{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T00:08:40Z","timestamp":1777421320956,"version":"3.51.4"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1009683","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T00:00:00Z","timestamp":1640217600000}}],"reference-count":58,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2021,12,13]],"date-time":"2021-12-13T00:00:00Z","timestamp":1639353600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL146723"],"award-info":[{"award-number":["R01 HL146723"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL146723 (Diversity Supplement)"],"award-info":[{"award-number":["R01 HL146723 (Diversity Supplement)"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01 HL142518"],"award-info":[{"award-number":["U01 HL142518"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P01 HL134605"],"award-info":[{"award-number":["P01 HL134605"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Thoracic aortopathy\u2013aneurysm, dissection, and rupture\u2013is increasingly responsible for significant morbidity and mortality. Advances in medical genetics and imaging have improved diagnosis and thus enabled earlier prophylactic surgical intervention in many cases. There remains a pressing need, however, to understand better the underlying molecular and cellular mechanisms with the hope of finding robust pharmacotherapies. Diverse studies in patients and mouse models of aortopathy have revealed critical changes in multiple smooth muscle cell signaling pathways that associate with disease, yet integrating information across studies and models has remained challenging. We present a new quantitative network model that includes many of the key smooth muscle cell signaling pathways and validate the model using a detailed data set that focuses on hyperactivation of the mechanistic target of rapamycin (mTOR) pathway and its inhibition using rapamycin. We show that the model can be parameterized to capture the primary experimental findings both qualitatively and quantitatively. We further show that simulating a population of cells by varying receptor reaction weights leads to distinct proteomic clusters within the population, and that these clusters emerge due to a bistable switch driven by positive feedback in the PI3K\/AKT\/mTOR signaling pathway.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1009683","type":"journal-article","created":{"date-parts":[[2021,12,13]],"date-time":"2021-12-13T18:36:31Z","timestamp":1639420591000},"page":"e1009683","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":26,"title":["Roles of mTOR in thoracic aortopathy understood by complex intracellular signaling interactions"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0311-1948","authenticated-orcid":true,"given":"Ana C.","family":"Estrada","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8912-7400","authenticated-orcid":true,"given":"Linda","family":"Irons","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6315-693X","authenticated-orcid":true,"given":"Bruno V.","family":"Rego","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guangxin","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7042-8190","authenticated-orcid":true,"given":"George","family":"Tellides","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1011-2025","authenticated-orcid":true,"given":"Jay D.","family":"Humphrey","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,12,13]]},"reference":[{"issue":"3","key":"pcbi.1009683.ref001","doi-asserted-by":"crossref","first-page":"767","DOI":"10.1152\/physrev.00041.2003","article-title":"Molecular regulation of vascular smooth muscle cell differentiation in development and disease","volume":"84","author":"GK Owens","year":"2004","journal-title":"Physiol Rev"},{"issue":"4","key":"pcbi.1009683.ref002","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1152\/physrev.00003.2017","article-title":"Vascular Smooth Muscle Cells and Arterial Stiffening: Relevance in Development, Aging, and Disease","volume":"97","author":"P Lacolley","year":"2017","journal-title":"Physiol Rev"},{"issue":"9","key":"pcbi.1009683.ref003","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1053\/hupa.2001.27107","article-title":"Smooth muscle cells of the media in the dilatative pathology of ascending thoracic aorta: Morphology, immunoreactivity for osteopontin, matrix metalloproteinases, and their inhibitors","volume":"32","author":"V Lesauskaite","year":"2001","journal-title":"Hum