{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T15:03:21Z","timestamp":1780412601711,"version":"3.54.1"},"reference-count":59,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2024,4,26]],"date-time":"2024-04-26T00:00:00Z","timestamp":1714089600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01 AI154242"],"award-info":[{"award-number":["R01 AI154242"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32GM136615"],"award-info":[{"award-number":["T32GM136615"]}],"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>With the generation of spatially resolved transcriptomics of microbial biofilms, computational tools can be used to integrate this data to elucidate the multi-scale mechanisms controlling heterogeneous biofilm metabolism. This work presents a Multi-scale model of Metabolism In Cellular Systems (MiMICS) which is a computational framework that couples a genome-scale metabolic network reconstruction (GENRE) with Hybrid Automata Library (HAL), an existing agent-based model and reaction-diffusion model platform. A key feature of MiMICS is the ability to incorporate multiple -omics-guided metabolic models, which can represent unique metabolic states that yield different metabolic parameter values passed to the extracellular models. We used MiMICS to simulate <jats:italic>Pseudomonas aeruginosa<\/jats:italic> regulation of denitrification and oxidative stress metabolism in hypoxic and nitric oxide (NO) biofilm microenvironments. Integration of <jats:italic>P<\/jats:italic>. <jats:italic>aeruginosa<\/jats:italic> PA14 biofilm spatial transcriptomic data into a <jats:italic>P<\/jats:italic>. <jats:italic>aeruginosa<\/jats:italic> PA14 GENRE generated four PA14 metabolic model states that were input into MiMICS. Characteristic of aerobic, denitrification, and oxidative stress metabolism, the four metabolic model states predicted different oxygen, nitrate, and NO exchange fluxes that were passed as inputs to update the agent\u2019s local metabolite concentrations in the extracellular reaction-diffusion model. Individual bacterial agents chose a PA14 metabolic model state based on a combination of stochastic rules, and agents sensing local oxygen and NO. Transcriptome-guided MiMICS predictions suggested microscale denitrification and oxidative stress metabolic heterogeneity emerged due to local variability in the NO biofilm microenvironment. MiMICS accurately predicted the biofilm\u2019s spatial relationships between denitrification, oxidative stress, and central carbon metabolism. As simulated cells responded to extracellular NO, MiMICS revealed dynamics of cell populations heterogeneously upregulating reactions in the denitrification pathway, which may function to maintain NO levels within non-toxic ranges. We demonstrated that MiMICS is a valuable computational tool to incorporate multiple -omics-guided metabolic models to mechanistically map heterogeneous microbial metabolic states to the biofilm microenvironment.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1012031","type":"journal-article","created":{"date-parts":[[2024,4,26]],"date-time":"2024-04-26T17:24:14Z","timestamp":1714152254000},"page":"e1012031","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":9,"title":["Spatial transcriptome-guided multi-scale framework connects P. aeruginosa metabolic states to oxidative stress biofilm microenvironment"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2491-1557","authenticated-orcid":true,"given":"Tracy J.","family":"Kuper","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad 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