{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T22:41:07Z","timestamp":1776120067412,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1010482","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T00:00:00Z","timestamp":1664236800000}}],"reference-count":61,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2022,9,15]],"date-time":"2022-09-15T00:00:00Z","timestamp":1663200000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Helmholtz Zentrum Hereon"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Magnesium (Mg<jats:sup>2+<\/jats:sup>) ions are frequently reported to regulate osteogenic activities of mesenchymal stem cells (MSCs). In this study, we propose a numerical model to study the regulatory importance of Mg<jats:sup>2+<\/jats:sup> ions on MSCs osteoblastic differentiation in the presence of an inflammatory response. A fuzzy logic controller was formulated to receive the concentrations of Mg<jats:sup>2+<\/jats:sup> ions and the inflammatory cytokines of TNF-\u03b1, IL-10, IL-1\u03b2, and IL-8 as cellular inputs and predict the cells\u2019 early and late differentiation rates. Five sets of empirical data obtained from published cell culture experiments were used to calibrate the model. The model successfully reproduced the empirical data regarding the concentration- and phase-dependent effect of Mg<jats:sup>2+<\/jats:sup> ions on the differentiation process. In agreement with the experiments, the model showed the stimulatory role of Mg<jats:sup>2+<\/jats:sup> ions on the early differentiation phase, once administered at low concentration, and their inhibitory role on the late differentiation phase. The numerical approach used in this study suggested 6\u20138 mM as the most effective concentration of Mg<jats:sup>2+<\/jats:sup> ions in promoting the early differentiation process. Also, the proposed model sheds light on the fundamental differences in the behavioral properties of cells cultured in different experiments, e.g. differentiation rate and the sensitivity of the cultured cells to stimulatory signals such as Mg<jats:sup>2+<\/jats:sup> ions. Thus, it can be used to interpret and compare different empirical findings. Moreover, the model successfully reproduced the nonlinearities in the concentration-dependent role of the inflammatory cytokines in early and late differentiation rates. Overall, the proposed model can be employed in studying the osteogenic properties of Mg-based implants in the presence of an inflammatory response.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1010482","type":"journal-article","created":{"date-parts":[[2022,9,15]],"date-time":"2022-09-15T18:01:20Z","timestamp":1663264880000},"page":"e1010482","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["The osteogenetic activities of mesenchymal stem cells in response to Mg2+ ions and inflammatory cytokines: a numerical approach using fuzzy logic controllers"],"prefix":"10.1371","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7539-4396","authenticated-orcid":true,"given":"Jalil","family":"Nourisa","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7562-9423","authenticated-orcid":true,"given":"Berit","family":"Zeller-Plumhoff","sequence":"additional","affiliation":[]},{"given":"Regine","family":"Willumeit-R\u00f6mer","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2022,9,15]]},"reference":[{"issue":"4","key":"pcbi.1010482.ref001","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1007\/s11837-019-03368-0","article-title":"The Interface Between Degradable Mg and Tissue","volume":"71","author":"R. Willumeit-R\u00f6mer","year":"2019","journal-title":"Jom"},{"issue":"15","key":"pcbi.1010482.ref002","doi-asserted-by":"crossref","first-page":"5178","DOI":"10.1039\/D0CS00103A","article-title":"Biological responses to physicochemical properties of biomaterial surface","volume":"49","author":"M Rahmati","year":"2020","journal-title":"Chem Soc Rev"},{"key":"pcbi.1010482.ref003","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.biomaterials.2015.02.097","article-title":"Magnesium modification of a calcium phosphate cement alters bone marrow stromal cell behavior via an integrin-mediated mechanism","volume":"53","author":"J Zhang","year":"2015","journal-title":"Biomaterials"},{"issue":"2","key":"pcbi.1010482.ref004","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1007\/s12011-020-02183-y","article-title":"Insights