Pathol"},{"issue":"1","key":"pcbi.1009683.ref004","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1146\/annurev.genom.8.080706.092303","article-title":"Genetic Basis of Thoracic Aortic Aneurysms and Dissections: Focus on Smooth Muscle Cell Contractile Dysfunction","volume":"9","author":"DM Milewicz","year":"2008","journal-title":"Annu Rev Genomics Hum Genet"},{"issue":"2","key":"pcbi.1009683.ref005","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3390\/genes12020183","article-title":"Insights on the Pathogenesis of Aneurysm through the Study of Hereditary Aortopathies","volume":"12","author":"TJ Creamer","year":"2021","journal-title":"Genes (Basel)"},{"key":"pcbi.1009683.ref006","first-page":"1448","volume-title":"Circulation Research","author":"JD Humphrey","year":"2015"},{"issue":"9","key":"pcbi.1009683.ref007","doi-asserted-by":"crossref","first-page":"5630","DOI":"10.1074\/jbc.M806962200","article-title":"p38 MAPK is an early determinant of promiscuous Smad2\/3 signaling in the aortas of fibrillin-1 (Fbn1)-null mice","volume":"284","author":"L Carta","year":"2009","journal-title":"J Biol Chem"},{"issue":"2","key":"pcbi.1009683.ref008","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1172\/JCI69942","article-title":"Tgfbr2 disruption in postnatal smooth muscle impairs aortic wall homeostasis","volume":"124","author":"W Li","year":"2014","journal-title":"J Clin Invest"},{"issue":"1","key":"pcbi.1009683.ref009","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1161\/ATVBAHA.116.303229","article-title":"Altered Smooth Muscle Cell Force Generation as a Driver of Thoracic Aortic Aneurysms and Dissections","volume":"37","author":"DM Milewicz","year":"2017","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"3","key":"pcbi.1009683.ref010","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1172\/JCI131048","article-title":"Chronic mTOR activation induces a degradative smooth muscle cell phenotype","volume":"130","author":"G Li","year":"2020","journal-title":"J Clin Invest"},{"key":"pcbi.1009683.ref011","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1146\/annurev-med-100415-022956","article-title":"Therapeutics Targeting Drivers of Thoracic Aortic Aneurysms and Acute Aortic Dissections: Insights from Predisposing Genes and Mouse Models","volume":"68","author":"DM Milewicz","year":"2017","journal-title":"Annu Rev Med"},{"issue":"1","key":"pcbi.1009683.ref012","doi-asserted-by":"crossref","first-page":"H169","DOI":"10.1152\/ajpheart.00205.2018","article-title":"Central artery stiffness and thoracic aortopathy","volume":"316","author":"JD Humphrey","year":"2019","journal-title":"Am J Physiol Heart Circ Physiol"},{"issue":"130","key":"pcbi.1009683.ref013","doi-asserted-by":"crossref","DOI":"10.1098\/rsif.2016.1036","article-title":"Comparison of 10 murine models reveals a distinct biomechanical phenotype in thoracic aortic aneurysms","volume":"14","author":"C Bellini","year":"2017","journal-title":"J R Soc Interface"},{"key":"pcbi.1009683.ref014","doi-asserted-by":"crossref","unstructured":"Cuomo F, Ferruzzi J, Agarwal P, Li C, Zhuang ZW, Humphrey JD, et al. Sex-dependent differences in central artery haemodynamics in normal and fibulin-5 deficient mice: implications for ageing. Proceedings Math Phys Eng Sci [Internet]. 2019 Jan 1;475(2221). Available from: \/pmc\/articles\/PMC6364598\/","DOI":"10.1098\/rspa.2018.0076"},{"issue":"10","key":"pcbi.1009683.ref015","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1008273","article-title":"Numerical knockouts-In silico assessment of factors predisposing to thoracic aortic aneurysms","volume":"16","author":"M Latorre","year":"2020","journal-title":"PLoS Comput Biol"},{"issue":"7","key":"pcbi.1009683.ref016","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1007\/s10439-020-02713-8","article-title":"From Transcript to Tissue: Multiscale Modeling from Cell Signaling to Matrix Remodeling","volume":"49","author":"L Irons","year":"2021","journal-title":"Ann Biomed Eng"},{"issue":"1","key":"pcbi.1009683.ref017","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/ng1494","article-title":"Dysregulation of the TSC-mTOR pathway in human disease","volume":"37","author":"K Inoki","year":"2005","journal-title":"Nat Genet"},{"issue":"5","key":"pcbi.1009683.ref018","first-page":"476","article-title":"Mammalian target of rapamycin: a central node of complex signaling cascades","volume":"4","author":"Y