J","article-title":"Reinforcement learning in crystal structure prediction","volume":"2","author":"E Zamaraeva","year":"2023","journal-title":"Digit Discov"},{"issue":"7","key":"pcbi.1012545.ref070","doi-asserted-by":"crossref","first-page":"eaap7885","DOI":"10.1126\/sciadv.aap7885","article-title":"Deep reinforcement learning for de novo drug design","volume":"4","author":"M Popova","year":"2018","journal-title":"Sci Adv"},{"issue":"20","key":"pcbi.1012545.ref071","doi-asserted-by":"crossref","first-page":"4034","DOI":"10.1002\/sim.9491","article-title":"Deep reinforcement learning for personalized treatment recommendation","volume":"41","author":"M Liu","year":"2022","journal-title":"Stat Med"},{"issue":"1","key":"pcbi.1012545.ref072","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1038\/s41746-023-00755-5","article-title":"A value-based deep reinforcement learning model with human expertise in optimal treatment of sepsis","volume":"6","author":"X Wu","year":"2023","journal-title":"NPJ Digit Med"},{"issue":"6","key":"pcbi.1012545.ref073","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1093\/scan\/nsaa089","article-title":"Using reinforcement learning models in social neuroscience: frameworks, pitfalls and suggestions of best practices","volume":"15","author":"L Zhang","year":"2020","journal-title":"Soc Cogn Affect Neurosci"},{"issue":"20","key":"pcbi.1012545.ref074","doi-asserted-by":"crossref","first-page":"14958","DOI":"10.1074\/jbc.275.20.14958","article-title":"S-adenosylmethionine and Pneumocystis carinii","volume":"275","author":"S Merali","year":"2000","journal-title":"J Biol Chem"},{"issue":"6","key":"pcbi.1012545.ref075","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1165\/rcmb.2011-0009OC","article-title":"Pneumocystis S-adenosylmethionine transport: a potential drug target","volume":"45","author":"O Perez-Leal","year":"2011","journal-title":"Am J Respir Cell Mol Biol"},{"issue":"2","key":"pcbi.1012545.ref076","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1128\/EC.00345-07","article-title":"Pneumocystis encodes a functional S-adenosylmethionine synthetase gene","volume":"7","author":"G Kutty","year":"2008","journal-title":"Eukaryot Cell"},{"issue":"4","key":"pcbi.1012545.ref077","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1051\/parasite\/2010174285","article-title":"Biochemical research elucidating metabolic pathways in Pneumocystis","volume":"17","author":"ES Kaneshiro","year":"2010","journal-title":"Parasite"},{"issue":"11","key":"pcbi.1012545.ref078","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/j.pt.2007.08.013","article-title":"Metabolic reconstruction and analysis for parasite genomes","volume":"23","author":"JW Pinney","year":"2007","journal-title":"Trends Parasitol"},{"issue":"5","key":"pcbi.1012545.ref079","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.copbio.2003.08.001","article-title":"Advances in flux balance analysis","volume":"14","author":"KJ Kauffman","year":"2003","journal-title":"Curr Opin Biotechnol"},{"issue":"8","key":"pcbi.1012545.ref080","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/nbt.4213","article-title":"Challenges in modeling the human gut microbiome","volume":"36","author":"P Babaei","year":"2018","journal-title":"Nat Biotechnol"},{"issue":"4","key":"pcbi.1012545.ref081","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1093\/bib\/bbp011","article-title":"Flux balance analysis of biological systems: applications and challenges","volume":"10","author":"K Raman","year":"2009","journal-title":"Brief Bioinform"},{"issue":"18","key":"pcbi.1012545.ref082","doi-asserted-by":"crossref","first-page":"2044","DOI":"10.1093\/bioinformatics\/btn352","article-title":"Integrating metabolic, transcriptional regulatory and signal transduction models in Escherichia coli","volume":"24","author":"MW Covert","year":"2008","journal-title":"Bioinformatics"},{"issue":"5","key":"pcbi.1012545.ref083","doi-asserted-by":"crossref","first-page":"e1000086","DOI":"10.1371\/journal.pcbi.1000086","article-title":"Dynamic analysis of integrated signaling, metabolic, and regulatory networks","volume":"4","author":"JM