{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:07:31Z","timestamp":1753891651108,"version":"3.41.2"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T00:00:00Z","timestamp":1747094400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000774","name":"Defense Threat Reduction Agency","doi-asserted-by":"publisher","award":["HDTRA1-23-1-0009"],"award-info":[{"award-number":["HDTRA1-23-1-0009"]}],"id":[{"id":"10.13039\/100000774","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Comput. Neurosci."],"abstract":"<jats:p>Venezuelan, eastern, and western equine encephalitis viruses (collectively referred to as equine encephalitis viruses---EEV) cause serious neurological diseases and pose a significant threat to the civilian population and the warfighter. Likewise, organophosphorus nerve agents (OPNA) are highly toxic chemicals that pose serious health threats of neurological deficits to both military and civilian personnel around the world. Consequently, only a select few approved research groups are permitted to study these dangerous chemical and biological warfare agents. This has created a significant gap in our scientific understanding of the mechanisms underlying neurological diseases. Valuable insights may be gleaned by drawing parallels to other extensively researched neuropathologies, such as traumatic brain injuries (TBI). By examining combined gene expression profiles, common and unique molecular characteristics may be discovered, providing new insights into medical countermeasures (MCMs) for TBI, EEV infection and OPNA neuropathologies and sequelae. In this study, we collected transcriptomic datasets for neurological disorders caused by TBI, EEV, and OPNA injury, and implemented a framework to normalize and integrate gene expression datasets derived from various platforms. Effective machine learning approaches were developed to identify critical genes that are either shared by or distinctive among the three neuropathologies. With the aid of deep neural networks, we were able to extract important association signals for accurate prediction of different neurological disorders by using integrated gene expression datasets of VEEV, OPNA, and TBI samples. Gene ontology and pathway analyses further identified neuropathologic features with specific gene product attributes and functions, shedding light on the fundamental biology of these neurological disorders. Collectively, we highlight a workflow to analyze published transcriptomic data using machine learning, which can be used for both identification of gene biomarkers that are unique to specific neurological conditions, as well as genes shared across multiple neuropathologies. These shared genes could serve as potential neuroprotective drug targets for conditions like EEV, TBI, and OPNA.<\/jats:p>","DOI":"10.3389\/fncom.2025.1529902","type":"journal-article","created":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T05:30:14Z","timestamp":1747114214000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Machine learning identifies genes linked to neurological disorders induced by equine encephalitis viruses, traumatic brain injuries, and organophosphorus nerve agents"],"prefix":"10.3389","volume":"19","author":[{"given":"Liduo","family":"Yin","sequence":"first","affiliation":[]},{"given":"Morgen","family":"VanderGiessen","sequence":"additional","affiliation":[]},{"given":"Vinoth","family":"Kumar","sequence":"additional","affiliation":[]},{"given":"Benjamin","family":"Conacher","sequence":"additional","affiliation":[]},{"given":"Po-Chien Haku","family":"Chao","sequence":"additional","affiliation":[]},{"given":"Michelle","family":"Theus","sequence":"additional","affiliation":[]},{"given":"Erik","family":"Johnson","sequence":"additional","affiliation":[]},{"given":"Kylene","family":"Kehn-Hall","sequence":"additional","affiliation":[]},{"given":"Xiaowei","family":"Wu","sequence":"additional","affiliation":[]},{"given":"Hehuang","family":"Xie","sequence":"additional","affiliation":[]}],"member":"1965","published-online":{"date-parts":[[2025,5,13]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"721","DOI":"10.2217\/fvl.11.50","article-title":"Endemic Venezuelan equine encephalitis in the Americas: hidden under the dengue umbrella","volume":"6","author":"Aguilar","year":"2011","journal-title":"Future Virol."},{"key":"ref2","article-title":"How can biomarkers be used to differentiate between infection and non-infectious causes of inflammation?","volume-title":"Evid. Based Pract. Crit. Care","author":"Alexandra Binnie","year":"2019"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"866","DOI":"10.3390\/toxics11100866","article-title":"Mechanisms of organophosphate toxicity and the role of acetylcholinesterase inhibition","volume":"11","author":"Aroniadou-Anderjaska","year":"2023","journal-title":"Toxics"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1186\/s40478-024-01845-5","article-title":"Organoids and chimeras: the hopeful fusion transforming traumatic brain injury research","volume":"12","author":"Bellotti","year":"2024","journal-title":"Acta Neuropathol. Commun."