Dobashi","year":"2011","journal-title":"Int J Clin Exp Pathol"},{"key":"pcbi.1009683.ref019","first-page":"1","article-title":"Recent insights into the pathophysiology of mTOR pathway dysregulation","volume":"6","author":"SB Gitto","year":"2015","journal-title":"Res Rep Biol"},{"issue":"1","key":"pcbi.1009683.ref020","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.atherosclerosis.2006.11.023","article-title":"Sirolimus blocks the accumulation of hyaluronan (HA) by arterial smooth muscle cells and reduces monocyte adhesion to the ECM","volume":"195","author":"Y Gou\u00ebffic","year":"2007","journal-title":"Atherosclerosis"},{"key":"pcbi.1009683.ref021","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.yjmcc.2016.01.016","article-title":"Polymerase delta-interacting protein 2 regulates collagen accumulation via activation of the Akt\/mTOR pathway in vascular smooth muscle cells","volume":"92","author":"M Fujii","year":"2016","journal-title":"J Mol Cell Cardiol"},{"issue":"10","key":"pcbi.1009683.ref022","doi-asserted-by":"crossref","first-page":"1908","DOI":"10.1093\/hmg\/ddq066","article-title":"Thoracic aortic disease in tuberous sclerosis complex: molecular pathogenesis and potential therapies in Tsc2+\/- mice","volume":"19","author":"J Cao","year":"2010","journal-title":"Hum Mol Genet"},{"issue":"11","key":"pcbi.1009683.ref023","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: a software environment for integrated models of biomolecular interaction networks","volume":"13","author":"P Shannon","year":"2003","journal-title":"Genome Res"},{"issue":"8","key":"pcbi.1009683.ref024","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1016\/j.cub.2007.03.016","article-title":"Positive-feedback loops as a flexible biological module","volume":"17","author":"NT Ingolia","year":"2007","journal-title":"Curr Biol"},{"issue":"4","key":"pcbi.1009683.ref025","article-title":"The combination of positive and negative feedback loops confers exquisite flexibility to biochemical switches. Phys Biol","volume":"6","author":"B Pfeuty","year":"2009","journal-title":"Internet]"},{"issue":"2","key":"pcbi.1009683.ref026","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.jvs.2004.05.020","article-title":"Rapamycin suppresses experimental aortic aneurysm growth","volume":"40","author":"DM Lawrence","year":"2004","journal-title":"J Vasc Surg"},{"issue":"5","key":"pcbi.1009683.ref027","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.ejvs.2014.02.006","article-title":"Rapamycin Limits the Growth of Established Experimental Abdominal Aortic Aneurysms","volume":"47","author":"M Rouer","year":"2014","journal-title":"Eur J Vasc Endovasc Surg"},{"key":"pcbi.1009683.ref028","doi-asserted-by":"crossref","first-page":"1110","DOI":"10.1152\/ajpheart.00677.2016","article-title":"Inhibition of the mTOR pathway in abdominal aortic aneurysm: implications of smooth muscle cell contractile phenotype, inflammation, and aneurysm expansion","volume":"312","author":"G Li","year":"2017","journal-title":"Am J Physiol Hear Circ Physiol"},{"issue":"4","key":"pcbi.1009683.ref029","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1161\/ATVBAHA.112.301006","article-title":"Everolimus Limits Aortic Aneurysm in the Apolipoprotein E\u2013Deficient Mouse by Downregulating C-C Chemokine Receptor 2 Positive Monocytes","volume":"33","author":"CS Moran","year":"2013","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"1","key":"pcbi.1009683.ref030","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s11596-018-1851-z","article-title":"Rapamycin Treatment Attenuates Angiotensin II -induced Abdominal Aortic Aneurysm Formation via VSMC Phenotypic Modulation and Down-regulation of ERK1\/2 Activity","volume":"38","author":"F Li","year":"2018","journal-title":"Curr Med Sci"},{"issue":"3","key":"pcbi.1009683.ref031","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1016\/j.jvs.2018.05.246","article-title":"Rapamycin prevents thoracic aortic aneurysm and dissection in mice","volume":"69","author":"B Zhou","year":"2019","journal-title":"J Vasc Surg"},{"issue":"9","key":"pcbi.1009683.ref032","doi-asserted-by":"crossref","first-page":"3341","DOI":"10.3390\/ijms21093341","article-title":"Therapeutic Effect of Rapamycin on Aortic Dissection in Mice","volume":"21","author":"M Hayashi-Hori","year":"2020","journal-title":"Int J Mol SciInternet]"},{"issue":"3","key":"pcbi.1009683.ref033","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.bbrc.2019.03.083","article-title":"Rapamycin