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This knowledge gap often results in difficulties in designing validation experiments, which are usually labor-intensive, expensive to perform, and hard to interpret. Here we propose PHENSIM, a computational tool using a systems biology approach to simulate how cell phenotypes are affected by the activation\/inhibition of one or multiple biomolecules, and it does so by exploiting signaling pathways. Our tool\u2019s applications include predicting the outcome of drug administration, knockdown experiments, gene transduction, and exposure to exosomal cargo. Importantly, PHENSIM enables the user to make inferences on well-defined cell lines and includes pathway maps from three different model organisms. To assess our approach\u2019s reliability, we built a benchmark from transcriptomics data gathered from NCBI GEO and performed four case studies on known biological experiments. Our results show high prediction accuracy, thus highlighting the capabilities of this methodology. PHENSIM standalone Java application is available at\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/github.com\/alaimos\/phensim\" xlink:type=\"simple\">https:\/\/github.com\/alaimos\/phensim<\/jats:ext-link>\n                    , along with all data and source codes for benchmarking. A web-based user interface is accessible at\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/phensim.tech\/\" xlink:type=\"simple\">https:\/\/phensim.tech\/<\/jats:ext-link>\n                    .\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1009069","type":"journal-article","created":{"date-parts":[[2021,6,24]],"date-time":"2021-06-24T13:27:37Z","timestamp":1624541257000},"page":"e1009069","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["PHENSIM: Phenotype Simulator"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4825-7617","authenticated-orcid":true,"given":"Salvatore","family":"Alaimo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosaria 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