{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T20:34:31Z","timestamp":1772138071271,"version":"3.50.1"},"reference-count":39,"publisher":"Oxford University Press (OUP)","issue":"3","license":[{"start":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T00:00:00Z","timestamp":1741737600000},"content-version":"vor","delay-in-days":11,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministero dell\u2019Univerisita\u2019 e della Ricerca"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,3,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Motivation<\/jats:title>\n                    <jats:p>Computational models are crucial for addressing critical questions about systems evolution and deciphering system connections. The pivotal feature of making this concept recognizable from the biological and clinical community is the possibility of quickly inspecting the whole system, bearing in mind the different granularity levels of its components. This holistic view of system behaviour expands the evolution study by identifying the heterogeneous behaviours applicable, e.g. to the cancer evolution study.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>To address this aspect, we propose a new modelling paradigm, UnifiedGreatMod, which allows modellers to integrate fine-grained and coarse-grained biological information into a unique model. It enables functional studies by combining the analysis of the system\u2019s multi-level stable states with its fluctuating conditions. This approach helps to investigate the functional relationships and dependencies among biological entities. This is achieved, thanks to the hybridization of two analysis approaches that capture a system\u2019s different granularity levels. The proposed paradigm was then implemented into the open-source, general modelling framework GreatMod, in which a graphical meta-formalism is exploited to simplify the model creation phase and R languages to define user-defined analysis workflows. The proposal\u2019s effectiveness was demonstrated by mechanistically simulating the metabolic output of Escherichia coli under environmental nutrient perturbations and integrating a gene expression dataset. Additionally, the UnifiedGreatMod was used to examine the responses of luminal epithelial cells to Clostridium difficile infection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Availability and implementation<\/jats:title>\n                    <jats:p>GreatMod https:\/\/qbioturin.github.io\/epimod\/, epimod_FBAfunctions https:\/\/github.com\/qBioTurin\/epimod_FBAfunctions, first case study E. coli \u00a0https:\/\/github.com\/qBioTurin\/Ec_coli_modelling, second case study C. difficile \u00a0https:\/\/github.com\/qBioTurin\/EpiCell_CDifficile.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btaf103","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T08:50:21Z","timestamp":1741683021000},"source":"Crossref","is-referenced-by-count":0,"title":["UnifiedGreatMod: a new holistic modelling paradigm for studying biological systems on a complete and harmonious scale"],"prefix":"10.1093","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8022-0211","authenticated-orcid":false,"given":"Riccardo","family":"Aucello","sequence":"first","affiliation":[{"name":"Department of Computer Science, University of Turin , Via Pessinetto 12 , Torino, 10149,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7124-4676","authenticated-orcid":false,"given":"Simone","family":"Pernice","sequence":"additional","affiliation":[{"name":"Department of Computer Science, University of Turin , Via Pessinetto 12 , Torino, 10149,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dora","family":"Tortarolo","sequence":"additional","affiliation":[{"name":"Department of Computer Science, University of Turin , Via Pessinetto 12 , Torino, 10149,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2848-628X","authenticated-orcid":false,"given":"Raffaele A","family":"Calogero","sequence":"additional","affiliation":[{"name":"Department of Molecular Biotechnology and Health Sciences, University of Torino , Via Nizza 52 , Torino, 10126,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Celia","family":"Herrera-Rincon","sequence":"additional","affiliation":[{"name":"Biomathematics Unit, Department of Biodiversity, Ecology and Evolution, Complutense University of Madrid , Madrid 28040,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giulia","family":"Ronchi","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences, University of Torino , Regione Gonzole 10 , Orbassano, 10143,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefano","family":"Geuna","sequence":"additional","affiliation":[{"name":"Department of Clinical and Biological Sciences, University of Torino , Regione Gonzole 10 , Orbassano, 10143,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3143-3330","authenticated-orcid":false,"given":"Francesca","family":"Cordero","sequence":"additional","affiliation":[{"name":"Department of Computer Science, University of Turin , Via Pessinetto 12 , Torino, 10149,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pietro","family":"Li\u00f3","sequence":"additional","affiliation":[{"name":"Department of Computer Science and Technology, University of Cambridge , Cambridge CB3 0FD,","place":["United Kingdom"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Beccuti","sequence":"additional","affiliation":[{"name":"Department of Computer Science, University of Turin , Via Pessinetto 12 , Torino, 10149,","place":["Italy"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,3,12]]},"reference":[{"key":"2025032423322578800_btaf103-B1","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1038\/s41598-017-18704-0","article-title":"Regulation of metabolism in Escherichia coli during growth on mixtures of the non-glucose sugars: arabinose, lactose, and xylose","volume":"8","author":"Ammar","year":"2018","journal-title":"Sci Rep"},{"key":"2025032423322578800_btaf103-B2","first-page":"227","author":"Amparore","year":"2016"},{"key":"2025032423322578800_btaf103-B3","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1038\/s43588-021-00074-3","article-title":"Dynamic flux balance analysis of whole-body metabolism for type 1 diabetes","volume":"1","author":"Ben Guebila","year":"2021","journal-title":"Nat Comput Sci"},{"key":"2025032423322578800_btaf103-B4","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/nrg3643","article-title":"Constraint-based models predict metabolic and associated cellular functions","volume":"15","author":"Bordbar","year":"2014","journal-title":"Nat Rev Genet"},{"key":"2025032423322578800_btaf103-B5","author":"Burden"},{"key":"2025032423322578800_btaf103-B6","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1186\/1752-0509-7-116","article-title":"Path2models: large-scale generation of computational models from biochemical pathway maps","volume":"7","author":"B\u00fcchel","year":"2013","journal-title":"BMC Syst Biol"},{"key":"2025032423322578800_btaf103-B7","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1186\/s12859-020-03648-6","article-title":"A computational framework for modeling and studying pertussis epidemiology and vaccination","volume":"21","author":"Castagno","year":"2020","journal-title":"BMC Bioinformatics"},{"key":"2025032423322578800_btaf103-B8","doi-asserted-by":"crossref","first-page":"e1011381","DOI":"10.1371\/journal.pcbi.1011381","article-title":"Genome scale metabolic network modelling for metabolic profile predictions","volume":"20","author":"Cooke","year":"2024","journal-title":"PLoS Comput Biol"},{"key":"2025032423322578800_btaf103-B9","doi-asserted-by":"crossref","first-page":"e1006733","DOI":"10.1371\/journal.pcbi.1006733","article-title":"Integration of single-cell rna-seq data into population models to characterize cancer metabolism","volume":"15","author":"Damiani","year":"2019","journal-title":"PLoS Comput Biol"},{"key":"2025032423322578800_btaf103-B10","author":"Di Filippo","year":"2021"},{"key":"2025032423322578800_btaf103-B11","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.1158\/2159-8290.CD-21-1273","article-title":"Human colon cancer\u2013derived Clostridioides difficile strains drive colonic tumorigenesis in mice","volume":"12","author":"Drewes","year":"2022","journal-title":"Cancer Discov"},{"key":"2025032423322578800_btaf103-B12","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1038\/nrmicro1949","article-title":"Reconstruction of biochemical networks in microorganisms","volume":"7","author":"Feist","year":"2009","journal-title":"Nat Rev Microbiol"},{"key":"2025032423322578800_btaf103-B13","doi-asserted-by":"crossref","DOI":"10.1186\/1752-0509-9-S3-S1","article-title":"A versatile