attenuates a murine model of thoracic aortic aneurysm by downregulating the miR-126\u20133p mediated activation of MAPK\/ERK signalling pathway","volume":"512","author":"M Liu","year":"2019","journal-title":"Biochem Biophys Res Commun"},{"issue":"5","key":"pcbi.1009683.ref034","doi-asserted-by":"crossref","first-page":"H1112","DOI":"10.1152\/ajpheart.00089.2018","article-title":"Proteomics reveals Rictor as a noncanonical TGF-\u03b2 signaling target during aneurysm progression in Marfan mice","volume":"315","author":"SJ Parker","year":"2018","journal-title":"Am J Physiol Heart Circ Physiol"},{"issue":"5","key":"pcbi.1009683.ref035","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1161\/ATVBAHA.116.307436","article-title":"Pharmacologically Improved Contractility Protects Against Aortic Dissection in Mice With Disrupted Transforming Growth Factor-\u03b2 Signaling Despite Compromised Extracellular Matrix Properties","volume":"36","author":"J Ferruzzi","year":"2016","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"3","key":"pcbi.1009683.ref036","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1161\/01.RES.76.3.412","article-title":"Rapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells","volume":"76","author":"SO Marx","year":"1995","journal-title":"Circ Res"},{"issue":"10","key":"pcbi.1009683.ref037","doi-asserted-by":"crossref","first-page":"2277","DOI":"10.1172\/JCI119038","article-title":"Rapamycin inhibits vascular smooth muscle cell migration","volume":"98","author":"M Poon","year":"1996","journal-title":"J Clin Invest"},{"issue":"3","key":"pcbi.1009683.ref038","doi-asserted-by":"crossref","DOI":"10.1152\/ajpcell.00201.2003","article-title":"The mTOR\/p70 S6K1 pathway regulates vascular smooth muscle cell differentiation","volume":"286","author":"KA Martin","year":"2004","journal-title":"Am J Physiol\u2014Cell Physiol"},{"issue":"49","key":"pcbi.1009683.ref039","doi-asserted-by":"crossref","first-page":"36112","DOI":"10.1074\/jbc.M703914200","article-title":"Rapamycin Promotes Vascular Smooth Muscle Cell Differentiation through Insulin Receptor Substrate-1\/Phosphatidylinositol 3-Kinase\/Akt2 Feedback Signaling *","volume":"282","author":"KA Martin","year":"2007","journal-title":"J Biol Chem"},{"issue":"9","key":"pcbi.1009683.ref040","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1161\/ATVBAHA.117.309653","article-title":"mTOR (Mechanistic Target of Rapamycin) Inhibition Decreases Mechanosignaling, Collagen Accumulation, and Stiffening of the Thoracic Aorta in Elastin-Deficient Mice","volume":"37","author":"Y Jiao","year":"2017","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"1","key":"pcbi.1009683.ref041","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-020-69267-6","article-title":"\u03b21 integrin, ILK and mTOR regulate collagen synthesis in mechanically loaded tendon cells","volume":"10","author":"R Mousavizadeh","year":"2020","journal-title":"Sci Rep"},{"issue":"6","key":"pcbi.1009683.ref042","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1161\/CIRCRESAHA.110.239343","article-title":"Aortic aneurysm generation in mice with targeted deletion of integrin-linked kinase in vascular smooth muscle cells","volume":"109","author":"D Shen","year":"2011","journal-title":"Circ Res"},{"issue":"5","key":"pcbi.1009683.ref043","first-page":"1205","article-title":"Deletion of integrin-linked kinase from neural crest cells in mice results in aortic aneurysms and embryonic lethality","volume":"6","author":"TD Arnold","year":"2013","journal-title":"Dis Model Mech"},{"issue":"21","key":"pcbi.1009683.ref044","doi-asserted-by":"crossref","first-page":"2731","DOI":"10.1161\/CIRCULATIONAHA.106.653980","article-title":"Biglycan deficiency causes spontaneous aortic dissection and rupture in mice","volume":"115","author":"A-M Heegaard","year":"2007","journal-title":"Circulation"},{"key":"pcbi.1009683.ref045","doi-asserted-by":"crossref","first-page":"104264","DOI":"10.1016\/j.jmbbm.2020.104264","article-title":"Adventitial remodeling protects against aortic rupture following late smooth muscle-specific disruption of TGF\u03b2 signaling","volume":"116","author":"Y Kawamura","year":"2021","journal-title":"J Mech Behav Biomed Mater"},{"issue":"6","key":"pcbi.1009683.ref046","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/s41569-019-0155-8","article-title":"Mechanical regulation of gene expression in cardiac