{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T08:50:23Z","timestamp":1782982223698,"version":"3.54.5"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1008490","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,1,4]],"date-time":"2021-01-04T00:00:00Z","timestamp":1609718400000}}],"reference-count":84,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2020,12,18]],"date-time":"2020-12-18T00:00:00Z","timestamp":1608249600000},"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":["HL137755"],"award-info":[{"award-number":["HL137755"]}],"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":["HL137100"],"award-info":[{"award-number":["HL137100"]}],"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":["HL127624"],"award-info":[{"award-number":["HL127624"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["1252854"],"award-info":[{"award-number":["1252854"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Cardiac hypertrophy is a context-dependent phenomenon wherein a myriad of biochemical and biomechanical factors regulate myocardial growth through a complex large-scale signaling network. Although numerous studies have investigated hypertrophic signaling pathways, less is known about hypertrophy signaling as a whole network and how this network acts in a context-dependent manner. Here, we developed a systematic approach, CLASSED (Context-specific Logic-bASed Signaling nEtwork Development), to revise a large-scale signaling model based on context-specific data and identify main reactions and new crosstalks regulating context-specific response. CLASSED involves four sequential stages with an automated validation module as a core which builds a logic-based ODE model from the interaction graph and outputs the model validation percent. The context-specific model is developed by estimation of default parameters, classified qualitative validation, hybrid Morris-Sobol global sensitivity analysis, and discovery of missing context-dependent crosstalks. Applying this pipeline to our prior-knowledge hypertrophy network with context-specific data revealed key signaling reactions which distinctly regulate cell response to isoproterenol, phenylephrine, angiotensin II and stretch. Furthermore, with CLASSED we developed a context-specific model of \u03b2-adrenergic cardiac hypertrophy. The model predicted new crosstalks between calcium\/calmodulin-dependent pathways and upstream signaling of Ras in the ISO-specific context. Experiments in cardiomyocytes validated the model\u2019s predictions on the role of CaMKII-G\u03b2\u03b3 and CaN-G\u03b2\u03b3 interactions in mediating hypertrophic signals in ISO-specific context and revealed a difference in the phosphorylation magnitude and translocation of ERK1\/2 between cardiac myocytes and fibroblasts. CLASSED is a systematic approach for developing context-specific large-scale signaling networks, yielding insights into new-found crosstalks in \u03b2-adrenergic cardiac hypertrophy.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1008490","type":"journal-article","created":{"date-parts":[[2020,12,18]],"date-time":"2020-12-18T19:31:47Z","timestamp":1608319907000},"page":"e1008490","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":28,"title":["Context-specific network modeling identifies new crosstalk in \u03b2-adrenergic cardiac hypertrophy"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9318-8433","authenticated-orcid":true,"given":"Ali","family":"Khalilimeybodi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8092-8105","authenticated-orcid":true,"given":"Alexander M.","family":"Paap","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0168-4881","authenticated-orcid":true,"given":"Steven L. 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