{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T18:46:53Z","timestamp":1770835613460,"version":"3.50.1"},"reference-count":53,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2013,3,1]],"date-time":"2013-03-01T00:00:00Z","timestamp":1362096000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2013,3,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Mathematical modelling is increasingly becoming an indispensable tool for the study of cellular processes, allowing their analysis in a systematic and comprehensive manner. In the vast majority of the cases, models focus on specific subsystems, and in particular describe either metabolism, gene expression or signal transduction. Integrated models that are able to span and interconnect these layers are, by contrast, rare as their construction and analysis face multiple challenges. Such methods, however, would represent extremely useful tools to understand cell behaviour, with application in distinct fields of biological and medical research. In particular, they could be useful tools to study genotype\u2013phenotype mappings, and the way they are affected by specific conditions or perturbations. Here, we review existing computational approaches that integrate signalling, gene regulation and\/or metabolism. We describe existing challenges, available methods and point at potentially useful strategies.<\/jats:p>\n                  <jats:p\/>","DOI":"10.1039\/c3mb25489e","type":"journal-article","created":{"date-parts":[[2013,3,1]],"date-time":"2013-03-01T15:07:33Z","timestamp":1362150453000},"page":"1576-1583","source":"Crossref","is-referenced-by-count":80,"title":["Bridging the layers: towards integration of signal transduction, regulation and metabolism into mathematical models"],"prefix":"10.1093","volume":"9","author":[{"given":"Emanuel","family":"Gon\u00e7alves","sequence":"first","affiliation":[{"name":"EMBL-EBI European Bioinformatics Institute, Wellcome Trust Genome Campus a , Hinxton CB10 1SD Cambridge UK saezrodriguez@ebi.ac.uk"}]},{"given":"Joachim","family":"Bucher","sequence":"additional","affiliation":[{"name":"Insilico Biotechnology AG b , Meitnerstra\u00dfe 8, D-70563 Stuttgart Germany"}]},{"given":"Anke","family":"Ryll","sequence":"additional","affiliation":[{"name":"Max Planck Institute for Dynamics of Complex Technical Systems c , Sandtorstra\u00dfe 1, D-39106 Magdeburg Germany"}]},{"given":"Jens","family":"Niklas","sequence":"additional","affiliation":[{"name":"Insilico Biotechnology AG b , Meitnerstra\u00dfe 8, D-70563 Stuttgart Germany"}]},{"given":"Klaus","family":"Mauch","sequence":"additional","affiliation":[{"name":"Insilico Biotechnology AG b , Meitnerstra\u00dfe 8, D-70563 Stuttgart Germany"}]},{"given":"Steffen","family":"Klamt","sequence":"additional","affiliation":[{"name":"Max Planck Institute for Dynamics of Complex Technical Systems c , Sandtorstra\u00dfe 1, D-39106 Magdeburg Germany"}]},{"given":"Miguel","family":"Rocha","sequence":"additional","affiliation":[{"name":"Computer Science and Technology Centre - CCTC, School of Engineering, University of Minho d , Portugal"}]},{"given":"Julio","family":"Saez-Rodriguez","sequence":"additional","affiliation":[{"name":"EMBL-EBI European Bioinformatics Institute, Wellcome Trust Genome Campus a , Hinxton CB10 1SD Cambridge UK saezrodriguez@ebi.ac.uk"}]}],"member":"286","published-online":{"date-parts":[[2013,3,1]]},"reference":[{"key":"2026012913122338400_cit1","volume-title":"Systems Biomedicine","author":"Liu","year":"2009"},{"key":"2026012913122338400_cit2","volume-title":"Molecular Biology of the Cell","author":"Alberts","year":"2008"},{"key":"2026012913122338400_cit3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/35081138","article-title":"The ins and outs of signaling","volume":"411","author":"Downward","year":"2001","journal-title":"Nature"},{"issue":"6","key":"2026012913122338400_cit4","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1002\/dmrr.863","article-title":"Regulation of hepatic glucose production and the role of gluconeogenesis in humans: is the rate of gluconeogenesis constant?","volume":"24","author":"Nuttall","year":"2008","journal-title":"Diabetes\/Metab. 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