},{"key":"ref5","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1186\/s12974-023-02960-1","article-title":"Post-exposure intranasal IFNalpha suppresses replication and neuroinvasion of Venezuelan equine encephalitis virus within olfactory sensory neurons","volume":"21","author":"Cain","year":"2024","journal-title":"J. Neuroinflammation"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.virol.2019.10.016","article-title":"EGR1 upregulation following Venezuelan equine encephalitis virus infection is regulated by ERK and PERK pathways contributing to cell death","volume":"539","author":"Dahal","year":"2020","journal-title":"Virology"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"1080","DOI":"10.3171\/2017.10.JNS17352","article-title":"Estimating the global incidence of traumatic brain injury","volume":"130","author":"Dewan","year":"2019","journal-title":"J. Neurosurg."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"1167","DOI":"10.3390\/biomedicines10051167","article-title":"Long-term anxiety-like behavior and microbiota changes induced in mice by sublethal doses of acute sarin surrogate exposure","volume":"10","author":"Francois","year":"2022","journal-title":"Biomedicines"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.3390\/biology12081139","article-title":"Cellular and molecular pathophysiology of traumatic brain injury: what have we learned so far?","volume":"12","author":"Freire","year":"2023","journal-title":"Biology (Basel)"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1186\/s12941-020-00360-4","article-title":"Venezuelan equine encephalitis virus: the problem is not over for tropical America","volume":"19","author":"Guzman-Teran","year":"2020","journal-title":"Ann. Clin. Microbiol. Antimicrob."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"154","DOI":"10.1186\/s12985-015-0385-2","article-title":"Eastern equine encephalitis virus in mice II: pathogenesis is dependent on route of exposure","volume":"12","author":"Honnold","year":"2015","journal-title":"Virol. J."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1016\/j.biopsych.2021.09.024","article-title":"Mental health consequences of traumatic brain injury","volume":"91","author":"Howlett","year":"2022","journal-title":"Biol. Psychiatry"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"872609","DOI":"10.3389\/fnins.2022.872609","article-title":"Advanced neuroimaging role in traumatic brain injury: a narrative review","volume":"16","author":"Hu","year":"2022","journal-title":"Front. Neurosci."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"1886","DOI":"10.3201\/eid2707.210315","article-title":"Fatal human infection with evidence of Intrahost variation of eastern equine encephalitis virus, Alabama, USA, 2019","volume":"27","author":"Hughes","year":"2021","journal-title":"Emerg. Infect. Dis."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"2919","DOI":"10.1080\/01431160110107743","article-title":"The role of feature selection in artificial neural network applications","volume":"23","author":"Kavzoglu","year":"2002","journal-title":"Int. J. Remote Sens."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"1456083","DOI":"10.3389\/fimmu.2024.1456083","article-title":"Identification of novel biomarkers, shared molecular signatures and immune cell infiltration in heart and kidney failure by transcriptomics","volume":"15","author":"Long","year":"2024","journal-title":"Front. Immunol."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.cveq.2022.11.007","article-title":"Eastern, Western, and Venezuelan equine encephalitis and West Nile viruses","volume":"39","author":"Luethy","year":"2023","journal-title":"Vet. Clin. N. Am. Equine Pract."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"eabn4776","DOI":"10.1126\/sciadv.abn4776","article-title":"Machine learning reveals distinct gene signature profiles in lesional and nonlesional regions of inflammatory skin diseases","volume":"8","author":"Martinez","year":"2022","journal-title":"Sci. Adv."},{"year":"1993","author":"Masters","key":"ref19"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"2761","DOI":"10.1089\/neu.2012.2498","article-title":"Repetitive mild traumatic brain injury in a mouse model produces learning and memory deficits accompanied by histological changes","volume":"29","author":"Mouzon","year":"2012","journal-title":"J. Neurotrauma"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1212\/CPJ.0000000000000641","article-title":"Therapy for acute nerve agent poisoning: an update","volume":"9","author":"Newmark","year":"2019","journal-title":"Neurol. Clin. Pract."