mathematical work-flow to explore how cancer stem cell fate influences tumor progression","volume":"9","author":"Fornari","year":"2015","journal-title":"BMC Syst Biol"},{"key":"2025032423322578800_btaf103-B14","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1186\/s12859-022-04967-6","article-title":"Combining denoising of RNA-seq data and flux balance analysis for cluster analysis of single cells","volume":"23","author":"Galuzzi","year":"2022","journal-title":"BMC Bioinformatics"},{"key":"2025032423322578800_btaf103-B15","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/s41596-018-0098-2","article-title":"Creation and analysis of biochemical constraint-based models: the cobra toolbox v3.0","volume":"14","author":"Heirendt","year":"2017","journal-title":"Nature Protocols"},{"key":"2025032423322578800_btaf103-B16","doi-asserted-by":"crossref","first-page":"1970","DOI":"10.3389\/fmicb.2018.01970","article-title":"Metabolic reprogramming of Clostridioides difficile during the stationary phase with the induction of toxin production","volume":"9","author":"Hofmann","year":"2018","journal-title":"Front Microbiol"},{"key":"2025032423322578800_btaf103-B17","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1099\/13500872-141-2-371","article-title":"A defined growth medium for Clostridium difficile","volume":"141(Pt 2)","author":"Karasawa","year":"1995","journal-title":"Microbiology (Reading)"},{"key":"2025032423322578800_btaf103-B18","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s12918-017-0395-3","article-title":"Making life difficult for clostridium difficile: augmenting the pathogen\u2019s metabolic model with transcriptomic and codon usage data for better therapeutic target characterization","volume":"11","author":"Kashaf","year":"2017","journal-title":"BMC Syst Biol"},{"key":"2025032423322578800_btaf103-B19","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1890\/0012-9658(1999)080[1789:WDPCAS]2.0.CO;2","article-title":"Why do populations cycle? A synthesis of statistical and mechanistic modeling approaches","volume":"80","author":"Kendall","year":"1999","journal-title":"Ecology"},{"key":"2025032423322578800_btaf103-B20","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.chom.2020.05.015","article-title":"Clostridioides difficile senses and hijacks host heme for incorporation into an oxidative stress defense system","volume":"28","author":"Knippel","year":"2020","journal-title":"Cell Host Microbe"},{"key":"2025032423322578800_btaf103-B21","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1097\/MRM.0000000000000135","article-title":"Clostridium difficile infection: a review","volume":"29","author":"Kouhsari","year":"2018","journal-title":"Rev Res Med Microbiol"},{"key":"2025032423322578800_btaf103-B22","doi-asserted-by":"crossref","first-page":"7542","DOI":"10.1093\/nar\/gky537","article-title":"Fast automated reconstruction of genome-scale metabolic models for microbial species and communities","volume":"46","author":"Machado","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"2025032423322578800_btaf103-B23","doi-asserted-by":"crossref","first-page":"e1003580","DOI":"10.1371\/journal.pcbi.1003580","article-title":"Systematic evaluation of methods for integration of transcriptomic data into constraint-based models of metabolism","volume":"10","author":"Machado","year":"2014","journal-title":"PLoS Comput Biol"},{"key":"2025032423322578800_btaf103-B24","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/nbt.3703","article-title":"Generation of genome-scale metabolic reconstructions for 773 members of the human gut microbiota","volume":"35","author":"Magn\u00fasd\u00f3ttir","year":"2017","journal-title":"Nat Biotechnol"},{"key":"2025032423322578800_btaf103-B25","doi-asserted-by":"crossref","first-page":"1331","DOI":"10.1016\/S0006-3495(02)73903-9","article-title":"Dynamic flux balance analysis of diauxic growth in Escherichia coli","volume":"83","author":"Mahadevan","year":"2002","journal-title":"Biophys J"},{"key":"2025032423322578800_btaf103-B26","doi-asserted-by":"crossref","volume-title":"Optimization Methods in Metabolic Networks","author":"Maranas","DOI":"10.1002\/9781119188902"},{"key":"2025032423322578800_btaf103-B27","volume-title":"Modelling with Generalized Stochastic Petri