Lee","year":"2008","journal-title":"PLoS Comput Biol"},{"issue":"5","key":"pcbi.1012545.ref084","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.1128\/JCM.40.5.1862-1865.2002","article-title":"Pneumocystis carinii f. sp. hominis is not infectious for SCID mice","volume":"40","author":"I Durand-Joly","year":"2002","journal-title":"J Clin Microbiol"},{"issue":"1","key":"pcbi.1012545.ref085","first-page":"e00428","article-title":"De novo assembly of the Pneumocystis jirovecii genome from a single bronchoalveolar lavage fluid specimen from a patient","volume":"4","author":"OH Ciss\u00e9","year":"2012","journal-title":"mBio"},{"key":"pcbi.1012545.ref086","doi-asserted-by":"crossref","first-page":"S89","DOI":"10.1111\/j.1550-7408.2006.00184.x","article-title":"Draft assembly and annotation of the Pneumocystis carinii genome","volume":"53","author":"BE Slaven","year":"2006","journal-title":"J Eukaryot Microbiol"},{"key":"pcbi.1012545.ref087","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1038\/s42003-021-01799-7","article-title":"Genomic insights into the host specific adaptation of the Pneumocystis genus","volume":"4","author":"OH Ciss\u00e9","year":"2021","journal-title":"Commun Biol"},{"key":"pcbi.1012545.ref088","doi-asserted-by":"crossref","first-page":"5975","DOI":"10.1038\/ncomms6975","article-title":"Co-infection alters population dynamics of infectious disease","volume":"6","author":"H Susi","year":"2015","journal-title":"Nat Commun"},{"issue":"2","key":"pcbi.1012545.ref089","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1099\/jmmcr.0.001578","article-title":"Recurrent pneumocystosis pneumonia\/chronic obstructive pulmonary disease and mild immunodeficiency in a human immunodeficiency virus-negative subject","volume":"1","author":"LE Prestes-Carneiro","year":"2014","journal-title":"JMM Case Rep"},{"issue":"10","key":"pcbi.1012545.ref090","doi-asserted-by":"crossref","first-page":"4990","DOI":"10.1128\/AAC.01161-13","article-title":"Trimethoprim resistance of dihydrofolate reductase variants from clinical isolates of Pneumocystis jirovecii","volume":"57","author":"S Queener","year":"2013","journal-title":"Antimicrob Agents Chemother"},{"issue":"1","key":"pcbi.1012545.ref091","doi-asserted-by":"crossref","first-page":"e02711","DOI":"10.1128\/mbio.02711-22","article-title":"Analysis of Pneumocystis transcription factor evolution and implications for biology and lifestyle","volume":"14","author":"R Ames","year":"2023","journal-title":"mBio"},{"issue":"3","key":"pcbi.1012545.ref092","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1016\/S0022-2836(05)80360-2","article-title":"Basic local alignment search tool","volume":"215","author":"SF Altschul","year":"1990","journal-title":"J Mol Biol"},{"issue":"D1","key":"pcbi.1012545.ref093","doi-asserted-by":"crossref","first-page":"D506","DOI":"10.1093\/nar\/gky1049","article-title":"UniProt: a worldwide hub of protein knowledge","volume":"47","author":"TU Consortium","year":"2019","journal-title":"Nucleic Acids Res"},{"issue":"D1","key":"pcbi.1012545.ref094","doi-asserted-by":"crossref","first-page":"D700","DOI":"10.1093\/nar\/gkr1029","article-title":"Saccharomyces Genome Database: the genomics resource of budding yeast","volume":"40","author":"JM Cherry","year":"2011","journal-title":"Nucleic Acids Res"},{"issue":"4","key":"pcbi.1012545.ref095","doi-asserted-by":"crossref","first-page":"iyab222","DOI":"10.1093\/genetics\/iyab222","article-title":"Fission stories: using PomBase to understand Schizosaccharomyces pombe biology","volume":"220","author":"MA Harris","year":"2022","journal-title":"Genetics"},{"issue":"D1","key":"pcbi.1012545.ref096","doi-asserted-by":"crossref","first-page":"D279","DOI":"10.1093\/nar\/gkv1344","article-title":"The Pfam protein families database: towards a more sustainable future","volume":"44","author":"RD Finn","year":"2016","journal-title":"Nucleic Acids Res"},{"issue":"D1","key":"pcbi.1012545.ref097","doi-asserted-by":"crossref","first-page":"D330","DOI":"10.1093\/nar\/gky1055","article-title":"The Gene Ontology Resource: 20 years and still GOing strong","volume":"47","author":"The Gene Ontology Consortium","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1012545.ref098","volume-title":"Enzyme Nomenclature","author":"(NC-IUBMB) NCotIUoBaMB","year":"1992"},{"key":"pcbi.1012545.ref099","unstructured":"https:\/\/gencovery.com."