{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T11:03:15Z","timestamp":1791198195153,"version":"4.1.0"},"reference-count":70,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000161","name":"National Institute of Standards and Technology","doi-asserted-by":"publisher","award":["70NANB24H293"],"award-info":[{"award-number":["70NANB24H293"]}],"id":[{"id":"10.13039\/100000161","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000161","name":"National Institute of Standards and Technology","doi-asserted-by":"publisher","award":["70NANB17H002"],"award-info":[{"award-number":["70NANB17H002"]}],"id":[{"id":"10.13039\/100000161","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000161","name":"National Institute of Standards and Technology","doi-asserted-by":"publisher","award":["70NANB21H086"],"award-info":[{"award-number":["70NANB21H086"]}],"id":[{"id":"10.13039\/100000161","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["CMMI\u20102442970"],"award-info":[{"award-number":["CMMI\u20102442970"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["OIA\u20101736123"],"award-info":[{"award-number":["OIA\u20101736123"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["EEC\u20102100442"],"award-info":[{"award-number":["EEC\u20102100442"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Biotech &amp;amp; Bioengineering"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Antibody productivity and glycosylation quality in CHO cell cultures emerge from a dynamically evolving metabolic environment, yet existing models often work in isolation or at a single scale. Here, we present a multiscale mechanistic framework linking molecular, cellular, and macroscopic scales to predict how inputs shape bioprocess trajectories. The framework combines a single\u2010cell kinetic model of metabolism and glycosylation with a stochastic population model that captures environment\u2010dependent transitions among growth, production, and decline states. To characterize metabolic adaptation, we introduce the cumulative variation in oxygen uptake rate, a trajectory\u2010based biomarker that quantifies the total metabolic adjustment experienced during culture. Unlike population\u2010averaged approaches, the model propagates cell\u2010resolved metabolic states\u2014including ammonia\u2010regulated Golgi pH, nucleotide sugar availability, manganese cofactors, and synthesis rates\u2014into glycan processing. The framework was evaluated using CHO\u2010K1 fed\u2010batch cultures producing VRC01 IgG1 under targeted ammonia stress, matched control conditions, and a pyramid\u2010feeding strategy with tighter control. It accurately reproduced trajectories of cell growth, metabolites, productivity, and harvest glycosylation, including increased G0F abundance and reduced galactosylation under ammonia stress. By mechanistically linking process conditions to cell\u2010state dynamics and glycosylation outcomes, the framework provides a unified foundation for digital bioprocessing, predictive biomanufacturing, and advanced process control.<\/jats:p>","DOI":"10.1002\/bit.70393","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T10:41:57Z","timestamp":1791196917000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["GlycoMAC: A Multiscale Metabolic\u2010Glycosylation Framework for Predicting Glycosylation Across Conditions in Mammalian Cell Cultures"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-1771-1448","authenticated-orcid":false,"given":"Yuming","family":"Zeng","sequence":"first","affiliation":[{"name":"Department of Mechanical and Industrial Engineering Northeastern University Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9417-0489","authenticated-orcid":false,"given":"Sarah W.","family":"Harcum","sequence":"additional","affiliation":[{"name":"Department of Bioengineering Clemson University Clemson South Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinxiang","family":"Pei","sequence":"additional","affiliation":[{"name":"Department of Mechanical and Industrial Engineering Northeastern University Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9563-4927","authenticated-orcid":false,"given":"Wei","family":"Xie","sequence":"additional","affiliation":[{"name":"Department of Mechanical and Industrial Engineering Northeastern University Boston Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.jbiotec.2014.05.024","article-title":"Effects of Nutrient Levels and Average Culture pH on the Glycosylation Pattern of Camelid\u2010Humanized Monoclonal Antibody","volume":"186","author":"Aghamohseni H.","year":"2014","journal-title":"Journal of Biotechnology"},{"issue":"5","key":"e_1_2_9_3_1","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.ymben.2011.07.002","article-title":"Metabolic Flux Analysis of CHO Cells at Growth and Non\u2010Growth Phases Using Isotopic Tracers and Mass Spectrometry","volume":"13","author":"Ahn W. S.","year":"2011","journal-title":"Metabolic Engineering"},{"issue":"1","key":"e_1_2_9_4_1","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1002\/biot.201100052","article-title":"Towards Dynamic Metabolic Flux Analysis in CHO Cell Cultures","volume":"7","author":"Ahn W. S.","year":"2012","journal-title":"Biotechnology Journal"},{"issue":"8","key":"e_1_2_9_5_1","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1093\/glycob\/11.8.633","article-title":"Neutralization of pH in the Golgi Apparatus Causes Redistribution of Glycosyltransferases and Changes in the O\u2010Glycosylation of Mucins","volume":"11","author":"Axelsson M. A.","year":"2001","journal-title":"Glycobiology"},{"key":"e_1_2_9_6_1","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.copbio.2014.06.010","article-title":"The Choice of Mammalian Cell Host and Possibilities for Glycosylation Engineering","volume":"30","author":"Butler M.","year":"2014","journal-title":"Current Opinion in Biotechnology"},{"issue":"1","key":"e_1_2_9_7_1","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1038\/s41598-023-27962-0","article-title":"Microevolutionary Dynamics of Eccdna in Chinese Hamster Ovary Cells Grown in Fed\u2010Batch Cultures under Control and Lactate\u2010Stressed Conditions","volume":"13","author":"Chitwood D. G.","year":"2023","journal-title":"Scientific Reports"},{"issue":"4","key":"e_1_2_9_8_1","doi-asserted-by":"crossref","DOI":"10.1093\/nargab\/lqae169","article-title":"Cell\u2010and Tissue\u2010Specific Glycosylation Pathways Informed by Single\u2010Cell Transcriptomics","volume":"6","author":"Chrysinas P.","year":"2024","journal-title":"NAR Genomics and Bioinformatics"},{"issue":"12","key":"e_1_2_9_9_1","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.3390\/cells11121929","article-title":"Metabolic Profiling of Cho Cells During the Production of Biotherapeutics","volume":"11","author":"Coulet M.","year":"2022","journal-title":"Cells"},{"issue":"3","key":"e_1_2_9_10_1","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1002\/bit.21141","article-title":"Amino Acid and Manganese Supplementation Modulates the Glycosylation State of Erythropoietin in a CHO Culture System","volume":"96","author":"Crowell C. 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