Nets","author":"Marsan","year":"1995"},{"key":"2025032423322578800_btaf103-B28","doi-asserted-by":"crossref","first-page":"219","DOI":"10.3389\/fmicb.2019.00219","article-title":"Metabolism the difficile way: the key to the success of the pathogen Clostridioides difficile","volume":"10","author":"Neumann-Schaal","year":"2019","journal-title":"Front Microbiol"},{"key":"2025032423322578800_btaf103-B29","doi-asserted-by":"crossref","first-page":"D614","DOI":"10.1093\/nar\/gky992","article-title":"The virtual metabolic human database: integrating human and gut microbiome metabolism with nutrition and disease","volume":"47","author":"Noronha","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"2025032423322578800_btaf103-B30","first-page":"D402","article-title":"Bigg models 2020: multi-strain genome-scale models and expansion across the phylogenetic tree","volume":"48","author":"Norsigian","year":"2020","journal-title":"Nucleic Acids Res"},{"key":"2025032423322578800_btaf103-B31","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.cels.2017.01.010","article-title":"A systematic evaluation of methods for tailoring genome-scale metabolic models","volume":"4","author":"Opdam","year":"2017","journal-title":"Cell Syst"},{"key":"2025032423322578800_btaf103-B32","author":"Palsson"},{"key":"2025032423322578800_btaf103-B33","first-page":"367","article-title":"Integrating petri nets and flux balance methods in computational biology models: a methodological and computational practice","volume":"171","author":"Pernice","year":"2020","journal-title":"Fundamenta Informaticae"},{"key":"2025032423322578800_btaf103-B34","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s12859-020-03823-9","article-title":"Computational modeling of the immune response in multiple sclerosis using epimod framework","volume":"21","author":"Pernice","year":"2020","journal-title":"BMC Bioinformatics"},{"key":"2025032423322578800_btaf103-B35","doi-asserted-by":"crossref","first-page":"104546","DOI":"10.1016\/j.jbi.2023.104546","article-title":"A new computational workflow to guide personalized drug therapy","volume":"148","author":"Pernice","year":"2023","journal-title":"J Biomed Inform"},{"key":"2025032423322578800_btaf103-B36","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.cpc.2009.09.018","article-title":"Variance based sensitivity analysis of model output. design and estimator for the total sensitivity index","volume":"181","author":"Saltelli","year":"2010","journal-title":"Comput Phys Commun"},{"key":"2025032423322578800_btaf103-B37","doi-asserted-by":"crossref","first-page":"3539","DOI":"10.1172\/JCI130008","article-title":"Human fecal metabolomic profiling could inform Clostridioides difficile infection diagnosis and treatment","volume":"129","author":"Theriot","year":"2019","journal-title":"J Clin Invest"},{"key":"2025032423322578800_btaf103-B38","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s12918-018-0675-6","article-title":"Dynamicme: dynamic simulation and refinement of integrated models of metabolism and protein expression","volume":"13","author":"Yang","year":"2019","journal-title":"BMC Syst Biol"},{"key":"2025032423322578800_btaf103-B39","doi-asserted-by":"crossref","first-page":"100383","DOI":"10.1016\/j.crmeth.2022.100383","article-title":"Metatranscriptomics-guided genome-scale metabolic modeling of microbial communities","volume":"3","author":"Zampieri","year":"2023","journal-title":"Cell Rep Methods"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btaf103\/62387315\/btaf103.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/41\/3\/btaf103\/62387315\/btaf103.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/41\/3\/btaf103\/62387315\/btaf103.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,29]],"date-time":"2025-03-29T00:52:01Z","timestamp":1743209521000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/doi\/10.1093\/bioinformatics\/btaf103\/8071862"}},"subtitle":[],"editor":[{"given":"Pier Luigi","family":"Martelli","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2025,3]]},"references-count":39,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,3,4]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btaf103","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.09.18.613635","asserted-by":"object"}]},"ISSN":["1367-4811"],"issn-type":[{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,3]]},"published":{"date-parts":[[2025,3]]},"article-number":"btaf103"}}