{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:37:51Z","timestamp":1771461471713,"version":"3.50.1"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"24","license":[{"start":{"date-parts":[[2018,6,1]],"date-time":"2018-06-01T00:00:00Z","timestamp":1527811200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"NSF","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"NSF","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000152","name":"MCB","doi-asserted-by":"publisher","award":["1546840"],"award-info":[{"award-number":["1546840"]}],"id":[{"id":"10.13039\/100000152","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Bioenergy Research Center"},{"DOI":"10.13039\/100014456","name":"Center for Bioenergy Innovation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100014456","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100005461","name":"CBI","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005461","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000015","name":"Department of Energy","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000015","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000015","name":"DOE","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000015","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006206","name":"Office of Biological and Environmental Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100006206","id-type":"DOI","asserted-by":"crossref"}]},{"name":"OBER","award":["DE-AC05-000R22725"],"award-info":[{"award-number":["DE-AC05-000R22725"]}]},{"name":"OBER","award":["DE-SC0012377"],"award-info":[{"award-number":["DE-SC0012377"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2018,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Genome-scale metabolic network models and constraint-based modeling techniques have become important tools for analyzing cellular metabolism. Thermodynamically infeasible cycles (TICs) causing unbounded metabolic flux ranges are often encountered. TICs satisfy the mass balance and directionality constraints but violate the second law of thermodynamics. Current practices involve implementing additional constraints to ensure not only optimal but also loopless flux distributions. However, the mixed integer linear programming problems required to solve become computationally intractable for genome-scale metabolic models.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We aimed to identify the fewest needed constraints sufficient for optimality under the loopless requirement. We found that loopless constraints are required only for the reactions that share elementary flux modes representing TICs with reactions that are part of the objective function. We put forth the concept of localized loopless constraints (LLCs) to enforce this minimal required set of loopless constraints. By combining with a novel procedure for minimal null-space calculation, the computational time for loopless flux variability analysis (ll-FVA) is reduced by a factor of 10\u2013150 compared to the original loopless constraints and by 4\u201320 times compared to the current fastest method Fast-SNP with the percent improvement increasing with model size. Importantly, LLCs offer a scalable strategy for loopless flux calculations for multi-compartment\/multi-organism models of large sizes, for example, shortening the CPU time for ll-FVA from 35\u2009h to less than 2\u2009h for a model with more than104 reactions.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>Matlab functions are available in the Supplementary Material or at https:\/\/github.com\/maranasgroup\/lll-FVA<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Supplementary information<\/jats:title>\n                  <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/bty446","type":"journal-article","created":{"date-parts":[[2018,5,29]],"date-time":"2018-05-29T19:12:41Z","timestamp":1527621161000},"page":"4248-4255","source":"Crossref","is-referenced-by-count":20,"title":["Accelerating flux balance calculations in genome-scale metabolic models by localizing the application of loopless constraints"],"prefix":"10.1093","volume":"34","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7707-656X","authenticated-orcid":false,"given":"Siu H J","family":"Chan","sequence":"first","affiliation":[{"name":"Department of Chemical Engineering, The Pennsylvania State University, University Park, PA, USA"}]},{"given":"Lin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, The Pennsylvania State University, University Park, PA, USA"}]},{"given":"Satyakam","family":"Dash","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, The Pennsylvania State University, University Park, PA, USA"}]},{"given":"Costas D","family":"Maranas","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, The Pennsylvania State University, University Park, PA, USA"}]}],"member":"286","published-online":{"date-parts":[[2018,6,1]]},"reference":[{"key":"2023012712245104100_bty446-B1","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1093\/bioinformatics\/btn589","article-title":"Decomposition of complex microbial behaviors into resource-based stress responses","volume":"25","author":"Carlson","year":"2009","journal-title":"Bioinformatics"},{"key":"2023012712245104100_bty446-B2","doi-asserted-by":"crossref","first-page":"3232","DOI":"10.1093\/bioinformatics\/btu529","article-title":"Estimating biological elementary flux modes that decompose a flux distribution by the minimal branching property","volume":"30","author":"Chan","year":"2014","journal-title":"Bioinformatics"},{"key":"2023012712245104100_bty446-B3","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1002\/9783527696130.ch6","volume-title":"Systems Biology","author":"Chan","year":"2017"},{"key":"2023012712245104100_bty446-B4","doi-asserted-by":"crossref","first-page":"e1005539","DOI":"10.1371\/journal.pcbi.1005539","article-title":"SteadyCom: predicting microbial abundances while ensuring community stability","volume":"13","author":"Chan","year":"2017","journal-title":"PLoS Comput. 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