myocytes and fibroblasts","volume":"16","author":"JJ Saucerman","year":"2019","journal-title":"Nat Rev Cardiol"},{"key":"pcbi.1009683.ref047","doi-asserted-by":"crossref","first-page":"2195","DOI":"10.1161\/ATVBAHA.120.314670","article-title":"Single-Cell Transcriptomic Profiling of Vascular Smooth Muscle Cell Phenotype Modulation in Marfan Syndrome Aortic Aneurysm","volume":"40","author":"AJ Pedroza","year":"2020","journal-title":"Arterioscler Thromb Vasc Biol"},{"issue":"7","key":"pcbi.1009683.ref048","article-title":"Computational Analysis of mTOR Signaling Pathway: Bifurcation, Carcinogenesis, and Drug Discovery","volume":"30","author":"G Wang","year":"2010","journal-title":"Anticancer Res"},{"issue":"11","key":"pcbi.1009683.ref049","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1038\/nrd2381","article-title":"Proteins, drug targets and the mechanisms they control: The simple truth about complex networks","volume":"6","author":"RP Araujo","year":"2007","journal-title":"Nat Rev Drug Discov"},{"issue":"1","key":"pcbi.1009683.ref050","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-017-18400-z","article-title":"Dynamic modelling of the mTOR signalling network reveals complex emergent behaviours conferred by DEPTOR","volume":"8","author":"TM Varusai","year":"2018","journal-title":"Sci Rep"},{"issue":"2173","key":"pcbi.1009683.ref051","article-title":"Quantification of model and data uncertainty in a network analysis of cardiac myocyte mechanosignalling","volume":"378","author":"S Cao","year":"2020","journal-title":"Philos Trans R Soc A"},{"key":"pcbi.1009683.ref052","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.coisb.2019.10.006","article-title":"Parameter estimation and uncertainty quantification for systems biology models","volume":"18","author":"ED Mitra","year":"2019","journal-title":"Curr Opin Syst Biol"},{"key":"pcbi.1009683.ref053","first-page":"2021.08.02.454803","article-title":"Uncertainty quantification in subject-specific estimation of local vessel mechanical properties","author":"V. Rego B","year":"2021","journal-title":"bioRxiv"},{"issue":"1","key":"pcbi.1009683.ref054","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1752-0509-4-157","article-title":"Modeling cardiac \u03b2-adrenergic signaling with normalized-Hill differential equations: comparison with a biochemical model","volume":"4","author":"MJ Kraeutler","year":"2010","journal-title":"BMC Syst Biol"},{"issue":"3","key":"pcbi.1009683.ref055","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1113\/jphysiol.1910.sp001366","article-title":"A new mathematical treatment of changes of ionic concentration in muscle and nerve under the action of electric currents, with a theory as to their mode of excitation","volume":"40","author":"A V. Hill","year":"1910","journal-title":"J Physiol"},{"issue":"15","key":"pcbi.1009683.ref056","doi-asserted-by":"crossref","first-page":"3216","DOI":"10.1021\/bi902202q","article-title":"Logic-based models for the analysis of cell signaling networks","volume":"49","author":"MK Morris","year":"2010","journal-title":"Biochemistry"},{"issue":"8","key":"pcbi.1009683.ref057","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1008161","article-title":"Cell signaling model for arterial mechanobiology","volume":"16","author":"L Irons","year":"2020","journal-title":"PLoS Comput Biol"},{"issue":"2","key":"pcbi.1009683.ref058","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1080\/13873950701742754","article-title":"New features of the software MatCont for bifurcation analysis of dynamical systems","volume":"14","author":"A Dhooge","year":"2008","journal-title":"Math Comput Model Dyn Syst"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1009683","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T00:00:00Z","timestamp":1640217600000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009683","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,23]],"date-time":"2021-12-23T18:59:01Z","timestamp":1640285941000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1009683"}},"subtitle":[],"editor":[{"given":"James R.","family":"Faeder","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2021,12,13]]},"references-count":58,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12,13]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1009683","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pcbi.1009683","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,13]]}}}