into the Role of Magnesium Ions in Affecting Osteogenic Differentiation of Mesenchymal Stem Cells","volume":"199","author":"T Qi","year":"2021","journal-title":"Biol Trace Elem Res"},{"issue":"12","key":"pcbi.1010482.ref005","doi-asserted-by":"crossref","first-page":"1900209","DOI":"10.1002\/advs.201900209","article-title":"A magnesium-enriched 3D culture system that mimics the bone development microenvironment for vascularized bone regeneration","volume":"6","author":"S Lin","year":"2019","journal-title":"Adv Sci"},{"issue":"1","key":"pcbi.1010482.ref006","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.gene.2015.08.028","article-title":"Effects of magnesium degradation products on mesenchymal stem cell fate and osteoblastogenesis","volume":"575","author":"BJC Luthringer","year":"2016","journal-title":"Gene"},{"issue":"41","key":"pcbi.1010482.ref007","doi-asserted-by":"crossref","first-page":"6615","DOI":"10.1039\/C8TB01746H","article-title":"Unraveling the osteogenesis of magnesium by the activity of osteoblasts in vitro","volume":"6","author":"Y Wang","year":"2018","journal-title":"J Mater Chem B"},{"issue":"12","key":"pcbi.1010482.ref008","first-page":"4346","article-title":"The influence of biodegradable magnesium alloys on the osteogenic differentiation of human mesenchymal stem cells","volume":"102","author":"RW Li","year":"2014","journal-title":"J Biomed Mater Res Part A"},{"key":"pcbi.1010482.ref009","doi-asserted-by":"crossref","DOI":"10.1155\/2019\/7908205","article-title":"Magnesium Enhances Osteogenesis of BMSCs by Tuning Osteoimmunomodulation","volume":"2019","author":"X Zhang","year":"2019","journal-title":"Biomed Res Int"},{"issue":"1","key":"pcbi.1010482.ref010","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-021-91070-0","article-title":"Evaluation of the immunomodulatory effects of cobalt, copper and magnesium ions in a pro inflammatory environment","volume":"11","author":"L D\u00edez-Tercero","year":"2021","journal-title":"Sci Rep"},{"issue":"2","key":"pcbi.1010482.ref011","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1007\/s00441-017-2598-8","article-title":"Macrophage type modulates osteogenic differentiation of adipose tissue MSCs","volume":"369","author":"Y Zhang","year":"2017","journal-title":"Cell Tissue Res"},{"issue":"1","key":"pcbi.1010482.ref012","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/cei.12929","article-title":"The influence of macrophages on mesenchymal stromal cell therapy: Passive or aggressive agents","volume":"188","author":"F Carty","year":"2017","journal-title":"Clin Exp Immunol"},{"issue":"1","key":"pcbi.1010482.ref013","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13287-020-1578-1","article-title":"Influence of inflammatory conditions provided by macrophages on osteogenic ability of mesenchymal stem cells","volume":"11","author":"G Valles","year":"2020","journal-title":"Stem Cell Res Ther"},{"issue":"1","key":"pcbi.1010482.ref014","first-page":"65","article-title":"The macrophage polarization regulates MSC osteoblast differentiation in vitro","volume":"46","author":"L Gong","year":"2016","journal-title":"Ann Clin Lab Sci"},{"issue":"19\u201320","key":"pcbi.1010482.ref015","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1089\/ten.tea.2020.0041","article-title":"Macrophage effects on mesenchymal stem cell osteogenesis in a three-dimensional in vitro bone model","volume":"26","author":"M Romero-L\u00f3pez","year":"2020","journal-title":"Tissue Eng\u2014Part A"},{"issue":"1","key":"pcbi.1010482.ref016","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.abb.2006.03.031","article-title":"Magnesium and the inflammatory response: potential physiopathological implications","volume":"458","author":"A Mazur","year":"2007","journal-title":"Arch Biochem Biophys"},{"issue":"2885","key":"pcbi.1010482.ref017","article-title":"TRPM7 kinase-mediated immunomodulation in macrophage plays a central role in magnesium ion- induced bone regeneration","volume":"12","author":"W Qiao","year":"2021","journal-title":"Nat Commun"},{"issue":"1","key":"pcbi.1010482.ref018","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1684\/mrh.2011.0271","article-title":"High magnesium inhibits human osteoblast differentiation in vitro","volume":"24","author":"M Leidi","year":"2011","journal-title":"Magnes Res"},{"issue":"xxxx","key":"pcbi.1010482.ref019","article-title":"Magnesium-based