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"528","DOI":"10.3389\/fncel.2019.00528","article-title":"Traumatic brain injuries: pathophysiology and potential therapeutic targets","volume":"13","author":"Ng","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1124\/jpet.123.001816","article-title":"Neurosteroids as novel anticonvulsants for refractory status epilepticus and medical countermeasures for nerve agents: a 15-year journey to bring ganaxolone from bench to clinic","volume":"388","author":"Reddy","year":"2024","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"e47","DOI":"10.1093\/nar\/gkv007","article-title":"Limma powers differential expression analyses for RNA-sequencing and microarray studies","volume":"43","author":"Ritchie","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"959","DOI":"10.3389\/fmicb.2016.00959","article-title":"Neurological sequelae resulting from encephalitic alphavirus infection","volume":"7","author":"Ronca","year":"2016","journal-title":"Front. Microbiol."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"188","DOI":"10.3389\/fmicb.2017.00188","article-title":"Mouse model of neurological complications resulting from encephalitic alphavirus infection","volume":"8","author":"Ronca","year":"2017","journal-title":"Front. Microbiol."},{"year":"2023","author":"Saalbach","key":"ref27"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"e02731","DOI":"10.1128\/mBio.02731-19","article-title":"Encephalitic alphaviruses exploit Caveola-mediated Transcytosis at the blood-brain barrier for central nervous system entry","volume":"11","author":"Salimi","year":"2020","journal-title":"MBio"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"W216","DOI":"10.1093\/nar\/gkac194","article-title":"DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update)","volume":"50","author":"Sherman","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref30","first-page":"5595","article-title":"A novel quick seizure detection and localization through brain data mining on ECoG dataset","volume-title":"Neural. Comput. & Applic.","author":"Siddiqui","year":"2019"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"1491","DOI":"10.1007\/s12008-020-00715-3","article-title":"Machine learning based novel cost-sensitive seizure detection classifier for imbalanced EEG data sets","volume":"14","author":"Siddiqui","year":"2020","journal-title":"Int. J. Interact. Des. Manuf. (IJIDeM)"},{"year":"2016","author":"Siddiqui","key":"ref32"},{"key":"ref33","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-319-69179-4_27","article-title":"Analyzing performance of classification techniques in detecting epileptic seizure","volume-title":"Advanced data mining and applications. ADMA 2017. Lecture notes in computer science, vol 10604","author":"Siddiqui","year":"2017"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s40708-020-00105-1","article-title":"A review of epileptic seizure detection using machine learning classifiers","volume":"7","author":"Siddiqui","year":"2020","journal-title":"Brain Inform."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"4940","DOI":"10.3389\/fnins.2024.1514940","article-title":"Neurological manifestations of encephalitic alphaviruses, traumatic brain injuries, and organophosphorus nerve agent exposure","volume":"18","author":"VanderGiessen","year":"2024","journal-title":"Front. Neurosci."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1186\/s12974-023-02847-1","article-title":"Disease-modifying effects of a glial-targeted inducible nitric oxide synthase inhibitor (1400W) in mixed-sex cohorts of a rat soman (GD) model of epilepsy","volume":"20","author":"Vasanthi","year":"2023","journal-title":"J. Neuroinflammation"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"439","DOI":"10.3390\/toxics10080439","article-title":"Current Progress for retrospective identification of nerve agent biomarkers in biological samples after exposure","volume":"10","author":"Wang","year":"2022","journal-title":"Toxics"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"2275","DOI":"10.1007\/s00204-020-02797-0","article-title":"Organophosphorus compounds and oximes: a critical review","volume":"94","author":"Worek","year":"2020","journal-title":"Arch. Toxicol."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/j.vetmic.2009.08.023","article-title":"Encephalitic alphaviruses","volume":"140","author":"Zacks","year":"2010","journal-title":"Vet. Microbiol."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"lqaa078","DOI":"10.1093\/nargab\/lqaa078","article-title":"ComBat-seq: batch effect adjustment for RNA-seq count data","volume":"2","author":"Zhang","year":"2020","journal-title":"NAR Genom. Bioinform."}],"container-title":["Frontiers in Computational Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncom.2025.1529902\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,13]],"date-time":"2025-05-13T05:30:17Z","timestamp":1747114217000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fncom.2025.1529902\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,13]]},"references-count":40,"alternative-id":["10.3389\/fncom.2025.1529902"],"URL":"https:\/\/doi.org\/10.3389\/fncom.2025.1529902","relation":{},"ISSN":["1662-5188"],"issn-type":[{"type":"electronic","value":"1662-5188"}],"subject":[],"published":{"date-parts":[[2025,5,13]]},"article-number":"1529902"}}