},{"issue":"1","key":"pcbi.1012545.ref100","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s40323-020-00147-4","article-title":"How to tell the difference between a model and a digital twin","volume":"7","author":"L Wright","year":"2020","journal-title":"Adv Model Simul Eng Sci"},{"key":"pcbi.1012545.ref101","unstructured":"https:\/\/www.ebi.ac.uk\/."},{"key":"pcbi.1012545.ref102","unstructured":"https:\/\/www.ncbi.nlm.nih.gov\/taxonomy."},{"issue":"1","key":"pcbi.1012545.ref103","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1038\/s41598-017-00170-3","article-title":"Robust analysis of fluxes in genome-scale metabolic pathways","volume":"7","author":"M MacGillivray","year":"2017","journal-title":"Sci Rep"},{"issue":"14","key":"pcbi.1012545.ref104","doi-asserted-by":"crossref","first-page":"i548","DOI":"10.1093\/bioinformatics\/btz315","article-title":"Bayesian metabolic flux analysis reveals intracellular flux couplings","volume":"35","author":"M Heinonen","year":"2019","journal-title":"Bioinformatics"},{"issue":"9","key":"pcbi.1012545.ref105","doi-asserted-by":"crossref","first-page":"btad450","DOI":"10.1093\/bioinformatics\/btad450","article-title":"Cardinality optimization in constraint-based modelling: application to human metabolism","volume":"39","author":"RM Fleming","year":"2023","journal-title":"Bioinformatics"},{"key":"pcbi.1012545.ref106","article-title":"editors. Robust flux balance analysis of metabolic networks. Proceedings of the 2011","author":"M Zavlanos","year":"2011","journal-title":"American Control Conference"},{"issue":"8","key":"pcbi.1012545.ref107","doi-asserted-by":"crossref","first-page":"e1003195","DOI":"10.1371\/journal.pcbi.1003195","article-title":"Flux imbalance analysis and the sensitivity of cellular growth to changes in metabolite pools","volume":"9","author":"E Reznik","year":"2013","journal-title":"PLoS Comput Biol"},{"issue":"3","key":"pcbi.1012545.ref108","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1038\/s41587-020-0446-y","article-title":"MEMOTE for standardized genome-scale metabolic model testing","volume":"38","author":"C Lieven","year":"2020","journal-title":"Nat Biotechnol"},{"issue":"4","key":"pcbi.1012545.ref109","first-page":"451","article-title":"In vitro cultivation of Pneumocystis isolated from infected rat lungs","volume":"55","author":"A Sobolewska","year":"2009","journal-title":"Wiad Parazytol"},{"issue":"8","key":"pcbi.1012545.ref110","doi-asserted-by":"crossref","first-page":"2989","DOI":"10.1128\/JCM.40.8.2989-2993.2002","article-title":"Development of a rapid real-time PCR assay for quantitation of Pneumocystis carinii f. sp. carinii","volume":"40","author":"HH Larsen","year":"2002","journal-title":"J Clin Microbiol"},{"key":"pcbi.1012545.ref111","first-page":"1707.06347","article-title":"Proximal Policy Optimization Algorithms2017","author":"J Schulman","journal-title":"arXiv"},{"issue":"268","key":"pcbi.1012545.ref112","first-page":"1","article-title":"Stable-baselines3: reliable reinforcement learning implementations","volume":"22","author":"A Raffin","year":"2021","journal-title":"J Mach Learn Res"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1012545","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,11,7]],"date-time":"2024-11-07T00:00:00Z","timestamp":1730937600000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1012545","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,11,7]],"date-time":"2024-11-07T18:50:32Z","timestamp":1731005432000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1012545"}},"subtitle":[],"editor":[{"given":"Christoph","family":"Kaleta","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,10,28]]},"references-count":112,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2024,10,28]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1012545","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pcbi.1012545","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,28]]}}}