biomaterials as emerging agents for bone repair and regeneration: from mechanism to application","author":"H Zhou","year":"2021","journal-title":"J Magnes Alloy"},{"key":"pcbi.1010482.ref020","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.jnutbio.2018.02.006","article-title":"An insight into the role of magnesium in the immunomodulatory properties of mesenchymal stem cells","volume":"55","author":"F da Silva Lima","year":"2018","journal-title":"J Nutr Biochem"},{"issue":"3","key":"pcbi.1010482.ref021","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1200\/CCI.18.00069","article-title":"A Review of Cell-Based Computational Modeling in Cancer Biology","author":"J Metzcar","year":"2019","journal-title":"JCO Clin Cancer Informatics"},{"key":"pcbi.1010482.ref022","first-page":"347","volume-title":"Trends in Biotechnology","author":"A Prasad","year":"2019"},{"issue":"5","key":"pcbi.1010482.ref023","doi-asserted-by":"crossref","DOI":"10.1142\/S0219519419500210","article-title":"Prediction of the trend of bone fracture healing based on the results of the early stages simulations: a finite element study","volume":"19","author":"J Nourisa","year":"2019","journal-title":"J Mech Med Biol"},{"key":"pcbi.1010482.ref024","doi-asserted-by":"crossref","DOI":"10.1016\/j.jmbbm.2015.10.029","article-title":"Biomechanical evaluation of intramedullary nail and bone plate for the fixation of distal metaphyseal fractures","volume":"56","author":"J Nourisa","year":"2016","journal-title":"J Mech Behav Biomed Mater"},{"key":"pcbi.1010482.ref025","doi-asserted-by":"crossref","first-page":"102112","DOI":"10.1016\/j.isci.2021.102112","article-title":"A data-driven computational model enables integrative and mechanistic characterization of dynamic macrophage polarization","author":"C Zhao","year":"2021","journal-title":"iScience"},{"issue":"5","key":"pcbi.1010482.ref026","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1109\/TCBB.2015.2424424","article-title":"Fuzzy Logic as a Computational Tool for Quantitative Modelling of Biological Systems with Uncertain Kinetic Data","volume":"12","author":"J Bordon","year":"2015","journal-title":"IEEE\/ACM Trans Comput Biol Bioinforma"},{"issue":"7","key":"pcbi.1010482.ref027","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.1093\/bioinformatics\/btz868","article-title":"Fuzzy modeling and global optimization to predict novel therapeutic targets in cancer cells","volume":"36","author":"MS Nobile","year":"2019","journal-title":"Bioinformatics"},{"issue":"4","key":"pcbi.1010482.ref028","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1000340","article-title":"Fuzzy Logic Analysis of Kinase Pathway Crosstalk in TNF\/EGF\/Insulin-Induced Signaling","volume":"5","author":"BB Aldridge","year":"2009","journal-title":"PLoS Comput Biol"},{"issue":"1","key":"pcbi.1010482.ref029","first-page":"1","article-title":"Three-dimensional computational model simulating the fracture healing process with both biphasic poroelastic finite element analysis and fuzzy logic control","volume":"8","author":"M Wang","year":"2018","journal-title":"Sci Rep"},{"issue":"3","key":"pcbi.1010482.ref030","doi-asserted-by":"crossref","first-page":"e0194500","DOI":"10.1371\/journal.pone.0194500","article-title":"Simulating lateral distraction osteogenesis","volume":"13","author":"F Niemeyer","year":"2018","journal-title":"PLoS One"},{"key":"pcbi.1010482.ref031","doi-asserted-by":"crossref","first-page":"4110","DOI":"10.1016\/j.csbj.2021.07.005","article-title":"Magnesium ions regulate mesenchymal stem cells population and osteogenic differentiation: a fuzzy agent-based modeling approach","volume":"19","author":"J Nourisa","year":"2021","journal-title":"Comput Struct Biotechnol J"},{"key":"pcbi.1010482.ref032","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1007\/978-3-642-30504-7_8","volume-title":"Handbook of optimization","author":"K V. Price","year":"2013"},{"issue":"9","key":"pcbi.1010482.ref033","doi-asserted-by":"crossref","first-page":"4917","DOI":"10.1096\/fj.201701256RRR","article-title":"Concentration-dependent, dual roles of IL-10 in the osteogenesis of human BMSCs via P38\/MAPK and NF-kB signaling pathways","volume":"32","author":"E Chen","year":"2018","journal-title":"FASEB J"},{"issue":"2","key":"pcbi.1010482.ref034","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1634\/stemcells.2004-0166","article-title":"Human