{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,27]],"date-time":"2026-03-27T18:59:24Z","timestamp":1774637964472,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1010383","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,9,12]],"date-time":"2022-09-12T00:00:00Z","timestamp":1662940800000}}],"reference-count":101,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2022,8,22]],"date-time":"2022-08-22T00:00:00Z","timestamp":1661126400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["3212070002\/TP2"],"award-info":[{"award-number":["3212070002\/TP2"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["259130777-SFB 1177"],"award-info":[{"award-number":["259130777-SFB 1177"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"name":"LOEWE Zentrum Ubiquitin Networks","award":["20120712\/B4"],"award-info":[{"award-number":["20120712\/B4"]}]},{"DOI":"10.13039\/501100003495","name":"Hessisches Ministerium f\u00fcr Wissenschaft und Kunst","doi-asserted-by":"publisher","award":["ACLF-I (Acute Liver Failure - Initiative)"],"award-info":[{"award-number":["ACLF-I (Acute Liver Failure - Initiative)"]}],"id":[{"id":"10.13039\/501100003495","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003495","name":"Hessisches Ministerium f\u00fcr Wissenschaft und Kunst","doi-asserted-by":"publisher","award":["ENABLE 2995\/1502\/11"],"award-info":[{"award-number":["ENABLE 2995\/1502\/11"]}],"id":[{"id":"10.13039\/501100003495","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005687","name":"Goethe-Universit\u00e4t Frankfurt am Main","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005687","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>The paper describes a mathematical model of the molecular switches of cell survival, apoptosis, and necroptosis in cellular signaling pathways initiated by tumor necrosis factor 1. Based on experimental findings in the literature, we constructed a Petri net model based on detailed molecular reactions of the molecular players, protein complexes, post-translational modifications, and cross talk. The model comprises 118 biochemical entities, 130 reactions, and 299 edges. We verified the model by evaluating invariant properties of the system at steady state and by <jats:italic>in silico<\/jats:italic> knockout analysis. Applying Petri net analysis techniques, we found 279 pathways, which describe signal flows from receptor activation to cellular response, representing the combinatorial diversity of functional pathways.120 pathways steered the cell to survival, whereas 58 and 35 pathways led to apoptosis and necroptosis, respectively. For 65 pathways, the triggered response was not deterministic and led to multiple possible outcomes. We investigated the <jats:italic>in silico<\/jats:italic> knockout behavior and identified important checkpoints of the TNFR1 signaling pathway in terms of ubiquitination within complex I and the gene expression dependent on NF-\u03baB, which controls the caspase activity in complex II and apoptosis induction. Despite not knowing enough kinetic data of sufficient quality, we estimated system\u2019s dynamics using a discrete, semi-quantitative Petri net model.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1010383","type":"journal-article","created":{"date-parts":[[2022,8,22]],"date-time":"2022-08-22T17:42:33Z","timestamp":1661190153000},"page":"e1010383","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["Mathematical modeling of the molecular switch of TNFR1-mediated signaling pathways applying Petri net formalism and in silico knockout analysis"],"prefix":"10.1371","volume":"18","author":[{"given":"Leonie K.","family":"Amstein","sequence":"first","affiliation":[]},{"given":"J\u00f6rg","family":"Ackermann","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2789-5540","authenticated-orcid":true,"given":"Jennifer","family":"Hannig","sequence":"additional","affiliation":[]},{"given":"Ivan","family":"\u0110iki\u0107","sequence":"additional","affiliation":[]},{"given":"Simone","family":"Fulda","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3621-003X","authenticated-orcid":true,"given":"Ina","family":"Koch","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,8,22]]},"reference":[{"key":"pcbi.1010383.ref001","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1017\/CBO9780511976094.003","volume-title":"Apoptosis: Physiology and Pathology","author":"H Walczak","year":"2011"},{"key":"pcbi.1010383.ref002","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1111\/j.1600-065X.2011.01066.x","article-title":"TNF and ubiquitin at the crossroads of gene activation, cell death, inflammation, and cancer","volume":"244","author":"H. 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