umbilical cord perivascular (HUCPV) cells: a source of mesenchymal progenitors","volume":"23","author":"R Sarugaser","year":"2005","journal-title":"Stem Cells"},{"key":"pcbi.1010482.ref035","first-page":"221","volume-title":"Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics)","author":"S Spolaor","year":"2019"},{"key":"pcbi.1010482.ref036","first-page":"24","volume-title":"Nature Medicine","author":"A Esteva","year":"2019"},{"issue":"1","key":"pcbi.1010482.ref037","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.jtbi.2007.11.008","article-title":"Angiogenesis in bone fracture healing: A bioregulatory model","volume":"251","author":"L Geris","year":"2008","journal-title":"J Theor Biol"},{"issue":"11","key":"pcbi.1010482.ref038","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pcbi.1007468","article-title":"A mechanistic integrative computational model of macrophage polarization: Implications in human pathophysiology","volume":"15","author":"C Zhao","year":"2019","journal-title":"PLoS Comput Biol"},{"issue":"MAR","key":"pcbi.1010482.ref039","first-page":"1","article-title":"Computational modeling to quantify the contributions of VEGFR1, VEGFR2, and lateral inhibition in sprouting angiogenesis","volume":"10","author":"C Kuhn","year":"2019","journal-title":"Front Physiol"},{"issue":"1","key":"pcbi.1010482.ref040","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/jor.24170","article-title":"Cellular biology of fracture healing","volume":"37","author":"CS Bahney","year":"2019","journal-title":"J Orthop Res"},{"key":"pcbi.1010482.ref041","unstructured":"Nourisa J. janursa\/MSC_OB_Mg_ICs: [Internet]. Zenodo; 2022."},{"key":"pcbi.1010482.ref042","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/j.actbio.2015.08.042","article-title":"Effects of extracellular magnesium extract on the proliferation and differentiation of human osteoblasts and osteoclasts in coculture","volume":"27","author":"L Wu","year":"2015","journal-title":"Acta Biomater"},{"issue":"6","key":"pcbi.1010482.ref043","doi-asserted-by":"crossref","first-page":"2834","DOI":"10.1016\/j.actbio.2014.02.002","article-title":"Magnesium ion stimulation of bone marrow stromal cells enhances osteogenic activity, simulating the effect of magnesium alloy degradation","volume":"10","author":"S Yoshizawa","year":"2014","journal-title":"Acta Biomater"},{"issue":"11","key":"pcbi.1010482.ref044","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0142117","article-title":"Influence of magnesium alloy degradation on undifferentiated human cells","volume":"10","author":"F Cecchinato","year":"2015","journal-title":"PLoS One"},{"key":"pcbi.1010482.ref045","doi-asserted-by":"crossref","first-page":"527","DOI":"10.1002\/term.1861","article-title":"Magnesium ions facilitate integrin alpha 2-and alpha 3-mediated proliferation and enhance alkaline phosphatase expression and activity in hBMSCs","volume":"10","author":"Yea-Hyun Leem","year":"2016","journal-title":"J Tissue Eng Regen Med"},{"issue":"1","key":"pcbi.1010482.ref046","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-018-28476-w","article-title":"High Magnesium Corrosion Rate has an Effect on Osteoclast and Mesenchymal Stem Cell Role during Bone Remodelling","volume":"8","author":"D Maradze","year":"2018","journal-title":"Sci Rep"},{"issue":"6","key":"pcbi.1010482.ref047","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.actbio.2017.08.051","article-title":"Ion channel functional protein kinase TRPM7 regulates Mg ions to promote the osteoinduction of human osteoblast via PI3K pathway: In vitro simulation of the bone-repairing effect of Mg-based alloy implant","volume":"63","author":"X Zhang","year":"2017","journal-title":"Acta Biomater"},{"issue":"1","key":"pcbi.1010482.ref048","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1002\/jbm.b.33542","article-title":"Behavior of bone cells in contact with magnesium implant material","volume":"105","author":"A Burmester","year":"2015","journal-title":"J Biomed Mater Res\u2014Part B Appl Biomater"},{"key":"pcbi.1010482.ref049","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.actbio.2015.04.011","article-title":"Recommendation for modifying current cytotoxicity testing standards for biodegradable magnesium-based materials","volume":"21","author":"J Wang","year":"2015","journal-title":"Acta Biomater"},{"issue":"1","key":"pcbi.1010482.ref050","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13287-019-1156-6","article-title":"Immunoregulatory potential of mesenchymal stem cells following activation by macrophage-derived soluble factors","volume":"10","author":"L Salda\u00f1a","year":"2019","journal-title":"Stem Cell Res Ther"},{"key":"pcbi.1010482.ref051","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.bone.2015.05.001","article-title":"Multiple roles of tumor necrosis factor-alpha in fracture healing","volume":"78","author":"JM Karnes","year":"2015","journal-title":"Bone"},{"issue":"4","key":"pcbi.1010482.ref052","doi-asserted-by":"crossref","first-page":"1585","DOI":"10.1073\/pnas.1018501108","article-title":"TNF-$\u03b1$ promotes fracture repair by augmenting the recruitment and differentiation of muscle-derived stromal cells","volume":"108","author":"GE Glass","year":"2011","journal-title":"Proc Natl Acad Sci"},{"issue":"5089","key":"pcbi.1010482.ref053","doi-asserted-by":"crossref","first-page":"1798","DOI":"10.1126\/science.1281554","article-title":"Interleukin-8 as a macrophage-derived mediator of angiogenesis","volume":"258","author":"AE Koch","year":"1992","journal-title":"Science (80-)"},{"issue":"1","key":"pcbi.1010482.ref054","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1159\/000491742","article-title":"IL-8 enhances therapeutic effects of BMSCs on bone regeneration via CXCR2-mediated PI3k\/Akt signaling pathway","volume":"48","author":"A Yang","year":"2018","journal-title":"Cell Physiol Biochem"},{"issue":"3\u20134","key":"pcbi.1010482.ref055","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1089\/ten.tea.2015.0425","article-title":"Synergistic action of IL-8 and bone marrow concentrate on cartilage regeneration through upregulation of chondrogenic transcription factors","volume":"22","author":"DS Yoon","year":"2016","journal-title":"Tissue Eng Part A"},{"key":"pcbi.1010482.ref056","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1056\/NEJM199502023320506","article-title":"Bone marrow cytokines, and bone remodeling","volume":"332","author":"SC Mondagas","year":"1995","journal-title":"N Engl J Med"},{"issue":"6","key":"pcbi.1010482.ref057","doi-asserted-by":"crossref","first-page":"7135","DOI":"10.1016\/j.eswa.2010.12.048","article-title":"Using Gaussian membership functions for improving the reliability and robustness of students\u2019 evaluation systems","volume":"38","author":"IA Hameed","year":"2011","journal-title":"Expert Syst Appl"},{"key":"pcbi.1010482.ref058","doi-asserted-by":"crossref","unstructured":"Sadollah A. Introductory Chapter: Which Membership Function is Appropriate in Fuzzy System? In: Sadollah A, editor. Fuzzy Logic Based in Optimization Methods and Control Systems and Its Applications [Internet]. Rijeka: IntechOpen; 2018.","DOI":"10.5772\/intechopen.79552"},{"key":"pcbi.1010482.ref059","first-page":"325","volume-title":"Fuzzy Log Control Concepts, Theor Appl","author":"I. Iancu","year":"2012"},{"issue":"1","key":"pcbi.1010482.ref060","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.abb.2011.05.010","article-title":"Cellular magnesium homeostasis","volume":"512","author":"AM Romani","year":"2011","journal-title":"Arch Biochem Biophys"},{"key":"pcbi.1010482.ref061","doi-asserted-by":"crossref","unstructured":"Mezura-Montes E, Vel\u00e1zquez-Reyes J, Coello Coello CA. A comparative study of differential evolution variants for global optimization. In: Proceedings of the 8th annual conference on Genetic and evolutionary computation. 2006. p. 485\u201392.","DOI":"10.1145\/1143997.1144086"}],"updated-by":[{"DOI":"10.1371\/journal.pcbi.1010482","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T00:00:00Z","timestamp":1664236800000}}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010482","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T17:43:23Z","timestamp":1664300603000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1010482"}},"subtitle":[],"editor":[{"given":"Adrianne","family":"Jenner","sequence":"first","affiliation":[]}],"short-title":[],"issued":{"date-parts":[[2022,9,15]]},"references-count":61,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,9,15]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1010482","relation":{"new_version":[{"id-type":"doi","id":"10.1371\/journal.pcbi.1010482","asserted-by":"object"}]},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,9,15]]}}}